HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1

Abstract

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Autoantibody presentation in drug-induced liver injury and idiopathic autoimmune hepatitis

“…Associations between HLA-DRB1*03:01, DRB1*04:01 and AIH patient characteristics and disease presentation have been reported [20]. Hence, we set out to analyse whether any such associations were present in our AIH cohort.…”

“…In addition to increasing susceptibility, HLA alleles have also been demonstrated to affect disease presentation and outcome in idiosyncratic DILI and AIH [19,20]. An unbalanced immune system may subsequently lead to AAB generation.…”

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis

“…The principal susceptibility alleles for type 1 autoimmune hepatitis in white North American and northern European adults are DRB1*0301 and DRB1*0401 [29][30][31][32] (Table 1). These alleles encode the antigen-binding groove of class II molecules of the major histocompatibility complex (MHC) [30], and they influence the selection of peptide that can be presented to naïve CD4 ?…”

“…Immune-mediated mechanisms favored by a genetic predisposition have been implicated in the occurrence of autoimmune hepatitis [29][30][31][32]. The disease is probably a consequence of immune intolerance to self-antigens and the failure of multiple homeostatic mechanisms to prevent a promiscuous immune response to these antigens [33][34][35][36][37].…”

Can Understanding the Pathogenesis of Autoimmune Hepatitis Lead to Rational Therapy?

“…Like in other autoimmune diseases, there is a strong genetic risk association, and this is primarily linked to defined HLA-alleles [13] . The DR0301 allele is the most common risk factor in Caucasian populations, and is associated with more severe AIH; it occurs more likely in younger patients.…”