scholarly journals O31 IL-27 regulates the magnitude of ectopic germinal centres in experimental sialadenitis but fails to modulate IL-17 and IFNg production in CD4 T cells from patients with Sjögren's syndrome

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Davide Lucchesi ◽  
Rachel Coleby ◽  
Elena Pontarini ◽  
Edoardo Prediletto ◽  
Felice Rivellese ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Sjögren’S Syndrome ◽  
Cd4 T Cells ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Expression Levels ◽  
Cellular Source ◽  
Sjögren‘S Syndrome

Abstract Background A third of Sjögren’s syndrome (SS) patients develop ectopic lymphoid structures (ELS) in their salivary glands (SG). ELS play an active role in autoimmunity and contribute to the development of MALT lymphoma. Interleukin 27 (IL-27) exerts key immunomodulatory actions on numerous immune cells but its role in the formation and regulation of ELS in the SG of SS is unknown. Here we used a murine model of SG ELS to elucidate the role of IL-27 and its interaction with IL-17 in the development, regulation and function of ELS. We extended our observations on a cohort of SS patients to identify IL-27 cellular source, target cells and functional properties in modulating CD4 T cells function. Methods A single dose of reporter-encoding adenovirus was delivered directly to the SG of wild-type (WT) and IL-27RA-deficient (KO) mice to trigger ELS formation. For IL-17 blockade, anti-mouse IL-17A antibody was used. ELS development and peripheral immune responses were tracked by immuno-histopathology, FACS, and qPCR. Minor SG biopsies were collected from SS and non-specific sialadenitis (sicca) patients. Peripheral blood mononuclear cells (PBMC) isolated from SS and rheumatoid arthritis (RA) patients and age/sex-matched healthy donors (HD). For in vitro experiments PBMCs were incubated with IL-27 and analysed by FACS and cytokines levels were measured in culture supernatants. Tissue IL-27 was assessed by multicolour immunofluorescence. Results In WT mice, SG ELS formation was preceded by upregulation of IL-27p28 and infiltration of IL-27 producing cells. KO mice displayed larger, more abundant ELS in the SG. Higher expression levels of ELS-related genes (Cxcl13, Ccl19, Ltb, Aid) compared to WT mice were measured. KO mice showed an uncontrolled SG Th17 response and systemic IL-17A blockade caused a reduction in ELS size and in the expression of ELS-related genes. In SS patients SG and serum, we observed higher expression levels of IL-27 transcripts and protein, compared to sicca. SG IL-27 was selectively increased in ELS+ patients. IL-27 staining was detected in the T cell-rich areas of SG ELS often co-localizing with DC-LAMP+ dendritic cells. While IL-27 was able to significantly downregulate IL-17 production in HD and RA, CD4 T cells from patients with SS failed to downregulate IL-17 but showed an aberrant IFNγ release upon IL-27 incubation. Conclusion The IL-27-mediated restriction of Th17 expansion plays a critical role in the regulation of germinal centre response. Both in murine inducible ELS and in patients with SS, dendritic cells appear as the main cellular source of IL-27. IL-27 consistently failed to downregulate IL-17 release in CD4 T cells from SS patients, albeit its expression was increased in the ELS+ subset of SS, suggesting that a profound dysregulation of the IL-27/IL-17 axis play an important role in ELS formation in this condition. Disclosures D. Lucchesi None. R. Coleby None. E. Pontarini None. E. Prediletto None. F. Rivellese None. D. Hill None. A. Derrac Soria None. S. Jones None. I. Humphreys None. N. Sutcliffe None. A. Tappuni None. C. Pitzalis None. G. Jones None. M. Bombardieri None.

scholarly journals Development of autoimmune exocrinopathy resembling Sjögren's syndrome in adoptively transferred mice with autoreactive CD4+ T cells

