Role of the IL-12/IL-35 balance in patients with Sjögren syndrome

Fogel, O.; Rivière, Élodie; Séror, Raphaèle; Nocturne, Gaëtane; Boudaoud, Saida; Ly, Bineta; Gottenberg, Jacques-Éric; Guern, Véronique Le; Dubost, Jean‐Jacques; Nititham, Joanne; Taylor, Kimberly E.; Chanson, Philippe; Dieudé, Philippe; Criswell, Lindsey A.; Jagla, Bernd; Thai, Alice; Mingueneau, Michaël; Mariette, Xavier; Miceli‐Richard, Corinne

doi:10.1016/j.jaci.2017.07.041

Cited by 38 publications

(16 citation statements)

References 65 publications

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“…Thus, pSS cDC2s have decreased expression of miR-130a and increased expression of MSK1, associated with increased production of TNF-α and IL-12. Both of these cytokines are increased in salivary glands and serum of pSS patients (41, 42). High levels of IL-12 promote immune cell infiltration into the salivary glands, which is associated with the presence of autoantibodies in pSS (43).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-130a Contributes to Type-2 Classical DC-activation in Sjögren's Syndrome by Targeting Mitogen- and Stress-Activated Protein Kinase-1

et al. 2019

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Objectives: Considering the critical role of microRNAs (miRNAs) in regulation of cell activation, we investigated their role in circulating type-2 conventional dendritic cells (cDC2s) of patients with primary Sjögren's syndrome (pSS) compared to healthy controls (HC). Methods: CD1c-expressing cDC2s were isolated from peripheral blood. A discovery cohort (15 pSS, 6 HC) was used to screen the expression of 758 miRNAs and a replication cohort (15 pSS, 11 HC) was used to confirm differential expression of 18 identified targets. Novel targets for two replicated miRNAs were identified by SILAC in HEK-293T cells and validated in primary cDC2s. Differences in cytokine production between pSS and HC cDC2s were evaluated by intracellular flow-cytometry. cDC2s were cultured in the presence of MSK1-inhibitors to investigate their effect on cytokine production. Results: Expression of miR-130a and miR-708 was significantly decreased in cDC2s from pSS patients compared to HC in both cohorts, and both miRNAs were downregulated upon stimulation via endosomal TLRs. Upstream mediator of cytokine production MSK1 was identified as a novel target of miR-130a and overexpression of miR-130a reduced MSK1 expression in cDC2s. pSS cDC2s showed higher MSK1 expression and an increased fraction of IL-12 and TNF-α-producing cells. MSK1-inhibition reduced cDC2 activation and production of IL-12, TNF-α, and IL-6. Conclusions: The decreased expression of miR-130a and miR-708 in pSS cDC2s seems to reflect cell activation. miR-130a targets MSK1, which regulates pro-inflammatory cytokine production, and we provide proof-of-concept for MSK1-inhibition as a therapeutic avenue to impede cDC2 activity in pSS.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-130a Contributes to Type-2 Classical DC-activation in Sjögren's Syndrome by Targeting Mitogen- and Stress-Activated Protein Kinase-1

et al. 2019

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“…A minor allele frequency of 5% was required. Sixteen SNPs were then selected, based on previous association studies (Table 8) [13,18,19,29,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51].…”

Section: Snp Selection and Genotypingmentioning

confidence: 99%

An integrative microenvironment approach for follicular lymphoma: roles of inflammatory cell subsets and immune-response polymorphisms on disease clinical course

