Identification of quantitative trait loci in experimental epidermolysis bullosa acquisita.
Epidermolysis bullosa acquisita (EBA) is a chronic mucocutaneous autoimmune skin blistering disease. Several lines of evidence underscore the contribution of autoantibodies against type VII collagen (COL7) to the pathogenesis of EBA. Furthermore, EBA susceptibility is associated with the MHC haplotype in patients (HLA-DR2) and in immunization-induced EBA in mice (H2s). The latter study indicated an additional contribution of non-MHC genes to disease susceptibility. To identify non-MHC genes controlling EBA susceptibility, we intercrossed EBA-susceptible MRL/MpJ with EBA-resistant NZM2410/J and BXD2/TyJ as well as Cast mice. Mice of the fourth generation of this four-way autoimmune-prone advanced intercross line were immunized with a fragment of murine COL7 to induce EBA. Anti-COL7 autoantibodies were detected in 84% of mice, whereas deposition of complement at the dermal-epidermal junction (DEJ) was observed in 50% of the animals; 33% of immunized mice presented with overt clinical EBA. Onset of clinical disease was associated with several quantitative trait loci (QTLs) located on chromosomes 9, 12, 14, and 19, whereas maximum disease severity was linked to QTLs on chromosomes 1, 15, and 19. This more detailed insight into the pathogenesis of EBA may eventually lead to new treatment strategies for EBA and other autoantibody-mediated diseases.
Department of Dermatology, University of Lübeck, Lübeck, Germany. ralf.ludwig@uk-sh.de
Ralf J
RJ
Ludwig
Susen
S
Müller
Andreia d C
Ad
Marques
Andreas
A
Recke
Enno
E
Schmidt
Detlef
D
Zillikens
Steffen
S
Möller
Saleh M
SM
Ibrahim
D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D001327:Autoimmune Diseases / Q000097:blood / Q000235:genetics*; D002874:Chromosome Mapping; D024143:Collagen Type VII / Q000276:immunology*; D003165:Complement System Proteins / Q000378:metabolism; D020405:Dermis / Q000276:immunology; D004817:Epidermis / Q000276:immunology; D016107:Epidermolysis Bullosa Acquisita / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D008297:Male; D051379:Mice; D040641:Quantitative Trait Loci
D001323:Autoantibodies; D024143:Collagen Type VII; D003165:Complement System Proteins