Enhancement of the Soluble Form of OX40 and OX40L Costimulatory Molecules but Reduction of the Membrane Form in Type 1 Diabetes (T1D)

An, Jingnan; Ding, Sisi; Li, Sicheng; Sun, Lirong; Chang, Xin; Huang, Ziyi; Zhou, Bin; Chen, Fang; Liu, Cuiping; Zhang, Xueguang

doi:10.1155/2019/1780567

Cited by 7 publications

(7 citation statements)

References 45 publications

(36 reference statements)

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“…We detected the plasma levels of sOX40 and sOX40L in patients with MG for the first time to explore the roles of the soluble molecules. The plasma sOX40 levels in the MG group, especially in the USMG group, were significantly decreased compared with those in the HC group, consistent with the findings of unbalanced expression of the membrane and soluble form of OX40 in individuals with type 1 diabetes [12]. Moreover, plasma sOX40 levels were positively correlated with QMGs and disease duration in the MG group.…”

Section: Discussionsupporting

confidence: 84%

“…Soluble costimulatory molecules are generated through the proteolytic cleavage [31] or mRNA splicing [32] of membranebound molecules. sOX40 and sOX40L may be cleaved from membrane molecules, but the specific mechanism remains unclear [12,33]. We detected the plasma levels of sOX40 and sOX40L in patients with MG for the first time to explore the roles of the soluble molecules.…”

Section: Discussionmentioning

confidence: 92%

“…OX40-OX40L interactions promote T cell proliferation, differentiation, memory, and survival, increase effector cytokine secretion, and suppress regulatory T cell function [8]. The OX40/OX40L pathway plays a significant role in the pathogenesis of human autoimmune diseases, including multiple sclerosis (MS) [9], systemic lupus erythematosus (SLE) [10], rheumatoid arthritis (RA) [11], and type 1 diabetes [12], and the expression of OX40 on CD4 + T cells correlates with disease severity in patients with SLE [13,14]. Blockade of OX40-OX40L interactions ameliorates disease in many animal models of autoimmunity [15].…”

mentioning

confidence: 99%

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Unbalanced expression of membrane-bound and soluble OX40 and OX40 ligand in patients with myasthenia gravis

Zhou¹,

Xue²

2021

Preprint

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

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Unbalanced expression of membrane-bound and soluble OX40 and OX40 ligand in patients with myasthenia gravis

Zhou¹,

Xue²

2021

Preprint

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“…The ligand-receptor pairs CD40L-CD40 and OX40L-OX40 represent critical immune checkpoints for B cell differentiation, antigen presenting cell activation, and T cell modulation (71). High serum levels sCD40L or sOX40L have been reported in lupus and other rheumatic autoimmune diseases (72,73). CD6, a lymphocyte surface receptor that associates with the T cell receptor/CD3 complex, acts as a co-stimulatory molecule for T cell activation (74).…”

Section: Discussionmentioning

confidence: 99%

Silica Induction of Diverse Inflammatory Proteome in Lungs of Lupus-Prone Mice Quelled by Dietary Docosahexaenoic Acid Supplementation

et al. 2022

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Repeated short-term intranasal instillation of lupus-prone mice with crystalline silica (cSiO2) induces inflammatory gene expression and ectopic lymphoid neogenesis in the lung, leading to early onset of systemic autoimmunity and rapid progression to glomerulonephritis. These responses are suppressed by dietary supplementation with the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA). Here, we tested the hypothesis that dietary DHA supplementation suppresses cSiO2-induced inflammatory proteins in bronchoalveolar alveolar lavage fluid (BALF) and plasma of lupus-prone mice. Archived tissue fluid samples were used from a prior investigation in which 6 wk-old lupus-prone female NZBWF1 mice were fed isocaloric diets containing 0 or 10 g/kg DHA for 2 wks and then intranasally instilled with 1 mg cSiO2 or vehicle once weekly for 4 wks. Cohorts were terminated at 1, 5, 9 or 13 wk post-instillation (PI). BALF and plasma from each cohort were analyzed by high density multiplex array profiling of 200 inflammatory proteins. cSiO2 time-dependently induced increases in the BALF protein signatures that were highly reflective of unresolved lung inflammation, although responses in the plasma were much less robust. Induced proteins in BALF included chemokines (e.g., MIP-2, MCP-5), enzymes (e.g., MMP-10, granzyme B), adhesion molecules (e.g., sE-selectin, sVCAM-1), co-stimulatory molecules (e.g., sCD40L, sCD48), TNF superfamily proteins (e.g., sTNFRI, sBAFF-R), growth factors (e.g., IGF-1, IGFBP-3), and signal transduction proteins (e.g., MFG-E8, FcgRIIB), many of which were blocked or delayed by DHA supplementation. The BALF inflammatory proteome correlated positively with prior measurements of gene expression, pulmonary ectopic lymphoid tissue neogenesis, and induction of autoantibodies in the lungs of the control and treatment groups. Ingenuity Pathway Analysis (IPA) revealed that IL-1β, TNF-α, and IL-6 were among the top upstream regulators of the cSiO2-induced protein response. Furthermore, DHA’s effects were associated with downregulation of cSiO2-induced pathways involving i) inhibition of ARE‐mediated mRNA decay, ii) bacterial and viral pattern recognition receptor activation, or iii) TREM1, STAT3, NF-κB, and VEGF signaling and with upregulation of PPAR, LXR/RXR and PPARα/RXRα signaling. Altogether, these preclinical findings further support the contention that dietary DHA supplementation could be applicable as an intervention against inflammation-driven autoimmune triggering by cSiO2 or potentially other environmental agents.

