HLA-DRB1 as a risk factor in children with autoimmune hepatitis and its relation to hepatitis A infection

Abstract

BackgroundThe human leukocyte antigens (HLAs) are proteins found in the membranes of nearly all nucleated cells. People with certain HLA antigens are more likely to develop certain autoimmune diseases. The aim of this study was to determine the frequency of HLA-DRB1 in children with autoimmune hepatitis (AIH) as a risk factor for occurrence, its relation to preceding hepatitis A infection and treatment outcome.Subjects and methods25 children with AIH were subjected to HLA-DRB 1 typing performed by sequence specific oligonucleotide probe technique and compared to HLA-DRB1 found in 548 normal populations.ResultsThe most frequent alleles found in our children with AIH were HLA-DRB1*13 (36%), HLA-DRB1*04 (18%) and HLA-DRB1*03 (14%). HLA-DRB1*13 was significantly more frequent in AIH patients compared to controls. In type I AIH patients HLA-DRB1*13 was the most frequent allele (32.4%), followed by HLA-DRB1*04 in (20.6%) and HLA-DRB1*03 in (14.7%), While in type II, the most frequent alleles were HLA-DRB1*13 in (40%), HLA-DRB1*07 (20%) and HLA-DRB1*15 in (20%). HLA-DRB1*12 was significantly more frequent in AIH patients with positive Hepatitis A IgM than in patients with negative hepatitis A IgM. No statistically significant difference between partial responders and complete responders to treatment as regards HLA-DRB1 subtypes.ConclusionIt is concluded from the previous study that HLA-DRB1*13 may be a susceptibility allele for the occurrence of autoimmune hepatitis in our population. HLA-DRB1*07 and HLA-DRB1*15 may be susceptibility alleles for occurrence of autoimmune hepatitis type 2. HLA-DRB1*12 association with AIH in patients triggered by hepatitis A needs further studies.

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis

“…DRB1*1301 has been associated with protracted recovery from acute hepatitis A [108], and children with autoimmune hepatitis in South America commonly have DRB1*1301 [69,70]. HLA DRB1*13 is the most frequent allele in Egyptian children with type 1 (32 %) or type 2 (40 %) autoimmune hepatitis, but the children with immunoglobulin M antibodies to hepatitis A virus have HLA DRB1*12 most frequently [109]. Genetic factors that affect the defense mechanisms against pathogens or the detoxification of drug-related or environmental agents may influence the occurrence of autoimmune hepatitis and be clues to the nature of the inciting element.…”

“…Positively charged K or R at DRb71 restricts peptides that can be displayed to those with negatively charged D or E at position P4 [60] Identification of principal self-antigen may suggest foreign antigenic homologues as triggers [68,114] Susceptibility allele, DRB1*1301, impairs clearance of HAV in Argentina and DRB1*12 associated with HAV in Egyptian children with AIH [108,109] Molecular modeling can predict properties of triggering antigen [60] Antigenic structure can be predicted from encoded binding groove of class II MHC molecules [60] Susceptibility alleles may identify triggering pathogens [108,109] Identification of pivotal autoantigen of type 2 AIH CYP2D6 targeted by anti-LKM1 [54,59] CYP2D6 activity inhibited by anti-LKM1 [120] CYP2D6-reactive lymphocytes in liver [121] Experimental AIH induced by CYP2D6 [122,123] Principal reactive peptide sequence, 193-212 [141] Homologies with multiple viruses [54,55,141] Useful in developing experimental models of type 2 AIH [122,123] Supports molecular mimicry of foreign and self-antigens [55] Suggests viral homologues as triggers [55] Numbers in brackets are references A alanine, AIH autoimmune hepatitis, CYP2D6 cytochrome mono-oxygenase P450 II D6, D aspartic acid, E glutamic acid, HAV hepatitis A virus, I isoleucine, K lysine, L leucine, LKM1 liver kidney microsome type 1, MHC major histocompatibility complex, Q glutamine, R arginine Dig Dis Sci against CYP2D6 [54], and they inhibit its activity in vitro [120]. Liver-infiltrating cytotoxic T cells are sensitized against CYP2D6 in patients with type 2 autoimmune hepatitis [121], and immunization with human CYP2D6 and human formiminotransferase cyclodeaminase [122] or infection with an adenovirus expressing human CYP2D6 [123] produces serological and histological changes of type 2 autoimmune hepatitis in mice.…”

Prevalence of Autoantibodies Reveals a Predominant Sma and Anca-Pr3/Mpo Pattern in Hiv Infection and Sma in Hav-Infected Children

“…Although HAV is mostly a self-limiting disease, prolonged infection has been reported in both adults and children (Vento et al, 1991;Fainboim et al, 2001;Elfaramawy et al, 2010). HAV infection has been associated with development of extrahepatic manifestations and autoimmune diseases that are related with the production of autoantibodies in susceptible individuals (Dan and Yaniv, 1990;Huppertz et al, 1995;Skoog et al, 2002;Moon et al, 2009;Ilan et al, 1990;Tabor, 1987;Segev et al, 2001;Cohen et al, 1993;Muñoz Bertrán et al, 2002;Fainboim et al, 2001;Elfaramawy et al, 2010;Singh et al, 2007). Transient increased levels of autoantibodies have been documented in acute HAV infection and after vaccination (Fainboim et al, 2001;Karali et al, 2011;Gutierrez et al, 1996;Vento et al, 1988;Holborow et al, 1971;Seok et al, 2011).…”

“…Transient increased levels of autoantibodies have been documented in acute HAV infection and after vaccination (Fainboim et al, 2001;Karali et al, 2011;Gutierrez et al, 1996;Vento et al, 1988;Holborow et al, 1971;Seok et al, 2011). However, persistent autoantibodies have been detected in prolonged HAV infection in children (Fainboim et al, 2001;Elfaramawy et al, 2010).…”

“…Particularly, SMA, ANA and antiasialoglycoprotein receptor antibodies have been associated with HAV infection (Moon et al, 2009;Fainboim et al, 2001;Elfaramawy et al, 2010;Karali et al, 2011;Gutierrez et al, 1996;Vento et al, 1988;Holborow et al, 1971;Seok et al, 2011).…”