Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis.
Genetic susceptibility to type 1 autoimmune hepatitis in white northern Europeans is related to female sex, HLA alleles encoding the six amino acid sequence LLEQKR at positions 67-72 of the DRB1 polypeptide, and CTLA-4 gene polymorphism. The principal HLA alleles associated with type 1 autoimmune hepatitis in Britain and North America are DRB1*0301 and DRB1*0401. In this model of susceptibility, lysine at position 71 of the expressed DR molecule is the critical amino acid. In Japan, Argentina and Mexico, susceptibility is linked to DRB1*0405 and DRB1*0404. These two alleles encode arginine at position 71 rather than lysine, but they share the motif LLEQ-R with DRB1*0401 and DRB1*0301. Thus, K or R at position 71 in the context of LLEQ-R may be critical for susceptibility. This "shared motif" or "epitope" may optimize T-cell recognition of autoantigen, and other alleles that encode lysine at DRbeta71 may also affect susceptibility and outcome, possibly by increasing the density of lysine or arginine 71 molecules on the surface of antigen-presenting cells. Since the DRB1*0301 allele is part of the extended ancestral 8.1 haplotype, it carries with it additional risk factors for autoimmunity, including TNFA*2 and C4A*Q0. Type 1 autoimmune hepatitis is a polygenic disorder and other yet undefined polymorphic genes may be non-specific immunoregulators. These additional MHC encoded genes and other non-MHC encoded genes may be important determinants of disease susceptibility and severity in type 1 autoimmune hepatitis.
Czaja
A J
AJ
Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. czaja.albert@mayo.edu
Donaldson
P T
PT
D000069594:Abatacept; D000328:Adult; D000483:Alleles; D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D017951:Antigen Presentation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics* / Q000502:physiology; D001118:Argentina / Q000453:epidemiology; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D001938:Brazil / Q000453:epidemiology; D060908:CTLA-4 Antigen; D002648:Child; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005060:Europe / Q000453:epidemiology; D019143:Evolution, Molecular; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D019693:Hepatitis, Autoimmune / Q000145:classification / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates; D007564:Japan / Q000453:epidemiology; D008297:Male; D008800:Mexico / Q000453:epidemiology; D018448:Models, Immunological; D018716:Molecular Mimicry; D011487:Protein Conformation; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000502:physiology; D044465:White People / Q000235:genetics
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D001324:Autoantigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; C553505:HLA-DRB1*04:01 antigen; D018796:Immunoconjugates; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept; D019389:Cytochrome P-450 CYP2D6