Ocular Pathology 8th Edition M.D.

Yanoff
Visit to download the full and correct content document:
https://textbookfull.com/product/ocular-pathology-8th-edition-m-d-yanoff/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...

Drug-Induced Ocular Side Effects: Clinical Ocular

Toxicology 8th Edition Frederick T. Fraunfelder

https://textbookfull.com/product/drug-induced-ocular-side-
effects-clinical-ocular-toxicology-8th-edition-frederick-t-
fraunfelder/

Gynecologic Pathology: A Volume in Foundations in

Diagnostic Pathology Series 2nd Edition M.D. Nucci

https://textbookfull.com/product/gynecologic-pathology-a-volume-
in-foundations-in-diagnostic-pathology-series-2nd-edition-m-d-
nucci/

Epidemiology of Diabetes 1st Edition M.D. Moini

https://textbookfull.com/product/epidemiology-of-diabetes-1st-
edition-m-d-moini/

Clinical Procedures for Ocular Examination Nancy B.

Carlson

https://textbookfull.com/product/clinical-procedures-for-ocular-
examination-nancy-b-carlson/
Diagnostic Pathology: Transplant Pathology 2nd Edition
Anthony C. Chang

https://textbookfull.com/product/diagnostic-pathology-transplant-
pathology-2nd-edition-anthony-c-chang/

3-Dimensional Modeling in Cardiovascular Disease 1st

Edition M.D. Zahn

https://textbookfull.com/product/3-dimensional-modeling-in-
cardiovascular-disease-1st-edition-m-d-zahn/

Textbook of Ocular Trauma Evaluation and Treatment 1st

Edition Stephen C. Kaufman

https://textbookfull.com/product/textbook-of-ocular-trauma-
evaluation-and-treatment-1st-edition-stephen-c-kaufman/

Ocular Surface Disease: A Case-Based Guide 1st Edition

Ali R. Djalilian (Eds.)

https://textbookfull.com/product/ocular-surface-disease-a-case-
based-guide-1st-edition-ali-r-djalilian-eds/

Ocular Fluid Dynamics Anatomy Physiology Imaging

Techniques and Mathematical Modeling Giovanna Guidoboni

https://textbookfull.com/product/ocular-fluid-dynamics-anatomy-
physiology-imaging-techniques-and-mathematical-modeling-giovanna-
guidoboni/
 OCULAR
PATHOLOGY
 OCULAR
PATHOLOGY
EIGHTH EDITION

MYRON YANOFF MD
Chair Emeritus, Ophthalmology
Professor of Ophthalmology & Pathology
Departments of Ophthalmology & Pathology
College of Medicine
Drexel University
Philadelphia, PA, USA

JOSEPH W. SASSANI MD MHA

Professor of Ophthalmology and Pathology
Pennsylvania State University
The Milton S. Hershey Medical Center
Hershey, PA, USA
For additional online content visit ExpertConsult.com

Edinburgh London New York Oxford Philadelphia St Louis Sydney 2020

© 2020, Elsevier Inc. All rights reserved.

First edition 1975

Second edition 1982
Third edition 1989
Fourth edition 1996
Fifth edition 2002
Sixth edition 2009
Seventh edition 2015

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about the
Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance
Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).

Notices

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds or experiments described herein. Because of rapid
advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages
should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors,
editors or contributors for any injury and/or damage to persons or property as a matter of products
liability, negligence or otherwise, or from any use or operation of any methods, products, instructions,
or ideas contained in the material herein.

ISBN: 978-0-323-54755-0
E-ISBN: 978-0-323-54756-7

Content Strategists: Russell Gabbedy/Kayla Wolfe

Content Development Specialist: Sharon Nash
Project Manager: Joanna Souch
Design: Brian Salisbury
Marketing Manager: Claire McKenzie

Printed in China

Last digit is the print number: 9 8 7 6 5 4 3 2 1

F O R E WO R D

Myron Yanoff did his residency at the Scheie Eye Institute of the This enabled correlation of findings in the eye as seen with the
University of Pennsylvania in Ophthalmology followed by a ophthalmoscope with cellular pathology viewed under the micro-
residency in the Department of Pathology. He then did a fel- scope. This led to important clinicopathologic correlations in
lowship at the Armed Forces Institute of Pathology (AFIP) in ocular pathology, including tumors such as retinoblastoma and
Washington, DC, under the directorship of Lorenz Zimmerman. melanoma. As time progressed, more and more disease entities
Yanoff ’s colleague, Ben Fine, was also Zimmerman’s student. were defined by clinicopathologic correlations. Zimmerman and
Ben Fine was an excellent electron microscopist, and he and his students, Yanoff being one of them, described the pathology
Yanoff authored the book, Ocular Histology: A Text and Atlas. of most ocular diseases during the so-called “golden age of eye
Dr. Yanoff developed a series of lectures presented at the Annual pathology” from the late 1950s through the 1980s. Subsequently,
Postgraduate Course in Ophthalmology at the Scheie Eye Institute many of Zimmerman’s students, and in turn, their students,
and the Lancaster Course in Colby College, Maine, as well as Sassani being one of them, applied newer technologies to the
the Biannual Course in Ophthalmic Pathology at the AFIP. These descriptions of these ocular diseases. This enabled updates of
lectures led to the first edition of Ocular Pathology: A Text and their book, Ocular Pathology. Ocular pathology has advanced
Atlas by Drs. Yanoff and Fine, which was published in 1975. The with the confluence of technologies now being molecular biology
text was presented in outline form, similar to the lecture series, and digital technology, including imaging technology such as
with ample illustrations in black and white and a few color confocal microscopy. The most important element in advancing
plates. This book became the standard ocular pathology text for knowledge and teaching of ocular pathology are individuals, in
residents in ophthalmology and, indeed, I used this textbook this case Drs. Yanoff and Sassani. Remarkably, they have updated
when I was an ophthalmology resident. Dr. Yanoff went on to their textbook, now in its eighth edition, keeping up with new
be Chair of the Department of Ophthalmology at the University discoveries in ocular pathology and clinicopathologic correla-
of Pennsylvania, then Chair at Hahnemann University and, sub- tions, including using modern methods of investigation, such
sequently, Drexel University, where he maintained a compre- as ocular coherence tomography. Some examples of the updates
hensive ophthalmology practice. He and Dr. Fine updated their in the eighth edition include the ocular manifestations of Zika
textbook every several years, with the second edition in 1982, virus infection, descriptions of the pathology of intravitreal
third edition in 1989, fourth edition in 1996, and fifth edition injections, ocular injuries associated with terrorism, stem cells
in 2002. in the conjunctiva, the latest genetic information regarding corneal
By that time, Yanoff’s resident, Joe Sassani, was ready to replace dystrophies, the genetics of retinal dystrophies, the TNM clas-
Ben Fine as the coauthor of this textbook. Dr. Sassani completed sification in the latest edition of the AJCC Cancer Staging Manual,
his ophthalmology residency and fellowship in Ophthalmic and others.
Pathology at the University of Pennsylvania, and developed a Indeed, Drs. Yanoff and Sassani have kept up with the times
practice focused on glaucoma. Dr. Sassani is currently on the in a remarkable fashion. The definition of a classic textbook is
faculty at Penn State University in Hershey, Pennsylvania. Drs. that it endures the test of time and builds upon itself to a point
Yanoff and Sassani completed the sixth edition of Ocular Pathol- where it becomes a standard text that remains current. In this
ogy in 2009 and the seventh edition in 2015. The textbook retained case, the text began as an outgrowth from the long-standing and
its outline format; however, virtually all of the illustrations are storied history of the venerable AFIP, including Yanoff, a disciple
now in color, and the book is replete with references. The text- of Zimmerman, and Sassani, a student of Yanoff. Ocular Pathol-
book has kept up with the times, as it has added new information ogy has stood the test of time, remains current, and remains a
including immunohistochemistry, molecular biology, and confocal standard textbook for the study of ocular pathology, the basis
microscopy over the years. of ocular disease. I congratulate Drs. Yanoff and Sassani for their
The story of ocular pathology is one of successive waves of continued efforts in the production of this beautiful textbook,
confluences of technology, clinicopathologic correlations and, which is now the classic textbook for ophthalmology residents
most importantly, people. An important confluence of technolo- and fellows and pathology residents and fellows.
gies occurred in the mid-1800s when Hermann von Helmholtz Hans E. Grossniklaus MD
in Heidelberg developed the ophthalmoscope and Rudolf Virchow Professor of Ophthalmology and Pathology
in Berlin established cellular pathology as the basis of disease. Emory University School of Medicine

vi
 F O R E WO R D S T O T H E F I R S T E D I T I O N

During the year of the observance of the 100th anniversary In the years that followed under succeeding chairmen of the
(1874–1974) of the University of Pennsylvania’s Department of Department, other aspects of ophthalmology were stressed. Then,
Ophthalmology, it is exciting to have the publication of a volume in 1947, during the chairmanship of Dr. Francis Heed Adler, Dr.
whose coauthors have contributed significantly to the strides in Larry L. Calkins was appointed to a residency. Dr. Calkins, like
ocular pathology taken by the Department in the past several Dr. Yanoff, displayed a keen interest in ocular pathology. Accord-
years. ingly, he was instrumental in its study being revitalized during
Myron Yanoff, a highly regarded member of our staff, began the three years of his residency. Another resident, Dr. William
a residency in ophthalmology in 1962, upon graduating from C. Frayer, who came to the Department in 1949, joined Dr.
the University’s School of Medicine. The residency continued Calkins in his interest in ocular pathology. Dr. Frayer received
for the next five years, during the first two of which he also held additional training in the Department of Pathology and then
a residency in the Department of Pathology. His keen interest became the ophthalmic pathologist of the Department.
and ability in ocular pathology were readily apparent, and I The importance of ocular pathology was increasingly evident,
encouraged him to apply for a fellowship at the Armed Forces but facilities for carrying out the work in the Department of Oph-
Institute of Pathology (AFIP), Washington, DC. From July 1964 thalmology were unfortunately limited. Until 1964, the pathology
through June 1965, he carried out exceptional research at the laboratory had been confined to a small room in the outpatient
AFIP in both ophthalmology and pathology. He returned to our area of the Department. Then we were able to acquire larger
Department in July 1965, where the caliber both of his clini- quarters in the Pathology Building of the Philadelphia General
cal and research work was of the highest. When he completed Hospital located next door to the Hospital of the University of
his residency in June 1967, I invited him to join the staff, and Pennsylvania. Although the building was earmarked for eventual
he has recently attained the rank of full professor. During the demolition, the space was fairly adequate for research and also for
ensuing years, he has contributed substantially to the litera- conducting weekly ophthalmic pathology teaching conferences.
ture, particularly in the fields of ophthalmic and experimen- Despite the physical aspects, we saw to it that Dr. Yanoff and his
tal pathology. He is Board certified in ophthalmology and in team of workers had a well-equipped laboratory.
pathology. During the next several years as I saw that my dream for an
Ben Fine, noted for his work in electron microscopy at AFIP eye institute with facilities for patient care, teaching, and research
and at George Washington University, has shared his expertise under one roof was to become a reality, I was delighted to be
in the field through lectures presented as part of the curriculum able to include prime space on the research floor for the ever
of the annual 16-week Basic Science Course in the Department’s enlarging scope of ocular pathology. In addition to all that Dr.
graduate program. Yanoff has had to build upon from the past tradition of our
It can be said that 100 years ago ophthalmology was a specialty Department of Ophthalmology, I would like to think that the
that had been gradually evolving during the preceding 100 years, new facilities at the Institute have in some measure contributed
dating from the time of the invention of bifocals by Benjamin to the contents of this excellent volume. With grateful apprecia-
Franklin in 1785. Few American physicians of that era, however, tion, therefore, I look upon this book as the authors’ birthday
knew how to treat diseases of the eye, but as medical education present to the Department. From these same facilities, as Dr.
became more specialized it was inevitable that ophthalmology Yanoff and Dr. Fine continue to collaborate, I can hope will
would also become a specialty. come insights and answers for which all of us are ever searching
With the invention of the ophthalmoscope in 1851, great in the battle against eye disease.
advances were made in the teaching and practice of ophthalmol- Harold G. Scheie, MD
ogy. This contributed greatly, of course, to setting the scene for Chairman, Department of Ophthalmology
the establishment of the University’s Department of Ophthal- University of Pennsylvania
mology. It was on February 3, 1874, that Dr. William F. Norris Director, Scheie Eye Institute
was elected First Clinical Professor of Diseases of the Eye. Similar
chairs had been established earlier in only three other institu- From their earliest days in ophthalmology, Myron Yanoff and
tions. The chair at the University of Pennsylvania later became Ben Fine impressed me as exceptional students. As they have
known as the William F. Norris and George E. de Schweinitz matured and progressed up the academic ladder, they have become
Chair of Ophthalmology. equally dedicated and effective teachers. Their anatomical studies
Both Dr. Norris and Dr. de Schweinitz actively engaged in of normal and diseased tissues have always been oriented toward
the study of ocular pathology. Dr. Norris stressed the importance providing meaningful answers to practical as well as esoteric
of the examination of the eye by microscopy and of the correla- clinical questions. Their ability to draw upon their large personal
tion of findings from pathology specimens with the clinical signs. experience in clinical ophthalmology, ocular pathology, and
Dr. de Schweinitz was instrumental in having a member of his laboratory investigation for their lectures at the Armed Forces
staff accepted as ophthalmic pathologist with the Department Institute of Pathology and at the University of Pennsylvania has
of Pathology. contributed immeasurably to the success of those courses. Now

vii
viii Forewords to the First Edition

they have used the same time-tested approach in assembling of this latest book. I am proud that both authors launched their
their material for this book. Beginning with their basic lecture respective careers with periods of intensive study at the Armed
outlines, then expanding these with just enough text to substitute Forces Institute of Pathology and that ever since, they have
for what would have been said verbally in lecture, adding a remained loyal, dedicated, and highly ethical colleagues. I admire
remarkable amount of illustrative material for the amount of their youthful energy, their patient, careful attitude, their friendly
space consumed, and then providing pertinent references to get cooperative nature, and their ability to get important things
the more ambitious student started in the pursuit of a subject, accomplished. I’m appreciative of this opportunity to express
Drs. Yanoff and Fine have provided us with a sorely needed my gratitude for the work they have been doing. If it is true that
teaching aid for both the student and the teacher of ocular pathol- “by his pupils, a teacher will be judged,” I could only wish to
ogy. It should prove to be especially popular among medical have had several dozen more like Drs. Yanoff and Fine.
students and residents in both ophthalmology and ocular pathol- Lorenz E. Zimmerman, MD
ogy. With it one gets good orientation from the well-conceived Chief, Ophthalmic Pathology Division
outlines and fine clinicopathologic correlations from the selection Armed Forces Institute of Pathology
of appropriate illustrations. Washington, DC
It is with considerable pride and admiration that I’ve watched
the evolution of the authors’ work and its fruition in the form
 P R E FA C E

