CD8+T-bet+ cells as a predominant biomarker for inclusion body myositis

Abstract

Background: Myositis is a heterogeneous group of muscular auto-immune diseases with clinical and pathological criteria that allow the classification of patients into different subgroups. Inclusion body myositis is the most frequent myositis above fifty years of age.Diagnosing inclusion body myositis requires expertise and is challenging. Little is known concerning the pathogenic mechanisms of this disease in which conventional suppressiveimmune therapies are inefficacious.Objectives: Our aim was to deepen our understanding of the immune mechanisms involved in inclusion body myositis and identify specific biomarkers.Methods: Using a panel of thirty-six markers and mass cytometry, we performed deep immune profiling of peripheral blood cells from inclusion body myositis patients and healthy donors, divided into two cohorts: test and validation cohorts. Potential biomarkers were compared to myositis controls (anti-Jo1-, anti-3-hydroxyl-3-methylglutaryl CoA reductase-, and anti-signal recognition particle-positive patients).Results: Unsupervised analyses revealed substantial changes only within CD8+ cells. We observed an increase in the frequency of CD8+ cells that expressed high levels of T-bet, and containing mainly both effector and terminally differentiated memory cells. The senescent marker CD57 was overexpressed in CD8+T-bet+ cells of inclusion body myositis patients. As expected, senescent CD8+T-bet+ CD57+ cells of both patients and healthy donors were CD28nullCD27nullCD127null. Surprisingly, non-senescent CD8+T-bet+ CD57-cells in inclusion body myositis patients expressed lower levels of CD28, CD27, and CD127, and expressed higher levels of CD38 and HLA-DR compared to healthy donors. Using classification and regression trees alongside receiver operating characteristics curves, we identified and validated a frequency of CD8+T-bet+ cells > 51.5% as a diagnostic biomarker specific to inclusion body myositis, compared to myositis control patients, with a sensitivity of 94.4%, a specificity of 88.5%, and an area under the curve of 0.97. Conclusion:Using a panel of thirty-six markers by mass cytometry, we identify an activated cell population (CD8+T-bet+ CD57-CD28lowCD27lowCD127low CD38+ HLA-DR+) which could play a role in the physiopathology of inclusion body myositis, and identify CD8+T-bet+ cells as a predominant biomarker of this disease.

Sirolimus for treatment of patients with inclusion body myositis: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial

“…31 Human CD8+ T cells in peripheral blood are heterogeneous and can be divided into four main sub-populations according to their level of surface expression of CCR7 and CD45RA : CCR7 high CD45RA high naïve phenotype (TN), CCR7 high CD45RA low central memory (TCM) phenotype, CCR7 low CD45RA low effector memory (TEM) phenotype, and CCR7 low CD45RA high CD8+ T cells that are considered to be terminally differentiated memory cells (TEMRA). 32 Using mass cytometry, 6 we showed that the percentages of blood-activated CD8 T cells were lower in the sirolimus group. This observation was characterized by reduced frequencies of CD38+ and HLA-DR+ TEM cell populations.…”

“…26,27 For the mass cytometric experiments, the barcoding, mass cytometric staining, data acquisition, data preprocessing (gating out of beads and dead cells) and statistical analyses were performed as previously described in a technical research article 25 and for IBM patients. 6 The list of antibodies used in this study is available in Supplementary table 2.…”

“…3 The pathophysiology of IBM is not well understood, but two categories of histopathological features are characteristic of this disease, suggesting inflammatory (the myositis) and degenerative (inclusion body) mechanisms. 1 Patients with IBM present with highly differentiated effector CD8+ T cells in their peripheral blood [4][5][6] that invade muscle tissues 5,7 as well as systemic CD4+FoxP3+ regulatory T-cell (Treg) deficiency. 4 IBM patients are markedly associated (p<10 -33 ) with HLA-DRB1, an autoimmune haplotype.…”

The role of interferons type I, II and III in myositis: A review

“…Expansion of highly differentiated T cells was also detected in blood of sIBM patients. sIBM patients have increased levels of differentiated populations of T cells such as CD8+CD28null (114), CD8+Tbet+ (115), CD8+CD57+ (106) and CD8+KLRG1+ T cells and high levels of Th1 chemokines and cytokines (CXCL9, CXCL10 and IL-12) (114,116). This specific T-cell population is prone to produce higher levels of IFN-II in sIBM compared to levels in healthy controls (114,116).…”

The Role of Immune Cells in the Pathogenesis of Idiopathic Inflammatory Myopathies

“…In addition, CD8+T-bet+ cells are reported to be a favourable diagnostic biomarker. When the frequency of these cells is > 51.5%, the sensitivity and specificity for distinguishing IBM patients from other myositis patients can reach 94.4% and 88.5%, respectively [79].…”