Major Histocompatibility Complex (MHC) and its encoding molecules

Weilin Chen, Ph. D.

Institute of Immunology, ZJU

1. Introduction

2. Structure of MHC genes and products

3. Polymorphism of MHC

4. Interactions of MHC molecules with antigenic peptides

5. HLA and clinical medicine

6. Biological function of MHC molecules

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

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

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

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1. Organization of MHC genes

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

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

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Location of MHC Class I and Class II molecules in tissues

3. Other immune function related genes1) 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

2. Serum complement encoded genes MHC class III3. Non-classical class I genes (HLA Ib) HLA-E, HLA-G: inhibit NK cell activity4. 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

Other immune function related genes

Ag processing-related genes

Complement encoding genes

Inflammation-related genes

Non-classical MHC I genes

Polymorphism of MHC1. Polymorphism The phenomenon of having multiple stable forms of

one gene in the population• HLA 8016 (HLA-A 2013; HLA-B 2605 ; HLA-DRB 1260)• HLA-A*0103 HLA-DRB1*1102 • Expression of MHC alleles is co-dominant

2. Linkage disequilibrium and haplotype A2-B46-Cw3-DR9-DQ9-Dw23

Ref: http://hla.alleles.org/

HLA Nomenclature

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.

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

MHC I MHC II

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Molecular mechanism• anchor site• anchor residue• consensus motif

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.

Biological function of HLA

1. 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)

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

* 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.

* MHC polymorphism is a crucial determinant of disease susceptibility in different individuals

* MHC contributes to the genetic heterogeneity of the population

2. Participates in the innate immunity serving as regulatory molecules

1) Classical MHC class III genes encode complement, hereby participating in complement reactions and in the pathogenesis of some immune diseases.

2) Non-classical HLA class I molecules (HLA-E, G) regulate the activity of NK cells.

3) Inflammation related genes initiate and control inflammation. They also play a role in stress responses (such as HSP).

HLA and clinical medicine1. HLA and transplantation HLA typing; cross-match2. Abnormal expression of HLA Tumor: class I molecule↓ Autoimmune diseases: class II molecule↑3. HLA and disease susceptibility Ankylosing spondylitis: B274. Adverse drug reaction: carbamazepine : HLA-B*15:02 (SJS) allopurinol: HLA-B*58:015. HLA and forensic medicine

Paternity Testing:

Wife: A2, A11; B27, Bw44Child 1: A2, A1; Bw44, B15, Cw3Child 2: A2, Aw24; Bw44, Bw54; Cw3

Husband: A1, A3; B15, -; Cw3Another man: A2, Aw24; B7, Bw54; Cw3