Sequential intramolecular epitope spreading of humoral responses to human BPAG2 in a transgenic model.
Bullous pemphigoid (BP) is a subepidermal autoimmune disease characterized by a humoral response to an epidermal basement membrane (BM) component, BP antigen 2 (BPAG2). BP patients have IgG autoantibodies against an immunodominant BPAG2 extracellular domain termed NC16A as well as additional epitopes located both in the intracellular and extracellular domains (ICD and ECD, respectively) of this autoantigen. To study the evolution of humoral responses to BPAG2, sequential serum samples obtained from C57BL/6Ncr mice grafted with otherwise syngeneic skin from transgenic mice expressing human BPAG2 (hBPAG2) in epidermal BM were studied for IgG reactivity to seven ECD and ICD hBPAG2 epitopes. All grafted mice developed specific IgG against hBPAG2 ECD and ICD epitopes. In seven of eight mice, anti-hBPAG2 IgG was initially directed against ECD epitopes; in six mice, humoral responses subsequently targeted additional ECD and ICD BPAG2 epitopes. In contrast to IgG specific for ECD epitopes, IgG against ICD epitopes was present at lower levels, detectable for shorter periods, and non-complement fixing. Interestingly, the appearance of IgG directed against ICD epitopes correlated with the development of graft loss in this experimental model. These studies provide a comprehensive and prospective characterization of the evolution of humoral immune responses to hBPAG2 in vivo.
Di Zenzo
Giovanni
G
Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy. g.dizenzo@idi.it
Calabresi
Valentina
V
Olasz
Edit B
EB
Zambruno
Giovanna
G
Yancey
Kim B
KB
D000818:Animals; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D003593:Cytoplasm / Q000276:immunology; D004817:Epidermis / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D005110:Extracellular Space / Q000276:immunology; D005260:Female; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024041:Non-Fibrillar Collagens / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D010391:Pemphigoid, Bullous / Q000276:immunology*; D017434:Protein Structure, Tertiary; D016038:Skin Transplantation / Q000276:immunology; D000097805:Collagen Type XVII
D001324:Autoantigens; D000939:Epitopes; D007074:Immunoglobulin G; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII