Absence of T and B lymphocytes modulates dystrophic features in dysferlin deficient animal model

Limb Girdle Muscular Dystrophies (LGMDs) are a group of muscular diseases characterized by wasting of muscles of the pelvic and shoulder girdle. LGMD-2B was found to arise from defects in the dysferlin gene. In LGMD-2B muscle affection predominates in proximal muscles. Dysferlin is localized at the muscle cell membrane and associated with cytoplasmic vesicles. LGMD-2B and MM are characterized by highly elevated levels of serum creatine kinase, often associated with subacute onset and marked muscle inflammation. Inflammatory cells were detected in both MM and LGMD patients, scattered or organized into clusters, around necrotic fibers. Inflammatory infiltrates around vessels mainly consisted of macrophages whereas in endomysial infiltrates were CD4+ and CD8+ cells. Four mice models of dysferlinopathies were described: SJL/J, AJ and 2 Dysf-/- models. The AJ model showed a slower progressive muscle disease compared to both Dysf -/- and SJL strains except for the highly compromised abdominal muscles. In order to verify the role of lymphocytes and immune cells on this disease, we generated the Scid/A/J transgenic mice and compared these animals with the the age-matched A/J mice. The absence of T and B lymphocytes in this animal model of dysferlinopathy resulted in an improvement of the muscle regeneration. The Scid/A/J mice showed increased specific force in the MHC 2A-expressing fibers of the diaphragm and abdominal muscles. Limb muscles of both Scid/A/J and A/J mice had similar specific force. T and B lymphocytes seems to have a role in the muscle damaging immune response. Establishing a link between dysferlin and immune cells is crucial to the development of targeted therapeutic