Is systemic sclerosis an antigen‐driven T cell disease?

Sakkas, Lazaros I.; Platsoucas, Chris D.

doi:10.1002/art.20315

Cited by 113 publications

(93 citation statements)

References 145 publications

(211 reference statements)

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“…Previous studies have reported that CD8 + T cells infiltrated the skin (6) and lung (7,8) in SSc patients and that CD8 + T cells in lung and peripheral blood showed an activated phenotype (7,9) and Agdriven oligoclonal expansion (8,10,11). These findings indicate that effector or memory CD8 + T cells, or both, are involved in SSc pathogenesis.…”

mentioning

confidence: 71%

“…The disease duration was calculated from the time of onset of the first non-Raynaud phenomenon. Skin sclerosis was evaluated with the modified Rodnan skin thickness score (MRSS) (19) and graded as mild (MRSS, [1][2][3][4][5][6][7][8][9][10][11][12][13][14] or moderateto-severe (MRSS, 15-39) (20). SSc-related interstitial lung disease (ILD) was classified as extensive or limited disease based on combined evaluation with chest high-resolution computed tomography (HRCT) and pulmonary functional tests (21).…”

Section: Patientsmentioning

confidence: 99%

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Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis

Ayano

Tsukamoto

Kohno

et al. 2015

The Journal of Immunology

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Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8+ T cells can be detected in peripheral blood and lungs of SSc patients, effector memory CD8+ T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8+ T cells remain incompletely understood. In this study, we performed DNA microarray analysis of the sort-purified effector memory CD8+ T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1 [DNAM-1]), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226highCD8+ T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Furthermore, CD226+CD8+ T cells produced higher amount of various cytokines than CD226− ones, and CD226highCD8+ T cells from SSc patients showed upregulated IL-13 production and positive correlation with the cytotoxic capacity of CD8+ T cells against HUVECs. Finally, the neutralization of CD226 in CD8+ T cells impaired costimulation, cytokine productions, and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8+ T cells reflects disease severity and is involved in SSc pathogenesis via the production of various cytokines, including profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc.

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mentioning

confidence: 71%

Section: Patientsmentioning

confidence: 99%

Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis

Ayano

Tsukamoto

Kohno

et al. 2015

The Journal of Immunology

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“…In SSc patients increased levels of circulating Th17 cell have been described, along with elevated IL-17 serum concentrations [58,59]. On the helper T cell side, an altered balance of the Th1 and Th2 cytokine profile may also be responsible for the development of fibrosis [60]. Previously we have depicted a wide spectrum of peripheral immune-competent cell types, reflecting overall disturbances in immune homeostasis, characteristic of systemic sclerosis [61].…”

Section: Systemic Sclerosismentioning

confidence: 99%

Cytokine Milieu in Undifferentiated Connective Tissue Disease: a Comprehensive Review

Nakken

Bodolay

Szodoray

2014

Clinic Rev Allerg Immunol

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Undifferentiated connective tissue disease (UCTD) is a unique clinical entity, a potential forerunner of well-established systemic autoimmune/rheumatic diseases. UCTD is characterized by the presence of various clinical symptoms, as well as a diverse repertoire of autoantibodies, resembling systemic autoimmune diseases. Since approximately one-third of these patients consequently transform into a full-blown systemic autoimmune/rheumatic disease, it is of major importance to assess pathogenic factors leading to this progression. In view of the fact that the serological and clinical picture of UCTD and systemic autoimmune diseases are very similar, it is assumed that analogous pathogenic factors perpetuate both disease entities. In systemic autoimmune conditions a quantitative and qualitative impairment of regulatory T cells have been shown previously and in parallel a relative dominance of proinflammatory Th17 cells has been introduced. Moreover the imbalance between regulatory and Th17 cells plays a pivotal role in the initiation and propagation of UCTD. Additionally, we depict a cytokine imbalance, which give raise to a biased T-cell homeostasis from the UCTD phase throughout the fully developed systemic autoimmune disease stage. The levels of IL-6, IL-12, IL-17, IL-23 and IFN- were pathologically increased with a parallel reduction of IL-10. We believe that the assessment of Th17/Treg cell ratio, as well as the simultaneous quantitation of cytokines may give a useful diagnostic tool at the early UCTD stage to identify patients with a higher chance of consecutive disease progression towards serious systemic autoimmune diseases. Moreover, the early-targeted immunomodulating therapy in these patients may decelerate, or even stop this progression, before the development of serious autoimmune conditions with organ damage.

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“…Важная роль в развитии фиброзного процесса при системной склеродермии отводится иммунным нарушени-ям [9,10]. Признаки активации Т и В лимфоцитов выяв-ляются уже на ранних стадиях развития болезни до гисто-логических проявлений фиброза [11].…”

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“…Установлены сти мулирующие эффекты этих клеток на фибробласты. Основное значение в развитии склеродермического фиброза придается нарушениям Т-клеточного звена имму-нитета, что проявляется функциональной поляризацией Т лимфоцитов периферической крови и тканей с пре-обладанием синтеза Th2 цитокинов, влияющих на рост, пролиферацию и продукцию компонентов внеклеточного матрикса [9,10,[12][13][14]. В последнее время установлена значительная роль В лимфоцитов в развитии аутоиммун-ных болезней.…”

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