| 1. |
- Aldridge, Jonathan, et al.
(författare)
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Sex-based differences in association between circulating T cell subsets and disease activity in untreated early rheumatoid arthritis patients
- 2018
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is not known if sex-based disparities in immunological factors contribute to the disease process in rheumatoid arthritis (RA). Hence, we examined whether circulating T cell subset proportions and their association with disease activity differed in male and female patients with untreated early rheumatoid arthritis (ueRA). Methods: Proportions of T cell subsets were analyzed in peripheral blood from 72 ueRA DMARD-and corticosteroid-naive patients (50 females and 22 males) and in 31 healthy age-and sex-matched controls. Broad analysis of helper and regulatory CD4(+) T cell subsets was done using flow cytometry. Disease activity in patients was assessed using DAS28, CDAI, swollen joint counts, tender joint counts, CRP, and ESR. Results: Multivariate factor analyses showed that male and female ueRA patients display distinct profiles of association between disease activity and circulating T cell subset proportions. In male, but not female, ueRA patients Th2 cells showed a positive association with disease activity and correlated significantly with DAS28-ESR, CDAI, and swollen and tender joint counts. Likewise, proportions of non-regulatory CTLA-4(+) T cells associated positively with disease activity in male patients only, and correlated with DAS28-ESR. In contrast, there was a negative relation between Th1Th17 subset proportions and disease activity in males only. The proportions of Th17 cells correlated positively with DAS28-ESR in males only, while proportions of Th1 cells showed no relation to disease activity in either sex. There were no significant differences in proportions of T cell subsets between the sexes in patients with ueRA. Conclusions: Our findings show sex-based differences in the association between T cell subsets and disease activity in ueRA patients, and that Th2 helper T cells may have a role in regulating disease activity in male patients.
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| 3. |
- Pandya, Jayesh M., et al.
(författare)
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Blood chemokine profile in untreated early rheumatoid arthritis: CXCL10 as a disease activity marker
- 2017
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 The Author(s).Background: We have recently analyzed the profile of T-cell subtypes based on chemokine receptor expression in blood from untreated early rheumatoid arthritis (ueRA) patients compared to healthy controls (HC). Here, we compared the levels of the respective chemokines in blood plasma of ueRA patients with those of HC. We also studied the association of chemokine levels with the proportions of circulating T-cell subsets and the clinical disease activity. Methods: Peripheral blood was obtained from 43 patients with ueRA satisfying the ACR 2010 criteria and who had not received any disease-modifying anti-rheumatic drugs (DMARD) or prednisolone, and from 14 sex- and age-matched HC. Proportions of T helper cells in blood, including Th0, Th1, Th2, Th17, Th1Th17, TFh, and regulatory T cells, were defined by flow cytometry. Fifteen chemokines, including several CXCL and CCL chemokines related to the T-cell subtypes as well as to other major immune cells, were measured in blood plasma using flow cytometry bead-based immunoassay or ELISA. Clinical disease activity in patients was evaluated by assessing the following parameters: Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), swollen joint counts (SJC), tender joint counts (TJC), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). The data were analyzed using multivariate factor analyses followed by univariate analyses. Results: Multivariate discriminant analysis showed that patients with ueRA were separated from HC based on the blood plasma chemokine profile. The best discriminators were CXCL9, CXCL10, CXCL13, CCL4, and CCL22, which were significantly higher in ueRA compared to HC in univariate analyses. Among the chemokines analyzed, only CXCL10 correlated with multiple disease activity measures, including DAS28-CRP, DAS28-ESR, CDAI, SJC in 66 joints, CRP, and ESR. Conclusions: High circulating levels of CXCL10 in the plasma of ueRA patients and the association with the clinical disease activity suggests that CXCL10 may serve as a disease activity marker in early rheumatoid arthritis.
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| 4. |
- Pandya, Jayesh M., et al.
(författare)
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CD4+and CD8+CD28(null) T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis
- 2016
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Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 68:8, s. 2016-2026
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Inflammatory T cell infiltrates in the skeletal muscle tissue of patients with polymyositis are dominated by CD28-negative effector (CD28(null)) T cells of both the CD4 and CD8 lineage. These cells are potentially cytotoxic, and the aim of the present study was to develop a fully autologous cell culture system in which to investigate the functional contribution of such CD28(null) T cells to myotoxicity. Methods. In vitro cocultures of autologous skeletal muscle cells and T cell subsets obtained from 5 polymyositis patients were performed. Myotoxicity of T cells was quantified by calcein release and flow cytometric analyses. T cell degranulation was blocked with concanamycin A. Specific blocking of perforin, cytokines, and HLA was performed using antibodies. Results. Both CD4+CD28(null) and CD8+CD28(null) T cells induced more muscle cell death than did their CD28+ counterparts. Differentiated muscle cells (myotubes) were more sensitive to T cell-mediated cell death than were their precursors (myoblasts). Both CD8+ and CD4+ CD28(null) T cells displayed perforin polarization toward muscle cells and secreted higher levels of granzyme B and interferon-gamma (IFN gamma) in coculture than did CD28+ T cells. The myotoxic effects of CD28(null) T cells were reduced upon the blocking of perforin, cytokines, and HLA. Addition of IFN gamma or tumor necrosis factor did not induce skeletal muscle cell death in the absence of T cells; however, it did up-regulate HLA expression on muscle cells. Conclusion. Myotoxicity of CD4+ and CD8+ CD28(null) T cells is mediated by directed perforin-dependent killing and can be further influenced by IFN gamma-induced HLA expression on muscle cells. The data suggest that CD28(null) T cells are key effector cells that contribute to the muscle cell damage in polymyositis.
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| 5. |
- Pandya, Jayesh M., et al.
(författare)
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Circulating T helper and T regulatory subsets in untreated early rheumatoid arthritis and healthy control subjects
- 2016
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Ingår i: Journal of Leukocyte Biology. - 0741-5400. ; 100:4, s. 823-833
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Tidskriftsartikel (refereegranskat)abstract
- The pathogenic role and frequency of T cell subtypes in early rheumatoid arthritis are still unclear. We therefore performed a comprehensive analysis of the circulating T cell subtype pattern in patients with untreated early rheumatoid arthritis compared to healthy control subjects. Peripheral bloodmononuclear cells were obtained from 26 patients with untreated early rheumatoid arthritis and from with 18 age-and sex-matched healthy control subjects. T helper cell types Th0, Th1, Th2, Th17, and Th1/17 and nonclassic T helper subsets were defined by flow cytometry based on the expression of chemokine receptors CCR4, CCR6, and CXCR3. Regulatory T cells were defined by expression of CD25(+) CD127(low) and also FOXP3. CXCR5(+) cells among regulatory and nonregulatory T cells were defined as T follicular regulatory and T follicular helper cells, respectively. The phenotype of T cell subsets was confirmed by transcription factor and cytokine secretion analyses. Multivariate discriminant analysis showed that patients with untreated early rheumatoid arthritis were segregated from healthy control subjects based on the circulating T cell subset profile. Among the discriminator subsets, CCR4(+)CXCR3(-) (Th2 and Th17), CTLA4(+) and FOXP3(+) subsets were present in significantly higher frequencies, whereas CCR42 (Th1/Th17, CCR6(+)CCR4(-) CXCR3(-), and Th1) subsets were present in lower frequencies in patients with untreated early rheumatoid arthritis compared with healthy control subjects. The proportions of Th2 and Th17 subsets associated positively with each other and negatively with the CXCR3(+)/interferon gamma-secreting subsets (Th1 and Th1/Th17) in patients with untreated rheumatoid arthritis. The proportions of Th2 cells increased with age in patients with untreated early rheumatoid arthritis and healthy control subjects. The dominance of circulating CCR4(+) CXCR3(-) T helper subsets (Th2 and Th17) in untreated early rheumatoid arthritis point toward a pathogenic role of these cells in early stages of the disease.
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| 6. |
- Pandya, Jayesh M., et al.
