Browsing by Subject "Autoimmune hepatitis (AIH)"

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    Genetic and Environmental Risk Factors for Autoimmune Hepatitis
    (Wiley, 2019-08-02) Lammer, Craig; Medicine, School of Medicine
    Autoimmune hepatitis (AIH) is a prototypical autoimmune disease, characterized by robust genetic associations with human leukocyte antigen (HLA) alleles, female predominance, and presence of serum autoantibodies; yet all AIH cases are not the same. This heterogeneous disease affects all population demographics and can lead to cirrhosis, liver failure, and liver transplantation depending on the diagnosis, treatment, and response to therapy. Similar to other autoimmune diseases, AIH is a result of immune intolerance and failure of immunological homeostasis. The etiology remains largely unresolved but is likely the result of various environmental exposures in the background of a permissive genetic architecture.
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    Novel HLA Class I Alleles Outside the Extended DR3 Haplotype Are Protective against Autoimmune Hepatitis
    (Wolters Kluwer, 2019-06) Lammert, Craig; McKinnon, Elizabeth J.; Chalasani, Naga; Phillips, Elizabeth J.; Gastroenterology & Hepatology, IU School of Medicine
    INTRODUCTION: HLA class II allele, DRB1*03:01, is the most common genetic risk factor for autoimmune hepatitis (AIH), but other unrecognized HLA related risks exist. METHODS: We compared the HLA class I (A, B, C) and class II (DR, DQ, DP) typing between patients with well-characterized AIH and healthy controls by high resolution sequencing of the HLA region. Seventy-three patients with AIH and 87 healthy controls were included. Association between HLA alleles and AIH was considered singly and in clusters and adjusted for age, gender, and DRB1*03:01. RESULTS: DRB1*03:01 was singly associated with AIH among whites (odds ratio [OR]: 3.09, P = 0.002) and carriers of DRB1*03:01 also carried DQA*05:01 and DQB1*02:01. Significant HLA class I alleles were associated with AIH including those belonging to the A03 (OR: 0.4, P = 0.01) and B44 supertype (OR: 0.44, P = 0.03). Further refinement of HLA-A by binding pocket structure revealed that the sequence Y(F/T)AVMENV(H/Q)Y, corresponding to HLA-A alleles A*03:01-02; *31:01; *32:02, was protective for AIH (OR: 0.3, P = 0.002). A protective association also existed for alleles belonging to the HLA-B binding pocket structure Y(H/Y)TVKEISNY (OR: 0.35, P = 0.01), corresponding to HLA-B alleles: B*40:01-02; *41:02; *44:02-03; *45:01; *49:01; *50:01-02. Associations with specific class I alleles belonging to the 8.1 ancestral haplotype (HLA-A*01:01, HLA-B*08:01, HLA-C*07:01) were not significant when considered jointly with DRB1*03:01 and reported protective class I alleles. DISCUSSION: Our study identified novel supertypes and HLA-A and B peptide binding structures protective against AIH. Further risk assessment of class I molecules remains important in AIH as they are key mediators of adaptive immunity.