title: Complement-fixing anti-type VII collagen antibodies are induced in Th1-polarized lymph nodes of epidermolysis bullosa acquisita-susceptible mice.
abstract: The environment encountered in secondary lymphoid organs (e.g., lymph nodes) influences the outcome of immune responses. Immunization of mice with type VII collagen, an adhesion protein expressed at the cutaneous basement membrane, induces experimental epidermolysis bullosa acquisita (EBA). In this model, clinical disease is associated with the H2s haplotype of the MHC found in SJL/J mice. Most other strains (e.g., BALB/c, C57BL/6, NZM2410/J) are resistant to clinical disease, despite autoantibody production. Comparison of autoantibody response in EBA-resistant and -susceptible mice showed an IgG2-dominated response in the latter. We hypothesized that EBA susceptibility is due to specific cytokine gene expression in draining lymph nodes (dLN). To challenge this hypothesis, EBA-susceptible (SJL/J) and -resistant (BALB/c, C57BL/6) mice were immunized with type VII collagen, followed by analysis of clinical phenotype, subclasses of circulating and tissue-bound autoantibodies, complement activation, and cytokine gene expression in dLN. Disease manifestation was associated with induction of complement-fixing autoantibodies, confirming previous observations. Furthermore, however, IFN-γ/IL-4 ratio in dLN of EBA-susceptible mice was significantly increased compared with EBA-resistant strains, suggesting a Th1 polarization. Immunization of H2s-congenic C57BL/6 mice (B6.SJL-H2s) led to Th1 polarization in dLN and clinical disease. In addition to their cytokine milieu, EBA-susceptible and -resistant mice also differed regarding the expression of FcγR on peripheral leukocytes, in which a higher FcγRIV expression in SJL/J and B6.SJL-H2s mice, compared with C57BL/6, was associated with skin lesions. In summary, blistering in experimental EBA is regulated by both adaptive (divergent class switch recombination due to polarized cytokine expression) and innate (FcγR expression) immune mechanisms.
authors.affiliation: Excellence Cluster Inflammation at Interfaces, Schleswig-Holstein, Germany.
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Hammers
authors.forename: Katja
authors.initials: K
authors.lastname: Bieber
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kalies
authors.forename: David
authors.initials: D
authors.lastname: Banczyk
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Ellebrecht
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
authors.forename: Jürgen
authors.initials: J
authors.lastname: Westermann
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology*; D024143:Collagen Type VII / Q000008:administration & dosage / Q000276:immunology*; D003168:Complement Fixation Tests / Q000379:methods*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004817:Epidermis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016107:Epidermolysis Bullosa Acquisita / Q000097:blood / Q000235:genetics / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D013045:Species Specificity; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D024143:Collagen Type VII; D016207:Cytokines; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes