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Structure and Function of MHC

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Topic updated on 05/19/17 5:58pm

Introduction
  •  Major histocompatibility complexes (MHC) are cell surface expressed proteins that
    • bind to protein peptides in a surface groove
    • present bound peptides to
      • receptors on circulating T-cells
    • participate in the
      • activation of the adaptive immune response
  •  MHC are encoded by HLA genes that are localized to several different genetic regions
    • different HLA regions encode for different types of MHC
  • Allogenic MHC can be recognized by T-cells of the adaptive immune system
    • mismatch of MHC is an important cause of transplant rejection
MHC Classes 
  • There are two different classes of MHC encoded in the human genome
    • class I MHC usually presents 
      • endogenous antigens to CD8+ killer T-cells
    • class II MHC usually presents 
      • endocytosed antigens to CD4+ helper T-cells
    • antigens may be "cross-presented" by the other MHC class in some cases
  • The two MHC classes differ in several characteristics including
    • HLA loci that encodes the gene
    • sites of expression
    • protein structure
    • antigen loading site
    • antigen loading mechanism
    • binding partners
Differences Between MHC Classes
Feature MHC Class I  MHC Class II 
HLA Loci
  • HLA-A
  • HLA-B
  • HLA-C
  • One letter
  • HLA-DP
  • HLA-DQ
  • HLA-DR
  • Two letters
Site of expression
  • All nucleated cells
  • Platelets
  • Antigen presenting cells
Protein structure
  • 1 long chain
  • 1 short chain called β2 - microglobulin
  • 2 equal length chains
  • Additional invariant chain
Antigen loading site
  • Rough endoplasmic reticulum (RER)
  • Acidified endosomes
Loading mechanism
  • Endogenous proteins are degraded by the proteosome
  • Antigenic peptides are transported into the RER by the TAP transporter
  • Antigens bind to MHC molecules directly
  • Exogenous proteins are endocytosed from the cell surface
  • Antigens are produced by degradation within the endosomal compartment
  • Antigens bind to MHC molecules after release of the invariant chain
Binding Partners
  • T-cell receptor
  • CD8 co-receptor
  • T-cell receptor
  • CD4 co-receptor


 
Disease Associations
  • Each individual possesses a set of MHC class I and class II subtypes
    • these "haplotypes" define the peptides that will be recognized
  • Some haplotypes are associated with specific diseases because they may
    • preferentially bind to certain self-peptides
    • lead to a failure of immune tolerance
MHC Subtypes Associated With Diseases
Class I Haplotype Diseases Class II Haplotype Diseases
A3
  • Hemochromatosis
DQ2/DQ8
  • Celiac disease 

B8

  • Addison disease
  • Myasthenia gravis
  • Graves disease
DR2
  • Multiple sclerosis
  • Hay fever
  • Systemic lupus erythematosis
  • Goodpasture syndrome 
B27 
  • Psoriatic arthritis
  • Ankylosing spondylitis
  • Inflammatory bowel disease
  • Reactive arthritis
DR3
  • Diabetes melliutus type I
  • Systemic lupus erythematosis
  • Graves disease
  • Hashimoto thyroiditis
  • Addison disease
- - DR4
  • Rheumatoid arthritis
  • Diabetes mellitus type 1
  • Addison disease
- - DR5
  • Pernicious anemia
  • Hashimoto thyroiditis

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