Abstract
BackgroundT-cell infiltrates may persist in muscle tissue of polymyositis (PM) and dermatomyositis (DM) patients despite aggressive immunosuppressive treatment. Here, we investigated to what extent persistent T cells in affected muscle were FOXP3+, a marker for regulatory T cells (Tregs), or CD244+, a marker for CD28null T cells, and whether their presence correlated to clinical outcome. The sensitivity of CD28null T cells towards glucocorticoid and Treg-mediated immunosuppression was also investigated.MethodsMuscle biopsies from 16 newly diagnosed or untreated patients with PM/DM were investigated by immunohistochemistry for expression of CD3, FOXP3 and CD244 before and after treatment with glucocorticoids and immunosuppressive agents. For clinical evaluation, serum levels of creatine kinase, muscle performance (FI and MMT8), disease activity (MITAX) and disability (HAQ) were measured. In vitro suppressive effects of glucocorticoids and Tregs on T-cell activation were measured by CD69 upregulation.ResultsBefore treatment, CD244+ cells were present at higher proportions compared to FOXP3+ cells in the inflamed muscle. Following treatment, FOXP3+ cell numbers decreased while CD244+ cells persisted. Patients with impaired muscle function (<75 % FI) post-treatment had higher levels of CD244+ cells in the follow-up biopsy compared to those with FI >75 %. MITAX and HAQ correlated with the number of CD244+ cells post-treatment. CD4+CD28null T cells displayed lower sensitivity towards both glucocorticoid and Treg-mediated immunosuppression in vitro compared to their CD28+ counterparts.ConclusionsPoor outcome in patients with myositis following immunosuppressive therapy was linked to persistence of CD244+ (CD28null) T cells in muscle tissue, suggesting their resistance against immunosuppression. A relative loss of regulatory T cells could also contribute to poor clinical outcome given their recently ascribed role in muscle tissue regeneration.
Highlights
T-cell infiltrates may persist in muscle tissue of polymyositis (PM) and dermatomyositis (DM) patients despite aggressive immunosuppressive treatment
We demonstrate here that a poor outcome following glucocorticoid therapy is linked to persistence of CD244+ cells in muscle tissue, i.e., CD28null T cells and a relative decrease of regulatory T cell (Treg) following such therapy
Out of the 14 patients included in the T-cell phenotyping, Serum levels of creatine kinase (s-CK) data were available from patients and Functional Index (FI) data were available from patients. sCK levels had decreased at follow-up, i.e., time of the second biopsy (Fig. 1a)
Summary
T-cell infiltrates may persist in muscle tissue of polymyositis (PM) and dermatomyositis (DM) patients despite aggressive immunosuppressive treatment. The inflammatory infiltrate in muscle tissue persists despite aggressive immunosuppressive treatment and is associated with remaining muscle weakness [6,7,8] In this context, the CD28null T cells are of particular interest as they are long-lived and suggested to be resistant to apoptosis [9,10,11,12]. Frequencies of CD28null T-cell subsets are higher in CD8 as compared to CD4 lineage, but still relatively low in healthy individuals [16] but are increased in the elderly [17] and in various chronic inflammatory and autoimmune conditions [14, 18,19,20,21,22] Contrary to these proinflammatory cells, FOXP3+ regulatory T cells (Tregs) are key players in the maintenance of peripheral tolerance by limiting T-cell activation and effector function [23, 24]. No data in this context are so far available for patients with myositis
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