Experimentally-induced autoimmune myocarditis: production of heart myosin-specific autoantibodies within the inflammatory infiltrate.

Immunization with cardiac myosin in complete Freund's adjuvant (CFA) induces severe autoimmune myocarditis in A H-2 congenic mouse strains. The disease shares a variety of characteristics with Coxsackie-virus B3 (CB3)-induced myocarditis and is strongly associated with high-titered autoantibodies to cardiac myosin. Using the spot ELISA-technique, we demonstrate here that in cardiac myosin-immunized mice myosin autoantibodies were not only produced within the spleen, but also at the site of the autoimmune attack, i.e., within the inflammatory heart infiltrate. At the level of single plasma cells we further showed that a substantial part of the myosin autoantibodies was specific for the cardiac myosin isoform, thereby supporting previous serologic data. The finding that cells of the inflammatory heart infiltrate significantly contribute to autoantibody production might explain why the occurrence of high-titered myosin autoantibodies is restricted to mice which develop the disease.

Cardiac myosin-induced myocarditis. Heart autoantibodies are not involved in the induction of the disease.

We recently demonstrated that cardiac myosin is capable of inducing autoimmune myocarditis in genetically predisposed mice. This disease parallels coxsackievirus B3-induced autoimmune myocarditis in many respects and is associated with high-titer autoantibodies specific for cardiac myosin. The following lines of evidence suggest that these autoantibodies are not involved in the induction of autoimmune myocarditis: 1) immunoperoxidase staining of heart sections from cardiac myosin-immunized A/J and A.SW mice revealed IgG depositions only along damaged muscle fibres in infiltrated areas, but not in intact tissue; 2) myosin autoantibodies did not bind to the surface of viable cardiac myocytes isolated from mice, but only reacted with myocytes permeabilized with detergent; 3) mice treated with a single high dose of cyclophosphamide, which reduces the humoral immune response, still developed severe myocarditis, despite the fact that their autoantibody titers were reduced to the level of adjuvant-injected controls; and 4) passive transfer of high-titer myosin autoantibodies failed to induce myocarditis, although the titers in the recipients were comparable to those found in mice with cardiac myosin-induced disease. Together, the results suggest that high-titer myosin autoantibodies are secondary rather than primary to the disease.