• Autoimmune disease
• Viral disease
• Neurologic disorders
• Allergic reactions
MHC and disease association
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
Certain HLA genotype are frequently found in diabetic patientsDR3/4 tight linkage to DQ
Affected siblings share 2 HLA haplotypes much more frequently than expected
Position of the DQ 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 cells2.) 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)
• 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
Significant associations of HLA Alleles with increased risk for various diseases
In the fight against viruses and tumors: high MHC I expression on target cells:
good or bad ??
NK cell
CD8 cell
Tumor cell: lots of MHC I
No lysis
Lysis
NK cell
CD8 cell
Tumor cell: little MHC I
Lysis
No Lysis
“Innate Immunity”, D080
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