Major Histocompatibility Complex (MHC) / HLA: Exam Notes

Definition

• In humans, MHC molecules are called Human Leukocyte Antigens (HLA).
• They were first identified on leukocytes but are present on many other cells.
• They act as an individual-specific genetic identity marker.
• They are important in:
  1. Antigen presentation to T cells
  2. Transplant rejection or graft acceptance
  3. Disease susceptibility

Location and Organization of HLA Genes

• Located on the short arm of chromosome 6 (6p).
• HLA complex spans about 4000 kb.
• Contains more than 100 genes.
• Divided into three regions:

Key point

MHC Class I

Genes

• HLA-A
• HLA-B
• HLA-C

Distribution

• All nucleated cells
• Platelets

• RBCs because they lack a nucleus

Structure

1. One α-chain
   • Glycoprotein, approximately 45 kDa
   • Encoded by HLA-A, HLA-B, or HLA-C
   • Has three extracellular domains: α1, α2, α3
   • Has a transmembrane segment and cytoplasmic tail
2. β2-microglobulin
   • Approximately 12 kDa
   • Non-glycosylated
   • Encoded on chromosome 15, not chromosome 6
   • Necessary for stable surface expression of MHC I

Peptide-binding groove

• Formed by the cleft between α1 and α2 domains.
• Binds peptides of 8-10 amino acids.

T-cell interaction

• α3 domain binds CD8 co-receptor.
• Therefore, MHC I presents antigen to CD8+ cytotoxic T cells.

Antigen source and pathway

• Presents endogenous / intracellular antigens.
• Examples:
  • Viral proteins
  • Tumor antigens
  • Other cytosolic proteins
• Antigen processing occurs through the cytosolic pathway.

One-line answer

MHC Class I presents endogenous peptides of 8-10 amino acids to CD8+ cytotoxic T cells.

MHC Class II

Genes

• HLA-DP
• HLA-DQ
• HLA-DR

Distribution

• Dendritic cells
• Macrophages
• B lymphocytes

Structure

1. α-chain
   • About 33 kDa
   • Domains: α1 and α2
2. β-chain
   • About 28 kDa
   • Domains: β1 and β2

Peptide-binding groove

• Formed by the cleft between α1 and β1 domains.
• Binds peptides of 13-18 amino acids.

T-cell interaction

• β2 domain binds CD4 co-receptor.
• Thus, MHC II presents antigen to CD4+ helper T cells.

Antigen source and pathway

• Presents exogenous antigens that are taken up by endocytosis or phagocytosis.
• Examples:
  • Extracellular bacteria
  • Toxins
  • Soluble proteins
• Antigen processing occurs through the endocytic pathway.

One-line answer

MHC Class II presents exogenous peptides of 13-18 amino acids to CD4+ helper T cells.

MHC Class III

Location and contents

• Lies between MHC Class I and MHC Class II regions.
• About 1000 kb long.
• Does not take part in antigen presentation.

• Complement components: C2, C4
• Factor B
• Properdin-related factors
• Heat shock protein 70 (HSP70)
• Tumor necrosis factor: TNF-α and TNF-β
• Steroid 21-hydroxylase

Exam point

MHC Class III genes code for inflammatory and complement-related proteins, not MHC antigen-presenting molecules.

Differences Between MHC Class I and MHC Class II

Mnemonic

• MHC I presents 8-10 aa peptides to CD8 T cells.

• MHC II presents to CD4 T cells.

• Class I = Inside antigen
• Class II = Ingested antigen

MHC in Transplantation

• The recipient can mount an immune response against donor MHC molecules.
• Greater donor-recipient MHC mismatch leads to a greater likelihood of rejection.
• Better HLA matching improves graft compatibility.

High-yield statement

HLA matching is important in organ and bone marrow transplantation because HLA disparity promotes graft rejection.

HLA and Disease Susceptibility

Must remember

• B27 = Ankylosing spondylitis
• DR4 = Rheumatoid arthritis
• DR3 = SLE
• DR3/DR4 = Type 1 diabetes mellitus
• DR2 = Multiple sclerosis

Very Short Notes for Revision

• MHC in humans = HLA system.
• Located on chromosome 6 short arm.
• MHC is polygenic and highly polymorphic.
• Class I: A, B, C, all nucleated cells, endogenous antigen, CD8, 8-10 aa peptide.
• Class II: DP, DQ, DR, APCs, exogenous antigen, CD4, 13-18 aa peptide.
• Class III: complement proteins, TNF, HSP70, no antigen presentation.
• MHC determines tissue compatibility and influences transplant rejection.
• β2-microglobulin is part of MHC I and is encoded on chromosome 15.
• Class I peptide groove = α1 + α2.
• Class II peptide groove = α1 + β1.

Common Exam Questions

1. Define MHC. State its functions.
2. Describe the genetic organization of human MHC.
3. Compare MHC Class I and Class II molecules.
4. Draw and label the structure of MHC Class I and Class II.
5. Explain endogenous and exogenous antigen presentation pathways.
6. Enumerate diseases associated with HLA alleles.
7. Why is HLA matching important in transplantation?

MHC / HLA: One-Page Revision Chart

1. Core Facts

2. MHC Gene Regions

3. MHC Class I vs Class II

Memory tricks

• MHC I = Inside = CD8
• MHC II = Ingested = CD4
• 1 × 8 = CD8: Class I presents 8-10 aa peptide to CD8 cells.
• 2 × 4 = CD4: Class II presents antigen to CD4 cells.

4. Structures

MHC Class I

α1 + α2  → peptide-binding groove
α3       → binds CD8
β2-microglobulin → stabilizes MHC I molecule

α-chain encoded by HLA-A, HLA-B, HLA-C
β2-microglobulin encoded on chromosome 15

MHC Class II

α1 + β1 → peptide-binding groove
β2      → binds CD4

Both α and β chains are encoded by HLA-DP, DQ, DR genes.

5. Transplantation

More HLA mismatch → stronger recipient immune response → greater graft rejection
Better HLA matching → better graft compatibility

6. HLA Disease Associations

Rapid recall

B27 → Back pain → Ankylosing spondylitis
DR4 → Rheumatoid arthritis
DR3 → SLE
DR3 + DR4 → Type 1 DM
DR2 → Multiple sclerosis

Last-Minute 5 Lines

1. MHC = HLA, located on chromosome 6.
2. Class I: A, B, C; all nucleated cells; endogenous antigen; CD8.
3. Class II: DP, DQ, DR; APCs; exogenous antigen; CD4.
4. Class III: complement and TNF genes, no antigen presentation.
5. HLA mismatch causes graft rejection; B27 is associated with ankylosing spondylitis.