Major Histocompatibility Complex (MHC)

Background

The Major Histocompatibility Complex (MHC) is a group of genes found in most vertebrates, including humans. It plays a vital role in the immune system by encoding cell surface proteins that are responsible for presenting antigens to T cells and regulating immune responses. The importance of MHC genes lies in their ability to enable the immune system to recognize and respond to a wide range of pathogens and foreign substances while maintaining tolerance to self-antigens. Here are the different types of MHC genes and their functions:

MHC genes are highly polymorphic, meaning they exist in multiple variants or alleles within a population. This polymorphism allows for a diverse range of antigen presentation and immune responses, enabling the immune system to recognize a broad array of pathogens.

The recognition of antigens by MHC molecules and subsequent activation of T cells is central to immune surveillance, the elimination of pathogens, and the coordination of immune responses. MHC genes also contribute to immune tolerance, ensuring that the immune system does not mount an immune response against the body's own cells and tissues.

The study of MHC genetics and their association with diseases has provided insights into the mechanisms of immune-related disorders, transplantation compatibility, and the development of vaccines and immunotherapies. Understanding the structure and function of MHC genes is essential for advancing our knowledge of the immune system and its role in health and disease.

Fig.1 MHC (major histocompatibility complex). (Ayala García MA, et al., 2012)
(A) MHC (major histocompatibility complex). (B) Class II antigens are expressed only on B lymphocytes, activated T lymphocytes, monocytes, macrophages, Langerhans cells, dendritic cells, endothelium, and epithelial cells. They are heterodimers composed of noncovalently associated α and β polypeptide chains chains encoded by genes of the HLA-D region. (C) Class I MHC antigens are present on all nucleated cells and are composed of a 45-kd transmembrane α heavy chain encoded by genes of the HLA-A, HLA-B, or HLA-C loci on chromosome 6.

Fig.2 The MHC-I antigen presentation pathway.

Fig.3 The MHC-II antigen presentation pathway.

Latest Advances and Techniques in MHC Research

MHC research has seen significant advancements in recent years, leading to a better understanding of the regulation of the MHC pathway and the relationship between MHC and immunotherapy. Here are some of the latest advances and techniques in MHC research:

Regulation of the MHC Pathway

• Epigenetic Regulation: Epigenetic modifications, such as DNA methylation and histone modifications, can impact the expression of MHC genes. Researchers are studying the epigenetic regulation of MHC to understand how it influences antigen presentation and immune responses.
• Transcriptional Regulation: Various transcription factors and regulatory elements control the expression of MHC genes. Identifying these regulators and understanding their mechanisms of action can provide insights into MHC regulation and its impact on immune function.
• Non-coding RNAs: Non-coding RNAs, including microRNAs and long non-coding RNAs, have emerged as important regulators of MHC gene expression. Investigating the roles of these non-coding RNAs in MHC regulation can uncover novel mechanisms of immune modulation.

High-Throughput Sequencing and Genomics

• Next-Generation Sequencing (NGS): NGS technologies have revolutionized MHC research by enabling comprehensive profiling of MHC genes and their variants. These techniques allow for detailed analysis of MHC polymorphisms, gene expression patterns, and allele-specific antigen presentation.
• Genome-Wide Association Studies (GWAS): GWAS studies have identified genetic variants within the MHC region that are associated with various diseases, including autoimmune disorders and infectious diseases. These studies provide insights into the contribution of MHC variants to disease susceptibility and pathogenesis.

Single-Cell Analysis

• Single-Cell RNA Sequencing (scRNA-seq): scRNA-seq allows profiling of gene expression in individual cells, providing a deeper understanding of the heterogeneity and functional diversity of MHC-expressing cells within a population. This technique can uncover rare cell subsets, identify novel MHC-related gene expression patterns, and investigate cellular interactions.
• Mass Cytometry (CyTOF): CyTOF combines flow cytometry with mass spectrometry, enabling simultaneous analysis of multiple markers at the single-cell level. This technique can be used to study MHC expression patterns on immune cells and their functional heterogeneity.

MHC and Immunotherapy

• Tumor Antigen Presentation: Understanding the MHC-mediated presentation of tumor antigens is crucial for developing effective cancer immunotherapies. Researchers are exploring ways to enhance MHC presentation of tumor antigens to improve the recognition and targeting of cancer cells by T cells.
• Neoantigen Vaccines: Neoantigens are antigens derived from tumor-specific mutations. Designing personalized vaccines targeting neoantigens that are presented on MHC molecules can stimulate potent anti-tumor immune responses.
• Adoptive Cell Therapies: Techniques such as Chimeric Antigen Receptor (CAR) T cell therapy and T cell receptor (TCR) gene therapy involve modifying T cells to express specific receptors that recognize tumor antigens presented on MHC molecules. These approaches exploit the MHC pathway to redirect T cell responses against cancer cells.

These advances in MHC research and techniques provide valuable insights into the regulation of the MHC pathway, the impact of MHC variability on immune responses, and the development of innovative immunotherapeutic strategies. Continued research in these areas holds promise for improving our understanding of immune-related diseases and advancing personalized immunotherapies.

