Altered expression of chemokine receptor CXCR5 on T cells of myasthenia gravis patients

Saito, Ryoko; Oda, Hiroshi; Tago, Hideaki; Suzuki, Yasushi; Shimizu, Masayuki; Matsumura, Yuichi; Kondo, Takashi; Itoyama, Yasuto

doi:10.1016/j.jneuroim.2005.09.001

Cited by 68 publications

(46 citation statements)

References 28 publications

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“…Although MG is primarily mediated by autoantibodies, the underlying cellular immune responses also play an important role in autoantibody responses because the anti-AChR Ab response is T cell dependent (44,52). T cell response to AChR was elevated in MG patients (52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

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Amelioration of Experimental Autoimmune Myasthenia Gravis in Rats by Neonatal FcR Blockade

García

Santoro

et al. 2007

The Journal of Immunology

106

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The neonatal FcR (FcRn) plays a critical role in IgG homeostasis by protecting it from a lysosomal degradation pathway. It has been shown that IgG has an abnormally short half-life in FcRn-deficient mice and that FcRn blockade significantly increases the catabolism of serum IgG in mice. Therefore, reduction of serum IgG half-life may have therapeutic benefits in Ab-mediated autoimmune diseases. We have studied the therapeutic effects of an anti-rat FcRn mAb, 1G3, in two rat models of myasthenia gravis, a prototypical Ab-mediated autoimmune disease. Passive experimental autoimmune myasthenia gravis was induced by administration of an anti-acetylcholine receptor (AChR) mAb, and it was shown that treatment with 1G3 resulted in dose-dependent amelioration of the disease symptoms. In addition, the concentration of pathogenic Ab in the serum was reduced significantly. The effect of 1G3 was also studied in an active model of experimental autoimmune myasthenia gravis in which rats were immunized with AChR. Treatment with 1G3 significantly reduced the severity of the disease symptoms as well as the levels of total IgG and anti-AChR IgG relative to untreated animals. These data suggest that FcRn blockade may be an effective way to treat Ab-mediated autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

“…T cell response to AChR was elevated in MG patients (52)(53)(54). Thus, ideal therapeutics for Ab mediated autoimmune diseases such as MG may be the combination of therapies that can reduce the autoantibody titer rapidly and, at the same time, control the underlying cellular immune response.…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Experimental Autoimmune Myasthenia Gravis in Rats by Neonatal FcR Blockade

García

Santoro

et al. 2007

The Journal of Immunology

106

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“…However, the thymic TFH cells in thymoma patients with MG remain controversial (19,20). In this study, we investigated the percentage of thymic TFH cells around the thymoma region and their activity in thymoma patients with MG.…”

Section: Abstract: Myasthenia Gravis (Mg); Thymoma; T Follicular Helpmentioning

confidence: 99%

Increased frequency of thymic T follicular helper cells in myasthenia gravis patients with thymoma

et al. 2016

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Results: Higher percentage of thymic TFH cells was found in MG patients with thymoma compared with both thymoma patients without MG and control group. The expression levels of the four markers in thymoma of MG patients were significantly higher than thymoma patients without MG and control group.No significant difference was found in the levels of programmed cell death 1 (PD-1) and Bcl-6 between thymoma patients without MG and the control, while the levels of CXCR5 and ICOS in thymoma patients without MG were higher than control group. Conclusions: These results suggested thymic TFH cells might involve in the pathogenesis of MG with thymoma. However, it needs further study to test if the inhibition of the function of TFH cells could effectively alleviate the severity of MG. 11,12). These cells are characterized by increased expression of numerous molecules including inducible co-stimulator (ICOS), program death 1 (PD-1) and CD40-ligand, the transcription factor B cell lymphoma 6 (Bcl-6) and regulatory cytokines which can promote the development of TFH cells and the interaction of T and B cells (13). Increased numbers of circulating TFH cells and aberrant activation of TFH cells are associated with the development of autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and IgA nephropathy (14-17). Keywords: Myasthenia gravis (MG); thymoma; T follicular helper cells (TFH cells)The numbers of TFH cells in peripheral blood of MG patients are significantly higher than that of healthy control, and the frequency of TFH cells are positively correlated with levels of serum AchR-Ab (18). However, the thymic TFH cells in thymoma patients with MG remain controversial (19,20). In this study, we investigated the percentage of thymic TFH cells around the thymoma region and their activity in thymoma patients with MG. Materials and methods SamplesA total of 50 patients were enrolled who underwent thymectomy at the Department of Thoracic Surgery, Huashan Hospital of FDU between 2013 and 2014. Thirty thymoma patients with MG were recruited as MG group (MG) while another twenty thymoma patients without MG were recruited as non-MG group (NMG). We collected ten control thymic biopsies from cardiac surgery cases of the Department of Cardiovascular Surgery, Huashan Double-labeled immunofluorescence (IF)Endogenous peroxide activity quench were performed with protocols similar to IHC staining. Tissues were incubated with rabbit anti-human CD4 antibody (EPR6855, Abcam) at 37 ℃ for 4 h. Tissues were incubated with mouse antihuman CXC chemokine receptor 5 (CXCR5) monoclonal antibody (Clone51505, Abcam) at 37 ℃ for 24 h. Sections were incubated with Goat anti-Rabbit IgG-heavy and light chain cross-adsorbed antibody dylight ® 488-conjugated affinipure (A90-516D2, Bethyl, USA) at 37 ℃ for 2 h. Sections were incubated with goat anti-mouse IgGheavy and light chain cross-adsorbed antibody dylight ® 594-conjugated affinipure (A120-201D4; Bethyl, USA) at 37 ℃ for 2 h. Finally, the sections were mounted and cov...