This edition of Ocular Pathology has been revised extensively to epidermolysis bullosa, and erythema multiforme. There is an
reflect the many developments in the field since the publication extensive revision of the sections on degenerative diseases, col-
of the 7th edition. While maintaining a focus on histopathologic lagen diseases, and other inflammatory skin conditions, such as
and immunohistopathologic features upon which most diagnoses the vasculitides. Particular attention has been given to the section
are made, we have expanded coverage of supplemental and cor- on adnexal tumors.
relative techniques such as clinical confocal microscopy and Chapter 7, Conjunctiva, contains an enhanced discussion of
optical coherence tomography. Moreover, we have placed addi- stem cells. The congenital anomalies section is expanded sig-
tional emphasis on the pathobiology underlying established and nificantly, with new entities added. The degenerations section
new diagnoses. This emphasis is reflected particularly in expanded has been revised to include the new classification of amyloidosis.
coverage of genetics as it relates to disease entities. For a more The information regarding multiple types of cystic and neoplastic
in-depth analysis of the latest developments in genetics please lesions has been expanded significantly, with a particular emphasis
see: Wiggs JL: Part 1 Genetics, in Yanoff M, Duker JS: Ophthal- on cancerous epithelial lesions.
mology (5th Ed). London: Elsevier 2018. There are many online Chapter 8, Cornea and Sclera, contains an extensive revision
resources to catalog these conditions, including Online Mendelian of the section on congenital lesions. The ever-changing classifi-
Inheritance in Man (OMIM, http://www.ncbi.nlm.nih.gov/omim), cation of corneal dystrophies is reflected in further revisions to
RetNet (https://sph.uth.edu/Retnet/), and Retina International that section that also include the latest genetic information
(http://www.retina-international.org/). impacting our understanding of these disorders. The section on
Virtually every chapter has seen extensive revision including nonheredofamilial disorders also has been revised extensively.
the addition of salient new material. Chapter 1, on the Basic Significant new information is found in the section on sclera.
Principles of Pathology, incorporates an expanded discussion Chapter 9, Uvea, includes updates on aniridia, coloboma, and
of the role of the complement system in ocular homeostasis and choroidal dystrophies such as those involving choriocapillaris
disease. The section on immunobiology includes the concept of atrophy.
the inflammasome as a component of innate immunity. A section Chapter 10, Lens, reflects particular attention on congenital
on autoimmunity and autoinflammation has been added. The cataracts and those associated with syndromes. The section on
discussion of HIV infection has been expanded including newer pseudoexfoliation has been revised, as have other sections includ-
developments relative to its complications. There are entirely ing lens-related complications and ectopic lens.
new sections on epigenetics and on modern molecular pathology Chapter 11, Neural (Sensory) Retina, reflects updates in
diagnostic techniques. All of these changes are found in only congenital and hereditary retinal disorders, vascular diseases,
the first chapter! and inflammatory disorders. Particular attention has been directed
Chapter 2, Congenital Anomalies, revises multiple topics to retinal degenerations. Multiple modifications have been made
including the phakomatoses, chromosomal anomalies, and syn- to the section on retinal dystrophies with a particular emphasis
dromes such as Noonan syndrome and Walker–Warburg syn- on the genetics of these disorders.
drome. Relevant genetic alterations are cited throughout the Chapter 12, Vitreous, has seen a revision on the amyloid section
chapter. and on familial exudative vitreoretinopathy and other familial
Chapter 3, Nongranulomatous Inflammation: Uveitis, End- disorders.
ophthalmitis, Panophthalmitis, and Sequelae, includes new atten- Chapter 13, Optic Nerve, reflects updates in the section on
tion on the ocular manifestations of Zika virus infection. congenital and familial disorders including relevant syndromes.
Chapter 4, Granulomatous Inflammation, updates the discus- The section on ischemic optic neuropathies has been revised, as
sion of sympathetic uveitis (ophthalmia, ophthalmitis) and has been the section on optic nerve tumors.
nontraumatic infectious causes, such as tuberculosis. Chapter 14, Orbit, has an extensively revised discussion of
Chapter 5, Surgical and Nonsurgical Trauma, includes an thyroid orbitopathy and muscular disorders. The section on the
expanded discussion of ophthalmic operative and postoperative reticuloendothelial system and related disorders, including rela-
surgical complications. A section on intravitreal injections has tive genetic anomalies, has been revised extensively, and the
been added. A discussion of ocular injuries associated with section on Lymphomas and related disorders has been signifi-
modern warfare and terrorism has been added to the section cantly expanded.
on nonsurgical trauma. Numerous sections have been expanded Chapter 15, Diabetes Mellitus, includes a new section on ocular
in scope including the information on radiation injuries. surface disease secondary to diabetes. Additional new informa-
Chapter 6, Skin and Lacrimal Drainage System, has an tion and pertinent diagnostic techniques are discussed relative
expanded discussion of congenital lesions and anomalies. The to diabetic complications for each anatomic region of the eye.
new classification system for ichthyosis has been added, as has The information on the pathobiology of ocular diabetic com-
information regarding its genetic correlates. The section on aging plications is expanded greatly.
has been expanded significantly, as has the discussion of numer- Chapter 16, Glaucoma, contains a comprehensively revised
ous individual entities, such as pseudoxanthoma elasticum, discussion of the anatomic basis for aqueous outflow and the

ix
x Preface

histopathologic correlates in glaucoma. The information on the retinoblastoma and the latest information on overall survival
genetics of glaucoma is revised extensively as is the discussion are included. The section on simulating lesions includes new
of pathobiology for each of the glaucomas where appropriate. entities and the latest terminology. Particular attention has been
Particular attention has been paid to the discussion of pseudo- paid to the latest developments in retinopathy of prematurity.
exfoliation. Much information has been added regarding the Adjunctive diagnostic techniques are discussed.
pathobiology of optic nerve damage in glaucoma. The 8th edition of Ocular Pathology is replete with new infor-
Chapter 17, Ocular Melanocytic Lesions, reflects the TMN mation reflecting the rapidly evolving world of ophthalmic
classification as found in the 8th edition of the AJCC Cancer pathology. Nevertheless, as we state in the very first line of our
Staging Manual. Additionally, particular emphasis has been placed textbook, “The most important tool that the pathologist has at
on genetic and chromosomal correlates to prognosis in ocular his/her disposal is meaningful communication with the patient’s
melanoma. The pathobiology underlying the correlations also clinician regarding the suspected diagnosis so that the patholo-
is discussed. gist can choose the appropriate strategy for processing whatever
Chapter 18, Retinoblastoma and Simulating Lesions, is revised tissue or other samples are received.” No matter how sophisticated
extensively, including the chapter title itself, which drops refer- our techniques become, accurate communication remains the
ence to “pseudoglioma.” The latest classifications for retinoblas- bedrock for accurate pathologic diagnoses in support of the best
toma are presented including the principles on which they are care for our patients.
based. Genetic mutations and chromosomal abnormalities relative MY, JS
to retinoblastoma have been revised. Prognostic factors for
 AC K N OW L E D G M E N T S

This book could not have been completed without the understanding and patience of our wives
Karin L. Yanoff, PhD, and Gloria Sassani, MA. We also wish to acknowledge the help of our
assistants, Kelly McAnally and Sherri Maslasics. Finally, the members of the Elsevier production
and editorial team lead by Russell Gabbedy, Kayla Wolfe and Sharon Nash, and including project
manager Joanna Souch, designer Brian Salisbury and illustration managers Paula Catalano and
Teresa McBryan all have provided invaluable help and guidance in the production of this 8th
edition of Ocular Pathology.

xi
We dedicate this book to our wives, Karin and Gloria, and to our children.
 1
Basic Principles of Pathology

The most important tool that the pathologist has at his/her dis- II. Infectious causes include viral, rickettsial, bacterial, fungal,
posal is meaningful communication with the patient’s clinician and parasitic agents.
regarding the suspected diagnosis so that the pathologist can
choose the appropriate strategy for processing whatever tissue Phases of Inflammation
or other samples are received. As will be seen in the discussion (Table 1.1 lists the actions of the principal mediators of
under Modern Molecular Pathology Diagnostic Techniques, there inflammation.)
is a dizzying array of techniques at the pathologist’s disposal; I. Acute (immediate or shock) phase (Fig. 1.1)
however, it is only through communication with the clinician A. Five cardinal signs: (1) redness (rubor) and (2) heat
that the pathologist can determine which of these techniques to (calor)—both caused by increased rate and volume of
utilize to best serve the patient. blood flow; (3) mass (tumor)—caused by exudation of
fluid (edema) and cells; (4) pain (dolor) and (5) loss
INFLAMMATION of function (functio laesa)—both caused by outpour-
ing of fluid and irritating chemicals. Table 1.2 lists the
Definition roles of various mediators in the different inflammatory
I. Inflammation is the response of a tissue or tissues to a reactions.
noxious stimulus. B. The acute phase is related to histamine release from
A. The tissue may be predominantly cellular (e.g., retina), mast cells and factors released from plasma (kinin,
composed mainly of extracellular materials (e.g., cornea), complement, and clotting systems).
or a mixture of both (e.g., uvea). 1. Histamine is found in the granules of mast cells, where
B. The response may be localized or generalized, and the it is bound to a heparin–protein complex. Serotonin
noxious stimulus may be infectious or noninfectious. (5-hydroxytryptamine), found in platelets and some
II. In a general way, inflammation is a response to a foreign neuroendocrine cells, has a similar effect to histamine.
stimulus that may involve specific (immunologic) or non- 2. The kinins are peptides formed by the enzymatic
specific reactions. Immune reactions arise in response to action of kallikrein on the α2-globulin kininogen.
specific antigens, but they may involve other components Kallikrein is activated by factor XIIa, which is the
(e.g., antibodies, T cells) or nonspecific components (e.g., active form of the coagulation factor XII (Hageman
natural killer [NK] cells, lymphokines). factor). Factor XIIa converts plasma prekallikrein
III. There is an interplay between components of the inflam- into kallikrein. Plasmin also can activate Hageman
matory process and blood clotting factors that shapes the factor.
inflammatory process. 3. Plasmin, the proteolytic enzyme responsible for fibri-
nolysis, has the capacity to liberate kinins from their
Causes precursors and to activate kallikrein, which brings
I. Noninfectious causes about the formation of plasmin from plasminogen.
A. Exogenous causes: originate outside the eye and body, Plasmin cleaves C3 complement protein, resulting
and include local ocular physical injury (e.g., perforating in the formation of C3 fragments. It also breaks down
trauma), chemical injuries (e.g., alkali), or allergic reac- fibrin to form fibrin split products.
tions to external antigens (e.g., conjunctivitis secondary 4. The complement system (see Table 1.3, which lists the
to pollen). complement molecules found in the normal eye, and
B. Endogenous causes: sources originating in the eye and Table 1.4, which lists the complement molecules found
body, such as inflammation secondary to cellular immu- in diseased eyes) consists of almost 60 proteins present
nity (phacoanaphylactic endophthalmitis [phacoantigenic in blood plasma, on the cell surfaces, or within the
uveitis]); spread from continuous structures (e.g., the cell. Its vital nature is evidenced by the fact that it
sinuses); hematogenous spread (e.g., foreign particles); has been preserved by evolution for more than a
and conditions of unknown cause (e.g., sarcoidosis). billion years.

1
2 CHAPTER 1 Basic Principles of Pathology

TABLE 1.1 The Actions of the Principal Mediators of Inflammation

Mediator Principal Sources Actions
Cell-Derived
Histamine Mast cells, basophils, platelets Vasodilation, increased vascular permeability, endothelial activation
Serotonin Platelets Vasodilation, increased vascular permeability
Prostaglandins Mast cells, leukocytes Vasodilation, pain, fever
Leukotrienes Mast cells, leukocytes Increased vascular permeability, chemotaxis, leukocyte adhesion and
activation
Platelet-activating factor Leukocytes, mast cells Vasodilation, increased vascular permeability, leukocyte adhesion,
chemotaxis, degranulation, oxidative burst
Reactive oxygen species Leukocytes Killing of microbes, tissue damage
Nitric oxide Endothelium, macrophages Vascular smooth muscle relaxation, killing of microbes
Cytokines (TNF, IL-1) Macrophages, endothelial cells, Local endothelial activation (expression of adhesion molecules), fever/
mast cells pain/anorexia/hypotension, decreased vascular resistance (shock)
Chemokines Leukocytes, activated macrophages Chemotaxis, leukocyte activation

Plasma Protein-Derived
Complement products (C5a, C3a, C4a) Plasma (produced in liver) Leukocyte chemotaxis and activation, vasodilation (mast cell
stimulation)
Kinins Plasma (produced in liver) Increased vascular permeability, smooth muscle contraction,
vasodilation, pain
Proteases activated during coagulation Plasma (produced in liver) Endothelial activation, leukocyte recruitment

IL-1, interleukin-1; MAC, membrane attack complex; TNF, tumor necrosis factor.
(Reproduced from Table 2.4, Kumar R, Abbas A, DeLancey A et al.: Robbins and Cotran Pathologic Basis of Disease, 8th edn. Philadelphia,
Saunders. © 2010 by Saunders, an imprint of Elsevier Inc.)