The Role of MHC in Disease and the MHC Variants Associated with Disease

The role of MHC genes in autoimmune diseases and infectious agents is significant, as they play a crucial role in immune recognition and response. The interaction between MHC molecules and T cells is central to the development and progression of these diseases. Additionally, specific variants or alleles of MHC genes have been associated with susceptibility or protection against certain autoimmune diseases and infectious agents.

Role of MHC in Autoimmune Diseases

• Antigen Presentation: MHC Class II molecules are involved in the presentation of self-antigens to CD4+ helper T cells. In autoimmune diseases, there is a breakdown of immune tolerance, leading to the recognition of self-antigens as foreign. MHC Class II molecules present these self-antigens, triggering an autoimmune response and inflammation.
• Genetic Associations: Certain MHC variants have been strongly associated with increased susceptibility to autoimmune diseases. For example, specific HLA-DRB1 alleles are strongly linked to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). These variants may present self-antigens more efficiently or lead to aberrant immune responses, contributing to disease development.
• Molecular Mimicry: MHC molecules can present antigens derived from infectious agents that share structural similarities with self-antigens. This molecular mimicry can lead to cross-reactive immune responses, where T cells recognizing the pathogen-derived antigen also target self-antigens. This mechanism has been implicated in autoimmune diseases such as multiple sclerosis (MS) and Guillain-Barré syndrome.

Role of MHC in Infectious Agents

• Antigen Presentation: MHC molecules, particularly MHC Class I and Class II, present antigens derived from infectious agents to T cells. This presentation is crucial for initiating an immune response and guiding the activation of appropriate immune effector mechanisms against the pathogens.
• Genetic Associations: Specific MHC alleles can influence an individual's susceptibility or resistance to certain infectious agents. For example, certain HLA variants have been associated with increased susceptibility to HIV infection or severe forms of malaria. These variants may affect the ability of MHC molecules to present pathogen-derived antigens effectively or modulate the immune response against the infection.
• Immune Escape: Pathogens can evolve strategies to evade immune recognition by altering their antigens or interfering with MHC antigen presentation. This immune escape mechanism allows the pathogens to evade immune responses and establish chronic or persistent infections.

Disease-Related MHC Variants

• Protective Alleles: In some cases, specific MHC alleles have been associated with protection against certain autoimmune diseases or infectious agents. For example, certain HLA variants have been linked to a lower risk of developing type 1 diabetes or severe forms of malaria. These variants may confer enhanced antigen presentation or more effective immune responses against the disease-causing agents.
• Susceptibility Alleles: On the other hand, certain MHC alleles are associated with an increased susceptibility to autoimmune diseases or infectious agents. These variants may present antigens less efficiently or lead to dysregulated immune responses, allowing the disease to develop or progress.

Understanding the role of MHC in autoimmune diseases and infectious agents, as well as disease-related MHC variants, provides valuable insights into disease mechanisms, immune responses, and susceptibility factors. It offers potential targets for therapeutic interventions, vaccine development, and personalized medicine approaches in the management of these diseases.

Fig.4 The alpha-synuclein (α-syn) induces pro-inflammatory behaviors in glial cells and MHC molecules recognize aggregated α-syn and drive the immune responses. (Gu R, et al., 2024)

Case Study

Case 1: Alroqi FJ, Alhezam MA, Almojali AI, et al. Novel presentation of major histocompatibility complex class II deficiency with hemophagocytic lymphohistiocytosis. J Clin Immunol. 2024;44(3):73.

A 7-year-old girl, a product of non-consanguineous marriage (Fig.1a) who was diagnosed at age of 2 years with MHC class II deficiency by genetic and immunological functional studies. Her testing showed a homozygous pathogenic mutation in RFXANK (Fig.1b) with an absent HLA-DR expression on monocytes (Fig.1c).

Fig.1 Patient's pedigree, RFXANK gene DNA sequencing chromatogram, and MHC class I and II expression on monocytes.

Case 2: Harrington EP, Catenacci RB, Smith MD, et al. MHC class I and MHC class II reporter mice enable analysis of immune oligodendroglia in mouse models of multiple sclerosis. Elife. 2023;12:e82938.

The MHC class II molecular chaperone invariant chain (Cd74 or Ii) and the MHC class I component, β-2-microglobulin (B2m), are required components of the antigen processing/presentation machinery and are expressed by a subset of oligodendrocytes in mouse models of inflammation and in human MS brains. We chose to target the B2m and Cd74 genes to generate MHC class I and MHC class II reporter mice, respectively. To facilitate the identification of these cells, the authors used CRISPR/Cas9-mediated gene editing to generate B2m-tdTomato (B2m tdT) and Cd74-tdTomato (Cd74 tdT) reporter mice by substituting the termination codon of these genes with the P2A-TdTomato-WPRE-pA sequence, in which the 2A cleaved self-peptide helps to cleave tdTomato from endogenous proteins without disrupting endogenous gene expression or antigen presentation.

Fig.6 Major histocompatibility complex (MHC) reporter mice validation.

References

• Ayala García MA, González Yebra B, López Flores AL, Guaní Guerra E. The major histocompatibility complex in transplantation. J Transplant. 2012;2012:842141.
• Gu R, Pan J, Awan MUN, et al. The major histocompatibility complex participates in Parkinson's disease. Pharmacol Res. 2024;203:107168.
• van den Elsen PJ. Expression regulation of major histocompatibility complex class I and class II encoding genes. Front Immunol. 2011;2:48.