Major Histocompatibility Complex (MHC): Critical Role in Antigen Presentation and Immune Recognition
Introduction
The Major Histocompatibility Complex (MHC) is a crucial component of the immune system responsible for antigen presentation to T cells. This complex plays a vital role in distinguishing self from non-self, which is essential for immune responses against pathogens, tumors, and transplanted tissues.
In this study module, we will explore the structure, functions, types, antigen presentation mechanisms, clinical significance, and role in immune regulation of MHC.
Role of MHC in immunity, MHC antigen processing steps, how MHC presents antigens, MHC and autoimmune diseases, MHC Class I vs Class II, antigen presentation process explained, immune response and MHC, diseases linked to MHC
1. What is the Major Histocompatibility Complex (MHC)?
- MHC is a set of cell surface glycoproteins encoded by genes on chromosome 6 (in humans, HLA complex) and chromosome 17 (in mice, H-2 complex).
- It plays a key role in presenting antigens to T cells to initiate an immune response.
- MHC molecules ensure that the immune system can recognize and respond to pathogens, tumors, and transplanted tissues.
2. Types of MHC Molecules
MHC molecules are classified into three main classes:
A) MHC Class I
- Found on all nucleated cells (except red blood cells).
- Presents endogenous antigens (e.g., viral or tumor antigens) to CD8+ cytotoxic T cells.
- Composed of:
- α (heavy) chain (three domains: α1, α2, α3)
- β2-microglobulin (stabilizing component)
B) MHC Class II
- Found on antigen-presenting cells (APCs) like macrophages, dendritic cells, and B cells.
- Presents exogenous antigens (e.g., bacterial peptides) to CD4+ helper T cells.
- Composed of:
- α chain (α1, α2) and β chain (β1, β2).
C) MHC Class III
- Encodes complement proteins, cytokines (TNF-α), and heat shock proteins.
- Plays an indirect role in immune responses.
3. Antigen Processing and Presentation
A) MHC Class I Pathway (Endogenous Pathway)
- Intracellular antigen processing:
- Viral or tumor antigens are degraded by the proteasome into peptides.
- Peptide transport into the ER:
- Transported via TAP (Transporter associated with Antigen Processing).
- Loading onto MHC-I:
- Peptide binds to MHC-I and moves to the cell surface.
- Presentation to CD8+ T cells:
- Activates cytotoxic T lymphocytes (CTLs) to kill infected cells.
B) MHC Class II Pathway (Exogenous Pathway)
- Extracellular antigen uptake:
- APCs engulf bacteria or pathogens through phagocytosis or endocytosis.
- Processing in lysosomes:
- Pathogen is broken down into peptides.
- MHC-II loading:
- Invariant chain (Ii) prevents premature binding.
- HLA-DM facilitates loading of antigenic peptides.
- Presentation to CD4+ T cells:
- Activates helper T cells to coordinate immune responses.
4. Role of MHC in Immune Response
- Pathogen recognition: Helps in detecting viral, bacterial, and parasitic infections.
- T cell activation: Essential for the adaptive immune response.
- Transplant compatibility: MHC mismatch leads to graft rejection.
- Autoimmune diseases: Abnormal MHC function is linked to diseases like type 1 diabetes, rheumatoid arthritis, and multiple sclerosis.
5. Clinical Significance of MHC
A) MHC in Transplantation
- HLA typing ensures compatibility between donor and recipient in organ transplants.
- MHC mismatch can cause graft-versus-host disease (GVHD).
B) MHC and Autoimmune Disorders
- Certain MHC alleles increase susceptibility to autoimmune diseases:
- HLA-B27 → Ankylosing spondylitis
- HLA-DR3, DR4 → Type 1 diabetes
- HLA-DR2 → Multiple sclerosis
C) MHC in Infectious Diseases
- HLA variations affect the severity of infections like HIV, tuberculosis, and COVID-19.
D) MHC and Cancer Immunotherapy
- Checkpoint inhibitors (e.g., PD-1/PD-L1 blockers) enhance MHC-mediated tumor recognition.
6. Research and Advancements in MHC Studies
- CRISPR gene editing: Modifying MHC to reduce transplant rejection.
- Personalized cancer vaccines: Targeting MHC-peptide complexes for better immune responses.
- MHC-based therapeutics: Development of MHC-mimicking molecules for immune modulation.
7. Conclusion
The Major Histocompatibility Complex (MHC) is fundamental in immune regulation, antigen presentation, and disease defense. Understanding MHC interactions is critical for advancements in transplant medicine, autoimmune disease treatment, and immunotherapy.
Relevant Website URL Links for Further Reading
🔗 Basic Immunology & MHC Overview
https://www.ncbi.nlm.nih.gov/books/NBK27156/
🔗 Antigen Presentation Pathways
https://www.nature.com/articles/s41577-020-0344-x
🔗 MHC & Transplantation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448937/
🔗 MHC & Autoimmune Diseases
https://www.frontiersin.org/articles/10.3389/fimmu.2018.02232/full
🔗 MHC and Cancer Immunotherapy
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/mhc
MCQs on Major Histocompatibility Complex (MHC): Importance in Antigen Presentation
1. What is the Major Histocompatibility Complex (MHC)?
A) A set of genes that code for proteins involved in antigen presentation
B) A group of antibodies that attack pathogens
C) A protein responsible for muscle contraction
D) A molecule that stores genetic information
✅ Answer: A
Explanation: The MHC is a set of genes that encode proteins essential for antigen processing and presentation to T cells, playing a key role in immune response.