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“…OX40-OX40L interactions promote T cell proliferation, differentiation, memory, and survival, increase effector cytokine secretion, and suppress regulatory T cell function [ 8 ]. The OX40/OX40L pathway plays a significant role in the pathogenesis of human autoimmune diseases, including multiple sclerosis (MS) [ 9 ], systemic lupus erythematosus (SLE) [ 10 ], rheumatoid arthritis (RA) [ 11 ], and type 1 diabetes [ 12 ], and the expression of OX40 on CD4 + T cells correlates with disease severity in patients with SLE [ 13 , 14 ]. Blockade of OX40-OX40L interactions ameliorates disease in many animal models of autoimmunity [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical Significance of OX40 and OX40 Ligand in the Peripheral Blood of Patients with Myasthenia Gravis

Zhou

Wang

et al. 2022

Journal of Immunology Research

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Background. A previous study on thymomas in myasthenia gravis (MG) patients indicated that OX40 expression may be upregulated in thymic tissues adjacent to germinal centers (GCs) and thymomas, and OX40 may interact with OX40L in GCs to enhance anti-acetylcholine receptor antibody production. However, little is known about the clinical significance of the expression of OX40 and OX40L in the peripheral blood of patients with MG. We aimed to characterize the expression of membrane-bound and soluble OX40 and OX40L in the peripheral blood of patients with MG and to identify their clinical significance. Methods. For membrane molecules, we collected peripheral blood (PB) from 39 MG patients at baseline, 22 patients in relapse, and 42 patients in remission, as well as from 36 healthy participants as controls. For soluble molecules, plasma from 37 MG patients at baseline, 34 patients in relapse, and 30 patients in remission, as well as plasma from 36 healthy controls (HC), was retrospectively collected from the sample bank of the First Hospital of Soochow University. The expression of membrane-bound OX40 and OX40L (mOX40 and mOX40L) by immune cells was measured using flow cytometry. Plasma levels of soluble OX40 and OX40L (sOX40 and sOX40L) were measured by ELISA. Results. (1) The expression of OX40 on CD4+ T cells and that of OX40L on B cells and monocytes were significantly increased, and the levels of sOX40 were significantly decreased in MG patients at baseline compared with HC, while the expression of sOX40L was not significantly different between the two groups. (2) Dynamic observation of the molecules showed significantly higher expression of OX40 on CD4+ T cells and higher levels of sOX40 in MG patients in relapse than in MG patients at baseline and MG patients in remission. Furthermore, the expression levels of sOX40 were significantly elevated in MG patients in remission compared with MG patients at baseline, and the expression of sOX40L was significantly lower in MG patients in remission than in MG patients at baseline and MG patients in relapse. (3) Plasma levels of sOX40 and sOX40L were significantly decreased in 13 patients with relapsed MG after immunosuppressive treatment compared with those before treatment. (4) Correlation analysis showed that the expression of OX40 on CD4+ T cells in patients with relapsed MG was positively correlated with the concentration of acetylcholine receptor antibodies (AchR-Ab), whereas the expression of OX40L on CD19+ B cells and CD14+ monocytes was negatively correlated with disease duration. (5) Binary regression analysis showed that patients with high CD4+ OX40 expression and high sOX40L levels had an increased risk of relapse. Conclusions. OX40 and OX40L are abnormally expressed in the peripheral blood of patients with MG and may be closely associated with disease status and treatment. The OX40/OX40L pathway may be involved in the immunopathological process of MG and may play a role mainly in the later stage of MG.

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Enhancement of the Soluble Form of OX40 and OX40L Costimulatory Molecules but Reduction of the Membrane Form in Type 1 Diabetes (T1D)

Cited by 7 publications

References 45 publications

Unbalanced expression of membrane-bound and soluble OX40 and OX40 ligand in patients with myasthenia gravis

Unbalanced expression of membrane-bound and soluble OX40 and OX40 ligand in patients with myasthenia gravis

Silica Induction of Diverse Inflammatory Proteome in Lungs of Lupus-Prone Mice Quelled by Dietary Docosahexaenoic Acid Supplementation

Clinical Significance of OX40 and OX40 Ligand in the Peripheral Blood of Patients with Myasthenia Gravis

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