A B

C D

Fig. 1.1 Acute inflammation. A, Corneal ulcer with hypopyon (purulent exudate). Conjunctiva hyperemic.
B, Polymorphonuclear leukocytes (PMNs) adhere to corneal endothelium and are present in the anterior
chamber as a hypopyon (purulent exudate). C, Leukocytes adhere to limbal, dilated, blood-vessel wall (mar-
gination) and have emigrated through endothelial cell junctions into edematous surrounding tissue. D, PMNs
in corneal stroma do not show characteristic morphology but are recognized by “bits and pieces” of nuclei
lining up in a row. (C and D are thin sections from rabbit corneas six hours post-corneal abrasion.)
 Inflammation 3

TABLE 1.2 Role of Mediators in Different TABLE 1.3 Complement Molecules Found
Reactions of Inflammation in the Normal Eye
Role in Inflammation Mediators Complement Molecules
Vasodilation Prostaglandins Expressed in the
Nitric oxide Healthy Eye Eye-Associated Remarks
Histamine Complement System Activators
Increased vascular permeability Histamine and serotonin Amyloid precursor proteins (APP) Retina
C3a and C5a (by liberating vasoactive C-reactive protein (CRP) Retina
amines from mast cells, other cells)
Bradykinin Complement Proteins
Leukotrienes C4, D4, E4 C1q, C2, C3 Cornea, choroid, inner retina, sclera,
PAF optic nerve, retinal pigmented
Substance P epithelium (RPE) cell
Chemotaxis, leukocyte TNF, IL-1 C4 Sclera
recruitment and activation Chemokines C5–8 Cornea, scleral tissue
C3a, C5a C9 Soft drusen from non-AMD eyes,
Leukotriene B4 retina, optic nerve
(Bacterial products; e.g., N-formyl C5b–9 Bruch’s membrane, increase with age
methyl peptides) in non-AMD eyes
Fever IL-1, TNF Factor B Cornea, sclera
Prostaglandins
Pain Prostaglandins Complement Regulators
Bradykinin Factor H Cornea, sclera, iris, ciliary body, retina,
Tissue damage Lysosomal enzymes of leukocytes choroidal tissue outside Bruch’s
Reactive oxygen species membrane, optic nerve
Nitric oxide Factor H-like protein 1 (FHL-1) Bruch’s membrane
C1 inhibitor (C1-INH) Cornea
IL-1, interleukin-1; PAF, platelet-activating factor; TNF, tumor necrosis CD46 (MCP) Cornea and corneal limbus, vitreous
factor. humor, RPE basolateral surface,
(Reproduced from Table 2.7, Kumar R, Abbas A, DeLancey A et al.: photoreceptors
Robbins and Cotran Pathologic Basis of Disease, 8th edn. CD55 (DAF) Cornea and corneal limbus, conjunctiva,
Philadelphia, Saunders. © 2010 by Saunders, an imprint of Elsevier
iris, ciliary body, vitreous humor,
Inc.)
retinal nerve fiber layer (NFL) and
photoreceptors
a. Initially named because it was seen to “comple- CD59 (protectin) Cornea and corneal limbus, conjunctiva,
ment” antibody and cell-mediated immune iris, ciliary body, choroid, vitreous
defenses against microbes. humor, vessels in the inner retina
b. Classic functions: Fig. 1.2 highlights some of the Vitronectin Soft drusen from non-AMD eyes
myriad functions performed by complement. Clusterin Soft drusen from non-AMD eyes
1) Removal of immune (antigen–antibody) Complement Receptors
complexes. Complement receptor-1 (CR1) RPE apical surface
2) Labeling (opsonization) of foreign antigens C3aR Retinal ganglion cells, NFL
for enhanced removal by phagocytes. C5aR Inner plexiform layer (IPL), Müller cells,
3) Recruitment and activation of nearby NFL
leukocytes.
AMD, age-related macular degeneration; RPE, retinal pigment
4) Direct cytolysis of invading microorganisms. epithelium.
c. Performs multiple functions in addition to those (From Mohlin et al.: The link between morphology and complement
“classically” ascribed to it. in ocular disease. Mol Immunol 89:84–99, 2017. Table 1. Elsevier.)
d. Complement achieves its effect through a cascade
of the separate components working in coordina-
tion and in specific sequences leading through 2) Cleavage of C3 produces the active fragments
activation of C3. (Fig. 1.3 is a schematic repre- C3a and C3b.
sentation of the three primary routes or pathways a) C3a is anaphylatoxin leading to chemotactic
of complement cascade activation through C3.) and proinflammatory responses.
1) The three pathways leading to activation of b) C5a also is an anaphylatoxin.
C3 are: c) C3b results in opsonization of foreign
a) Classical pathway. surfaces.
b) Lectin pathway. 3) Thus, C3 has a major role in complement acti-
c) Alternative pathway. vation and generation of immune responses.
4 CHAPTER 1 Basic Principles of Pathology

TABLE 1.4 Complement Molecules Found in the Human Diseased Eye, i.e., in Age-Related
Macular Degeneration (AMD), Glaucoma, Neuromyolitis Optica (NMO) and in Uveitis
Complement Molecules Complement Molecules
Expressed in the Eye Disease–Associated Expressed in the Eye Disease–Associated
Diseased Eye Remarks Diseased Eye Remarks
Complement System Age-Related Macular Complement System Activators
Activators Degeneration (AMD) Immunoglobulin Retina, optic nerve
Amyloid precursor proteins (APP) Drusen
C-reactive protein (CRP) Drusen, choroid Complement Proteins/Activation Products
Immunoglobulin Drusen C1q Retina, ganglion cells (GCL) and
Lipoprotein Drusen nerve fiber layer (NFL)
C3, C3b Retina, GCL and NFL
Complement Proteins/Activation Products C5b-9 (MAC) Retina, GCL
C1q Drusen
Mannose binding protein (MBL) Drusen Complement Regulators
C2a Factor H GCL
C3a, C3c, C3d, C3dg, C3b, iC3b, Bb Choroid, drusen, retinal pigmented Uveitis
epithelial (RPE) cell
C5b–9 (MAC) and sC5b−9a Drusen, RPE, choroid, macula Complement System Activators
Factor Ba Drusen, choroid Immunoglobulin Ocular proteins
Factor Da Drusen, retina
Complement Proteins/Activation Products
Complement Regulators C3c, C3d Aqueous humor
Factor Ia Drusen, inner retina C4a Aqueous humor
Factor Ha Drusen, retinal pigmented epithelial Factor B and Bb Aqueous humor
(RPE) cell, choroid, macula
Complement Anaphylatoxins
FHL-1 Drusen, choroid
C3a, C5a Aqueous humor
Complement receptor 1 (CR1, CD35) Drusen, RPE
Neuromyelitis optica (NMO)
CD46 (MCP) Drusen, choroidal vessels,
basolateral RPE Complement System Activators
Vitronectin Drusen, RPE Immunoglobulin Optic nerve
Clusterin Drusen

Complement Anaphylatoxins
C3a Aqueous humor, drusen
C5a Drusen
Glaucoma
a
Complement-associated genes connected with AMD: (Adamus et al., 2017; Edwards et al., 2005; Hageman et al., 2005; Haines et al., 2005;
Heckner et al., 2010; Klein et al., 2005; Gold et al., 2006; Maller et al., 2007; Park et al., 2009) and uveitis: (Thompson et al., 2013; Yang et al.,
2011, 2013; Xu et al., 2015).
(From Mohlin et al., The link between morphology and complement in ocular disease. Mol Immunol 89:84–99, 2017. Table 2. Elsevier.)

e. C1 has been called the “defining component” of (PRRs) and/or internally produced danger-
the classical complement pathway. associated molecular patterns (DAMPs).
1) Functions as a molecular scaffold for binding g. Activation of complement pathways results in a
of other complement components. proinflammatory response that includes the gen-
2) Activates and cleaves complement components eration of membrane attack complexes (MACs),
to continue the complement cascade. which mediate cell lysis, the release of chemokines
3) Helps to trigger Wnt receptor signaling. to attract inflammatory cells to the site of damage,
4) Participates in the process of apoptosis. and the enhancement of capillary permeability.
5) Cleaves MHC class I molecule and other (See Fig. 1.3 for the steps leading to activation of
proteins. MAC.)
6) Can adapt to multiple molecular and cellular 1) Composed of five terminal complement pro-
processes besides the complement system. teins: C5b, C6, C7, C8, and C9. Multiple C9
f. Complement plays major roles in immune defense molecules may be involved.
against microorganisms and in clearing damaged 2) There are numerous levels regulating the
host components. activity of MAC and protecting heathy cells
1) It responds to recognition of pathogen- from attack. In fact, control of the system
associated molecular patterns (PAMPs) when is the responsibility of almost half of its
they bind to host pattern-recognition receptors components.
 Inflammation 5

m. Helps maintain tissue homeostasis and cellular

integrity, and functions in tissue regeneration.
Also functions in early sperm–egg interactions
in fertilization, regulation of epiboly and organo-
Increased
vascular genesis, and in refinement of cerebral synapses.
Lysis of permeability Smooth n. The complement system is implicated in mul-
foreign muscle tiple ocular diseases including age-related macular
cells contraction
1 degeneration, glaucoma, and neuromyelitis optica
8 2 (Table 1.4 lists elements of the complement system
Lysis of Mast cell and how they may be involved in these disorders).
7 Complement 3
bacteria degranulation
6 4
o. Complement system, components and their genetic
5 deficiency.
Neutrophil Localization
activation and of complexes
1) Deficiency of early components of the classical
chemotaxis in germinal pathway (C1q, C1r/s, C2, C4, and C3) is asso-
Opsonization centers
and phagocytosis
ciated with autoimmune diseases resulting
of bacteria from failure of clearance of immune complexes
and apoptotic materials and impairment of
humoral response.
2) Deficiencies of mannan-binding lectin and
Fig. 1.2 Summary of the actions of complement and its role in the the early components of the alternative (factor
acute inflammatory reaction. Note how the elements of the reaction D and properdin) and terminal pathways (from
are induced. Increased vascular permeability (1) due to the action of C3 onward components C5, C6, C7, C8, and
C3a and C5a on smooth muscle (2) and mast cells (3) allows exudation C9) increase susceptibility to infections and
of plasma protein. C3 facilitates both the localization of complexes in
to their recurrence.
germinal centers (4) and the opsonization and phagocytosis of bacteria
(5). Neutrophils, which are attracted to the area of inflammation by 3) See also the discussion of monogenic autoin-
chemotaxis (6), phagocytose the opsonized microorganisms. The mem- flammatory syndromes later in this chapter.
brane attack complex, C5–C9, is responsible for the lysis of bacteria (7) p. Activation of complement in the tumor micro-
and other cells recognized as foreign (8). (Adapted with permission from environment enhances tumor growth and increases
Roitt IM, Brostoff J, Male DK: Immunology, 2nd edn. London, Gower
metastasis.
Medical. © Elsevier 1989.)
5. Prostaglandins (prostanoids), which have both inflam-
matory and anti-inflammatory effects, are 20-carbon,
cyclical, unsaturated fatty acids with a 5-carbon ring
a) Disorders resulting from impaired regulation of and two aliphatic side chains.
complement are termed complementopathies. a. They are produced by mast cells, macrophages,
h. Complement proteins opsonize or lyse cells. There- endothelial cells, and others.
fore, they may injure healthy tissue, particularly b. With leukotrienes, they are designated eicosanoids.
when there is a defect in complement regulation. Leukotrienes are metabolized through the lipoxy-
i. Complement is important in such diseases as genase pathway and prostaglandins through the
macular degeneration, rheumatoid arthritis, mul- cyclooxygenase pathway.
tiple sclerosis, Alzheimer’s disease, schizophrenia, c. Active in vascular and systemic reactions of inflam-
and angioedema. mation, oxidative stress, and physiologic functions.
j. T cells and other cell types contain multi­ d. Cyclooxygenase helps catalyze the biosynthesis
ple complement components, which have been of prostaglandins from arachidonic acid.
called the “complosome” in analogy to the in- e. Prostaglandins, cytokines, and leukotrienes func-
flammasome, which will be discussed later in tion to dilate lymphatics at a site of injury.
this chapter. (Fig. 1.4 provides an overview of f. Prostaglandins play an important role in nocicep-
the multiple ways in which the cell complosome tion and pain.
and other complement components may im- 6. Major histocompatibility complex (MHC), called the
pact key cell processes when faced with various human leukocyte antigen (HLA) complex in humans,
challenges.) is critical to the immune response.
k. Other immune system cells that may produce or a. HLAs are present on all nucleated cells of the
be involved in complement function are poly- body and platelets.
morphonuclear leukocytes, mast cells, monocytes,
macrophages, dendritic cells, natural killer (NK)
cells, and B cells.
l. Plays a role in adaptive immune response involv- The HLA region is on autosomal chromosome
6. In practice, the blood lymphocytes are the
ing T and B cells, and functions as a bridge
cells tested for HLA.
between innate and adaptive immunity.
6 CHAPTER 1 Basic Principles of Pathology

Fig. 1.3 Schematic of the complement cascade. The three primary routes for activation of complement are:
(1) the lectin pathway (LP), (2) the classical pathway (CP), and (3) the alternative pathway (AP). The LP and
CP are activated when specific triggers are recognized by host pattern-recognition receptors (PRRs). The AP
is constitutively active. Initial activation through the LP or CP generates a shared C3 convertase (C4b•C2a).
In the AP, C3b pairs with factor B (FB) to form the AP proconvertase (C3b•B), which is processed by factor
D (FD) to form the AP C3 convertase (C3b•Bb). Both types of C3 convertases cleave C3 to generate C3a
and C3b. C3a is an anaphylatoxin, a substance that promotes an inflammatory response. C3b that lands on
the surface of a healthy host cell is quickly inactivated; C3b that attaches to the surface of a pathogen or
altered host cell triggers a rapid amplification loop to generate more C3b, resulting in opsonization. C3b also
complexes with the C3 convertases to form the C5 convertases (C4b•C2a•C3b and C3b•Bb•C3b). In the
terminal complement cascade, C5 convertases cleave C5 into C5a (an anaphylatoxin) and C5b. C5b combines
with C6–9 to form the membrane attack complex (MAC), also referred to as the terminal complement
complex (TCC). Regulatory factors act at various stages of the cascade to control complement activation via
their decay accelerating activity and/or cofactor activity. Additional abbreviations: MASPs, mannose-binding
lectin-associated serine proteases; MBL, mannose-binding lectin; PAMPs, pathogen-associated molecular
patterns. (From Baines AC, Brodsky RA: Complementopathies. Blood Rev 31:213–223, 2017. Figure 1.
Elsevier.)