2003 ◽  
Vol 48 (12) ◽  
pp. 3603-3609 ◽  
Author(s):  
Rieko Arakaki ◽  
Naozumi Ishimaru ◽  
Ichiro Saito ◽  
Masaru Kobayashi ◽  
Natsuo Yasui ◽  
...  
Keyword(s):  
T Cells ◽  
Sjögren’S Syndrome ◽  
Cd4 T Cells ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Autoimmune Exocrinopathy ◽  
Sjögren‘S Syndrome

scholarly journals Effect of the Chinese Herbal Medicine SS-1 on a Sjögren’s Syndrome-Like Disease in Mice

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 530
Author(s):  
Po-Chang Wu ◽  
Shih-Chao Lin ◽  
Lauren Panny ◽  
Yu-Kang Chang ◽  
Chi-Chien Lin ◽  
...  
Keyword(s):  
T Cells ◽  
Sjögren’S Syndrome ◽  
Cd4 T Cells ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Herbal Formula ◽  
Chinese Herbal Formula ◽  
Chinese Herbal ◽  
Sjögren‘S Syndrome

Sjögren’s syndrome (SS) is an inflammatory autoimmune disease primarily affecting the exocrine glands; it has a major impact on patients’ lives. The Chinese herbal formula SS-1 is composed of Gan Lu Yin, Sang Ju Yin, and Xuefu Zhuyu decoction, which exerts anti-inflammatory, immunomodulatory, and antifibrotic effects. Our previous study demonstrated that SS-1 alleviates clinical SS. This study aimed to evaluate the efficacy and mechanism of the Chinese herbal formula SS-1 for salivary gland protein-induced experimental Sjögren’s syndrome (ESS). These results showed that ESS treatment with the Chinese herbal formula SS-1 (1500 mg/kg) significantly alleviated the severity of ESS. We found that SS-1 substantially improved saliva flow rates in SS mice and ameliorated lymphocytic infiltrations in submandibular glands. In addition, salivary gland protein-induced SS in mice treated with SS-1 significantly lowered proinflammatory cytokines (including IFN-γ, IL-6, and IL-17A) in mouse salivary glands and decreased serum anti-M3R autoantibody levels. In addition, we found that CD4+ T cells isolated from SS-1-treated SS mice significantly reduced the percentages of IFN-γ-producing CD4+ T cells (Th1) and IL-17A-producing CD4+ T cells (Th17). Our data show that SS-1 alleviates ESS through anti-inflammatory and immunomodulatory effects, which provides new insight into the clinical treatment of SS.

scholarly journals AB0035 TWO DIFFERENT ABNORMAL BEHAVIORS IN CD4+T LYMPHOCYTES IN FIBROMYALGIA PATIENTS AND FIBROMYALGIA ASSOCIATED TO SJÖGREN’S SYNDROME

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1320-1321
Author(s):  
J. Monserratsanz ◽  
A. Movasat ◽  
M. D. Sosa Reina ◽  
A. M. Gomez Lahoz ◽  
C. Bohórquez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Sjögren’S Syndrome ◽  
Cd4 T Cells ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Primary Fibromyalgia ◽  
Sjögren‘S Syndrome