(författare)
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Effects of conventional immunosuppressive treatment on CD244+(CD28null) and FOXP3+T cells in the inflamed muscle of patients with polymyositis and dermatomyositis
- 2016
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: T-cell infiltrates may persist in muscle tissue of polymyositis (PM) and dermatomyositis (DM) patients despite aggressive immunosuppressive treatment. Here, we investigated to what extent persistent T cells in affected muscle were FOXP3+, a marker for regulatory T cells (Tregs), or CD244+, a marker for CD28null T cells, and whether their presence correlated to clinical outcome. The sensitivity of CD28null T cells towards glucocorticoid and Treg-mediated immunosuppression was also investigated. Methods: Muscle biopsies from 16 newly diagnosed or untreated patients with PM/DM were investigated by immunohistochemistry for expression of CD3, FOXP3 and CD244 before and after treatment with glucocorticoids and immunosuppressive agents. For clinical evaluation, serum levels of creatine kinase, muscle performance (FI and MMT8), disease activity (MITAX) and disability (HAQ) were measured. In vitro suppressive effects of glucocorticoids and Tregs on T-cell activation were measured by CD69 upregulation. Results: Before treatment, CD244+ cells were present at higher proportions compared to FOXP3+ cells in the inflamed muscle. Following treatment, FOXP3+ cell numbers decreased while CD244+ cells persisted. Patients with impaired muscle function (< 75 % FI) post-treatment had higher levels of CD244+ cells in the follow-up biopsy compared to those with FI > 75 %. MITAX and HAQ correlated with the number of CD244+ cells post-treatment. CD4+CD28null T cells displayed lower sensitivity towards both glucocorticoid and Treg-mediated immunosuppression in vitro compared to their CD28+ counterparts. Conclusions: Poor outcome in patients with myositis following immunosuppressive therapy was linked to persistence of CD244+ (CD28null) T cells in muscle tissue, suggesting their resistance against immunosuppression. A relative loss of regulatory T cells could also contribute to poor clinical outcome given their recently ascribed role in muscle tissue regeneration.
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| 7. |
- Pandya, Jayesh
(författare)
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T cell subsets and disease mechanisms in inflammatory myopathies
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of chronic muscle disorders, typically displaying infiltrating T cells in skeletal muscle tissue and classified into polymyositis, dermatomyositis and sporadic inclusion body myositis. Several studies involving both humans and animal models point towards a role for T cells in the pathogenesis of IIMs, however, the precise phenotype, functionality and specificity of pathogenic T cells remain elusive. Increased frequencies of a subset of T cells, known as CD28null T cells, in peripheral blood and affected organs in various chronic inflammatory disorders, are reported by several studies. Such CD28null T cells are highly differentiated T cells lacking the co-stimulatory molecule CD28, which acquire expression of other receptors commonly associated with natural killer cells, and display proinflammatory, cytotoxic and apoptosis resistant features. In contrast to CD28null T cells, regulatory T cells are T cell subset critical for maintaining immune tolerance and also described to assist in the muscle repair process. The aims of this thesis were to investigate CD28null T cell subsets in both muscle tissue and peripheral blood of patients with IIMs, by evaluating frequencies, phenotype, function and clinical relevance of these cells. The cytotoxic mechanisms of CD28null T cells towards autologous muscle cells were investigated using in vitro T cell - muscle cell co-cultures. Muscle tissues of patients were investigated for the effects of conventional immunosuppressive therapies on CD28null and regulatory T cell subsets. Glucocorticoid and regulatory T cells mediated immunosuppressive effects on circulating CD28nulls T cells were evaluated using in vitro assays. We demonstrate that muscle-infiltrating T cells are predominantly CD4+CD28null and CD8+CD28null T cells in patients with polymyositis and dermatomyositis. Also in sporadic inclusion body myositis, where the role of immune system is controversial, T cell infiltrates in muscle tissue are dominated by CD28null T cells. Circulating CD28null T cell subsets of both CD4 and CD8 lineage were more common in patients compared to healthy controls, and were associated with human cytomegalovirus infection. These cells displayed oligoclonal expansions, proinflammatory cytokine secretion and degranulation potential, and also contained perforin. Using autologous in vitro co-cultures, we showed that the cytotoxic effects of CD28null T cells towards muscle cells are mediated largely via perforin-dependent mechanisms and regulated by IFNγ-induced HLA expression on muscle cells. Interestingly, poor clinical response in patients following immunosuppressive therapy was linked to persistence of CD28null T cells in muscle tissue. CD4+CD28null T cells were also found to be resistant towards glucocorticoid and regulatory T cell mediated immunosuppression in in vitro assays. These findings imply that CD28null T cells represent clinically important effector cells in IIMs, capable of attacking muscle fibers and inducing chronic inflammation mediated pathogenesis. Ineffectiveness of current immunosuppressive therapies appears to be linked with persistent CD28null T cells in muscle tissue as well as their immunosuppression resistant properties; therefore, these cells represent potential target candidates for future therapies.
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