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“…7,12,[15][16][17][18][19][20] These blood T FH cells (CD45RA -) express similar markers as lymphoid T FH cells (including CXCR5, ICOS, CD40L and IL-21), 21 but do not express the Bcl-6 protein. 7,12,[15][16][17]22 Importantly, cT FH levels correlate with auto-antibodies and levels of protective antibodies following vaccination.…”

Section: T Follicular Helper (T Fh ) Cells Have Emerged As the Main Ementioning

confidence: 99%

TIGIT-positive circulating follicular helper T cells display robust B-cell help functions: potential role in sickle cell alloimmunization

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nphoid T FH , cT FH cells can express significant levels of surface programmed cell death-1 (PD-1), 31 although the function of PD-1 on T FH cells remains controversial since it is associated with both promotion 16,17 and inhibition of B-cell responses. 18,[32][33][34] Taken together, these reports underscore the need for better characterization of markers for cT FH cells displaying defined functions not only in steady state but also in diseases. Remarkably, PD-1 has been described as a member of the growing family of inhibitory receptors also referred to as immune checkpoints, responsible for aborting T-cell responses. 35 Interestingly, another member of the immune checkpoint family, TIGIT (T-cell immunoreceptor with Ig and immunoreceptor tyrosinebased inhibitory domains), was reported to be overexpressed on both tonsillar and cT FH cells, 17 and was shown to be involved in interactions between T cells and follicular dendritic cells to regulate B-cell responses. 36,37 However, the functional activity of TIGIT on T FH cells, including cT FH cells, has not been studied to date.In this study, we took the approach of using TIGIT and PD-1 to characterize the phenotype and function of circulating T FH subsets and to investigate whether expression of these molecules on cT FH cells modulated their functions in healthy volunteer donors and in a group of chronically transfused SCD patients with or without alloantibodies. Methods Human samplesAll studies were approved by the Institutional Review Boards of the New York Blood Center (NYBC). De-identified fresh leukopaks were obtained from healthy donors at the NYBC. For SCD patients' samples, blood was obtained solely from discard apheresis waste bags obtained during erythrocytapheresis procedures at the Children's Hospital of Philadelphia (see Online Supplementary Material for details). T-cell studiesFreshly-sorted CD4 + T-cell subsets and autologous naïve or memory B cells were used (see Online Supplementary Material for details). Blocking antibodies for TIGIT 38 and PD-1 34,39 were preincubated with sorted T cells before being co-cultured with autologous B cells. Results PD- Expression of ICOS, CD40L and IL-21 by TIGIT + cT FH cellsWe next tested whether TIGIT + cT FH cells were functionally different from cT FH + cT FH populations from a small number of healthy donors (n=3 or 4) were sorted and their ability to express T FH -associated co-stimulatory markers and cytokines following stimulation was compared to those of sorted autologous PD-1 -/TIGIT -subsets (gating strategy shown in Online Supplementary Figure S1). As a control, sort-purified autologous CXCR5 -non-cT FH cells expressing TIGIT E. Godefroy et al. 1416haematologica | 2015; 100(11) A B C© F e r r a t a S t o r t i F o u n d a t i o n ("TIGIT+") or not ("TIGIT-") were also tested. We first monitored expression of co-stimulatory molecules CD40L and ICOS, both specialized in providing Bcell help, on T-cell subsets before or after stimulation by immunos...

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Altered expression of chemokine receptor CXCR5 on T cells of myasthenia gravis patients

Cited by 68 publications

References 28 publications

Amelioration of Experimental Autoimmune Myasthenia Gravis in Rats by Neonatal FcR Blockade

Amelioration of Experimental Autoimmune Myasthenia Gravis in Rats by Neonatal FcR Blockade

Increased frequency of thymic T follicular helper cells in myasthenia gravis patients with thymoma

TIGIT-positive circulating follicular helper T cells display robust B-cell help functions: potential role in sickle cell alloimmunization

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