Background:Primary fibromyalgia syndrome is a prevalent rheumatic condition characterized by widespread pain and whose etiopathogenesis is not well understood. Fibromyalgia can also be secondary to other rheumatic diseases like Sjogren’s syndrome; however, its relation to this disease is unknown. It has been suggested that the immune system is involved in their pathogenesis. The role of activation stages and cytokines profiles of CD4+T lymphocytes in fibromyalgia or fibromyalgia secondary to Sjogren´s syndrome are completely unclear and could play a key role in the pathophysiology of these diseases.Objectives:The objective of this study is to investigate the counts and distribution of the CD4+T lymphocyte activation subsets and their pattern of cytokine production in women with primary fibromyalgia, fibromyalgia secondary to Sjogren´s, Sjogren´s syndrome and healthy controls (HC). The counts and distribution of naïve (TN), central memory (TCM), effector memory (TEM) and effector (TE) CD4+T lymphocyte subsets were analyzed in these diseases. Furthermore, we investigated their pattern of IL-4, IL-10, IL-17A, IFNγ, and TNFα production.Methods:Counts and distribution of CD4+T subsets (TN, TCM, TEM, TE)and their cytokine producing capacity were measured using multiparametric flow cytometry in peripheral blood mononuclear cells (PBMC) from 20 primary fibromyalgia, 15 fibromyalgia associated to Sjögren and 15 primary Sjögren patients and 15 female controls. Fibromyalgia and/or Sjögren’s syndrome were diagnosed based on ACR criteria. CD4+T cell activation stages were analyzed by the expression of the CD3, CD4, CD45RA, CD27 and CCR7 antigens. Cytokine CD4+T producing cells subsets were assayed stimulating PBMC during 6 hours, fixed, permeabilized and simultaneously stained with IL-4, IL-10, IL-17A, IFNγ, and TNFα intracellular cytokines.Results:Fibromyalgia patients showed a significant increase in the CD4+T, TNand TCMcells counts with compared to fibromyalgia secondary to Sjogren, Sjogren´s syndrome and HC. The counts of IL-17A, IL-4 and IFNγ producing CD4+T cells were increased in fibromyalgia patients with respect to HC. However, only IL17A and IFNγ, but not IL-4 producing CD4+T lymphocytes were increased with respect fibromyalgia secondary to Sjogren. These alterations were due to an increment of TEMIL-17A, TCMand TEMIL-4 and TNTCMand TEMIFNγ producing CD4+T cell subsets in fibromyalgia patients. Furthermore, IFNγ producing CD4+T cells were decreased in fibromyalgia secondary to Sjogren´s with respect to fibromyalgia patients and HC. Counts of TNTNFα producing CD4+ T cells were increased in fibromyalgia with respect fibromyalgia secondary to Sjogren. IL-10 producing CD4+T cells were normal in fibromyalgia but decreased in fibromyalgia secondary to Sjogren.Conclusion:Fibromyalgia patients show an abnormal circulating activation stages of CD4+T cells, as well as, express unusual elevated counts of CD4+T cells producing IL-17A, IL-4 and IFNγ. These alterations could differentiate two different pathologic and inflammatory behaviors of the T cell compartment between fibromyalgia and fibromyalgia secondary to Sjogren patients.References:[1]T helper 1 response is correlated with widespread pain, fatigue, sleeping disorders and the quality of life in patients with fibromyalgia.. Guggino G et al, Clin Exp Rheumatol. 2019.[2]A Comparative Study of Fibromyalgia, Rheumatoid Arthritis, Spondyloarthritis, and Sjögren’s Syndrome. Bucourt E et al, Pain Med. 2019Disclosure of Interests:None declared

scholarly journals POS0776 CORRELATION OF PERIPHERAL CD4+GRANZB+CTLS WITH DISEASE SEVERITY IN PATIENTS WITH PRIMARY SJÖGREN’S SYNDROME

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 641.3-642
Author(s):  
Q. Wang ◽  
L. Gu ◽  
M. Zhang
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Sjögren’S Syndrome ◽  
Mhc Class Ii ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Healthy Controls ◽  
Extraglandular Manifestations ◽  
Sjögren‘S Syndrome