2. Where are MHC genes located in humans?
A) Chromosome 6
B) Chromosome 11
C) Chromosome 1
D) Chromosome 21
✅ Answer: A
Explanation: The MHC genes in humans are found on the short arm of chromosome 6 and are called the human leukocyte antigen (HLA) complex.
3. Which type of MHC molecule is found on all nucleated cells?
A) MHC Class I
B) MHC Class II
C) MHC Class III
D) None of the above
✅ Answer: A
Explanation: MHC Class I molecules are present on all nucleated cells and are responsible for presenting endogenous antigens to CD8+ T cells.
4. Which cells primarily express MHC Class II molecules?
A) Neurons
B) Red blood cells
C) Antigen-presenting cells (APCs)
D) Platelets
✅ Answer: C
Explanation: MHC Class II molecules are expressed mainly on APCs like dendritic cells, macrophages, and B cells and are crucial for presenting antigens to CD4+ T cells.
5. What type of T cell recognizes antigens presented by MHC Class I molecules?
A) CD4+ T cells
B) CD8+ T cells
C) B cells
D) Natural Killer (NK) cells
✅ Answer: B
Explanation: CD8+ T cells, also known as cytotoxic T cells, recognize antigens presented by MHC Class I molecules, leading to the destruction of infected cells.
6. Which of the following is a function of MHC molecules?
A) Oxygen transport
B) Antigen presentation
C) Enzyme secretion
D) Nerve impulse transmission
✅ Answer: B
Explanation: MHC molecules help in presenting antigenic peptides to T cells, triggering an immune response against pathogens.
7. What is the role of MHC Class II molecules?
A) Present intracellular pathogens
B) Present extracellular antigens
C) Transport oxygen
D) None of the above
✅ Answer: B
Explanation: MHC Class II molecules present extracellular antigens to CD4+ T cells, which then help activate other immune cells.
8. Which enzyme helps in antigen processing for MHC Class I presentation?
A) DNA polymerase
B) Proteasome
C) Lysozyme
D) Amylase
✅ Answer: B
Explanation: The proteasome degrades intracellular proteins into peptides that bind to MHC Class I molecules for presentation.
9. Which protein helps transport peptides to MHC Class I molecules in the endoplasmic reticulum?
A) TAP (Transporter Associated with Antigen Processing)
B) Hemoglobin
C) Actin
D) Myosin
✅ Answer: A
Explanation: TAP transports peptide fragments from the cytoplasm to the endoplasmic reticulum, where they bind to MHC Class I molecules.
10. MHC molecules exhibit which type of genetic inheritance?
A) Dominant
B) Co-dominant
C) Recessive
D) X-linked
✅ Answer: B
Explanation: MHC genes are co-dominantly expressed, meaning both maternal and paternal alleles are expressed in an individual.
(Continuing in the same pattern…)
11. What is the main function of antigen-presenting cells (APCs)?
A) Destroy pathogens directly
B) Present antigens to T cells
C) Secrete antibodies
D) Produce red blood cells
✅ Answer: B
Explanation: APCs such as dendritic cells, macrophages, and B cells process and present antigens to activate T cells.
12. What type of immune response is initiated by MHC Class I molecules?
A) Humoral immunity
B) Cell-mediated immunity
C) Innate immunity
D) Autoimmunity
✅ Answer: B
Explanation: MHC Class I molecules trigger cell-mediated immunity by activating CD8+ T cells.
13. Which type of antigen is presented by MHC Class II molecules?
A) Intracellular
B) Extracellular
C) Viral peptides
D) Self-antigens
✅ Answer: B
Explanation: MHC Class II molecules present extracellular antigens that are phagocytosed by APCs.
14. The peptide-binding groove of MHC Class I molecules is formed by which domains?
A) α1 and α2
B) β1 and β2
C) α2 and β2
D) γ and δ
✅ Answer: A
Explanation: The peptide-binding groove of MHC Class I molecules is formed by the α1 and α2 domains, allowing peptide binding.
15. What is the main characteristic of MHC molecules?
A) High polymorphism
B) Low mutation rate
C) Secreted in plasma
D) Found only in neurons
✅ Answer: A
Explanation: MHC genes are highly polymorphic, meaning they have a large number of different alleles in the population.
16. What is cross-presentation?
A) MHC Class I molecules presenting extracellular antigens
B) MHC Class II molecules presenting intracellular antigens
C) Both MHC I and II presenting the same antigen
D) None of the above
✅ Answer: A
Explanation: Cross-presentation allows extracellular antigens to be presented by MHC Class I molecules, a process important for activating CD8+ T cells.
17. Which MHC class is involved in transplant rejection?
A) MHC Class I
B) MHC Class II
C) Both MHC I and II
D) None of the above
✅ Answer: C
Explanation: Both MHC Class I and II play roles in transplant rejection as they are recognized as foreign by the recipient’s immune system.
18. Which immune disorder is associated with MHC malfunction?
A) Diabetes mellitus
B) Rheumatoid arthritis
C) Alzheimer’s disease
D) Parkinson’s disease
✅ Answer: B
Explanation: Autoimmune diseases like rheumatoid arthritis are linked to MHC gene variations.
