Immunity • Immunity (immunis- Latin-exempt, state of protection from infectious diseases) • Immunity is body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells History: what imparts Immunity? • Thucydides, the great historian of the Peloponnesian War (430 BC)- who had recovered from the plague could nurse the sick because they would not contract the disease a second time
• Emil von Behring and Kitasato (1890)
– Serum from vaccinated animals was protective (diptheria)
• Metchinkoff (1880) – Cell based Immunity
• Merrill Chase (1940)- Transfer of WBC (immunity to tuberculosis)
Both serum and cells contribute to immunity
Immunology
• Study of the components and function of the
immune system
• Since 1901 there have been 20 Nobel Prizes for
immunology-related research. The immune system • Crucial to human survival • A functional system – NOT an organ system: Molecules, cells, tissues and organs which provide non-specific and specific protection • Complex system – includes – Skin – physical barrier – Lining of mucus membranes – physical barrier – Secretions – tears, mucus etc - antimicrobial – Blood cells and vasculature – WBCs – Bone marrow – Liver – makes complement proteins – Lymphatic system and lymphoid organs – Most tissues – have resident immune cells Functions of the immune system
– Defense against invading pathogens (viruses &
bacteria) – Removal of 'worn-out' cells (e.g., old RBCs) & tissue debris (e.g., from injury or disease) – Identification & destruction of abnormal or mutant cells (primary defense against cancer) – Rejection of 'foreign' cells (e.g., organ transplant) – Inappropriate responses: • Allergies - response to normally harmless substances • Autoimmune diseases Innate immunity vs Adaptive Immunity
Innate Immunity Adaptive Immunity
(first line of defense) (second line of defense)
• No time lag • A lag period
• Not antigen specific • Antigen specific
• No memory • Development of memory NATURALLY ACQUIRED IMMUNITY • Active – Antigens enter body naturally with response of • Innate and adaptive immune systems – Provides long term protection
• Passive – Antibodies pass from mother to • Fetus across placenta • Infant in breast milk – Provides immediate short term protection ARTIFICIALLY ACQUIRED IMMUNITY • Active – Antigens enter body through vaccination with response of • Innate and adaptive immune systems – Provides long term protection • Passive – Antibodies from immune individuals injected into body • Referred to as – Immune serum globulins (ISG) – Immune globulins (IG) – Gamma globulins – Provides immediate short term protection DEFENSE MECHANISMS OF THE HUMAN HOST Cells and Organs of the Immune System Cells and Organs of the Immune System
• Cells – Leukocytes a. Lymphocytes – specialized for adaptive immunity b. Granulocytes/Agranulocytes – function in accessory roles in adaptive immunity
• Immune Organs – 2 major groups
a. 1° lymphoid organs – where lymphocytes develop and mature b. 2° lymphoid organs – where lymphocytes interact with Ag ORIGIN OF CELLS OF THE IMMUNE SYSTEM • Derived from common progenitor cell in bone marrow – Pluripotent hematopoietic stem cell
• Progenitor Stem Cells
– Myeloid lineage • Monocyte/macrophage, dendritic cells, PMN’s, mast cells – Lymphoid lineage • Small and large lymphocytes Hematopoiesis • HSC (Hematopoietic Stem Cell) – Reside in Bone Marrow – Pluripotent – 1 HSC Per 50,000 BM Cells (~3x108 cells in Mouse Bone Marrow) – Extremely Proliferative If Need Arises • HSC Differentiates to LPC (lymphoid progenitor cell) or MSC (myeloid stem cell) • Growth Factors and Cytokines Determine Path • Once LPC or MSC, Committed • Stromal Cells are Supporting Cells in BM (endothelial, fat cells, fibroblasts, macrophages) Immune cells: Myeloid Lineage Granulocytes
– Neutrophil • Principal phagocytic cell of innate immunity – Eosinophil • Principal defender against parasites – Basophil • Functions similar to eosinophils and mast cells
Referred to as 1. Polymorphonuclear leukocytes (PMN’s) ⮚ Nuclei are multilobed (2 to 5)
• Monocytes in Blood, MΦ in Tissues – Monocytes 5-10 times smaller than MΦ • Secretes cytokines and Produces Hydrolytic Enzymes • Activated By Phagocytosis or Cytokines (IFNγ) • Antigen Presenting Capacity through MHC II Mononuclear Cells – Monocytes • Leukocytes with bean shaped or brain-like convoluted nuclei • Circulate in blood with half life of 8 hours • Precursors of tissue macrophages