b. The three genetic loci belonging to HLA class I d. The HLA system is the main human leukocyte
are designated by the letters HLA-A, HLA-B, and isoantigen system and the major human histo-
HLA-C. Class II MHC molecules are encoded at compatibility system.
the locus HLA-D with three subregions HLA-DP, 1) HLA-B 27 is positive in a high percentage of
HLA-DQ, and HLA-DR. young women who have acute anterior uveitis
1) Class I MHC molecules display proteins and in young men who have ankylosing spon-
derived from foreign antigens, which are rec- dylitis or Reiter’s disease.
ognized by CD8+ T lymphocytes. 2) HLA-B 51 is strongly associated with Behçet’s
2) Class II MHC molecules present antigens that disease.
are contained in intracellular vesicles and 7. Nonspecific soluble mediators of the immune system
derived from foreign organisms and soluble include cytokines, such as interleukins, which
proteins. are mediators that act between leukocytes, inter-
c. A tentatively identified specificity carries the ferons (IFNs), colony-stimulating factors (CSFs),
additional letter “W” (workshop) and is inserted tumor necrosis factor (TNF), transforming
between the locus letter and the allele number— growth factor-β, and lymphokines (produced by
for example, HLA-BW 15. lymphocytes).
 Inflammation 7

sĞƐŝĐƵůĂƌ
^ƚŽŵĂƚŝƚŝƐ ƵƌŬŚŽůĚĞƌŝĂ
ǀŝƌƵƐ ŬůĞďƐŝĞůůĂ

Fig. 1.4 Suggestions on the potential impact of complosome-derived and/or pathogen-shunted intracellular
complement on key cell processes during the host/pathogen interaction. Pathogens trigger an array of
responses when interacting with complement during cell infection processes – some of which are beneficial
for the microbe and some of which support host protection. For example, infection of human papillomavirus
(HPV) triggers globular C1q receptor signaling (gC1qR), which leads to mitochondrial dysfunction and apoptosis
(1). Opsonized bacteria trigger mitochondrial antiviral signaling, which increases the expression of AP-1- and
NF-κB-controlled genes and proinflammatory cytokine responses. C3-opsonized viruses, on the other hand,
are targeted for degradation via the proteosome (2). Opsonized Listeria is also targeted in an intracellular
complement-dependent fashion for degradation after cell entry through v-set immunoglobulin domain con-
taining 4 (VSIG4)-driven autophagosome formation (3). Supporting viral and bacterial propagation, gC1R
signaling on mitochondria was also shown to block retinoic acid-inducible gene I (RIG-I) activation in a process
that promoted the replication of vesicular stomatitis virus (4), while opsonized Klebsiella and other species
use vitronectin to gain entry in nonphagocytic cells (5). Although in most of these processes, complement
fragments were “dragged” into the cell by microbes, we propose that there will also be (subsequent) inter-
actions of invading intracellular pathogens with components of the complosome, for example C3 and C5
activation fragments (6). In line with the “scheme” observed for the role of serum-derived complement, we
further predict that in some cases the complosome will mediate clearance of the pathogen while in other
cases, it will be utilized by the pathogen to promote its survival. (From Arbore G et al.: Intracellular comple-
ment – the complosome – in immune regulation. Mol Immunol 89:2–9, 2017. Figure 2. Elsevier.)

a. The TNF ligand family encompasses a large group After the transient arteriolar constriction terminates,
of secreted and cell surface proteins (e.g., TNF and blood flow increases above the normal rate for a
lymphotoxin-α and -β) that may affect the regula- variable time (up to a few hours) but then diminishes
tion of inflammatory and immune responses. to below normal (or ceases) even though the vessels
b. The actions of the TNF ligand family are some- are still dilated. Part of the decrease in flow is caused
what of a mixed blessing in that they can protect by increased viscosity from fluid loss through the
against infection, but they can also induce shock capillary and venular wall. The release of heparin by
and inflammatory disease. mast cells during this period probably helps to prevent
C. Immediately after an injury, the arterioles briefly widespread coagulation in the hyperviscous intra-
vascular blood.
contract (for approximately five minutes) and then
gradually relax and dilate because of the chemical medi-
ators discussed previously and from antidromic axon D. During the early period after injury, the leukocytes (pre-
reflexes. dominantly the PMNs) stick to the vessel walls, at first
8 CHAPTER 1 Basic Principles of Pathology

momentarily, but then for a more prolonged time; this PMNs, macrophages, and eosinophils mainly, but
is an active process called margination (see Fig. 1.1C). also of megakaryocytes and dendritic cells.
1. Ameboid activity then moves the PMNs through 3. PMNs are the most numerous of the circulating leu-
the vessel wall (intercellular passage) and through kocytes, making up 50–70% of the total.
the endothelial cell junctions (usually taking 2–12 4. PMNs function at an alkaline pH and are drawn to
minutes); this is an active process called emigration. a particular area by chemotaxis (e.g., by neutrophilic
2. PMNs, small lymphocytes, macrophages, and imma- chemotactic factor produced by human endothelial
ture erythrocytes may also pass actively across endo- cells).
thelium through an intracellular passage in a process 5. The PMNs remove noxious material and bacteria by
called emperipolesis. phagocytosis and lysosomal digestion.
3. Mature erythrocytes escape into the surrounding
tissue, pushed out of the blood vessels through open-
PMNs produce highly reactive metabolites, includ-
ings between the endothelial cells in a passive process ing hydrogen peroxide, which is metabolized to
called diapedesis. hypochlorous acid and then to chlorine, chlora-
E. Chemotaxis, a positive unidirectional response to a chemi- mines, and hydroxyl radicals—all important in
cal gradient by inflammatory cells, may be initiated by killing microbes. Lysosomes are saclike cytoplas-
lysosomal enzymes released by the complement system, mic structures containing digestive enzymes and
thrombin, or the kinins. other polypeptides. Lysosomal dysfunction or lack
F. PMNs (neutrophils; Fig. 1.5) are the main inflammatory of function has been associated with numerous
cells in the acute phase of inflammation. heritable storage diseases: Pompe’s disease (gly-
cogen storage disease type 2) has been traced
to a lack of the enzymes α-1,4-glucosidase in liver
All blood cells originate from a small, common pool lysosomes (see Chapter 11); Gaucher’s disease
of multipotential hematopoietic stem cells. Regulation is caused by a deficiency of the lysosomal enzyme
of the hematopoiesis requires locally specialized bone β-glucosidase (see Chapter 11). Metachromatic
marrow stromal cells and a coordinated activity of a leukodystrophy is caused by a deficiency of the
group of regulatory molecules—growth factors con- lysosomal enzyme arylsulfatase-A (see Chapter
sisting of four distinct regulators known collectively 11). Most of the common acid mucopolysaccha-
as CSFs. ride, lipid, or polysaccharide storage diseases are
caused by a deficiency of a lysosomal enzyme
specific for the disease (see under appropriate
1. PMNs are born in the bone marrow and are consid- diseases in Chapters 8 and 11). Chédiak–Higashi
ered “the first line of cellular defense.” syndrome may be considered a general disorder
2. CSFs (glycoproteins that have a variable content of of organelle formation (see section on congenital
anomalies in Chapter 11) with abnormally large
carbohydrate and a molecular mass of 18–90 kDa)
and fragile leukocyte lysosomes.
control the production, maturation, and function of

A B

Fig. 1.5 Polymorphonuclear leukocyte (PMN). A, Macroscopic appearance of abscess—that

is, a localized collection of pus (purulent exudate)—in vitreous body. B, PMNs are recog-
nized in abscesses by their segmented (usually three parts or trilobed) nucleus. C, Electron
micrograph shows segmented nucleus of typical PMN, and its cytoplasmic spherical and C
oval granules (storage granules or primary lysosomes).
 Inflammation 9

A B

Fig. 1.6 A, Eosinophils are commonly seen in allergic conditions

such as this case of vernal catarrh. B, Eosinophils are character-
ized by bilobed nucleus and granular, pink cytoplasm. C, Electron
micrograph shows segmentation of nucleus and dense cytoplasmic
crystalloids in many cytoplasmic storage granules. Some granules
appear degraded.

6. PMNs are end cells; they die after a few days and H. The acute phase is an exudative phase (i.e., an outpour-
liberate proteolytic enzymes, which produce tissue ing of cells and fluid from the circulation) in which the
necrosis. nature of the exudate often determines and characterizes
G. Eosinophils and mast cells (basophils) may be involved an acute inflammatory reaction.
in the acute phase of inflammation. 1. Serous exudate is primarily composed of protein (e.g.,
1. Eosinophils (Fig. 1.6) originate in bone marrow, seen clinically in the aqueous “flare” in the anterior
constitute 1% or 2% of circulating leukocytes, increase chamber or under the neural retina in a rhegmatog-
in number in parasitic infestations and allergic reac- enous neural retinal detachment).
tions, and decrease in number after steroid admin- 2. Fibrinous exudate (Fig. 1.8) has high fibrin content
istration or stress. They elaborate toxic lysosomal (e.g., as seen clinically in a “plastic” aqueous).
components (e.g., eosinophil peroxidase) and generate 3. Purulent exudate (see Figs. 1.1 and 1.5) is composed
reactive oxygen metabolites. primarily of PMNs and necrotic products (e.g., as
2. Mast cells (basophils; Fig. 1.7) elaborate heparin, seen in a hypopyon).
serotonin, and histamine, and they are imperative
for the initiation of the acute inflammatory reaction.
The term “pus” as commonly used is synonymous
with a purulent exudate.

Except for location, mast cells appear identical

to basophils; mast cells are fixed-tissue cells, 4. Sanguineous exudate is composed primarily of
whereas basophils constitute approximately 1% erythrocytes (e.g., as in a hyphema).
of circulating leukocytes. Basophils are usually II. Subacute (intermediate or reactive countershock and adap-
recognized by the presence of a segmented tive) phase.
nucleus, whereas the nucleus of a mast cells is
A. The subacute phase varies greatly and is concerned
large and nonsegmented.
with healing and restoration of normal homeostasis
10 CHAPTER 1 Basic Principles of Pathology

A B

C D

Fig. 1.7 A, Mast cell seen in center as round cell that contains slightly basophilic cytoplasm and round to
oval nucleus. B, Mast cells show metachromasia (purple) with toluidine blue (upper right and left and lower
right) and C, positive (blue) staining for acid mucopolysaccharides with Alcian blue. D, Electron microscopy
of granules in cytoplasm of mast cell often shows typical scroll appearance.

(formation of granulation tissue and healing) or with 3. CSFs (glycoproteins that have a variable content of
the exhaustion of local defenses, resulting in necrosis, carbohydrate and a molecular mass of 18–90 kDa)
recurrence, or chronicity. control the production, maturation, and function of
B. PMNs at the site of injury release lysosomal enzymes MN cells.
into the area. 4. These cells are the “second line of cellular defense,”
1. The enzymes directly increase capillary permeability arrive after the PMN, and depend on release of che-
and cause tissue destruction. motactic factors by the PMN for their arrival.
2. Indirectly, they increase inflammation by stimulating a. Once present, MN cells can live for weeks, and
mast cells to release histamine, by activating the kinin- in some cases even months.
generating system, and by inducing the chemotaxis b. MN cells cause much less tissue damage than do
of mononuclear (MN) phagocytes. PMNs, and they are more efficient phagocytes.
C. Mononuclear (MN) cells (Fig. 1.9) include lymphocytes 5. Monocytes have an enormous phagocytic capacity
and circulating monocytes. and are usually named for the phagocytosed material
1. Monocytes constitute 3%–7% of circulating leuko- (e.g., blood-filled macrophages [erythrophagocytosis]
cytes, are bone marrow-derived, and are the progenitor and lipid-laden macrophages; Fig. 1.10).
of a family of cells (monocyte–histiocyte–macrophage 6. Monocytes replace neutrophils as the predominate
family) that have the same fundamental character- cell 24–48 hours after the onset of inflammation.
istics, including cell surface receptors for complement D. Lysosomal enzymes, including collagenase, are released
and the Fc portion of immunoglobulin, intracellular by PMNs, MN cells, and other cells (e.g., epithelial cells
lysosomes, and specific enzymes; production of mono- and keratocytes in corneal ulcers) and result in consider-
kines; and phagocytic capacity. able tissue destruction.
2. Circulating monocytes may subsequently become
tissue residents and change into tissue histiocytes, In chronic inflammation, the major degradation of
collagen may be caused by collagenase produced
macrophages, epithelioid histiocytes, and inflamma-
by lymphokine-activated macrophages.
tory giant cells.
 Inflammation 11

E. If the area of injury is tiny, PMNs and MN cells alone

can handle and “clean up” the area with resultant healing.
F. In larger injuries, granulation tissue is produced.
1. Granulation tissue (Fig. 1.11) is composed of leuko-
cytes, proliferating blood vessels, and fibroblasts.
2. MN cells arrive after PMNs, followed by an ingrowth
of capillaries that proliferate from the endothelium
of pre-existing blood vessels.

The new blood vessels tend to leak fluid and

A leukocytes, especially PMNs.

3. Fibroblasts (see Fig. 1.11), which arise from fibrocytes

and possibly from other cells (monocytes), prolifer-
ate, lay down collagen (Table 1.5), and elaborate
ground substance.
4. With time, the blood vessels involute and disappear,
the leukocytes disappear, and the fibroblasts return
to their resting state (fibrocytes). This involutionary
process results in shrinkage of the collagenous scar
and a reorientation of the remaining cells into a par-
allel arrangement along the long axis of the scar.
5. If the noxious agent persists, the condition may not
B C
heal as described previously, but instead may become
chronic.
Fig. 1.8 A, Cobweb appearances of fibrinous exudate, stained with 6. If the noxious agent that caused the inflammation
periodic acid–Schiff. Cells use fibrin as scaffold to move and to lay down is immunogenic, a similar agent introduced at a future
reparative materials. B, Electron micrograph shows periodicity of fibrin
date can start the cycle anew (recurrence).
cut in longitudinal section. C, Fibrin cut in cross-section.

Histiocyte/macrophage Activated macrophage Activated macrophages

? ?
?

Multinucleated
inflammatory
?
giant cell

Langhans Foreign body Touton

Epithelioid cells
A B
Fig. 1.9 A, Monocytes have lobulated, large, vesicular nuclei and moderate amounts of cytoplasm, and they
are larger than the segmented polymorphonuclear leukocytes and the lymphocytes, which have round nuclei
and scant cytoplasm. B, Possible origins of multinucleated inflammatory giant cells and of epithelioid cells.
12 CHAPTER 1 Basic Principles of Pathology

A B

Fig. 1.10 A, Foamy and clear lipid-laden macrophages in subneural retinal space. B, Cytoplasm of macro-
phages stains positively for fat with oil red-O technique.

A B

Fig. 1.11 Granulation tissue. A, Pyogenic granuloma, here in region of healing chalazion, is composed of
granulation tissue. B, Three components of granulation tissue are capillaries, fibroblasts, and leukocytes.

