Intravenous Immunoglobulin Attenuates Experimental Autoimmune Arthritis by Inducing Reciprocal Regulation of Th17 and Treg Cells in an Interleukin‐10–Dependent Manner

Lee, Seon‐Yeong; Jung, Young Ok; Ryu, Jun-Geol; Kang, Chang-Suk; Kim, Min Jung; Son, Hye-Jin; Yang, Eun Ae; Ju, Ji-hyun; Kang, Young‐Sun; Park, Sung-Hwan; Kim, Ho-Youn; Cho, Mi‐La

doi:10.1002/art.38627

Cited by 35 publications

(35 citation statements)

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“…Immunoglobulins further promote production of Treg cells and immune-suppressive function. Immunoglobulins may modulate the number of Treg cells by modification of the DC phenotype to immature or tolerogenic DCs and promotion of STAT5 expression, an essential molecule related to the production of Treg cells [17]. They also increase Treg cells suppressive potency by increasing the percentage of Treg cells in the CD4 population and/or by increasing the percentage of Treg cells expressing IL-10, as well as promoting FOXP3 expression and the secretion of effector molecules [18].…”

Section: Discussionmentioning

confidence: 99%

“…IVIG can promote Treg cell function and the corresponding cytokines secretion, by modifying DCs phenotype to tolerogenic activity and promotion of the STAT5 expression. STAT5 is considered an essential molecule in Treg cell generation [16,17,18]. Based on these findings, the present study investigated the effects of IVIG on Treg cells derived from immunosuppressed mice with PA pneumonia, via the detection of FOXP3 mRNA expression level in lung tissue and the serum TGF-β concentration.…”

Section: Introductionmentioning

confidence: 99%

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Effect of intravenous immunoglobulin on the function of Treg cells derived from immunosuppressed mice with Pseudomonas aeruginosa pneumonia

Chen

Yuan

et al. 2017

PLoS ONE

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AimThe present study aimed to investigate the effect of intravenous immunoglobulin (IVIG) on regulatory T (Treg) cells derived from immunosuppressed mice with Pseudomonas aeruginosa (PA) pneumonia.MethodsA total of 108 BALB/c mice were randomly divided into the following groups: control group (Control), immunosuppressed group (IS), PA pneumonia group (PA), PA pneumonia in immunosuppressed group (IS + PA), PA pneumonia with IVIG treatment in immunocompetent group (PA + IVIG) and PA pneumonia with IVIG treatment in immunosuppressed group (IS + PA + IVIG). Each group comprised 18 mice. The combined PA pneumonia in immunosuppressed model and the treatment models were established. The mice in each group were sacrificed at 4, 8, and 24 h time points. The general condition and pathological changes in the lung tissues of the mice were monitored. Reverse transcription-polymerase chain reaction was used to detect the forkhead box P3 (FOXP3) mRNA relative expression level in the lung tissues. The enzyme-linked immunosorbent assay was used to detect the serum concentration of active transforming growth factor beta (TGF-β).ResultsNo inflammatory response were exhibited in the lung tissues of the mice in Control group and IS group, while varying degrees of acute lung injury were revealed in the mice in PA group, IS + PA group, PA + IVIG group and IS + PA + IVIG group. Lung tissue injury was most apparent at the 8 h time point, and it indicated the greatest effect in IS + PA group. Whereas tissue damages were alleviated in PA + IVIG group and IS + PA + IVIG group compared with IS + PA group. In addition, tissue damage lessened in PA + IVIG group compared with PA group and IS + PA + IVIG group. FOXP3 mRNA expression levels in the lung tissues and the serum concentration of TGF-β were lower in IS group, PA group, IS + PA group and IS + PA + IVIG group at the 4, 8 and 24 h time points, respectively compared with Control group. FOXP3 mRNA expression levels decreased in PA + IVIG group at the 4h time point and TGF-β serum concentrations decreased at the 4 and 8h time points compared with Control group, and subsequently increased.ConclusionsIn the immunosuppred model with PA pneumonia, the immune system was greatly compromised. IVIG partially restored the immunosuppressed functions of Treg cells, suppressed the overactivated immune system and ameliorated the development of the disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of intravenous immunoglobulin on the function of Treg cells derived from immunosuppressed mice with Pseudomonas aeruginosa pneumonia

Chen

Yuan

et al. 2017

PLoS ONE

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“…Nevertheless, this hypothesis appears very unlikely as it has recently been shown in a model of collagen-induced arthritis that IVIg therapy leads to a decrease in TFH and B-cell differentiation, whereas TFRegs are increased. 56 Of importance, complete response to this question requires the assessment of the spleen from ITP patients who responded to medical therapy, which is impossible as these patients do not undergo splenectomy. Conversely, the increase in TFH associated with B-cell differentiation is more likely to be because of chronic antigen stimulation (ie, platelet GPs during ITP), similarly to what is observed in tonsils during chronic bacterial infection 1 or in lymph nodes during HIV infection.…”

