An attempt to develop mouse model for anti-laminin γ1 pemphigoid
Department of Dermatology, Kurume University School of Medicine, and Kurume University Institute of Cutaneous Cell Biology,Kurume, Japan. Journal of dermatological science
(Impact Factor: 3.42).
01/2013; 70(2). DOI: 10.1016/j.jdermsci.2013.01.001
BACKGROUND: We recently reported that the autoantibodies of anti-p200 pemphigoid sera react with laminin γ1 and renamed this entity as anti-laminin γ1 pemphigoid. However, it has not been clarified whether the anti-laminin γ1 autoantibodies, particularly those to the C-terminal integrin binding site, affect the dermoepidermal junction and cause subepidermal blisters. OBJECTIVE: The aim of this study was to develop animal models for anti-laminin γ1 pemphigoid. METHODS: We attempted to produce two mouse models for anti-laminin γ1 pemphigoid; (1) a passive transfer model: injection of rabbit IgG to shorter bacterial recombinant protein of the murine laminin γ1 C-terminal 107 amino acids, and (2) an active disease model: direct immunization to mice with this recombinant protein. RESULTS: Immunoblotting revealed that 70% of patient sera reacted with the shorter recombinant protein of human laminin γ1 C-terminus. In the passive transfer model, rabbit IgG to the murine laminin γ1 C-terminus was deposited, without C3 deposition, at the epidermal basement membrane zone. In contrast, in the active disease model, direct immunofluorescence of mouse skin sections showed no deposition of either murine IgG or C3. Blister formation was not seen in either model both phenotypically and histopathologically. CONCLUSION: In the two different mouse animal models for anti-laminin γ1 pemphigoid, although rabbit IgG to the recombinant laminin γ1 C-terminus bound to the epidermal basement membrane zone in passive transfer model, no obvious blister formation was seen. To reproduce skin lesions in mouse models for anti-laminin γ1 pemphigoid, further improvement should be needed.
Available from: Xiaoguang Li
- ". However, subsequent studies failed to show pathogenic role , or suggested other pathogenic antibodies . Detection of LMg1 by immunoblotting (IB) of normal human dermal extract (NHDE) is diagnostic hallmark  . "
Available from: Michael Hertl
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ABSTRACT: Blister formation in skin and mucous membranes results from a loss of cell-cell or cell-matrix
adhesion and is a common outcome of pathological events in a variety of conditions, including autoimmune
and genetic diseases, viral and bacterial infections, or injury by physical and chemical factors. Autoantibodies
against structural components maintaining cell-cell and cell-matrix adhesion induce tissue damage in
autoimmune blistering diseases. Detection of these autoantibodies either tissue-bound or circulating in serum
is essential to diagnose the autoimmune nature of disease. Various immunofluorescence methods as well as
molecular immunoassays, including enzyme-linked immunosorbent assay and immunoblotting, belong to the
modern diagnostic algorithms for these disorders. There is still a considerable need to increase awareness of
the rare autoimmune blistering diseases, which often show a severe, chronic-relapsing course, among
physicians and the public. This review article describes the immunopathological features of autoimmune
bullous diseases and the molecular immunoassays currently available for their diagnosis and monitoring.
Available from: Marzia Caproni
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ABSTRACT: Autoimmunity against laminins has been described in several autoimmune diseases (including mucous membrane pemphigoid, anti-laminin γ1 pemphigoid, and connective tissue diseases), in pregnancy loss, and in infections such as Chagas disease. Except for anti-laminin-332 mucous membrane pemphigoid, adequate evidence has been lacking for the tissue injury potential of laminin-specific antibodies and the pathogenic epitopes. We evaluated the pathogenic potential of antibodies targeting laminin γ1, a major constituent of basement membranes and the main antigen in anti-laminin γ1 pemphigoid. Rabbit antibodies were generated against fragments of the N-terminus and C-terminus of murine laminin γ1, and their ability to disrupt ligand interactions and/or to activate complement and granulocytes was assessed using previously established ex vivo assays. Our findings document a pathogenic potential of antibodies targeting the laminin γ1 N-terminus. These antibodies interfere with the binding of nidogen to laminin and can activate granulocytes and the complement cascade. We detected antibodies with different degrees of reactivity with laminin γ1 N-terminus in patients with anti-laminin γ1 pemphigoid, cutaneous lupus erythematosus, and scleroderma. Our results provide mechanistic insights into the tissue damage associated with laminin autoimmunity and could facilitate development of appropriate diagnostic tools and therapeutic strategies.
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