III. Chronic phase (Fig. 1.13), and is identified by the presence of

A. The chronic phase results from a breakdown in the pre- immunoglobulin on its surface; (2) the thymus-
ceding two phases, or it may start initially as a chronic dependent T lymphocyte participates in cellular
inflammation (e.g., when the resistance of the body and immunity, produces a variety of lymphokines,
the inroads of an infecting agent, such as the organisms and is identified by various surface antigens.
of tuberculosis or syphilis, nearly balance; or in condi- 1) Helper-inducer T lymphocytes (CD4-positive)
tions of unknown cause such as sarcoidosis). initiate the immune response in conjunction
B. Chronic nongranulomatous inflammation is a prolifera- with macrophages and interact with (helper)
tive inflammation characterized by a cellular infiltrate B lymphocytes.
of lymphocytes and plasma cells (and sometimes PMNs
or eosinophils). CD4+ T cells are activated after interaction
1. The lymphocyte (Fig. 1.12) constitutes 15%–30% of with antigen–MHC complex and differenti-
circulating leukocytes and represents the competent ate into Helper subsets. These functionally
immunocyte. distinct T-helper subsets participate in host
a. All lymphocytes probably have a common stem defense and immunoregulation. Classically,
T-helper 1 (Th1) and T-helper 2 (Th2) cells
cell origin (perhaps in the bone marrow) from
secrete a distinctive suite of cytokines:
which they populate the lymphoid organs: the Th1 express T-bet and produce interferon-γ
thymus, spleen, and lymph nodes. and are involved predominantly in cell-
b. Two principal types of lymphocytes are recognized: mediated immunity (e.g., cytotoxic T-cell
(1) The bone marrow-dependent (or bursal equiv- response); Th2 express Gata3 and produce
alent) B-lymphocyte is active in humoral immu- interleukins-4, -5, and -13. Regulatory T
nity, is the source of immunoglobulin production (Treg) cells also are CD4+-derived cells,
 Inflammation 13

TABLE 1.5 Heterogeneity of Collagens in the Cornea*

Type Polypeptides Monomer Polymer
I [α1(I)]2α2(I)

II [α1(II)]3

III [α1(III)]3

IV [α1(IV)]2α2(IV)

V [α1(V)]2α2(V)

VI [α1(VI)]2α2(VI)α3(VI)

VII [α1(VII)]3?

VIII [α1(VIII)]2α2(VIII)?

IX [α1(IX)]2α2(IX)α3(IX)

XII [α1(XII)]3

*At least 10 genetically distinct collagens have been described in the corneas of different animal species, ages, and pathologies. Types I, II, III,
and V collagens are present as fibrils in tissues. Types IV, VI, VII, and VIII form filamentous structures. Types IX and XII are fibril-associated
collagens. The sizes of the structures are not completely known. Type II collagen is found only in embryonic chick collagen associated with the
primary stroma. Type III collagen is found in Descemet’s membrane and in scar tissue. Types I and V form the heterotypic fibrils of lamellar
stroma. Type VII has been identified with the anchoring fibrils, and type VIII is present only in Descemet’s membrane. Type IX collagen,
associated with type II fibrils in the primary stroma, and type XII collagen, associated with type I/V fibrils, are part of a family of fibril-associated
collagens with interrupted triple helices. Both type IX and type XII are covalently associated with a chondroitin sulfate chain.
(Reproduced from Cintron C: The molecular structure of the corneal stroma in health and disease. In Podos SM, Yanoff M, eds: Textbook of
Ophthalmology, vol. 8. London, Mosby. © Elsevier 1994.)

serve an immunosuppressive function, and 2) Suppressor-cytotoxic T lymphocytes (CD8-

express the master transcription factor positive) suppress the immune response and
FoxP3. There are thymic-derived natural, are capable of killing target cells (e.g., cancer
nTreg cells and peripherally induced iTreg cells) through cell-mediated cytotoxicity.
cells that relate to autoimmunity. T-helper 3) MHC molecules present antigenic peptides
17 (Th17) cells participate in protective
to CD8+ T cells, thereby providing the founda-
tumor immunity; however, Th17-associated
cytokines may be associated with tumor
tion for immune recognition.
initiation and growth and also with auto- 2. The plasma cell (Fig. 1.15) is produced by the bone
immune diseases. Finally, there are fol- marrow–derived B lymphocyte, elaborates immuno-
licular T-helper (Tfh) cells that are in globulins (antibodies), and occurs in certain modified
proximity to B cells in the germinal centers forms in tissue sections.
of lymphoid tissue. They promote class
switching of B cells and express the After germinal center B cells undergo somatic
master regulator Bc16 and the effector mutation and antigen selection, they become
cytokine IL-21 as well as other surface either memory B cells or plasma cells. CD40 ligand
molecules. Fig. 1.14 illustrates the com- directs the differentiation of germinal center B
plexity, flexibility and plasticity of the rela- cells toward memory B cells rather than toward
tionships between T-helper cells. plasma cells.
14 CHAPTER 1 Basic Principles of Pathology

rbc

Fig. 1.12 Lymphocyte. A, Low magnification shows cluster of many lymphocytes appearing as a deep blue
infiltrate. Cluster appears blue because cytoplasm is scant and mostly nuclei are seen. B, Electron micrograph
shows lymphocyte nucleus surrounded by small cytoplasmic ring containing several mitochondria, diffusely
arrayed ribonucleoprotein particles, and many surface protrusions or microvilli (rbc, red blood cell). C, Lym-
phocytes seen as small, dark nuclei with relatively little cytoplasm. Compare with polymorphonuclear leuko-
cytes (segmented nuclei) and with larger plasma cells (eccentric nucleus surrounded by halo and basophilic
cytoplasm).

N VL
N
a. Plasmacytoid cell (Fig. 1.16A and B): This has a
CL
single eccentric nucleus and slightly eosinophilic
VH granular cytoplasm (instead of the normal baso-
C
philic cytoplasm of the plasma cell).
Antigen- CH1 C b. Russell body (Fig. 1.16C and D): This is an inclu-
binding CH2 CH3
sites
sion in a plasma cell whose cytoplasm is filled
C
and enlarged with eosinophilic grapelike clusters
C Heavy chain
(morular form), with single eosinophilic globular
structures, or with eosinophilic crystalline struc-
tures; usually the nucleus appears as an eccentric
N
Light chain
rim or has disappeared.
N
Fig. 1.13 The basic immunoglobulin structure. The unit consists of two
identical light polypeptide chains linked together by disulfide bonds (gray). The eosinophilic material in plasmacytoid cells
The amino-terminal end (N) of each chain is characterized by sequence and in Russell bodies appears to be immuno-
variability (VL, VH), whereas the remainder of the molecule has a relatively globulin that has become inspissated, as if
constant structure (CL, CH1–CH3). The antigen-binding sites are located the plasmacytoid cells can no longer release
at the N-terminal end. (Adapted with permission from Roitt IM, Brostoff the material because of defective transport
J, Male DK: Immunology, 2nd edn. London, Gower Medical. © Elsevier by the cells (“constipated” plasmacytoid cells).
1989.)
 Inflammation 15

C. Chronic granulomatous inflammation is a proliferative b. They are often found oriented around necrosis as
inflammation characterized by a cellular infiltrate of large polygonal cells that contain pale nuclei and
lymphocytes and plasma cells (and sometimes PMNs abundant eosinophilic cytoplasm whose borders
or eosinophils). blend imperceptibly with those of their neighbors
1. Epithelioid cells (Fig. 1.17) are bone marrow–derived in a pseudosyncytium (“palisading” histiocytes in
cells in the monocyte–histiocyte–macrophage family a granuloma).
(Fig. 1.18). c. All cells of this family interact with T lymphocytes,
a. In particular, epithelioid cells are tissue monocytes are capable of phagocytosis, and are identified by
that have abundant eosinophilic cytoplasm, some- the presence of surface receptors for complement
what resembling epithelial cells. and the Fc portion of immunoglobulin.
2. Inflammatory giant cells, probably formed by fusion
of macrophages rather than by amitotic division,
Tfh predominate in three forms:
a. Langhans’ giant cell (Fig. 1.19; see Fig. 1.17): This
Plasticity Bcl6 is typically found in tuberculosis, but it is also seen
in many other granulomatous processes. When
Th1 Th2 sectioned through its center, it shows a perfectly
Bcl6
Bcl6 FoxP3 Bcl6
homogeneous, eosinophilic, central cytoplasm
T-bet T-bet Gata3 Gata3 with a peripheral rim of nuclei.
Flexibility
T-bet Gata3 If the central portion is not homogeneous,
RORyt FoxP3
foreign material such as fungi may be present:
RORyt T-bet the cell is then not a Langhans’ giant cell but
FoxP3 FoxP3
a foreign-body giant cell. When a Langhans’
giant cell is sectioned through its periphery,
RORyt FoxP3
it simulates a foreign-body giant cell.
Th17 Tregs

b. Foreign-body giant cell (Fig. 1.20): This has its

Fig. 1.14 Flexibility and plasticity of helper T cells. Recent studies con- nuclei randomly distributed in its eosinophilic
tinue to reveal surprising flexibility in expression of “master regulator” cytoplasm and contains foreign material.
transcription factors. In addition, there are now many examples in which c. Touton giant cell (Fig. 1.21), frequently associated
helper T cell phenotypes can change their pattern of expression of sig-
nature cytokines and gene expression. Striking examples exist in which with lipid disorders such as juvenile xanthogranu-
apparently fully committed “lineages” readily switch their phenotype, loma, appears much like a Langhans’ giant cell
and there are now many circumstances in which helper T cells have with the addition of a rim of foamy (fat-positive)
been shown to express more than one master regulator. This may be cytoplasm peripheral to the rim of nuclei.
advantageous in terms of host defense, but it needs to be borne in 3. Three patterns of inflammatory reaction may be found
mind in thinking about effective therapies for immune-mediated disease
and vaccine development. (From Nakayamada S, Takahashi H, Kanno Y in granulomatous inflammations:
et al.: Helper T cell diversity and plasticity. Curr Opin Immunol 24:297, a. Diffuse type (Fig. 1.22A): This typically occurs in
2012.) sympathetic uveitis, disseminated histoplasmosis

A B

Fig. 1.15 Plasma cell. A, Plasma cells are identified by eccentrically located nucleus containing clumped
chromatin and perinuclear halo in basophilic cytoplasm that attenuates opposite to nucleus. Plasma cells are
larger than small lymphocytes, which contain deep blue nuclei and scant cytoplasm. B, Electron microscopy
shows exceedingly prominent granular endoplasmic reticulum that accounts for cytoplasmic basophilia and
surrounds nucleus. Mitochondria are also present in cytoplasm.
16 CHAPTER 1 Basic Principles of Pathology

A B

C D

Fig. 1.16 Altered plasma cells. A, Electron micrograph shows that left plasmacytoid cell contains many small
pockets of inspissated material (γ-globulin) in segments of rough endoplasmic reticulum; right cell contains
large globules (γ-globulin), which would appear eosinophilic in light microscopy. B, Plasmacytoid cell in center
has eosinophilic (instead of basophilic) cytoplasm that contains tiny pink globules (γ-globulin). C, Russell body
appears as large anuclear sphere or D, multiple anuclear spheres.

Activated ?
macrophage Langerhans’
cell

Lymphokine
?
Monocyte/ Giant cell Foreign
macrophage body

? ?

Epithelioid Touton
cell
Fig. 1.17 Epithelioid cells in conjunctival, sarcoidal granuloma, here
Fig. 1.18 Proposed scheme for the terminal differentiation of cells of
forming three nodules, which are identified by eosinophilic color resem-
the monocyte/macrophage system. The pathologic changes result from
bling epithelium. Giant cells, simulating Langhans’ giant cells, are seen
the inability of the macrophage to deal effectively with the pathogen.
in nodules.
Lymphokines from active T cells induce monocytes and macrophages
to become activated macrophages. Where prolonged antigenic stimula-
tion exists, activated macrophages may differentiate into epithelioid
cells and then into giant cells in vivo, in granulomatous tissue. The
multinucleated giant cell may be derived from the fusion of several
epithelioid cells. (Adapted with permission from Roitt IM, Brostoff J,
Male DK: Immunology, 2nd edn. London, Gower Medical. © Elsevier
1989.)
 Inflammation 17

and other fungal infections, lepromatous leprosy, are distributed randomly against a background
juvenile xanthogranuloma, Vogt–Koyanagi–Harada of lymphocytes and plasma cells.
syndrome, cytomegalic inclusion disease, and toxo- b. Discrete type (sarcoidal or tuberculocidal; see Fig.
plasmosis. The epithelioid cells (sometimes with 1.22B): This typically occurs in sarcoidosis, tuber-
macrophages or inflammatory giant cells or both) culoid leprosy, and miliary tuberculosis. An accu-
mulation of epithelioid cells (sometimes with
inflammatory giant cells) forms nodules (tuber-
cles) surrounded by a narrow rim of lymphocytes
(and perhaps plasma cells).
c. Zonal type (see Fig. 1.22C): This occurs in caseation
tuberculosis, some fungal infections, rheumatoid
scleritis, chalazion, phacoanaphylactic (phacoanti-
genic) endophthalmitis, toxocara endophthalmitis,
and cysticercosis.
1) A central nidus (e.g., necrosis, lens, and foreign
body) is surrounded by palisaded epithelioid
cells (sometimes with PMNs, inflammatory
giant cells, and macrophages) that in turn are
surrounded by lymphocytes and plasma cells.
Fig. 1.19 Langhans’ giant cells have homogeneous central cytoplasm 2) Granulation tissue often envelops the entire
surrounded by rim of nuclei. inflammatory reaction.

A B

Fig. 1.20 A, Foreign-body giant cell (FBGC) simulating Langhans’ giant cells, except that homogeneous
cytoplasm is interrupted by large, circular foreign material. B, Anterior-chamber FBGCs, here surrounding
clear clefts where cholesterol had been, have nuclei randomly distributed in cytoplasm.

A B

Fig. 1.21 A, Touton giant cells in juvenile xanthogranuloma closely resemble Langhans’ giant cells except
for the addition of peripheral rim of foamy (fat-positive) cytoplasm in the former. B, Increased magnification
showing fat positivity of peripheral cytoplasm with oil red-O technique. (Case presented by Dr. M Yanoff to
the Eastern Ophthalmic Pathology Society, 1993, and reported in Arch Ophthalmol 113:915, 1995.)
18 CHAPTER 1 Basic Principles of Pathology

A B

Fig. 1.22 Patterns of granulomatous inflammation. A, Diffuse type

in sympathetic uveitis. B, Discrete (sarcoidal or tuberculocidal) type
in sarcoidosis. C, Zonal type in phacoanaphylactic endophthalmitis.

