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 patients DR3/4 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 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)

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