Th1 Response and Systemic Treg Deficiency in Inclusion Body Myositis

Abstract

ObjectiveSporadic inclusion body myositis (sIBM), the most frequent myositis in elderly patients, is characterized by the presence muscle inflammation and degeneration. We aimed at characterizing immune responses and regulatory T cells, considered key players in the maintenance of peripheral immune tolerance, in sIBM.MethodsSerum and muscle tissue levels of 25 cytokines and phenotype of circulating immune cells were measured in 22 sIBM patients and compared with 22 healthy subjects. Cytokine data were analysed by unsupervised hierarchical clustering and principal components analysis.ResultsCompared to healthy controls, sIBM patients had increased levels of Th-1 cytokines and chemokines such as IL-12 (261±138 pg/mL vs. 88±19 pg/mL; p<0.0001), CXCL-9 (186±12 pg/mL vs. 13±7 pg/mL; p<0.0001), and CXCL-10 (187±62 pg/mL vs. 13±6 pg/mL; p<0.0001). This was associated with an increased frequency of CD8+CD28− T cells (45.6±18.5% vs. 13.5±9.9%; p<0.0001), which were more prone to produce IFN-γ (45.6±18.5% vs. 13.5±9.9%; p<0.0001). sIBM patients also had a decreased frequency of circulating regulatory T cells (CD4+CD25+CD127lowFOXP3+, 6.9±1.7%; vs. 5.2±1.1%, p = 0.01), which displayed normal suppressor function and were also present in affected muscle.ConclusionsIBM patients present systemic immune activation with Th1 polarization involving the IFN-γ pathway and CD8+CD28− T cells associated with peripheral regulatory T cell deficiency.

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…A more recent report shows a significant decrease in circulating Tregs in IBM patients compared to nonmyositic controls 82. Functionality of the remainder of peripheral Tregs with regard to proliferation‐suppression of autologous T cells, however, was unaffected 82. This study also confirmed the previous finding that Tregs are indeed present in inflamed muscle of IBM patients 82.…”

“…Functionality of the remainder of peripheral Tregs with regard to proliferation‐suppression of autologous T cells, however, was unaffected 82. This study also confirmed the previous finding that Tregs are indeed present in inflamed muscle of IBM patients 82. To which degree this report is specific to IBM or if similar results were to be obtained in other inflammatory myopathies remains to be investigated.…”

“…However, these results are not specific for IBM but could be obtained in PM and DM muscle as well 121. A more recent report shows a significant decrease in circulating Tregs in IBM patients compared to nonmyositic controls 82. Functionality of the remainder of peripheral Tregs with regard to proliferation‐suppression of autologous T cells, however, was unaffected 82.…”

“…Aside from the previously described cytotoxic CD8 + T cells, inflammatory infiltrates in IBM additionally harbor myeloid cells,105 plasma cells,106 and CD4 + T cells 44, 48, 82, 83, 107, 108. Early studies have previously revealed that the antigen‐presenting properties of human myocytes exceed the mere bearing of MHC class I molecules.…”

“…Furthermore, muscle‐infiltrating CD8 + T cells in patients suffering from PM and DM have been reported to be mainly CD28 − 81. Two recent studies showed that frequencies of highly cytotoxic CD8 + CD28 − T cells in inflamed muscle and in peripheral blood of IBM patients are significantly increased and their capability to secrete IFN γ was superior compared to healthy controls 82, 83. CD8 + CD28 − T cells are devoid of costimulatory interaction between CD80:CD28, however, it is reported that CD8 + CD28 − T cells after CD3 ligation in turn upregulate alternative costimulatory molecules such as inducible costimulator (ICOS), CD134 and CD13784 which could facilitate T cell: muscle fiber interaction and is in keeping with the observed upregulation of ICOS‐L on muscle fibers during IBM 48…”