Background:Sjögren’s syndrome (SS) is a chronic autoimmune disorder. The major histopathologic lesion of it is a focal lymphocytic infiltrate around ductal and acinar epithelial cells, which include a majority of CD4+T. Several studies have shown that the epithelial cells in SS present diverse phenomena, such as MHC class II overexpression. CD4+T cells with cytotoxic activity (CD4 CTL) have been detected in various immune responses. They are characterized by their ability to secrete perforin and granzyme B to kill the target cells in an MHC class II-restricted fashion.Objectives:So this study was to investigate the correlation of peripheral CD4+GranzB+CTLs with disease severity and organ involvement in patients with primary Sjögren’s syndrome.Methods:We recruited 116 pSS patients and 46 healthy controls using flow cytometry to examine proportion of CD4+GranzB+CTLs in their peripheral blood, and immunofluorescence to test the expression of CD4+GranzB+CTLs in labial gland. The correlations of CD4+GranzB+CTLs and the relevant clinical data were analyzed.Results:We analyzed the percentage of CD4+GranzB+cytotoxic T cells in peripheral blood mononuclear cells (PBMCs) by flow cytometry. Frequency of peripheral CD4+GranzB+CTLs were measured in 116 patients with pSS and 46 healthy controls matched for age and sex. The percentage of CD4+GranzB+CTLs were significantly up-regulated in pSS patients than healthy controls (7.1%±4.9% vs 3.1%±1.9%, p <0.0001) and positive correlation with ESSDAI in pSS patients(r = 0.6332, p<0.001). The percentage of CD4+GranzB+CTLs were markedly higher in pSS patients with extraglandular manifestations. Moreover, CD4+GranzB+CTLs were observed in the lymphocytic foci and periductal areas of the LSGs and were elevated with increased foci index (FI). After excluding the other risk factors associated with pSS, CD4+GranzB+CTLs were still related to ESSDIA and extraglandular manifestations independently(p<0.05). ROC curve analysis indicated that the area under the curve (AUC) of CD4+GranzB+CTLs was 0.796 to predict the activity of pSS, and 0.851 to presume extraglandular manifestations. The best diagnostic cut-off point was 4.865 for pSS patients.Conclusion:In this study, We provide new evidence indicating involvement of CD4+GranzB+CTLs over activation in the disease pathophysiology of pSS, which may serve as a new biomarker to evaluate the activity and severity of pSS.References:[1]Takeuchi A, Saito T. Front Immunol. (2017) 23:194.[2]Brown DM, et al. Front Immunol. (2016) 9:93.[3]Polihronis M, et al. Clin Exp Immunol. (1998) 114:485-90.[4]Xanthou G, et al. Clin Exp Immunol. (1999) 118:154-63.[5]Maehara T, et al. Ann Rheum Dis. (2017) 76:377-385.[6]Goules AV, et al. Clin Immunol. (2017) 182:30-40.[7]Hashimoto K, et al. Proc Natl Acad Sci U S A. (2019) 116:24242-24251.[8]Croia C, et al. Arthritis Rheumatol. (2014) 66:2545-57.[9]Schmidt D,et al. J Clin Invest. (1996) 97:2027–37.[10]Pandya JM, et al. Arthritis Rheum. (2010) 62:3457–66.[11]Moosig F, et al. Clin Exp Immunol. (1998) 114:113–8.[12]Peeters LM, et al. Front Immunol. (2017) 20:1160.Table 1.Multivariate analysis of CD4+GranzB+CTLs influenced by pSS-related factorsregression coefficientstandard errort-statisticsp value95%CICD8+GranzB+CTLs(%)0.1440.0334.3346.9E-50.077, 0.211ESSDAI0.2560.1222.0950.0410.011, 0.502extraglandular manifestations2.6121.2682.0590.0450.065, 5.158Figure 1.Receiver operating characteristic (ROC) curve of the frequency of CD4+GranzB+CTLs to predict ESSDAI and extraglandular manifestations responseDisclosure of Interests:None declared

Activation of MKK4 (SEK1), JNK, and c-Jun in labial salivary infiltrating T cells in patients with Sjögren’s syndrome

2006 ◽  
Vol 27 (4) ◽  
pp. 329-333 ◽  
Author(s):  
Kazutaka Soejima ◽  
Hideki Nakamura ◽  
Mami Tamai ◽  
Atsushi Kawakami ◽  
Katsumi Eguchi
Keyword(s):  
T Cells ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Sjögren‘S Syndrome
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