Section: Discussionmentioning

confidence: 99%

Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia

Audia

Rossato

Santegoets

et al. 2014

Blood

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Key Points• Human splenic TFH expansion during ITP participates in B-cell differentiation and antiplateletantibody production.• IL-21 and CD40 are key TFH molecules that could be promising targets in the treatment of ITP.Antiplatelet-antibody-producing B cells play a key role in immune thrombocytopenia (ITP) pathogenesis; however, little is known about T-cell dysregulations that support B-cell differentiation. During the past decade, T follicular helper cells (TFHs) have been characterized as the main T-cell subset within secondary lymphoid organs that promotes B-cell differentiation leading to antibody class-switch recombination and secretion. Herein, we characterized TFHs within the spleen of 8 controls and 13 ITP patients. We show that human splenic TFHs are the main producers of interleukin (IL)-21, express CD40 ligand (CD154), and are located within the germinal center of secondary follicles. Compared with controls, splenic TFH frequency is higher in ITP patients and correlates with germinal center and plasma cell percentages that are also increased. In vitro, IL-21 stimulation combined with an anti-CD40 agonist antibody led to the differentiation of splenic B cells into plasma cells and to the secretion of antiplatelet antibodies in ITP patients. Overall, these results point out the involvement of TFH in ITP pathophysiology and the potential interest of IL-21 and CD40 as therapeutic targets in

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“…Intravenous immunoglobulin (IVIg) therapy has been shown to be beneficial in various autoimmune diseases . IVIg has a therapeutic effect in RA in human and animal models such as collagen‐induced arthritis (CIA) . IVIg immunomodulate the humoral and cellular responses of the immune network through the Fab and Fc portions of the immunoglobulins .…”

Section: Introductionmentioning

confidence: 99%

Anti-citrullinated-protein-antibody-specific intravenous immunoglobulin attenuates collagen-induced arthritis in mice

Svetlicky

Kivity

Odeh

et al. 2015

Clinical and Experimental Immunology

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SummaryAdministration of intravenous immunoglobulin (IVIg) is a recognized safe and efficient immunomodulation therapy for many autoimmune diseases. Anti-idiotypic antibody binding to pathogenic autoantibodies was proposed as one of the mechanisms attributed to the protective activity of IVIg in autoimmunity. The aim of this study was to fractionate the anti-anticitrullinated protein anti-idiotypic-antibodies (anti-ACPA) from an IVIg preparation and to test it as a treatment for collagen-induced arthritis in mice. IVIg was loaded onto an ACPA column. The eluted fraction was defined as ACPA-specific-IVIg (ACPA-sIVIg). Collagen-induced-arthritis (CIA) was induced in mice. Mice were treated weekly with ACPA-sIVIg, lowdose-IVIg, high-dose-IVIg and phosphate-buffered saline (PBS). Sera-ACPA titres, anti-collagen anitbodies and cytokine levels were analysed by enzymelinked immunosorbent assay (ELISA); antibody-forming-cell activity by enzyme-linked imunospot (ELISPOT) assay; and expansion of regulatory T cell (T reg ) population by fluorescence activated cell sorter (FACS). ACPAsIVIg inhibited ACPA binding to citrullinated-peptides (CCP) in vitro 100 times more efficiently than the IVIg compound. ACPA-sIVIg was significantly more effective than the IVIg-preparation in attenuating the development of collagen-induced arthritis. Splenocytes from CIA mice treated with ACPA-sIVIg reduced the ACPA and anti-collagen-antibody titres, including the number of anti-collagen and ACPA antibody-forming cells. In parallel, splenocytes from ACPA-sIVIg treated mice secreted higher levels of anti-inflammatory cytokines and lower proinflammatory cytokines. The ACPA-sIVIg inhibitory potential was accompanied with expansion of the T reg population. Low-dose IVIg did not affect the humoral and cellular response in the CIA mice in comparison to the PBS-treated mice. Based on our results, IVIg may be considered as a safe compound for treating patients with rheumatoid arthritis by neutralizing pathogenic autoantibodies, reducing proinflammatory cytokines and expanding the T reg population.

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Intravenous Immunoglobulin Attenuates Experimental Autoimmune Arthritis by Inducing Reciprocal Regulation of Th17 and Treg Cells in an Interleukin‐10–Dependent Manner

Cited by 35 publications

References 50 publications

Effect of intravenous immunoglobulin on the function of Treg cells derived from immunosuppressed mice with Pseudomonas aeruginosa pneumonia

Effect of intravenous immunoglobulin on the function of Treg cells derived from immunosuppressed mice with Pseudomonas aeruginosa pneumonia

Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia

Anti-citrullinated-protein-antibody-specific intravenous immunoglobulin attenuates collagen-induced arthritis in mice

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