A new murine model to define the critical pathologic and therapeutic mediators of polymyositis

Abstract

Objective. To establish a new murine model of polymyositis (PM) for the understanding of its pathologic mechanisms and the development of new treatment strategies.Methods. C protein-induced myositis (CIM) was induced by a single immunization of recombinant human skeletal C protein in C57BL/6 mice, as well as in CD4-depleted, CD8-depleted, and mutant mice as controls. Some mice were treated with high-dose intravenous immunoglobulin (IVIG) after disease induction. Muscle tissues were examined histologically.Results. In mice with CIM, inflammation was confined to the skeletal muscles. Polymyositis (PM) is a chronic autoimmune inflammatory myopathy affecting striated muscles (1). Damage of muscles results in varying degrees of muscle weakness. Dysphagia with choking episodes and respiratory muscle weakness can occur in acute cases of PM. Currently, the pathogenesis of PM is unknown, and patients are therefore treated with nonspecific immunosuppressants. High-dose corticosteroids are the first-line treatment but are not effective in all patients. Improvement of disease often depends on the dosage of corticosteroids, making a dosage reduction difficult and thus, in many cases, necessitating administration of methotrexate or other immunosuppressants as adjunctive treatment. Because these medications can elicit a wide variety of adverse drug reactions, new therapies to address the specific pathologic features of PM are needed.In affected muscles of patients with PM, infiltration of mononuclear cells leads to muscle fiber necrosis. These cells are found in the endomysial site, where non-necrotic muscle fibers are damaged, and also in the perimysial and perivascular sites of the muscles. Immunohistochemical studies have disclosed that CD8 T cells are most abundant in the endomysial site and invade

Biologic Mechanism of C Protein–Induced Myositis: Comment on the Article by Okiyama et al

“…This study highlights the role of ANCA specificity for myeloperoxidase (MPO) or proteinase 3 (PR3) in the classification of AAV in patients with renal disease. Their results are consistent with those in a study of a European cohort of patients (2). In both studies, the classification of AAV according to ANCA specificity improves prognostic ability with regard to clinical outcomes when compared with classification according to the Chapel Hill Consensus Conference (CHCC) nomenclature (3).…”

“…In the study by Okiyama et al, the authors examined the role of local innate immunity in C protein-induced myositis (CIM) (1), a recently developed murine model of myositis (2). They treated C57BL/6 mice with Freund's complete adjuvant (CFA) and Toll-like receptor (TLR) ligands with or without C protein fragments to reinduce myositis after myositis had regressed following the first immunization.…”

“…Third, the rate of MPO ANCA versus PR3 ANCA differs among geographic areas (6). Fourth, the age at diagnosis or the signs and symptoms are different according to ANCA specificity (1,2). Fifth, besides the differences shown in uncontrolled trials or cohort reports (7), the Rituximab in ANCA-Associated Vasculitis randomized controlled trial comparing rituximab versus cyclophosphamide (8) showed that the percentage of patients who became ANCA negative differed according to the study drug and ANCA specificity.…”

“…The classification of AAV according to the CHCC nomenclature (3) or the American College of Rheumatology criteria (9) produces overlapping and conflicting classifications (1). Differentiation between MPA and GPA is difficult in most patients, especially in patients with renal disease, which is the most common clinical presentation (2), and renal biopsy is the principal tool for confirmation of the diagnosis. Pathologic differentiation between the 2 entities is virtually impossible based on kidney tissue samples.…”

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“…The notion that parasitic worms can protect against the development of allergic and autoimmune inflammatory conditions in humans has recently been accepted by many researchers (1,2). This has triggered a race to find the individual worm components that protect against disease development.…”