Ex vivo pathogenicity of antilLaminin ?1 autoantibodies
02.12.2014
Florea F, Bernards C, Caproni M, Kleindienst J, Hashimoto T, Koch M, Sitaru C.
Am J Pathol. 2014;184(2):494-506
Autoimmunity against laminins has been described in several autoimmune diseases (including mucous membrane pemphigoid, anti-laminin ?1 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 ?1, a major constituent of basement membranes and the main antigen in anti-laminin ?1 pemphigoid. Rabbit antibodies were generated against fragments of the N-terminus and C-terminus of murine laminin ?1, 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 ?1 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 ?1 N-terminus in patients with anti-laminin ?1 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.
