Interferon‐α/β–mediated innate immune mechanisms in dermatomyositis

Abstract

Dermatomyositis has been modeled as an autoimmune disease largely mediated by the adaptive immune system, including a local humorally mediated response with B and T helper cell muscle infiltration, antibody and complement-mediated injury of capillaries, and perifascicular atrophy of muscle fibers caused by ischemia. To further understand the pathophysiology of dermatomyositis, we used microarrays, computational methods, immunohistochemistry and electron microscopy to study muscle specimens from 67 patients, 54 with inflammatory myopathies, 14 with dermatomyositis. In dermatomyositis, genes induced by interferon-alpha/beta were highly overexpressed, and immunohistochemistry for the interferon-alpha/beta inducible protein MxA showed dense staining of perifascicular, and, sometimes all myofibers in 8/14 patients and on capillaries in 13/14 patients. Of 36 patients with other inflammatory myopathies, 1 patient had faint MxA staining of myofibers and 3 of capillaries. Plasmacytoid dendritic cells, potent CD4+ cellular sources of interferon-alpha, are present in substantial numbers in dermatomyositis and may account for most of the cells previously identified as T helper cells. In addition to an adaptive immune response, an innate immune response characterized by plasmacytoid dendritic cell infiltration and interferon-alpha/beta inducible gene and protein expression may be an important part of the pathogenesis of dermatomyositis, as it appears to be in systemic lupus erythematosus.

A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti–Jo‐1 or anti–Ro 52/anti–Ro 60 autoantibodies

“…This was found in patients with or without autoantibodies, but with slightly different expression patterns, and was present even during immunosuppressive treatment. Thus, we confirmed previously reported increased expression of MX-1 in capillaries in muscle tissue of DM patients (10). The IFN␣ in the muscle tissue of these patients did not seem to be produced locally by BDCA-2-positive cells, since these were only seen as scattered cells in a few DM patients.…”

“…One such proposed mechanism is viral or bacterial infection. The low number of BDCA-2-positive cells in muscle tissue of DM patients is in contrast to a previous finding (10). One possible explanation for this discrepancy is a difference in the selection of patients.…”

“…One possible explanation for this discrepancy is a difference in the selection of patients. Consistent with this, the DM patients in our study lacked anti-RNP or anti-DNA autoantibodies, in contrast to the DM patients studied by Greenberg et al (10). Anti-RNP and anti-DNA autoantibodies can have an IFN-inducing capacity (14,15).…”

“…One cause could be type I interferon (IFN), one of the strongest inducers of class I MHC expression (7,8). In fact, type I IFN appears to be involved in both adult and juvenile DM, because muscle biopsy specimens display up-regulation of type I IFN-induced genes, induction of IFN␣/␤-inducible human myxovirus resistance 1 (MX-1) protein, and the presence of plasmacytoid dendritic cells (PDCs), the major type I IFN producers (9,10). An additional role for IFN␣ in PM is suggested by the induction of this disease in patients treated with IFN␣ (11)(12)(13).…”

The type I interferon system in systemic lupus erythematosus

“…Thus, infiltration of NIPCs/PDCs and expression of IFN␤ and the type I IFN-inducible protein MxA can be detected in the synovia of patients with rheumatoid arthritis (99)(100)(101). Patients with dermatomyositis have a typical IFN gene signature and IFN␣-containing BDCA-2-positive cells in muscle tissue (102,103). In a recent study, we found IFN␣-producing cells in the salivary glands of patients with pSS (104).…”