Proinflammatory Histidyl–Transfer RNA Synthetase–Specific CD4+ T Cells in the Blood and Lungs of Patients With Idiopathic Inflammatory Myopathies

Abstract

Objective Autoantibodies targeting histidyl–transfer RNA synthetase (HisRS; anti–Jo‐1) are common in the idiopathic inflammatory myopathies (IIMs) and antisynthetase syndrome. This study was undertaken to investigate immunity against HisRS in the blood and lungs of patients with IIM/antisynthetase syndrome. Methods Bronchoalveolar lavage (BAL) fluid, BAL fluid cells, and peripheral blood mononuclear cells (PBMCs) from patients with IIM/antisynthetase syndrome (n = 24) were stimulated with full‐length HisRS protein or a HisRS‐derived peptide (HisRS11–23). BAL fluid and PBMCs from patients with sarcoidosis (n = 7) and healthy subjects (n = 12) were included as controls. The CD4+ T cell response was determined according to levels of CD40L up‐regulation and cytokine expression using flow cytometry. Anti–Jo‐1 autoantibody responses in the serum and BAL fluid were assessed by enzyme‐linked immunosorbent assay. Lung biopsy samples from patients with IIM/antisynthetase syndrome (n = 14) were investigated by immunohistochemistry. Results In BAL fluid, CD4+ T cells from 3 of 4 patients with IIM/antisynthetase syndrome responded to stimulation with HisRS protein, as measured by the median fold change in CD40L expresssion in stimulated cells compared to unstimulated cells (median fold change 3.6, interquartile range [IQR] 2.7–14.7), and 2 of 3 patients with IIM/antisynthetase syndrome had the highest responses to HisRS11–23 (median fold change 88, IQR 27–149). In PBMCs, CD4+ T cells from 14 of 18 patients with IIM/antisynthetase syndrome responded to HisRS protein (median fold change 7.38, IQR 2.69–31.86; P < 0.001), whereas a HisRS11–23 response was present in 11 of 14 patients with IIM/antisynthetase syndrome (median fold change 3.4, IQR 1.87–10.9; P < 0.001). In the control group, there was a HisRS11–23 response in 3 of 7 patients with sarcoidosis (median fold change 2.09, IQR 1.45–3.29) and in 5 of 12 healthy controls (median fold change 2, IQR 1.89–2.42). CD4+ T cells from patients with IIM/antisynthetase syndrome displayed a pronounced Th1 phenotype in the BAL fluid when compared to the PBMCs (P < 0.001), producing high amounts of interferon‐γ and interleukin‐2 following stimulation. Anti–Jo‐1 autoantibodies were detected in BAL fluid and germinal center (GC)–like structures were seen in the lung biopsy samples from patients with IIM/antisynthetase syndrome. Conclusion The results of this study demonstrate a pronounced presence of HisRS‐reactive CD4+ T cells in PBMCs and BAL fluid cells from patients with IIM/antisynthetase syndrome as compared to patients with sarcoidosis and healthy controls. These findings, combined with the presence of anti–Jo‐1 autoantibodies in BAL fluid and GC‐like structures in the lungs, suggest that immune activation against HisRS might take place within the lungs of patients with IIM/antisynthetase syndrome.

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

“…The presence of histidine RNA‐Synthetase(HisRS)‐reactive CD4 + T cells in the bronchioalveolar lavage fluids as reported in ASyS patients (99). Along that line, shared oligoclonal CD4 + and CD8 + T cells were reported in the lungs and skeletal muscles associated with different myositis subsets (100).…”

“…In the peripheral blood of ASyS, the presence of HisRS‐reactive CD4 + T cells was also reported (99) even though the Th1 involvement was less significant in the lungs. Along that line, increased levels of IFNγ‐induced chemokines CXCL9 and CXCL10 are observed in the serum of patients with anti‐Jo‐1 antibodies (102).…”

“…In the bronchoalveolar lavage fluids, these cells display a Th1 phenotype and produce high levels of IFNγ (99). In addition, these Th1 cells are characterised by the expression of C-C chemokine receptor type 5 (CCR5), involved in T cell homing.…”

Roles of aminoacyl-tRNA synthetases in immune regulation and immune diseases

“…Of note, murine Jo-1 induced autoreactive B and T cells targeting its own epitopes, and the epitope spreading occurred uniformly 8 weeks after the single immunization, suggesting that autoantibody Jo-1 was able to drive a sustained immune response. When PBMCs and bronchoalveolar lavage fluid (BALF) cells from ASSD patients were stimulated with HisRS or a HisRS-derived peptide (HisRS [11][12][13][14][15][16][17][18][19][20][21][22][23] ), the expression of CD40L in CD4 + T cells from the corresponding compartments was upregulated 78 . Compared with PBMCs, BALF CD4 + T cells showed a remarkable Th1 phenotype after stimulation, such as the production of more IFN-γ and IL-2, indicating the presence of HisRS-specific CD4 + T cells in the blood and lung of patients with ASSD.…”

In vitro and ex vivo functional characterization of human HLA-DRB1∗04 restricted T cell receptors

“…A common model explaining the increased risk relates to the ability of different class II HLA proteins to present peptides linked to disease development, and consequently activation of autoreactive CD4 + T cells [ [5] , [6] , [7] ]. In line with this concept, increasing numbers of peptides have been identified as activating T cells in patients with different HLA-restricted autoimmune diseases [ [8] , [9] , [10] , [11] , [12] , [13] , [14] ]. The fact that RA and T1D patients demonstrate reduced symptoms of disease when treated with Abatacept (a CTLA4-Ig complex that reduces T cell activation) further highlights the role of interactions between antigen presenting cells and T cells in the disease pathogenesis [ [15] , [16] , [17] ].…”