et al. 2020

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The study of the tumor microenvironment (TME) in follicular lymphoma (FL) has produced conflicting results due to assessment of limited TME subpopulations, and because of heterogeneous treatments among different cohorts. Also, important genetic determinants of immune response, such as single-nucleotide polymorphisms (SNPs), remain underexplored in this disease. We performed a detailed study of the TME in 169 FL biopsies using immunohistochemistry, encompassing lymphocytes, macrophages, and cytokines. We also genotyped 16 SNPs within key immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, and IL17F) in 159 patients. We tested associations between SNPs, clinicopathological features and TME composition, and proposed survival models in R-CHOP/R-CVP-treated patients. Presence of the IL12A rs568408 "A" allele associated with the follicular pattern of FOXP3+ cells. The IL12A AA haplotype included rs583911 and rs568408 and was an independent predictor of worse survival, together with the follicular patterns of T-cells (FOXP3+ and CD8+) and high IL-17F tumor levels. The patterns of CD3+, CD4+ and CD8+ cells, displayed as a principal component, also associated with survival. Hierarchical clustering of the TME proteins demonstrated a cluster that was associated with worse prognosis (tumors enriched in IL-17A, IL-17F, CD8, PD1, and Ki-67). The survival of FL patients who were treated in the rituximab era shows a strong dependence on TME signals, especially the T-cell infiltration patterns and IL-17F tumor levels. The presence of the AA haplotype of IL12A in the genome of FL patients is an additional prognostic factor that may modulate the composition of T-reg cells in this disease.

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“…IL‐35 may inhibit inflammation during the process of pSS. Evidently, decreased serum levels of IL‐35, p35, and EBI3 messenger RNA (mRNA) transcripts and CD4 + EBI3 + T cells have been detected in pSS patients and inversely correlated with the erythrocyte sedimentation rate and the European League Against Rheumatism Sjögren’s syndrome disease activity index scores in these patients 71,77 . These findings suggest that these measures may be valuable for evaluating disease activity.…”

Section: Primary Sjögren’s Syndromementioning

confidence: 95%

“…However, 1 study detected an increased frequency of Tregs in pSS patients 76 . Furthermore, the imbalance of IL‐12 and IL‐35 responses may be associated with the development of pSS, 77 and the frequency of peripheral blood Bregs is increased in pSS patients 78 . However, the precise mechanisms underlying the action of the imbalance of IL‐12 and IL‐35 responses and Bregs in the development and progression of pSS remain to be investigated.…”

Section: Primary Sjögren’s Syndromementioning

confidence: 97%

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Interleukin‐35 regulates the balance of Th17 and Treg responses during the pathogenesis of connective tissue diseases

Wang

Lei

2020

Int J of Rheum Dis

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Interleukin (IL)-35 belongs to the IL-12 cytokine family and is a heterodimer of the p35 and Epstein-Barr virus-induced gene 3 (EBI3) subunits. Functionally, IL-35 can promote the proliferation and activation of regulatory T cells (Tregs) and suppress the function of T helper 17 (Th17) cells and other inflammatory cells to inhibit immune responses. In recent years, an abnormal IL-35 expression causing a Th17/Treg imbalance has been associated with the development and progression of several connective tissue diseases (CTDs), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis (DM)/polymyositis (PM), and primary Sjögren's syndrome (pSS). Here, we review the role of IL-35 in regulating the balance of Th17/Treg responses in different types of CTDs and provide new insights into the role of IL-35 in these diseases.

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Role of the IL-12/IL-35 balance in patients with Sjögren syndrome

Abstract: Our findings emphasize involvement of the IL-12/IL-35 balance in the pathogenesis of pSS. Serum IL-35 levels were associated with low disease activity, in contrast with serum IL-12p70 levels, which were associated with more active disease.

Cited by 38 publications

References 65 publications

MicroRNA-130a Contributes to Type-2 Classical DC-activation in Sjögren's Syndrome by Targeting Mitogen- and Stress-Activated Protein Kinase-1

MicroRNA-130a Contributes to Type-2 Classical DC-activation in Sjögren's Syndrome by Targeting Mitogen- and Stress-Activated Protein Kinase-1

An integrative microenvironment approach for follicular lymphoma: roles of inflammatory cell subsets and immune-response polymorphisms on disease clinical course

Interleukin‐35 regulates the balance of Th17 and Treg responses during the pathogenesis of connective tissue diseases

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