Published online before print February 14, 2008

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(American Journal of Pathology. 2008;172:774-785.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070327

Dysferlin Deficiency Enhances Monocyte Phagocytosis

A Model for the Inflammatory Onset of Limb-Girdle Muscular Dystrophy 2B

Kanneboyina Nagaraju^*, Rashmi Rawat^*, Edina Veszelovszky^*, Rachana Thapliyal, Akanchha Kesari^*, Susan Sparks^*, Nina Raben, Paul Plotz and Eric P. Hoffman^*

From the Research Center for Genetic Medicine,^*Children’s National Medical Center, Washington, District of Columbia; the Department of Medicine,Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore Maryland; and the Arthritis and Rheumatism Branch,National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland

Dysferlin deficiency causes limb-girdle muscular dystrophy type 2B (LGMD2B; proximal weakness) and Miyoshi myopathy (distal weakness). Muscle inflammation is often present in dysferlin deficiency, and patients are frequently misdiagnosed as having polymyositis. Because monocytes normally express dysferlin, we hypothesized that monocyte/macrophage dysfunction in dysferlin-deficient patients might contribute to disease onset and progression. We therefore examined phagocytic activity, in the presence and absence of cytokines, in freshly isolated peripheral blood monocytes from LGMD2B patients and in the SJL dysferlin-deficient mouse model. Dysferlin-deficient monocytes showed increased phagocytic activity compared with control cells. siRNA-mediated inhibition of dysferlin expression in the J774 macrophage cell line resulted in significantly enhanced phagocytosis, both at baseline and in response to tumor necrosis factor-. Immunohistochemical analysis revealed positive staining for several mononuclear cell activation markers in LGMD2B human muscle and SJL mouse muscle. SJL muscle showed strong up-regulation of endocytic proteins CIMPR, clathrin, and adaptin-, and LGMD2B muscle exhibited decreased expression of decay accelerating factor, which was not dysferlin-specific. We further showed that expression levels of small Rho family GTPases RhoA, Rac1, and Cdc 42 were increased in dysferlin-deficient murine immune cells compared with control cells. Therefore, we hypothesize that mild myofiber damage in dysferlin-deficient muscle stimulates an inflammatory cascade that may initiate, exacerbate, and possibly perpetuate the underlying myofiber-specific dystrophic process.