– Macrophages • Mononuclear phagocytic cells in tissue • Derive from blood monocytes • Participate in innate and adaptive immunity Monocyte vs MΦ MΦ Effective APC MΦ Capturing Bacteria Immune cells: Lymphoid Lineage Lymphoid Cells – B-cells, T-cells and NK cells – 20-40% of body’s leukocytes – 99% of lymph node – If inactivated said to be naïve – Nucleus occupies almost entire cell – 6 μm diameter Lymphoid Cells – Large lymphocytes (large granular lymphocytes) • Natural killer (NK) cells (CD16, CD56) • Innate immunity to viruses and other intracellular pathogens • Participate in antibody-dependent cell-mediated cytotoxicity (ADCC) – Small lymphocytes • B cells (CD19) • T cells (CD3, CD4 or CD8) • Adaptive immunity ✔Lymphocytes refers to small lymphocytes NK Cells
• Do Not Express Classical Lymphocyte
Markers • Predominantly NK Cells (CD56) • Eliminate Tumor Cells and Virally Infected Cells THE CLUSTER OF DIFFERENTIATION (CD) • A protocol for identification and investigation of cell surface molecules • CD number assigned on basis of 1 cell surface molecule recognized by 2 specific monoclonal antibodies • CD nomenclature established in 1982 – 1st International Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA) • Over 300 CD Markers THE CLUSTER OF DIFFERENTIATION (CD) • CD markers on leukocytes
Granulocyte CD45+, CD15+
Monocyte CD45+, CD14+ T lymphocyte CD45+, CD3+ T helper lymphocyte CD45+, CD3+, CD4+ T cytotoxic lymphocyte CD45+, CD3+, CD8+ B lymphocyte CD45+, CD19+ Natural killer cell CD45+, CD16+, CD56+, CD3- Dendritic Cells • Scarce Cell Type • Discovered in 1972 • Professional APCs • Interstitial DCs, populate organs such as heart, lungs, liver, intestines • Interdigitating DCs, T-cell areas of lymph nodes and Thymic medulla Dendritic Cells
http:www.coleypharma.com Developmental Pathway of DCs Overview of the Immune System
Immune System
Innate Adaptive (Nonspecific) (Specific) 1o line of defense 2o line of defense Interactions between the two systems The innate immune System
Innate Immune System
External Internal defenses defenses
Interactions between the two systems
A typical immune response INNATE IMMUNITY ACQUIRED IMMUNITY Rapid responses to a Slower responses to broad range of microbes specific microbes
• Flushing action of saliva, tears, urine Anatomical Barriers – Chemical factors Antimicrobial HCl in stomach Lysozyme in tears /saliva Peptides in sweat Anatomical Barriers – Biological factors
Normal flora – microbes in many parts of
the body
Normal flora – > 1000 species of
bacteria
Normal flora – competes with pathogens
for nutrients and space A typical immune response INNATE IMMUNITY ACQUIRED IMMUNITY Rapid responses to a Slower responses to broad range of microbes specific microbes
Release of granules with perforins and proteases Toll-like receptors (TLRs) • Transmembrane proteins
• Present on macrophages / few other cells
• Conserved across vertebrates
• Important part of innate immune system
TLRs – What do they do ? They look out for microbes (or their components)
They bind to the microbes (or their components)
They trigger a cascade of events to kill or protect
against pathogens
THEY ARE INNATE IMMUNE SENSORS
TLRs – look out for microbes TLRs – bind to microbes / components of microbes Which microbial components are recognized by TLRs ? What happens when a TLR bind to a microbe ?
Secretion of Cytokines / Interferon
Phagocytosis Inflammation TLR binding of infected to microbe cell
Complement proteins: role in innate immune system C`proteins
Facilitates phagocytosis Direct lysis of pathogens Inflammation
How do C` proteins facilitate phagocytosis ? Bacteria coated with C` Neutrophils have C` receptors
Initiation of phagocytosis How do C` proteins lyse pathogens? Membrane attack complex formed by C` proteins Summary: innate response – internal defenses
Cellular Extracellular
• Neutrophils • Cytokines
• Monocytes /macrophages • Complement • NK cells
• TLRs A typical immune response INNATE IMMUNITY ACQUIRED IMMUNITY Rapid responses to a Slower responses to broad range of microbes specific microbes
