1. Institute of Immunology, ZJU
Major Histocompatibility Complex (MHC) and its encoding molecules
Weilin Chen, Ph. D.
Institute of Immunology, ZJU

2. Introduction
Structure of MHC genes and products
Polymorphism of MHC
Interactions of MHC molecules with antigenic peptides
HLA and clinical medicine
Biological function of MHC molecules

3. Introduction 1. Histocompatibility
The ability to accept grafts between individuals.
2. Histocompatibility antigen
The Ags primarily responsible for rejection of genetically different tissues are known as histocompatibility Ags.
3. Histocompatibility antigen system
4. Major histocompatibility antigen system
5. Minor histocompatibility antigen system

4. 6. Major histocompatibility complex,MHC
A cluster of genes (complex) on chromosome 6 in humans, encoding cell surface molecules that are polymorphic and that code for antigens causing rapid graft rejection between members of a single species that differ at these loci.
Several classes of protein such as MHC class I and II proteins are encoded in this region.
Human: Human leukocyte antigens (HLA)
Mouse: H-2

5. Organization and Structure of MHC Genes and Products
1. Organization of MHC genes 2. Products of MHC class I and MHC class II genes---HLA molecules 3. Other immune function related genes

6. 1. Organization of MHC genes
Downloaded from: StudentConsult (on 1 June :08 PM)
© 2005 Elsevier

7. 2. Products of MHC class I and class II genes---HLA molecules
1) HLA class I molecules Genes: A, B, C Distribution: every nucleated cell Structure: α chain (45kD) β2m (12kD) peptide-binding cleft: α1+α2 CD8 binding: α3 Function: recognize and present endogenous and cross-present exogenous Ags to CD8+ T cells

8. 2) HLA class II molecules
Genes: DR, DQ, DP
Distribution: APC (B, DC, MΦ)
thymic epithelial cells, activated T cells
Structure: α chain (35kD)
β chain (28kD)
peptide-binding cleft: α1+β1
CD4 binding: β2
Function: recognize and present the
exogenous Ags to CD4 T cells

9. Downloaded from: StudentConsult (on 1 June 2006 02:08 PM)
© 2005 Elsevier

10. Location of MHC Class I and Class II molecules in tissues

11. 3. Other immune function related genes
1) Antigen presenting function related genes LMP (low molecular weight polypeptide): LMP2/7 Function: processes endogenous Ag TAP (transporter associated with Ag processing): TAP1, TAP2 Function: transports endogenous Ag peptides HLA-DM: participates in the exogenous pathway HLA-DO: negative regulation of DM tapasin (TAP associated protein): participates in the endogenous pathways

12. 2. Serum complement encoded genes
MHC class III
3. Non-classical class I genes (HLA Ib)
HLA-E, HLA-G: inhibit NK cell activity
4. Inflammation related genes
TNF gene family: TNF, LTA, LTB
Transcription factor gene family: I-κBL, ZNF173
MIC family: MIC A, MIC B (ligand for KAR)
Heat shock protein gene family: HSP70

13. Other immune function related genes
Ag processing-related genes
Complement encoding genes
Inflammation-related genes
Non-classical MHC I genes

14. Polymorphism of MHC 1. Polymorphism
The phenomenon of having multiple stable forms of one gene in the population
HLA (HLA-A 2013; HLA-B 2605 ; HLA-DRB 1260)
HLA-A* HLA-DRB1*1102
Expression of MHC alleles is co-dominant
2. Linkage disequilibrium and haplotype
A2-B46-Cw3-DR9-DQ9-Dw23
Ref:

15. HLA Nomenclature

18. 3. Production of MHC Polymorphism
The significance of MHC polymorphism:
Almost all of the polymorphism among MHC alleles involves amino acid residues located in and around the peptide-binding groove. As a result, each allelic form has its own unique peptide-binding properties.
Affects the ability to make immune responses
(e.g. resistance or susceptibility to infectious diseases).
Ensures survival of the population as a whole when they encounter any new pathogens by presenting new microbial epitopes.

19. Interactions of MHC molecules with antigenic peptides
1. Molecular basis
(1) Antigen-binding cleft
class I Molecules: 1/2
closed at both ends
8~10 amino acids
class II Molecules: 1/1
open at both ends
11~15 amino acids
(2) Anchor site and anchor residue

20. MHC I
MHC II

21. Downloaded from: StudentConsult (on 1 June 2006 02:08 PM)
© 2005 Elsevier

22. Molecular mechanism
anchor site
anchor residue
consensus motif

24. 2. Characteristics of peptide-MHC binding
(1) Specificity: special anchor residues
The important point is that peptide binding by a given MHC protein is selective but less specific than antigen binding by a TCR or a BCR.
(2) Flexibility: a series of different antigenic peptides with the same consensus binding motif can be presented by a given MHC molecule.

25. Biological function of HLA
Participates in the adaptive immune response serving as antigen presenting molecules
* T cells recognize both the antigenic peptide and MHC molecules by TCR (double recognition)

26. Separate antigen-presenting pathways are utilized for endogenous (green) and exogenous (red) antigens.

27. * MHC molecules can present both autoantigens and MHC molecules themselves. Such that MHC molecules participate in autoimmunity,in the response to non-self MHC molecules as well as in the differentiation of T cells in the thymus.

28. * MHC polymorphism is a crucial determinant of disease susceptibility in different individuals * MHC contributes to the genetic heterogeneity of the population

29. 2. Participates in the innate immunity serving as regulatory molecules
Classical MHC class III genes encode complement, hereby participating in complement reactions and in the pathogenesis of some immune diseases.
Non-classical HLA class I molecules (HLA-E, G) regulate the activity of NK cells.
Inflammation related genes initiate and control inflammation. They also play a role in stress responses (such as HSP).

30. HLA and clinical medicine
1. HLA and transplantation
HLA typing; cross-match
2. Abnormal expression of HLA
Tumor: class I molecule↓
Autoimmune diseases: class II molecule↑
3. HLA and disease susceptibility
Ankylosing spondylitis: B27
4. Adverse drug reaction:
carbamazepine : HLA-B*15:02 (SJS)
allopurinol: HLA-B*58:01
5. HLA and forensic medicine

32. Paternity Testing:
Wife: A2, A11; B27, Bw44 Child 1: A2, A1; Bw44, B15, Cw3 Child 2: A2, Aw24; Bw44, Bw54; Cw3 Husband: A1, A3; B15, -; Cw3 Another man: A2, Aw24; B7, Bw54; Cw3