title: 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.
authors.affiliation: Department of Dermatology, University of California Irvine, Irvine, California.
authors.forename: K T
authors.identifier: 0000-0002-2906-2454
authors.initials: KT
authors.lastname: Amber
authors.affiliation: Department of Dermatology, University of California Irvine, Irvine, California.
authors.forename: J
authors.initials: J
authors.lastname: Zikry
authors.affiliation: Department of Dermatology and Allergology, Philipps University of Marburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hertl
mesh_terms: D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D000071821:Dystonin / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D059866:HLA-DQ beta-Chains / Q000235:genetics / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D019636:Neurodegenerative Diseases / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D024041:Non-Fibrillar Collagens / Q000235:genetics / Q000276:immunology*; D010391:Pemphigoid, Bullous / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D000097805:Collagen Type XVII
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D000071821:Dystonin; D000939:Epitopes; D059866:HLA-DQ beta-Chains; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII; C486268:DST protein, human; C069051:HLA-DQB1 antigen
keywords: 
  HLA
  ; bullous pemphigoid; epitope spreading; immunobullous disease