A. Anatomical and physiological barriers

Staining Patterns of Inflammation 1. Examples are the skin, enzymes in secretions, mucoid
I. Patterns of inflammation are best observed microscopically surface secretions, surfactant, and gastric pH.
under the lowest (scanning) power. B. Innate immunity (See also discussion of complement
II. With the hematoxylin and eosin (H&E) stain, an infiltrate earlier in this chapter.)
of deep blue tint (basophilia) usually represents a chronic 1. This system has few receptors for antigens, but ones
nongranulomatous inflammation. The basophilia is pro- that are widespread among potential invaders.
duced by lymphocytes that have blue nuclei (when stained 2. Inflammasome (Fig. 1.25) illustrates how activation
with hematoxylin) and practically no cytoplasm (if it were of one of the upstream sensors precipitates inflam-
present, it would stain pink with eosin) and by plasma cells masome formation leading to cell membrane breach
that have blue nuclei and blue cytoplasm. and cell death through pyroptosis.
III. A deep blue infiltrate with scattered gray (pale pink) areas a. It is a multiprotein complex composed of a sensor
(“pepper and salt”) usually represents a chronic granulo- protein, the adapter protein ASC (apoptosis-
matous inflammation, with the blue areas lymphocytes and associated speck-like protein containing caspase
plasma cells, and the gray areas islands of epithelioid cells. recruitment domain), and the inflammatory pro-
IV. A “dirty” gray infiltrate usually represents a purulent reac- tease caspase-1.
tion with PMNs and necrotic material. b. Downstream substrates are gasdermin D, IL-1β,
A. If the infiltrate is diffuse (Fig. 1.23; e.g., filling the vitre- and IL-18 and are responsible for an inflamma-
ous [vitreous abscess]), the cause is probably bacterial. tory form of cell death called pyroptosis with
B. If the infiltrate is localized into two or more small areas gasdermin D functioning as the actual instru-
(Fig. 1.24; i.e., multiple abscesses or microabscesses), ment of cell death by forming pores in the cell
the cause is probably fungal. membrane.
1) Following its activation, caspase-1 induces
IMMUNOBIOLOGY activation of IL-1β, and IL-18 thereby resulting
in inflammation.
Background c. Upstream sensors include NLRP (nucleotide-
I. There are three levels of human defense against invading binding domain and leucine-rich repeat contain-
organisms: ing) 1, NLRP3, NLRC4, AIM2, and pyrin.
Another random document with
no related content on Scribd:
doorways and along the nave. It was a crowd of many languages and of all
conditions, and an immense hum of excitement surged from it, breaking
readily into applause and acclamation—though there were hours to wait
before the climax should be reached and expectation crowned. It was a grand
event, I suppose, but not of the grandest; it was a reception of some few
thousands of votaries, for whom the basilica was this morning the chamber
of audience. How many thousands will the chamber hold? It had filled to
over-flowing before the morning had passed, and the hum as it deepened
grew fervid and passionate with the loyalty of a strangely mingled army.
These people had been drawn to Rome from afar like the rest of us, like
myself, like Deering and Cooksey; but the voice of their enthusiasm had a
profounder note than ours. I picked my way among the assembling tribes,
listening to snatches of their talk and trying to identify the outlandish forms
of their gabble. My place, however, was not in their midst; for by the
kindness of Cooksey I had admission to some special enclosure or tribune,
lifted above the heads of the mob; and that is why I was dressed for a party
at this untimely hour—it is the rule.
I found my place of honour on a kind of scaffold, raised in the choir at a
point that commanded the splendid scene. The pilgrims thronged and
thickened just beneath us; but they seemed far away in their murmurous
confusion when I had taken my seat on the scaffold, among the black-
arrayed group already established there aloft. We were a dozen or so, men
and women; we looked not at all like pilgrims, and instead of joining in the
jubilant roar that soon began to sway to and fro in the thousands of throats
beneath us—instead of crying aloud in our homage before the shrine of
Rome—what could we do but look on as at a spectacle, a display which we
had luckily chanced upon and overtaken in time? We had nothing to do with
it, no share in that rising passion of fidelity;—or perhaps indeed I should
speak for myself alone, for my neighbour on the scaffold had presently
attracted my attention by a sudden movement, springing to her feet (she was
a middle-aged woman), throwing up her hands and cheering—cheering with
a strange uncertain bird-like note that shockingly embarrassed the rest of us.
She had been carried away by a sympathetic enthusiasm and she wanted to
join in the full-throated roar; but she was detached from it, isolated in a little
ring of decorous silence; so that her queer hoo-hoo-hoo fell upon her own
ears too with disconcerting effect, and she faltered rather lamentably in the
middle of her outcry. Discreet ladies, black-veiled as they all were, sitting
around her on the scaffold, looked rigidly in front of them; and the poor
enthusiast subsided as best she could, blushing and effacing herself. That
was our only demonstration; the company of the scaffold sat otherwise
unmoved to the end of the great affair, talking unobtrusively under that vast
dome-full of human sound.
There was a long while to wait before the august and magnificent entry
which we were expecting. Cooksey appeared very soon, and with him was a
neat and slender and priestly figure to which I instantly gave the name of
Father Holt. You remember the figure, of course, in Thackeray’s gallery—
the polished and enigmatic gentleman of the world, who wrought so vividly
upon the boyhood of Esmond. If Cooksey’s friend had chanced to take me in
hand when I was a boy, he would indeed have found me easy moulding. He
was dark, he was very handsome in the clear-eyed and hard-lipped manner;
he had the ghost of a smile and a most musical voice. Cooksey came
bustling to the front of the platform, where I was, and Father Holt dropped
behind. One of the black-veiled ladies put out a hand to him and he dealt
with it urbanely; but he disengaged himself, he held himself aloof in the
background; and indeed we were not a party of much distinction, and I
didn’t wonder that Father Holt found us a little plebeian. Cooksey breathed
heavily in my ear to the effect that the female just behind me was the old
wretch of whom he had spoken the other evening, the pet votaress of Father
Jenkins—“and I know I shall put my foot in it again,” he said, “because I
always make a fool of myself on these solemn occasions.” He chuckled
wickedly, and he added that “these old cats” took it all so seriously, one had
to be desperately careful.
The elderly gentlewoman in question was taking it very seriously indeed,
though she didn’t commit herself to the point of standing up and cheering.
She had forgiven Cooksey his assault upon her in church, and she now drew
him into a conversation that I followed with interest. I can’t reproduce it, for
it was highly technical, full of odd phrases and allusions that were strange to
me; Cooksey and Lady Mullinger (that was her name) conversed in the
language of a secret society from which I was excluded. It struck me as very
picturesque, and it exhaled a cloud of suggestion—“puff on puff,” not
exactly of “grated orris-root,” but of a pleasant and pungent effluence that
reminded me of many things. This vein of Roman talk never seems to me to
have any of the associations of an ancient history, of a long-seasoned
tradition, of a bygone grace denied to those who are not of the society. Oh
no, it is intensely modern and angular; it reminds me of raw new buildings,
filled with chalk-blue and shrimp-pink imagery; it reminds me of deal
praying-chairs and paper roses and inscriptions in ugly French lettering.
When Cooksey and Lady Mullinger talk together they appear to delight in
emphasizing their detachment, their disconnexion from all the sun-mellowed
time-hallowed sweetness of antiquity; but of course it is exactly this odd
modernity of their tone which makes their talk so picturesque in the hearing
of an outsider. I was a complete outsider; and the manner in which these two
spoke of the rites and forms and festivals of their society was a manner quite
fresh to me, and I enjoyed it.
Lady Mullinger was elderly and plain. Catching sight of Father Holt, she
made him signals so urgent that he had to come forward; she beset him with
smiles and gestures and enquiries under which he stood patient and
courteous, a picture of well-bred disdain. Lady Mullinger had no misgiving,
and she rallied him archly, she appealed to him, she bunched her untidy
amplitude together to make room for him at her side. He looked at her
sidelong with his bright eyes, and he took no notice of her advances beyond
answering her large sloppy questions with a neatly worded phrase. She made
the foolish mistake of coupling Father Holt and Cooksey together in her
broadly beaming patronage; Cooksey was well aware that it was a mistake,
and his assurance failed him. Father Holt (I can’t call him anything else)
glanced from one to the other with a single flit of his cool observation, and it
was enough. Cooksey was ill at ease; he had been gossiping quite
comfortably with her ladyship, but with Father Holt’s quiet glance on him he
tried to disown her. He saw that she was stout and ordinary, and that he
himself looked terribly like her; he edged away and did his best to range
himself on Father Holt’s side of the colloquy. But Father Holt kept them
serenely at a distance, the pair of them; it was easy to see that it was not for
Cooksey to stand by his side uninvited.
“No, Lady Mullinger,” said Father Holt, “I can’t, I fear, make you a
definite promise in that matter.” He spoke with a charming vibrating bell-
tone; it was like the striking of a rod of polished silver in the midst of the
sawing of strings out of tune. Lady Mullinger, unsuspecting and unabashed,
flung herself the more vehemently into her demand; she wanted him to do
this and that, but mainly she wanted him to come to tea with her on
Thursday and to have a little talk with “poor Charlotte”; she pressed it as an
opportunity for poor Charlotte which he mustn’t deny her. Poor Charlotte
was in a sad way; nothing seemed to ease her, nobody had proved able to
open “the door of her spirit.” So Lady Mullinger said, and she was positive
that Father Holt would open the door, he alone, and she would arrange that
nobody should disturb them, her salottino would be free (they would have
tea in the big room), and he and poor Charlotte could then have a “nice little
talk.” Lady Mullinger had set her heart on it—“just a nice little talk, quite
informal”; she shouldn’t tell poor Charlotte that he was expected, and he
could just draw her aside, after tea, and help the poor thing to “find her
way.” The convenience of the salottino was urged once more, and the tact
with which Lady Mullinger would keep her other guests out of it; and the
ghost of the smile was upon the lips of Father Holt as he repeated, very
distinctly, his refusal to make her a promise. Poor Charlotte would evidently
have to find the way for herself, and Lady Mullinger abounded in despair.
Cooksey had introduced me to the beautiful priest, and I had one of his
sharp glances to myself. For half a second I thought he was going to be
interested in me, and I sat up with pleasure; but then I was turned down, I
was placed with the rest of the company, and I perceived that I was no finer
or rarer or more exquisite than Cooksey himself. It was worse, however, for
Cooksey than for me, and the contrast between his natural exuberance and
his shrivelled loose-jawed malease under the eye of Father Holt was
melancholy indeed. Father Holt was the real thing, Cooksey could only
pretend to be the real thing in his absence. You can’t attain to the heart of
Rome, after all, by the simple and obvious methods of a Cooksey; you can’t
set off from Bath and Wells, travelling to Rome because Rome attracts you,
and then expect to find yourself on terms of equality with Father Holt, whose
foot was on the stair of the Vatican when Doctor Tusher (your spiritual
forbear) was scraping to his lordship and marrying the waiting-maid.
Cooksey could impose upon me with the airy flourish of his intimacy with a
world from which I was locked out; but he was reduced to the position of a
very raw new boy in the company of the born initiate. Poor old Cooksey—it
was a shame that I should be there to see it.
He couldn’t renew his pleasant gossip with Lady Mullinger, and he rather
stupidly persisted in trying to range himself with Father Holt. He received
his measured stint of Father Holt’s admirable manners, and his uneasy
gratitude was pathetic. Where was now my Cooksey of the liberal jest, of the
gay scuffle with Monsignor Mair? The conversation drooped, and presently
Father Holt had slipped off again into the background, where there now
arose a small stir of a new arrival. He was at the head of the staircase which
ascended to the scaffold, he was welcoming somebody who emerged from
below; and this was a little old lady, at whom the eyes of the company were
turned with cautious curiosity. Cooksey nudged me, whispering her name
and her title, both very splendid; as discreetly as I might, I stared at her with
all my attention. None of us ventured to join Father Holt in the graceful and
natural ceremony that he made of handing her to her place in the front of the
platform. He dropped into the chair by her side, he engaged in a talk with her
that we couldn’t overhear, and he was subtly transfigured as he did so. There
was no change in his composure and his bland dignity; but he seemed to sink
with relief into a society where he felt at home. The rest of us were silent, we
couldn’t set up a rival society in the face of that exhibition; and besides we
wished, I think, to miss nothing of its effect.
She was small and shabby and very neat; her hair, under her black veil,
was scraped together in a little grey knob; she had a strange old mantle upon
her, short to her waist, of much-worn black, and her tiny arms appeared
beneath it, with hard white cuffs, ending in gloves that were like the Russia-
binding of a prayer-book. She was not pretty, but she was perfect; her eyes
were very sweet and soft, and her face had no colour in it at all, and the light
that shone out of her eyes seemed to shine equally through the diaphanous
pallor of her cheek. I never saw any one so transparent; she looked infinitely
fragile—because it was as though you could see through her and could see
that she hadn’t a drop of common life to give her substance. I could hear the
gentle purity of her voice, with its quiet and even intonation. She was
English, though the name and the title that Cooksey had spluttered in my ear
were not; she was intensely English—she couldn’t otherwise have talked
with that smooth silk-thread of a monotone which was so well in keeping
with the pearl-glimmer of her face. She was perfect indeed; and if she
dressed in her rusty black and wrung her hair into its knob with the purpose
of making the utmost of her wondrous distinction—why then she did rightly
and her style was consummately chosen, for her distinction was enhanced
beyond measure by her queer little white-cuffed dowdiness. All the rest of us
were things of such tawdry attractions, such twopenny pretensions; she must
have walked in a moving circle of perpetual vulgarity, for I can scarcely
imagine a face or a word or a movement that wouldn’t strike you, at the
moment when you looked away from her, as the commonest trash.
 Didn’t I even perceive that Father Holt’s distinction was not what it had
appeared a minute ago? It was now just a thought too sleek, too glossy, too
well-appointed; and I wondered wildly if I was never to come to the end in
my discovery of finer shades and finer. So the best has still a better—but
indeed I had come to the end at this point, for I have never reached a better
in her kind than the great little old lady of that morning in St. Peter’s. Lady
Mullinger positively creaked with reverential contemplation; she didn’t
aspire to attracting any sign of notice from the great lady—who seemed,
however, to ignore our company in modest and delicate shyness, not in pride
—but she pored, she gloated upon the vision with all her being. Poor
Charlotte was forgotten, Cooksey had dropped out of the world; Lady
Mullinger was intently committing to memory the details of so historic an
impression. Much would be heard of it, no doubt, at tea in the big room on
Thursday. Meanwhile I was not far behind her, I confess, in using the
opportunity of the moment; I was fascinated by this sudden exaltation of my
standard in the grace of the highest style.
But the brilliance and the rumour of the great church, filled more and
more with crowding movement, made it soon impossible to attend to any
other than its own distinction. This was a staring and thumping affair by
comparison with the small voice of perfection; but mere size, when it is
miles high, and mere gold, when it is inches thick, and mere noise, when it is
in the throats of all the tribes, will use their overbearing power and assert
their dignity. There was nothing perfect in the seethe and clamour of the
pilgrims, nothing in the sprawl of ostentation over the whole adornment of
the scene; but it was a vast and riotous and haphazard work of genius, all of
it together—the overflow of an imagination no better than my own, or not so
good, but as large as an ocean against my own poor painful tap-trickle. The
passion that rolled along the nave and swept round the hollow of the dome,
toppling, breaking in uncontrollable excitement—I hung over it, clinging to
my perch on the tribune, and I flung into it my own small cup-full; but how
could I think to swell it with these few drops, claiming to ally myself with
genius of that enormity? It was vain, I was the flimsiest of onlookers; and
the pilgrims could bring a tribute to Rome that was profuse enough,
indiscriminate and coarse enough, to fill the chamber prepared to receive it,
to brim the church of St. Peter in an hour or two. Their capacity was well-
matched; Rome and the pilgrims, they wrought upon the same scale, they
understood each other.
 Rome, yes—but what about the Romans? Father Holt surveyed the
struggle of the pilgrims with something like the high indifference of the
philosopher at a show of gladiators; he inclined his ear to the little
transparent old princess beside him, he received her remarks with courteous
care; and as for her, she was as far aloof from the common scramble as a
flower that unfolds upon the cliff-edge above the booming ravine. Cooksey
indeed was intent on the display with all the eager bulge of his eyes; but he
had frankly relapsed into sight-seeing, he was just a Briton in foreign parts.
Lady Mullinger, though she murmured to her neighbour that the zeal of the
crowd had “filled her heart,” couldn’t really attend to anything but the
princess; she glanced perfunctorily at the crowd, but she was trying all the
while to catch the silvery murmur that was holding the privileged ear of
Father Holt. It was altogether evident that our party on the scaffold was
neither of Rome nor of the pilgrimage, and the great affair proceeded
beneath us with a roar and a rush that sounded more and more remote in my
hearing, even while now it mounted to its culmination. That “real Rome,” of
which I thought I had been learning so much, was magnificently bestirring
itself to accept the homage of its swarming subjects, and I tried to look
through their eyes and to see what they saw in their jubilation.
They at least had no doubt, they knew where to look for the genius of
Rome. Far away across the church and down the nave, somewhere near the
great portals at the end, there was a side-door, and a broad lane from this
door had been cleared through the crowd. Rome was very soon to issue from
the door, it was for Rome that the lane was kept open along the roaring
church. But a church, do I say?—it was the temple of Rome, the “great main
cupola” of the Roman genius. It stands upon the hill of the Vatican in our
day, and it has stood there for some little time; but its rightful place is the
Capitol, the mount of triumph—it is there that the temple belongs. Kings and
queens were led captive to that shrine, the multitude mocked and jeered at
their abasement; and I see what is wanting to the due completeness of the
resounding assembly in St Peter’s—it is the presence of captive kings and
queens, brought low by the power of Rome, over whom the multitude might
exult with glee and ferocity. And indeed the multitude would, it is easy to
see; I shouldn’t, nor Father Holt, nor the rest of us up here, and that is why
we feel thus cut off from the tumult beneath us; but the pilgrims would
delight in deriding the poor dazed wretches, and their reverence for the
majesty of Rome would be the more enhanced. This joy, which they would
have tasted upon the Capitol, is denied them upon the tomb of Peter; but
they have lost nothing else by the shifting of the shrine. Rome above all,
Rome the wonder of the world, is still the attraction of their worship; and
from the door of the temple that we watch with strained expectation,
suddenly hushed as the great moment approaches, Rome is about to emerge
and appear before us. Look, it is there—a high swaying throne or pedestal,
borne upon the shoulders of faithful knaves, and an ancient white-robed
figure that sits aloft, springing upright and subsiding again with outstretched
hand, and a smile, a fixed immemorial smile in a blanched face, beneath a
pair of piercing eyes: Rome, Rome indeed.
 V. VIA GIULIA

