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MHC and disease association
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Autoimmune disease
Viral disease
Neurologic disorders
Allergic reactions
MHC genes and Pathogen defence
Significant associations of HLA Alleles with
increased risk for various diseases
Population studies show association of susceptibility
to IDDM with HLA genotype
Affected siblings share 2 HLA haplotypes
much more frequently than expected
Certain HLA genotype are
frequently found in diabetic patients
DR3/4 tight linkage to DQb,
Position of the DQb chain affects susceptibility to
insulin-dependent diabetes mellitus
AA 57 forms a salt bridge
Across the peptide
binding cleft of DQ
Possible explanation:
1.) Allelic variants of MHC
molecules differ in ability
to present the
autoantigenic peptides to
autoreactive T cells
2.) Shaping of the
T cell repertoire
Hereditary hemochromatosis
• Defective regulation of iron
absorption
• Disease associated with mutation
in the nonclassical MHC class I
gene HLA-H
• Onset with 40 or 50 years,
nonspecific symptoms
• Iron overload and accumulation
eg in the liver, leads to severe
illness and cancer
• HLA-H carries mutation at
position 283 (no association with
b2-microglobulin possible)
Significant associations of HLA Alleles with
increased risk for various diseases
• Both inherited and environmental factors play a role in
the induction of autoimmune disease
• Inbred mice show uniform susceptibility to autoimmune
disease
• But also other independly segregating disease
susceptibility loci have been defined
• Also amount of self antigen transcribed in the thymus
plays a role
In the fight against viruses and tumors: high MHC I
expression on target cells:
good or bad ??
NK cell
NK cell
Lysis
No lysis
CD8 cell
CD8 cell
Lysis
Tumor cell: lots of MHC I
No Lysis
Tumor cell: little MHC I
“Innate Immunity”, D080