Ex Vivo Pathogenicity of Anti–Laminin γ1 Autoantibodies

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 exvivo 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.