A ND Cooksey took me to tea, that same day, with his little old friend Mr.
Fitch. I was greatly charmed by Mr. Fitch, who was small and frail and
wore a dust-coloured beard; and his first suspicion of me (he was afraid
of the young) was allayed when he found that I knew and adored a particular
Roman church or two, remote and neglected, which he didn’t suppose that a
casual intruder like myself would have discovered. I remember how
Cooksey threw an arm of patronage around me and explained that he had
been my guide to the holy places of the city; but Mr. Fitch caught my eye
with a twinkle of intelligence, quickly withdrawn, which set up a happy
understanding between us on the spot. He did the honours of his apartment
with pleasant chirps and fidgets, hospitably bustling about the tea-tray,
beaming and fussing and apologizing, with bird-like cries to the stout maid-
servant who was energetically seconding his welcome.
Mr. Fitch was a scholar, a student, who worked daily in the library of the
Vatican. I believe he was a hundred years old, and indeed he looked it; but
he didn’t appear to have grown old, only to have suffered a slow deposit of
time to accumulate upon his person. Time was deep upon his hair and face
and clothes; but a few score years more or less could have made no
difference to the cheerful little bird-spirit in his breast, and it was because he
was shy and defenceless, not because he was old, that he feared the
onslaught of the young. A young person, however, who was found to have
made his way unaided to the church of San Cesareo, far away among the
vineyards on the verge of the city, was one towards whom Mr. Fitch could
hop and twitter in kindly confidence, and he did so. Before we parted he
invited me to lunch with him a day or two later, and I fully understood that
this was for him a remarkable demonstration. “Gina!” he called, and Gina,
the voluble maid-servant, came from the kitchen with a run, to receive his
command concerning the festival. She was delighted, she swept me into the
happy plan, she seemed to be immediately arranging a treat for two merry
little children, for me and Mr. Fitch. We were like children between her
broad palms, all but hugged to her bosom; and with dancing eyes she told us
to leave it all to her—she would do something splendid. “Gina will see to it,”
said Mr. Fitch; and he asked her whether he shouldn’t invite some other
young thing to join the party—what about the giovanotto who had called the
other day? “Quel poverino?” said Gina—yes, the very thing. So we should
be a party of three; and Gina clapped her hands and ran back to the kitchen,
as though to set about her preparations there and then.
Mr. Fitch lived in the Via Giulia, deep in the depth of Rome, not far from
the great mass of the Farnese palace. He had the craziest little apartment, a
tangle of rooms with bare tiled floors, in which his funny frumpy English
furniture, which might have come straight (and no doubt it had) from his
mother’s parlour at Cheltenham, looked strangely shocked and ill at ease.
Forty years of the Via Giulia (it can hardly have been less) had not
reconciled the mahogany overmantel and the plush-topped tea-table to the
ramshackle ways of foreign life; mutely they protested, keeping themselves
to themselves, wrapped in their respectability. Mr. Fitch, I think, had never
so much as noticed their plight; he sat on a chair, he made tea on a table, and
one chair or table was as good as another for the purpose. He himself looked
homely and frumpy enough, to be sure, lodged there under the wing, so to
speak, of Julius the Pope; but he didn’t feel at a loss, and he tripped along
the proud-memoried street of his abode, with his decent English beard and
his little mud-gaiters on his boots, as brisk as a sparrow. He accompanied us
down the street and left us to go and invite the “poverino” to meet me at
lunch; I see him waving us good-bye at some grand dark street-corner, where
he turned and pattered off on his errand. Cooksey treated him with large
protective kindness and contempt, out of which the old man seemed to slip
with a duck of his head and a gleam of fright and amusement in his two
bright eyes.
The luncheon-party, a day or two later, was a great success. I climbed to
the apartment on the stroke of the hour, but the other young man was already
there before me, and Mr. Fitch ceremoniously performed an introduction.
The name of the youth was Maundy, and he proved to be one of those
aspiring priests, novices, seminarists—I don’t know what their rightful name
may be, but you know them well, you remember how they converge in long
lines upon the Pincian Hill towards evening, how they pick up their skirts
and romp with the gaiety of the laity upon the greensward of the Villa
Borghese. Maundy was his name, and he didn’t look, for his part, as though
he had had much romping; he was pale and meagre, he reclined in a
contorted cat’s-cradle of thin arms and legs on one of Mr. Fitch’s fringed and
brass-nailed arm-chairs. If Gina’s word for him meant a poor young
specimen of chilly lankness she was right; his limp black soutane (is it a
soutane?) couldn’t disguise his sharp-set knees or the lean little sticks of his
arms. He jumped up, however, quite alert and spritely for our introduction,
and he greeted me with a friendly high-piping composure that made it
unnecessary to pity him. I had begun to pity him, as I always do feel
compassionate, so gratuitously, at the sight of his kind—at the sight of the
young novices, caught and caged and black-skirted in their innocence,
renouncing the world before they have had the chance to taste it; but
Maundy turned the tables upon me in a moment, and he revealed himself as
a perfectly assured young son of the world, with whom I had no call to be
sympathetically considerate. He shook hands with me, using a gesture which
at that time, so long ago, was reputed a mark of distinction—I forget how it
went exactly, but I think the pair of clasped hands was held high and waved
negligently from side to side. Maundy achieved it with an air, not failing to
observe that I had stepped forward to meet him with the ordinary pump-
handle of the vulgar.
And so we sat down to Gina’s admirable meal, and Mr. Fitch was in a
flutter of pleasure and excitement, and Maundy talked and talked—he led
the conversation, he led it almost beyond our reach, he led it so masterfully
that it hardly escaped him at all. Mr. Fitch lost his hold on it at once; he sat
with his head on one side, making small clucking noises of assent and
question now and then, while Maundy piped and swept away from us in his
monologue. But no, I oughtn’t to say that he left us both behind, for he kept
turning and waiting for me to catch him up, he flatteringly showed me that
he wished for my company. “Such a blessing,” he said, “to get away from
piety”—and he intimated with a smile that it was I who represented the
impious. He desired my company, not my talk; and he might have been
breaking out with the relief of unwonted freedom, soaring forth into topics
that were discouraged in the congregation of the poor caged lambs; and I
dare say he enjoyed the spread of his wings among the tinted and perfumed
vapours of his fancy. It was all beyond Mr. Fitch, who clearly couldn’t
explain him with my ready mixture of metaphor; Mr. Fitch was bewildered.
But to me the fancies of Maundy were sufficiently familiar; I knew the like
of them from of old, and I fear we both took a certain pleasure in noting the
bedazzlement of our host. The good soul, he sat and plied us with food and
wine, while Maundy rattled away in his emancipation and I assumed the
most impious look (I had small opportunity for more than looks) that I could
accomplish.
 Maundy threw off a light word or two about his place of residence and
instruction in Rome—the seminary, the college, I forget how he referred to
it. He seemed disdainful of all its other inmates; he couldn’t regard them as
companions for a person of intelligence and fine feeling. How he came to
have placed himself among them, submitting to their rule, he didn’t explain
at the time, but I afterwards made out a little of his history. He had written a
great deal of poetry at Oxford, and he had kept an old silver oil-lamp
burning night and day before a Greek statuette, and he had had his favourite
books bound in apricot linen, and he had collected thirty-five different kinds
of scented soap—and I know it sounds odd, but he appeared to consider
these achievements as natural stages on the path to Rome. He didn’t go quite
so far as to say that he repented of having made the journey and embraced
the Roman discipline; but after a year in the college or the seminary his
mind, I think, was in a state of more painful confusion than he allowed me to
see. Somehow the argument at one end, the Oxford end, where he had
draped his dressing-table with an embroidered rochet (he told me so),
seemed to have so little in common with the argument at the other, the
Roman end, where he walked out with his young associates for exercise in
the Villa Borghese and not one of them had heard of the poetry of Lionel
Johnson; and somehow he had perceived the discrepancy without
discovering where the chain of his reasoning had failed, and in the privacy of
his discontent he was still floundering backwards and forwards, trying to
persuade himself of the soundness of all the links—and perhaps seeking with
a part of his mind (a growing part) to be convinced that he had reasoned
wrong. Something of this kind, I believe, was fretting his life in Rome, and
how it may have ended I never knew; he didn’t confide his troubles to me—
he simply hailed me as one who would possibly understand what it meant to
him to have once, in an eating-house of Soho, been introduced to Aubrey
Beardsley.
“The passion of his line,” he said, referring to that artist; and again, “The
passion of his line!”—and he described the scene in Soho, mentioning that
the impression had wrought upon him so potently that afterwards he had sat
up all night, with some golden Tokay beside him in a blue Venetian glass
(not drinking it, only refreshed by the sight of it), and had written a poem, a
sonnet of strange perfumes and fantastic gems, which he had dedicated in
Latin to the hero of the evening. And then he had gone out into the dawn,
and had wandered through Leicester Square to Covent Garden, and had
bought a bunch of mauve carnations; and he had thought of sending them,
with the sonnet, to the master who had inspired him—but then he had
returned to his lodging and had burnt the sonnet, heaping the carnations for a
pyre, having resolved to guard the experience, whole and rounded and
complete, in the secrecy of a faithful memory. He pointed out that to share
these things is to lose them; as soon as you turn them into words for
another’s eye they cease to be perfectly yours, they are dissipated into the
common air; which was why a friend of his, at Oxford, had insisted that one
should write no words, paint or carve no colour or line, but only make one’s
images and pictures and poems out of the rainbow-tinted substance of
memory, that exquisite material always awaiting and inviting the hand of an
artist. So one avoids, you see, the sick disillusion of the writer who flings
forth his maiden fancy to the ribaldry of the crowd; and Maundy himself had
tried to rise to this height of disinterested passion, and in the dying perfume
of the mauve carnations he had sacrificed what he saw to be a vulgar
ambition. Oh yes, depend upon it, the greatest works of art have never been
seen of any but their maker; and to Maundy it was a beautiful thought, the
thought of the white secret statues locked away by the thousand in their
secluded shrines, safe from the world, visited now and again by the one and
only adorer who possessed the key. “But stay,” said Mr. Fitch, “have you
considered—” oh yes, Maundy had felt the weight of that objection, and
Dickson after all (Dickson was the friend at Oxford) had written and printed
his volume, but that was because he had found no other way to rid himself of
an obsession; the white statue in his case had become more real than life,
and he had cast it forth to retain—to retain, you might say, his sanity.
Well, we must publish or go mad; that is the melancholy conclusion. Mr.
Fitch stared doubtfully, and I shook my head like one whose hold upon his
senses is precarious indeed. Maundy was quick to interpret my movement,
and it encouraged him to yet giddier flights. He was hovering upon the
climax of one of these when Gina happened to come clattering in with a
dish; and she paused, sinking back upon her heels, the dish held high before
her, and she threw up her head and she flashed out such an amusing
challenging bantering look at Maundy, where he flourished his thin fingers
in the zest of his eloquence, that I have never forgotten the picture of her
mirth and her plumpness as it was framed at that moment in the doorway.
“Ah, the poor little fellow,” she said to herself, “he loves to talk!” And she
too began to talk, breaking into his monologue with unabashed and ringing
frankness; she set down her dish on the table with a dancing gesture,
whipping her hands away from it like an actress in a play, and she stood by
his side, patting him on the shoulder, approving him, scolding him, bidding
him eat, eat!—and Maundy turned round to her with a peal of sudden light
laughter, a burst of naturalness that changed his whole appearance; so that
Gina had transformed the temper of the party and had raised it at once to a
breezier level of gaiety than it would ever have touched without her. It was
delightful; I couldn’t understand a word she said, for her words flew shining
and streeling over our heads as quick as thought, and I dare say Maundy
answered their spirit rather than their meaning; but he responded well, he
had some good neat conversational turns of idiom that he shot back at her
with a knowing accent, and she chuckled, she threatened him, she bustled
out of the room with a smile for me and Mr. Fitch and a last fling of
playfulness over her shoulder for Maundy. Mr. Fitch had said that Gina
would “see to it,” and he was quite right; we started afresh in a much better
vein, all three of us, after her incursion.
Mr. Fitch produced a bottle of “vino santo” at the end of the meal and
charged our glasses. The sacred liquor was exceedingly good, and he took
heart from it to talk more freely. Gina had relaxed the strain of Maundy’s
preciosity, and he had begun to cross-question our host about his occupation,
his early life, his establishment in Rome, with an inquisitive and youthful
familiarity under which the old man shyly and prettily expanded. He told us
how in the dim ages he had received a commission to do a little historical
research among the manuscripts of the Vatican, and how he had taken his
seat in the library, with a pile of volumes around him, and had never left it
again from that moment to this. His first commission was long ago fulfilled,
but it had revealed a point of singular interest, some debatable matter in
connexion with a certain correspondence about a question raised in a
contemporary version of an unofficial report of a papal election in the
seventeenth century—yes, a matter which had chanced to be overlooked by
previous investigators; and Mr. Fitch, sitting fast in his chair at the library,
day after day, year after year, had been enabled to throw a little light upon
the obscurity, and had even published a small pamphlet—“not, I must admit,
for the very cogent reason that prompted your friend at Oxford, but from a
motive that I justify as a desire for historical accuracy, and that I condemn as
vanity”; and Mr. Fitch, so saying, beamed upon us with a diminutive
roguishness, more sparrow-like than ever, which he immediately covered by
plying us anew with the sacred bottle.
And then he told us of the long evenings he had spent, year after year, in
wandering among the ancient byways of the city—every day, when he was
turned out of the library at the closing hour, he had set forth to explore the
grand shabby old city that had now perished, he said, bequeathing little but
its memory to the smart new capital of to-day. Rome had changed around
him, he only had remained the same; but he could truthfully claim that he
knew nothing, save by report, of Rome’s rejuvenation—say rather of its
horrible pretentious bedizenment in the latest fashion; for he had long
abandoned his old pious pilgrimages, he now went no farther than his
lodging here and the library over there, and he was proud to declare that he
had never set eyes on a quarter of the monstrosities of which he heard tell.
There was a break of indignation in his voice as he spoke of them; he had
loved that Rome of the far-away golden evenings, it was all he ever had
loved except his work, and he had been robbed of it, bit by bit, till nothing
was left him but his well-worn seat among the state-papers and the pontifical
dust that nobody had taken the trouble to clear away. I don’t mean that he
said all this, but it was all in his gentle regretful tone; he seemed to stand
solitary and disregarded among the riot of modernity, and to utter a little tiny
dismal reproach, barely audible in the din—the plaintive “how can you, how
can you?” of a small bird whose nest has been trampled down by a pack of
stupid louts on a holiday. It was hard on him; the louts might just as well
have stamped and scuffled somewhere else; but so it was, they had violated
his wonderful Rome, and nobody noticed the sad small squeak of protest that
arose here and there from a scholar, a student, a lover.
What did Maundy think of it all? Mr. Fitch brightened in hospitable care
for our amusement; he didn’t often have two young things to lunch with him,
and he mustn’t blight the occasion with his griefs; and so he recovered his
spirit and tried to set Maundy off again in one of his droll tirades. What did
Maundy think of it? Oddly enough the question of Rome, in the light in
which it appeared to Mr. Fitch, hadn’t seemingly occurred to him; Maundy’s
Rome had been predominantly a matter of Spanish altar-lace and rose-tinted
chasubles, and a year by the Tiber had brought him to think that Oxford is
now more purely, more daintily Roman than the city of the Popes; and that
was really his only conclusion on the subject, and I don’t believe he had
given a thought to the Roman romance, vanished or vanishing, that had
inspired the tenderness of Mr. Fitch. Maundy knew nothing of San Cesareo,
nothing of the enchanted evenings among the ruins and the cypresses that
were still to be recaptured, I could give Mr. Fitch my word for it, even in the
desolation of to-day. “Ah yes, no doubt of it,” said Mr. Fitch, “if one
happens to be twenty years old to-day!”—but this he threw out in passing,
and he returned to the strange case of Maundy, which perplexed and troubled
him. It seemed that Maundy, whenever he went wandering through Rome,
had only one interest in view; I forget what it was, but it had something to do
with a point of ritual that Maundy excessively cherished; and he used to go
hunting round the city to discover the churches in which it was properly
observed, keeping a black-list of those which failed to make good. It was the
only aspect in which San Cesareo could engage him, and Mr. Fitch and I had
both neglected it.
With Rome ancient or modern Maundy was otherwise little concerned.
He listened blankly to Mr. Fitch’s melancholy regrets; for him they were the
mild ravings that you naturally expect from the very old. He was ignorant of
the past, so ignorant that it couldn’t raise the least stir in his imagination; he
had lived upon flimsiness, upon a little sentiment and a little second-hand
art, and he hadn’t the stomach, I suppose, for Rome. It was curious to see
how his insensibility puzzled Mr. Fitch. Maundy’s glibness about unknown
artists, about poems that hadn’t been written and statues that drove you mad,
had certainly surprised and impressed him; but the gulf of vacuity that
yawned beneath Maundy’s culture was a shock. Of course it only showed
what a featherweight of a tatter it was, that culture; if you are thus artistic in
the void, with the empty inane below you, it proves that your art hasn’t
substance enough to make it drop. But Mr. Fitch was too humble and kindly
for that harsh judgment, and he seemed to be beating about in his courtesy to
find an explanation more honourable to Maundy. Surely the young man was
very able, very original and brilliant; if he spurned the treasures of the past
he must have some clever new reason for doing so. I think I could have told
Mr. Fitch that Maundy’s reason was no newer than simple ignorance; and
perhaps I began to parade my own slender stock of learning to mark the
contrast. But Mr. Fitch was unconvinced, and I still see him eyeing young
Maundy with a sort of hesitating admiration, hovering on the edge of a
question that he couldn’t formulate. As for Maundy, he was thoroughly at
ease; Mr. Fitch had confessed that the name of Aubrey Beardsley was
unknown to him.
 Anyhow the party had been most successful, and Mr. Fitch might go
trotting back to his afternoon’s work with the pleased sense that two very
young people had made friends under his and Gina’s auspices. He liked to
observe that Maundy and I were making a plan to meet next day, and he
blessed our alliance, taking credit for the good thought of acquainting
Maundy’s brilliance with my—my what?—my honest and old-fashioned
enthusiasm. Gina too was satisfied; she stood at her kitchen-door as we went
out, and she cordially invited us to come again. She pointed out that Maundy
set me an example with his soutane and his aspiration to the priesthood, and
she assured me that I couldn’t do better than to place myself under his
guidance; but at the same time she allowed that it wasn’t for all of us to aim
so loftily, and perhaps I was wise to be content with a lower standard. She
cheerily dismissed us; she had developed these reflections in twenty seconds
of farewell. We descended to the street, the three of us, and Mr. Fitch waved
his hat as he sped off to his happy labours, and Maundy and I turned away in
the direction of his seminary, where it was now time for him to rejoin his
black-skirted brethren. I was rather proud to be seen walking beside his
sweeping robe and clerical hat; it seemed so intimately Roman. But I found
to my surprise that Maundy was quite uneasy and apologetic about it; he
hated his uniform, he well understood that a man should feel shy of its
company. “If I were you,” he said, twitching his skirt disdainfully, “I should
hate to appear in public along with this.” He was an odd jumble of cross-
purposes, poor Maundy, and here was another glimpse of his natural mind.
He was more of a self-conscious school-boy than ever he was of a musk-
scented sonnetteer; but in either character I am afraid, or I hope, that he
didn’t fit comfortably into his Roman retreat. I can’t think that the cage was
to hold him much longer.
 VI. VILLA BORGHESE

