Generation of Antibodies of Distinct Subclasses and Specificity Is Linked to H2s in an Active Mouse Model of Epidermolysis Bullosa Acquisita

Abstract

Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease, characterized by antibodies to type VII collagen (COL7). EBA can be induced in mice by immunization with a fragment of the non-collagenous 1 domain of murine COL7. Contrary to other autoimmune diseases, e.g., rheumatoid arthritis, little is known about the genetic susceptibility for EBA. We therefore used the EBA mouse model to address the hypothesis that disease induction depends on the major histocompatibility complex (MHC) haplotype. Mice from different inbred strains were immunized with recombinant murine COL7. Five distinct responses were observed: induction of (i) severe disease in SJL/J (H2s) and female MRL/MpJ (H2k), (ii) mild and transient disease in C57Bl/10.s (H2s), (iii) microscopic blistering in DBA/1J (H2q), (iv) only presence of non-pathogenic autoantibodies in C57Bl/6J (H2b), NZM2410/J (H2z), BXD2 (H2b), and male MRL/MpJ, and (v) complete resistance to EBA in NOD/ShiLtJ (H2g7) and C57Bl/10.q (H2q) mice. Overall, susceptibility to EBA was strongly associated with H2s. In addition, the diseased phenotype was associated with autoantibodies to specific regions of COL7. Our findings show that induction of antibodies with a distinct specificity is linked to the MHC haplotype in experimental EBA. Furthermore, our data are the basis for future studies with the goal of identifying non-MHC EBA susceptibility genes.

B Cells, Dendritic Cells, and Macrophages Are Required To Induce an Autoreactive CD4 Helper T Cell Response in Experimental Epidermolysis Bullosa Acquisita

“…Using timerestricted depletion of certain cell subsets, this new model was applied to investigate the cellular requirements for the early stages of EBA pathogenesis. Based on the findings presented in this article and elsewhere, we propose the following model of the early EBA pathogenesis: Both human (41,42) and experimental EBA (22) are strongly associated with certain MHC alleles. In addition, genes outside the MHC locus have recently been shown to influence susceptibility to experimental EBA (43).…”

“…Yet, so far, detailed investigations on the cellular requirements in the early pathogenesis of these animal models had not been performed. The MHC association of immunization-induced AIBD (19,22) pointed toward a contribution of T cells, which was confirmed by a resistance of T cell-deficient mice to develop epidermolysis bullosa acquisita (EBA) (23). It has so far remained unclear which T cell subsets and which APCs contribute to the loss of tolerance to structural proteins of the skin in AIBD.…”

Radiosensitive Hematopoietic Cells Determine the Extent of Skin Inflammation in Experimental Epidermolysis Bullosa Acquisita

“…Intrigued by the striking differences in clinically evident blistering disease in the different inbred mouse lines, we aimed at excluding an impact of the MHC locus on Ab-induced blistering because this locus is a major susceptibility locus in immunizationinduced EBA (9). The similar extent of blistering in MHC congenic B6 mice (H2d, H2k, H2s, and H2b as a control) in Ab transfer-induced EBA, however, argues against a major contribution of the MHC locus in controlling the blistering phenotype.…”

“…Consistent with this observation of a differential response to treatment, disease induction in mice is strain dependent. This strain dependency has been identified for both immunization-induced (8,9) and Ab transfer-induced models of autoimmune diseases (10,11). These observations led to the identification of the C5 locus as an important modulator of joint destruction in the K/B3N serum transfer arthritis model (10).…”

In vitro and in vivo models to investigate the pathomechanisms and novel treatments for pemphigoid diseases

“…In this model, mice were immunized with a recombinant peptide fragment from the immunogenic NC-1 domain of mCOL7 to produce a GST fusion protein. [61] Th1 polarization [62] and the formation of complement-binding autoantibodies of the IgG2a and IgG2b subclasses. [60] Subsequently, a dependency on T cells was identified, as evidenced by mice lacking T cells (SJL nu/nu mice) that were resistant to disease induction.…”