T Cells Are Required for the Production of Blister-Inducing Autoantibodies in Experimental Epidermolysis Bullosa Acquisita

Abstract

Epidermolysis bullosa acquisita is a prototypical organ-specific autoimmune disease caused by autoantibodies against type VII collagen of the dermal-epidermal junction. Although mechanisms of autoantibody-induced blister formation were extensively characterized, the initiation of autoantibody production in autoimmune blistering diseases is still poorly defined. In the current study, we addressed the role of T cells for the production of blister-inducing autoantibodies in mice immunized with type VII collagen. To detect autoreactive type VII collagen-specific T cells, lymph node cells from immunized SJL mice were stimulated in vitro with recombinant Ag, and their proliferation was measured by radioactive thymidine incorporation and flow cytometry analysis of CFSE-labeled cells. Interestingly, using synthetic peptides of the immunogen, partly different T and B cell epitopes in mice immunized with type VII collagen were demonstrated. In contrast to wild-type mice, immunization with type VII collagen of SJL athymic nude mice lacking T cells did not induce an autoimmune response and blistering phenotype. Importantly, SJL nude mice repleted with T cells from immunized wild-type mice showed a robust and durable autoantibody production resulting in subepidermal blistering disease in the recipients. Our present results demonstrate that T cells are required for the initiation of autoimmunity against type VII collagen in experimental epidermolysis bullosa acquisita and provide a basis for developing T cell-directed immunomodulatory strategies for this and related autoimmune diseases.

In situ immune response evaluation via immunohistochemistry in skin biopsies from patients affected by autoimmune blistering diseases

“…ABD have been classically defined as B cellmediated diseases due to the presence of both 1) spontaneously appearing, intraepidermal clinical blisters after injection of human sera into neonatal mice, and 2) epidermal-specific autoantibodies whose serum titers classically correlate with clinical activity and disease severity as demonstrated by IIF and ELISA [1][2][3][4]20]. Our in situ results document the involvement of other immune cells in ABD lesional skin, indicating that other immune system components may be important in these diseases [21][22][23][24][25][26][27]. In our study, we did not attempt to demonstrate a precise pathogenic role of these molecules; however, further investigation is warranted in this area.…”

“…Previous authors have found some alteration in the T cell immune response, and/or alterations in T cell numbers detected by several methods including FACS analysis in ABD [21][22][23][24][25][26][27][28]. One group of authors have shown that T cells are required for the production of blister inducing autoantibodies in experimental epidermolysis bullosa acquisita [24]. Another study with untreated BP patients compared to controls has shown low CD4+, CD25 bright+, FOXP3+ cells were significantly reduced in BP [25].…”

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

“…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.…”

Heat-shock protein 90 inhibition in autoimmunity to type VII collagen: evidence that nonmalignant plasma cells are not therapeutic targets

“…4 In addition, a key role of T cells in the initiation of autoimmunity against type VII collagen has been demonstrated recently. 5 Experimental EBA, which reproduces both the autoimmune response and immunopathologic, histologic, and clinical findings in patients with EBA, can be induced in susceptible mice by immunization with recombinant murine type VII collagen. 6 Therefore, EBA emerges as a model disease to study fundamental biologically and clinically crucial aspects of antibody-mediated, organ-specific autoimmune diseases.…”