Mucous membrane pemphigoid: HLA-DQB1*0301 is associated with all clinical sites of involvement and may be linked to antibasement membrane IgG production

Abstract

Background Class I human leucocyte antigens (HLA) ‐A, ‐B, ‐Cw and class II HLA‐DRB1, ‐DQB1 alleles were determined in 131 British Caucasian patients with mucous membrane pemphigoid (MMP) using serological and DNA‐based methods. Objectives To analyse the class I and II alleles expressed in well‐defined clinical and immunopathological subgroups of MMP, in order to establish whether specific alleles or haplotypes might in part explain disease susceptibility, clinical sites of involvement or disease severity. Methods Subgroups of patients were analysed according to the following clinical criteria: age of onset, sex, sites of clinical involvement (oral, ocular, skin, nasal, genital, pharyngeal, oesophageal, laryngeal, perianal), disease severity and history of autoimmune disease. Subgroups were also analysed according to the following immunopathological criteria: autoantibody profile, the presence of circulating antibasement membrane IgG or IgA antibodies and the detection of target basement membrane zone (BMZ) antigens (BP230 and BP180) by IgG autoantibodies. Results Class I HLA typing showed no significant disease or subgroup associations. Class II DRB1 typing showed a significantly increased allelic frequency in MMP vs. controls for DRB1*11 (RR = 2·08, Pc < 0·0000056). For DQB1, MMP vs. controls, there was a significantly increased allelic frequency for DQB1*0301 (Pc < 0·00000028) in both males and females; all clinical sites of involvement, with the exception of laryngeal, oesophageal and perianal sites and in patients with detectable circulating anti‐BMZ IgG compared with those negative for IgG (P < 0·0096, Pc < 0·019). A positive trend was noted in patients with ocular involvement compared with no ocular involvement and in patients with a clinical score 10 compared with < 10. We found no difference in DQB1*0301 allele frequency between subgroups with or without BP180 or BP230 target antigens. Haplotype frequencies showed an increase in DRB1*04, DQB1*0301 (Pc < 0·000066) and DRB1*11, DQB1*0301 (Pc < 0·000002) among patients compared with controls. Conclusions The DQB1*0301 allele confers a predisposition to all subgroups of MMP and may have a role in T‐cell recognition of basement membrane antigens, resulting in the production of anti‐BMZ IgG autoantibodies. The positive trend between increased allelic expression of DQB1*0301 in patients with ocular disease and in those with a higher clinical score, further suggests a role for this allele in disease severity.

Relationship between target antigens and major histocompatibility complex (MHC) class II genes in producing two pathogenic antibodies simultaneously

“…In group 2, there were 18 patients with subsets of MMP and BP, all of which are characterized by in-vivo deposition of anti-BMZ antibodies on direct immunofluorescence. These patients had MHC II gene HLA-DQb1*0301 that is observed typically in patients with all the variants of Pg [16,[67][68][69][70][71][72][73][74]. In addition, many of these patients also carry the MHC II genes associated typically with PV patients.…”

The 2016 Bowman Lecture Conjunctival curses: scarring conjunctivitis 30 years on

“…Many patients have a genetic predisposition to MMP, expressing the HLA-DQB*0301 gene. 45 For the majority of patients there are no identifiable precipitating factors. However, in subsets of patients, including cases of ocular MMP following SJS/TEN 33,46 and topical glaucoma treatment, 34,47 it is possible that damage to the conjunctival basement membrane precipitates the disease by exposing basement membrane epitopes triggering a pathological autoimmune response to neoantigens.…”

Malignancy in Relation to Autoimmune Blistering Dermatoses: Molecular and Clinical Aspects

“…HLA-DQB1*0301 allele, associated with MMP [111][112][113][114], was reported in patients with esophageal squamous cell carcinoma [113], gastric cancer [115], HPV-associated cervical neoplasia [116]. It was hypothesized, that the gene may have a role in T-cell recognition of basement membrane antigens resulting in production of IgG autoantibodies binding basement membrane antigens [117]. It is also possible, that the link exists between certain malignancies and HLA or autoimmunity predisposition connected to defective apoptotic genes.…”