A multi‐hit hypothesis of bullous pemphigoid and associated neurological disease: Is HLA‐DQB1*03:01, a potential link between immune privileged antigen exposure and epitope spreading?

Abstract

Bullous pemphigoid (BP) is the most common autoimmune blistering disease and is linked to IgG recognition of 2 hemidesmosomal antigens, that is, BP230 (BP antigen 1) and BP180 (BP antigen 2, collagen XVII). The association of BP with other systemic diseases, particularly neurocognitive diseases, provides a potential clue in the underlying pathogenesis of BP. The role of HLA‐DQB1*03:01 binding to the immunogenic portion of BP180 provides a potential mechanism by which exposure to neuronal collagen BP180 may lead to cutaneous disease. In our proposed multi‐hit hypothesis, patients with underlying neuronal disease are exposed to previously sequestered self‐antigen, most importantly BP180. Patients with the HLA‐DQB1*03:01 allele show an increased T‐cell avidity to several epitopes of BP180, particularly the BP180‐NC16a domain. Thus, they have a genetic susceptibility to developing BP upon exposure to the target antigen. In a patient with dysregulation of Th1/Th2 balance, anergy is lost and T‐cells are subsequently primed resulting in the development of functional autoimmunity against the BP180‐NC16a domain leading to clinically overt disease.

Alogliptin‐induced bullous pemphigoid associated with HLA‐DQB1*03:01: a case report

“…reported that HLA‐DQB1*03:01 is a biomarker of genetic susceptibility to BP induced by DPP‐4 inhibitors. The negative DLST result for alogliptin and associations with HLA‐DQB1*03:01 in gliptin‐unrelated BP suggested that the drugs are not solely responsible for the restriction of the HLA class II presentation . DQB1*06:02 and DRB1*11:01 alleles, which were reported to be associated with BP or MMP and might induce BP, were found in our patient …”

“…which were reported to be associated with BP or MMP and might induce BP, were found in our patient. 4 The reporting odds ratio (ROR) of the Japanese adverse drug event report for alogliptin is very low (8.6), in contrast to those for vildagliptin (105.3). 5 The latter is confirmed to induce BP.…”

A review of bullous pemphigoid associated with PD‐1 and PD‐L1 inhibitors

“…22 In particular, the major histocompatibility complex class-II allele, HLA-DQB 1*03:01, has been implicated as a predisposing factor in the development of BP. Previous studies have identified overexpression of specific HLA subtypes in patients with BP.…”

Localized bullous pemphigoid: Four clinical cases and a literature review

“…Patients carrying the HLA‐DQb1*0301 allele might present an increased need for T lymphocytes for many epitopes of BP180, particularly in the field of BP180‐NC16a. Therefore, these patients would have an increased genetic sensitivity toward developing LBP during exposure to the target antigene . In addition, patients suffering from an underlying neurologic disease might be exposed to predetermined sequestered auto‐antigens, mainly BP180.…”

“…Therefore, these patients would have an increased genetic sensitivity toward developing LBP during exposure to the target antigene. 18 In addition, patients suffering from an underlying neurologic disease might be exposed to predetermined sequestered auto-antigens, mainly BP180. They are henceforth also more likely to develop BP-type illnesses.…”