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Arthritis Rheumatol. 2019 Aug 12. doi: 10.1002/art.41075. [Epub ahead of print]

Pro-inflammatory histidyl-tRNA synthetase-specific CD4+ T cells in the blood and lung of patients with idiopathic inflammatory myopathies.

Author information

1
Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
2
Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, 17176, Stockholm, Sweden.
3
Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
4
Science for Life Laboratory, Department of Medicine Solna, Karolinska Institute, and Division of Infectious Diseases, Karolinska University Hospital, Solna, SE-17176, Stockholm, Sweden.
5
Department of Medical Sciences, Rheumatology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
6
Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden.
7
Respiratory Medicine Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Abstract

OBJECTIVES:

Autoantibodies targeting histidyl-tRNA synthetase (HisRS, or anti-Jo1) are common in idiopathic inflammatory myopathies (IIM) and anti-synthetase syndrome (ASS). We aimed to investigate immunity against HisRS in blood and lungs of patients with IIM/ASS.

METHODS:

Bronchoalveolar lavage fluid (BALF), BALF cells and peripheral blood mononuclear cells (PBMCs) from IIM/ASS (n=24) patients were stimulated with full-length HisRS-protein or a HisRS-derived peptide (HisRS11-23 ). BALF and PBMCs from sarcoidosis patients (n=7) and healthy controls (HCs, n=12) were included as controls. CD4+ T-cell response was assessed by CD40L upregulation and cytokine expression using flow cytometry. Anti-Jo1 autoantibody response in serum and BALF was assessed by ELISA. Lung biopsies (n=14) were investigated by immunohistochemistry.

RESULTS:

In BALF, CD4+ T cells from 3/4 IIM/ASS responded to HisRS-protein stimulation (median CD40L fold-change: 3.6; 2.7-14.7) and 2/3 IIM/ASS had the highest responses to HisRS11-23 (median CD40L fold-change: 88; 27-149). In PBMCs, CD4+ T cells from 14/18 IIM/ASS responded to HisRS-protein (median fold-change: 7.38; IQR, 2.69-31.86, p<0.001) whereas HisRS11-23 response was present in 11/14 IIM/ASS (median fold-change: 3.4, IQR 1.87-10.9, p<0.001). In the control group, there was a HisRS11-23 response in 3/7 sarcoidosis (median CD40L fold-change: 2.09; IQR, 1.45-3.29), and in 5/12 HCs (median fold-change: 2; IQR, 1.89-2.42). CD4+ T cells from IIM/ASS displayed a pronounced Th1 phenotype in BALF when compared to PBMCs (p<0.001), producing high amounts of IFNγ and IL-2 following stimulation. Anti-Jo1 autoantibodies were detected in BALF as well as germinal center (GC)-like structures in lung biopsies of IIM/ASS.

CONCLUSIONS:

We report the pronounced presence of HisRS-reactive CD4+ T cells in PBMCs and BALF cells of IIM/ASS patients compared to sarcoidosis patients and HCs. This combined with the presence of anti-Jo1 autoantibodies in BALF, and GC-like structures in the lungs suggest that immune activation against HisRS might take place within the lungs of IIM/ASS patients. This article is protected by copyright. All rights reserved.

PMID:
31403245
DOI:
10.1002/art.41075

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