Abstract
BackgroundAutoimmune 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.MethodsThe 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.ResultsA 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.ConclusionsThese 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.
Highlights
Autoimmune hepatitis (AIH) is a chronic, progressive liver disease, characterized by continuing hepatocellular inflammation and necrosis
Sequence similarity and structure analysis Databank searches identified a set of 120 KDa surface antigens from Rickettsia prowazekii, sharing a region of high (Score = 29.6 bits; Identities = 16/29 (55%); Positives = 19/29 (66%), Gaps = 0/29 (0%)) and significant (E-value = 2e−04) similarity with residues 451–479 of soluble liver antigen/liver-pancreas (SLA/LP) (Figure 1)
The sequence segment DDIYNKTQDV at positions 808–817 (Figure 1) is almost invariant. This sequence is conserved in SLA/LP antigen where it has been shown to be essential for immune response [16]
Summary
Autoimmune hepatitis (AIH) is a chronic, progressive liver disease, characterized by continuing hepatocellular inflammation and necrosis. Autoantibodies to soluble liver antigen and to liver-pancreas (SLA/LP) have been described as disease specific, suggesting their potential involvement in the pathogenesis of AIH, at least in the subgroup of patients presenting SLA/LP autoantibodies (about 20% of AIH cases) [2,3]. Expression, cloning and absorption experiments identified a protein with homology to a putative UGA suppressor tRNA-associated protein, as the sole target antigen of SLA/LP autoantibodies [4]. This protein had been previously identified as it coprecipitated with tRNASec, when mammalian cell extracts were treated with serum from patients with AIH [5]. By studying carboxy-terminally truncated SepSecS, Wies et al [4] identified an immunodominant region that is recognized by SLA/LP autoantibodies, and which is located between residues 450–490
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