A multi‐hit hypothesis of bullous pemphigoid and associated neurological disease: Is HLA‐DQB103:01, a potential link between immune privileged antigen exposure and epitope spreading?

• Published in: HLA Vol. 89; no. 3; pp. 127 - 134
• Main Authors: Amber, K. T., Zikry, J., Hertl, M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.03.2017
• Subjects: Autoantibodies - biosynthesis; Autoantibodies - immunology; Autoantigens - genetics; Autoantigens - immunology; bullous pemphigoid; Collagen Type XVII; Dystonin - genetics; Dystonin - immunology; epitope spreading; Epitopes - genetics; Epitopes - immunology; Gene Expression; Genetic Predisposition to Disease; Histocompatibility Testing; HLA; HLA-DQ beta-Chains - genetics; HLA-DQ beta-Chains - immunology; Humans; immunobullous disease; Neurodegenerative Diseases - complications; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - immunology; Neurodegenerative Diseases - physiopathology; Non-Fibrillar Collagens - genetics; Non-Fibrillar Collagens - immunology; Pemphigoid, Bullous - complications; Pemphigoid, Bullous - genetics; Pemphigoid, Bullous - immunology; Pemphigoid, Bullous - physiopathology; T-Lymphocytes - immunology; T-Lymphocytes - pathology; bullous pemphigoid; immunobullous disease; HLA; epitope spreading
• ISSN: 2059-2302; 2059-2310
• DOI: 10.1111/tan.12960

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.