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- Galindo-Feria, Angeles S., et al.
(författare)
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Proinflammatory Histidyl-Transfer RNA Synthetase-Specific CD4+T Cells in the Blood and Lungs of Patients With Idiopathic Inflammatory Myopathies
- 2020
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Ingår i: Arthritis & Rheumatology. - : WILEY. - 2326-5191 .- 2326-5205. ; 72:1, s. 179-191
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Tidskriftsartikel (refereegranskat)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 (HisRS(11-23)). 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 HisRS(11-23) (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 HisRS(11-23) 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 HisRS(11-23) 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-gamma 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.
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| 2. |
- Fathi, Maryam
(författare)
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Interstitial lung disease in polymyositis and dermatomyositis
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Polymyositis and dermatomyositis are rare disease entities affecting skeletal muscle and other organs such as the lungs. Interstitial lung disease (ILD) is increasingly recognized as a serious complication of poly-/dermatomyositis. The reported prevalence of pulmonary involvement varies widely due to use of different clinical, radiological, functional and pathological criteria. The etiology and pathogenesis of myositis as well as myositisassociated ILD are still unclear and it is not known when during the course of disease ILD develops. Infiltration of T cells and macrophages in the muscle tissue suggests an important role of T cell-mediated immunity in the pathogenesis of the diseases. It is still unknown which antigen these cells recognize and which cytokines are important in the inflammatory process. The role of autoantibodies in disease mechanisms of myositis is also not clear. In order to establish the prevalence, characteristics and the course of myositis associated ILD, as well as putatively relevant pathogenetic factors we investigated an unselected group of patients with newly diagnosed poly-/dermatomyositis using chest radiography/ high resolution tomography and pulmonary function tests. Furthermore, we investigated T cell receptor (TCR) V gene usage in bronchoalveolar lavage (BAL), muscle biopsy and peripheral blood T cells by using T cell specific monoclonal antibodies. Moreover, we analyzed the relationship between presence of ILD-related autoantibodies, genotype and balance between serum levels of cytokines suggested to be involved in the disease (tumor necrosis factor (TNF), interleukin (IL)-10). ILD, defined by radiographic changes and/or restrictive ventilatory impairment, was recorded in up to 79% of the patients. The number of patients with ILD had been even higher with the use of bronchoscopy and BAL, as alveolitis was also evident in patients without evidence of ILD through radiographic examinations or lung function tests. Arthritis and positive anti-Jo-1 autoantibodies were more common in ILD-patients than in patients without ILD. The course of myositis-associated ILD varied. In most cases pulmonary function tests stabilized, improved or even normalized after initiation of immunosuppressive therapy. A common targeted antigen in muscle and lung tissue was suggested by a restricted TCR BV gene usage in the lungs and muscle. The presence of anti-Jo-1 antibodies and antiRo52 antibodies was associated with higher TNF/IL-10 ratios in myositis patients and this ratio seemed to have a genetic basis, thus suggesting a role of genes as a predisposing factor for ILD. In conclusion, ILD is a common manifestation of myositis. We propose that all newly diagnosed patients, regardless of pulmonary symptoms, should be screened for ILD by physical examination, chest radiographic examination, lung function tests and screening for anti-Jo-1 antibodies in order to identify patients with ILD early in the course of disease, when it is likely that the clinical course may improve by immunosuppressive treatment. Restricted TCR BV usage in the lungs and muscle make it important to include the lungs in the search for etiology of myositis. Patients with anti-Jo-1 antibodies have a high risk for developing ILD. This could be genetically determined, mediated through altered cytokine production. An increased knowledge concerning the pathogenesis will hopefully make it possible to develop more selective therapies for myositis patients.
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| 5. |
- Notarnicola, Antonella, et al.
(författare)
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Longitudinal assessment of reactivity and affinity profile of anti-Jo1 autoantibodies to distinct HisRS domains and a splice variant in a cohort of patients with myositis and anti-synthetase syndrome
- 2022
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Ingår i: Arthritis Research & Therapy. - : Springer Nature. - 1478-6362. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Background To address the reactivity and affinity against histidyl-transfer RNA synthetase (HisRS) autoantigen of anti-Jo1 autoantibodies from serum and bronchoalveolar lavage fluid (BALF) in patients with idiopathic inflammatory myopathies/anti-synthetase syndrome (IIM/ASSD). To investigate the associations between the reactivity profile and clinical data over time. Methods Samples and clinical data were obtained from (i) 25 anti-Jo1(+) patients (19 sera with 16 longitudinal samples and 6 BALF/matching sera at diagnosis), (ii) 29 anti-Jo1(-) patients (25 sera and 4 BALF/matching sera at diagnosis), and (iii) 27 age/gender-matched healthy controls (24 sera and 3 BALF/matching sera). Reactivity towards HisRS full-length (HisRS-FL), three HisRS domains (WHEP, antigen binding domain (ABD), and catalytic domain (CD)), and the HisRS splice variant (SV) was tested. Anti-Jo1 IgG reactivity was evaluated by ELISA and western blot using IgG purified from serum by affinity chromatography. In paired serum-BALF, anti-Jo1 IgG and IgA reactivity was analyzed by ELISA. Autoantibody affinity was measured by surface plasmon resonance using IgG purified from sera. Correlations between autoantibody reactivity and clinical data were evaluated at diagnosis and longitudinally. Results Anti-Jo1 IgG from serum and BALF bound HisRS-FL, WHEP, and SV with high reactivity at the time of diagnosis and recognized both conformation-dependent and conformation-independent HisRS epitopes. Anti-HisRS-FL IgG displayed high affinity early in the disease. At the time of IIM/ASSD diagnosis, the highest autoantibody levels against HisRS-FL were found in patients ever developing interstitial lung disease (ILD) and arthritis, but with less skin involvement. Moreover, the reactivity of anti-WHEP IgG in BALF correlated with poor pulmonary function. Levels of autoantibodies against HisRS-FL, HisRS domains, and HisRS splice variant generally decreased over time. With some exceptions, longitudinal anti-HisRS-FL antibody levels changed in line with ILD activity. Conclusion High levels and high-affinity anti-Jo1 autoantibodies towards HisRS-FL were found early in disease in sera and BALF. In combination with the correlation of anti-HisRS-FL antibody levels with ILD and ILD activity in longitudinal samples as well as of anti-WHEP IgG in BALF with poor pulmonary function, this supports the previously raised hypothesis that the lung might have a role in the immune reaction in anti-Jo1-positive patients.
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