Human Leukocyte Antigen Class II Haplotypes Affect Clinical Characteristics and Progression of Type 1 Autoimmune Hepatitis in Japan

Although we earlier demonstrated that the human leukocyte antigen (HLA) DRB1*04:05 allele was associated with susceptibility to autoimmune hepatitis (AIH) in Japan, the precise relationship of HLA haplotype and the role of amino acid alignment with disease susceptibility and progression has not been fully clarified. We reinvestigated HLA class I A, B, and C and HLA class II DRB1, DQB1, and DPB1 alleles and haplotypes in a larger new cohort of 156 Japanese patients with type 1 AIH and compared them with the published data of 210 healthy subjects. The DRB1*04:05-DQB1*04:01 haplotype was significantly associated with AIH susceptibility (30% vs. 11%, P = 1.2×10(-10); odds ratio [OR]  = 3.51) and correlated with elevated serum IgG (3042 vs. 2606 mg/dL, P = 0.041) and anti-smooth muscle antigen positivity (77% vs. 34%, P = 0.000006). No associations with HLA-DPB1 alleles were found. The HLA A*24:02 and C*01:02 alleles were associated with disease susceptibility (corrected P = 0.0053 and 0.036, respectively), but this likely constituents of a long ranged haplotype including DRB1*04:05-DQB1*04:01 haplotype. Conversely, the DRB1*15:01-DQB1*06:02 haplotype was associated with protection from both disease onset (5% vs. 13%, P = 0.00057; OR = 0.38) and the development of hepatocellular carcinoma (25% vs. 5%, P = 0.017; OR = 6.81). The frequency of the DRB1*08:03-DQB1*06:01 haplotype was significantly higher in patients who developed hepatic failure (22% vs. 6%, P = 0.034; OR = 4.38). In conclusion, this study established the role of HLA haplotypes in determining AIH susceptibility and progression in the Japanese population. Additional sequencing of the entire HLA region is required to more precisely identify the genetic components of AIH

Genetic background of autoimmune hepatitis in Japan

Autoimmune hepatitis (AIH) is an organ-specific autoimmune disease characterized by chronic inflammation of the liver. Several studies from ethnically different countries have clarified that the genetic predisposition to type 1 AIH is linked mainly to human leukocyte antigen (HLA)-class II genes. Recently, molecular analysis using polymerase chain reaction (PCR)-based DNA typing has revealed that susceptibility to type 1 AIH is primarily associated with the HLA class II DRB1 locus, which encodes a polymorphic beta chain of the HLA-DR antigen. However, additional susceptibility genes (either HLA or non-HLA) and/or environmental factors may also contribute to the development of type 1 AIH; in Japanese type 1 AIH patients, although the most influential gene in disease susceptibility is HLA-DRB1*04:05, several other genes have been identified as being involved in AIH pathogenesis or resistance and are the currently the focus of single nucleotide polymorphism analysis.ArticleJOURNAL OF GASTROENTEROLOGY. 46(1):42-47 (2011)journal articl

Genetic factors affect the etiology, clinical characteristics and outcome of autoimmune hepatitis

Autoimmune hepatitis (AIH) is characterized by chronic inflammation of the liver, hypergammaglobulinemia, the presence of serum autoantibodies, histologic evidence of interface hepatitis, and a favorable response to immunosuppressive treatment. Although the etiology of AIH remains undefined, human leukocyte antigen (HLA) class II alleles have been associated with disease onset for decades. AIH resistance and severity are presumably linked to HLA alleles as well. Individuals in different geographic regions of the world may have varying susceptibility alleles that reflect indigenous triggering antigens. In this review, we describe the influence of HLA alleles and gene polymorphisms on AIH, along with the results of genome-wide association studies on this disease

Structural mimicry between SLA/LP and Rickettsia surface antigens as a driver of autoimmune hepatitis: insights from an in silico study

Background: Autoimmune hepatitis (AIH) is a chronic, progressive liver disease, characterized by continuing hepatocellular inflammation and necrosis. A subgroup of AIH patients presents specific autoantibodies to soluble liver antigen/liver-pancreas (SLA/LP) protein, which is regarded as a highly specific diagnostic marker. Autoantigenic SLA/LP peptides are targeted by CD4(+) T cells, and restricted by the allele HLA-DRB1*03:01, which confers disease susceptibility in Europeans and Americans. A positively charged residue at position 71 has been indicated as critical for AIH susceptibility in all of the HLA alleles identified to date. Though the exact molecular mechanisms underlying pathogenesis of AIH are not clear, molecular mimicry between SLA/LP and viral/bacterial antigens has been invoked. Methods: The immunodominant region of SLA/LP was used as query in databank searches to identify statistically significant similarities with viral/bacterial peptides. Homology modeling and docking was used to investigate the potential interaction of HLA-DRB1*03:01 with the identified peptides. By molecular mechanics means, the interactions and energy of binding at the HLA binding site was also scrutinized. Results: A statistically significant structural similarity between the immunodominant regions of SLA/LP and a region of the surface antigen PS 120 from Rickettsia spp. has been detected. The interaction of the SLA/LP autoepitope and the corresponding Rickettsia sequence with the allele HLA-DRB1*03:01 has been simulated. The obtained results predict for both peptides a similar binding mode and affinity to HLA-DRB1*03:01. A "hot spot" of interaction between HLA-DRB1*03:01 and PS 120 is located at the P4 binding pocket, and is represented by a salt bridge involving Lys at position 71 of the HLA protein, and Glu 795 of PS120 peptide. Conclusions: These findings strongly support the notion that a molecular mimicry mechanism can trigger AIH onset. CD4(+) T cells recognizing peptides of SLA/LP could indeed cross-react with foreign Rickettsia spp. antigens. Finally, the same analysis suggests a molecular explanation for the importance of position 71 in conferring the susceptibility of the allele HLA-DRB1*03:01 to AIH. The lack of a positive charge at such position could prevent HLA alleles from binding the foreign peptides and triggering the molecular mimicry event