Distribution of the NF‐κB Complex in the Inflammatory Exudates Characterizing the Idiopathic Inflammatory Myopathies

Abstract

The transcription factor nuclear factor-kappaB (NF-kappaB) is a ubiquitously expressed protein family that is considered crucial in autoimmunity. We describe NF-kappaB p50 and p65, and the inhibitor I-kappaB alpha in the inflammatory exudates characteristic for the different idiopathic inflammatory myopathies (IIM), that is, endomysial CD8(+) cytotoxic T cells invading non-necrotic fibers in polymyositis (PM) and sporadic inclusion body myositis (sIBM), and the perimysial/perivascular CD20(+) B cells and CD4(+) T cells in dermatomyositis (DM). We also analyzed other inflammatory cells in the vicinity of active inflammation sites. Strikingly, actively invading CD4(+) cells in PM and sIBM contained both p65 and p50, whereas I-kappaB alpha was absent. This could point to a high activation state in which these cells are capable of expressing a variety of inflammatory mediators, contributing to the degradation of non-necrotic fibers. Secondly, CD68(+) macrophages in the infiltrates in all three IIM subtypes showed strong nuclear p50 and I-kappaB alpha staining. This may point to a role for p50 in counteracting inflammation, a reaction that could be enhanced by an upregulation of I-kappaB alpha as we observed with immunofluorescence. These results shed further light on the immunopathology of PM, sIBM and DM. CD4(+) and CD68(+) mononuclear cells may play a more prominent role than previously assumed.

Foxo/Atrogin induction in human and experimental myositis

“…Similar prevalence of CD4+ and CD8+ T cells were observed (Fig. 8 and not shown), reminiscent of recent reports in sIBM (Creus et al, 2009; Pandya et al, 2010). Centralized nuclei in both severely affected (Fig.…”

“…There is no agreement however, as to their relative contributions to the initiation and progression of disease (Greenberg, 2009). The in-flammatory component consists of scattered infiltrates of cytotoxic CD8+ (and CD4+) T lymphocytes and macrophages (Creus et al, 2009; Dimitri et al, 2006; Pandya et al, 2010), invasion of MHC-1 bearing myofibers and overexpression of pro-inflammatory chemokines and cytokines (Confalonieri et al, 2000; Raju et al, 2003; Tews and Goebel, 1996). These immune characteristics are shared with polymyositis (PM).…”

Genetic association study of NF-κB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopathy

“…In human IIM, NF-κB activation has been demonstrated by western blot analysis and electrophoretic mobility shift assays on muscle biopsies in patients with PM and DM [38]. Furthermore, NF-κB p50 and p65 is found in CD4 + T cells in muscle biopsies from both PM and IBM [5]. In human IBM and a myositis mouse model, overexpression of MHC Class I on muscle fibres results in activation of NF-κB and an endoplasmic reticulum stress response [4, 39, 40].…”

“…TNF-α is thought to induce protein loss via oxidative activation of the myogenic transcription factor nuclear factor-kappa B (NF-κB). Furthermore, NF-κB p50 and p65 have been described within the inflammatory exudates of different IIM subtypes [5]. Several genes have been identified that share homology with the NF-κB family of proteins, including NFKB1 , NFKB1A , NFKB1B , NFKB1E , IKBL (NFKBIL1) , REL , RELB and BCL3 .…”

Entering a new phase of immunogenetics in the idiopathic inflammatory myopathies

“…The p50 and p65 NF-kB subunits have been described in inflammatory exudates of polymyositis and IBM [7]. A candidate gene study [8] tested for genetic associations between eight genes of the NF-kB family of proteins and IIMs.…”