W E had planned nothing more enterprising than a stroll in the Villa

Borghese; and we wandered freely in the ilex-shade, we inspected the
children at play in the grass, we stood awhile to watch the young
Roman athletes smiting the ball in their ancestral game, we took another turn
beneath the magnificent umbrellas of the pines, we lingered for the finish of
a bicycle-race in the great Greek stadium; and I don’t deny that we loitered
and strolled and looked for something else to watch because we found it
difficult to make an excuse for separating. The fact is that we hadn’t very
much to talk about after all, without Mr. Fitch between us to be dazzled.
Apart from him we made no very stimulating audience for each other, and
we clutched at an interest in the games and the races to cover the bare
patches of our conversation.
That very small interest was cracking under the strain when there
appeared a fortunate diversion. Maundy, after a pause, had said that the
leading bicyclist was a splendid Roman type, which was just what I had said
before the pause; and he had remembered this and had hastily suggested
another stroll, and I (after a pause) had observed that the park was
extraordinarily classic (an earlier remark of Maundy’s); when it chanced that
in a green alley we came in sight of an old gentleman seated on a bench, a
battered but dignified relic of a man, who faced the prospect mildly and
blankly, waiting, as it seemed, till some one should happen to pass by and
sweep him up. “There’s old Rossi,” cried Maundy, and he rapidly explained
that he had lodged with the old man’s family when he first came to Rome,
and he was sorry, but he must stop for a minute—we both jumped at the
diversion, a timely one.
We were still a little way off, and as we began to move towards the old
man two women appeared, an older and a younger, bearing down upon him
from the opposite direction. They were delayed for the moment, as they
approached, by their own conversation, which seemed to shoot up into an
argument demanding settlement before other matters could be taken in hand.
We hung back, Maundy and I, and finally the old man was taken in hand,
literally enough, and in a style which suggested that the argument had ended
to neither lady’s satisfaction. He apparently needed a good deal of rousing
and re-arranging of shawls and wraps, and I noticed that the argument
showed signs of beginning again over his heedless head. At length he was
brought to his feet, his stick was put in his hand, and the party prepared to
set forth. Immediately the two ladies caught sight of us, recognized Maundy
and raised a cry of delight. Ah, what a fortunate meeting! They had been
arguing in Italian, but they now spoke a free crisp English; they greeted us
with much politeness, dropping the old man as one might put down a parcel
on a chair. He blinked and subsided upon his bench again, while I was
introduced to the ladies—Miss Teresa Shacker (so the name reached me at
least) and Miss Berta Rossi; in these terms Maundy referred to them, and
they were good enough to express their extreme pleasure in making the
acquaintance of his friend.
They quickly took his friend into their confidence; I learned that they
were aunt and niece, sister-in-law and daughter of the speechless old bundle
on the bench. Aunt and niece were very much alike. Teresa the aunt was tall
and spare, with pouched white cheeks, a coil of black hair on which her
headgear stood high, and long arms assertively kid-gloved and buttoned and
tight. Berta the niece was white with slightly more lustre, black with a little
more profusion, gloved and hatted with the same defiance. The loose
luxuriant evening flowered around us while Berta and Teresa established
their effect; and their effect stood forth, hard and high-lighted as a bit of
china, quite eclipsing the lazy sprawl of sun and shadow among the trees.
There was an artistic passion in their looks and tones as they wrought. The
accidents of a dim old man, a dark grove and an April sunset, fell away from
them, were forgotten, and in the cleared space they created a social occasion
out of the slender material that we offered, Maundy and I. They found it
sufficient, they set to work with lucid determination. Long practice had
made them perfect, and the entertainment ran without a hitch. All the talking
was theirs; they talked in an antiphon so glib that it must have been
rehearsed—only that was impossible, since it fitted the chance of our
encounter; so they talked, let me say, with the skill of the old Roman
improvisers, who never hesitated for a rhyme on any subject you could set
them. Half an hour later I knew a prodigious amount about Teresa and Berta,
and I don’t think they knew anything at all about me.
Who were they, and what? Their English dialect, in the first place, was a
study by itself. “What a pleasure,” said one of them, “to hear some English
speaking!”—and immediately they explained to me that they were “mad for
England,” such was their phrase, and that I must talk to them of nothing but
England for their pleasure. “For we,” said Teresa, “being English maternally,
love to talk our language like anything, and we are both a little wee bit
cracked on the head about England”; and Berta put in that they weren’t
English, not strictly, but rather Virginian—“Ah,” said Teresa, “but Virginian
is most English of all, as you know so well—and you mustn’t come down on
us for a couple of Yankee women, no, not at all.” “Yankee, good God!” cried
out Berta, “ah no, not a bit of it; our family came of England in the
beginning by origin; I ’ope you haven’t thought that we spoke as Americans,
so very ogly, all in the nose!” “We are always fewrious at everybody,” said
Teresa, “who will believe us American.” “But Mr. Maundy has told you
about us—is it true?” asked Berta; and Teresa chimed in with the next
versicle, and Berta caught her up with the response, and between them they
brought out their history in much profusion of detail and folded me into their
family circle with a will.
They bethought themselves of the old man on the bench and proceeded to
display him. He was enrolled for the part of a benignant Œdipus, tired at the
end of a long day, weighted with his knowledge of the jealousies and
vindictive passions of the world, but not embittered by them, only mellowed
by many hoary years of patience and fortitude. It was a fine exhibition of
patriarchal and republican simplicity. He neither spoke nor moved nor
seemed to hear anything that was said, but his attendant maidens gave life to
the part on his behalf. The grand old man, survivor of a heroic age—had he
been the inspiration of Mazzini, the counsellor of Cavour, Garibaldi’s right
hand?—all three perhaps, and anyhow a flaming brand of freedom in the bad
days of which we younger folk knew only the eloquent tale. To think of
those terrible times of oppression, of persecution and bigotry! This patriot
had given all, had sacrificed fortune and strength to the cause of Italy in her
woe, when the land lay groaning beneath the yoke of tyrant and priest. But
there were traitors even in the camp of enlightenment, and his feelings had
suffered the cruelest laceration. His feelings were more to him than any
personal hopes or ambitions, so that little need be said of the utter collapse
of these also. He had withdrawn from the struggle, had married a wife who
was all sympathy, and had passed into a profound retirement. The struggle of
poverty was hard; but what is poverty when it is sweetened by the heart’s
affections? The poor lady, Teresa’s sister, was dead these many years; she
had bequeathed her husband, her two young children, to Teresa’s care. Poor
Leonora had had a soul too great for her frame; the artistic inheritance in her