Humoral autoimmunity: a failure of regulatory T cells?

Regulatory T cells (Tregs) are essential in maintaining tolerance to self. Several lines of evidence indicate that Tregs are functionally impaired in a variety of autoimmune diseases, leading to inefficient regulation of autoimmune T cells. Recent findings also suggest that Tregs are essential in controlling autoreactive B cells. The recently identified follicular regulatory T cell subset (TFR) is thought to regulate the production of autoantibodies in the germinal center (GC) response. Here we provide an update on the role of Tregs in controlling the GC response, and whether defective control over B cell tolerance contributes to autoimmunity.publisher: Elsevier articletitle: Humoral autoimmunity: A failure of regulatory T cells? journaltitle: Autoimmunity Reviews articlelink: http://dx.doi.org/10.1016/j.autrev.2015.04.006 content_type: article copyright: Copyright © 2015 Elsevier B.V. All rights reserved.status: publishe

Compositional Changes of B and T Cell Subtypes during Fingolimod Treatment in Multiple Sclerosis Patients: A 12-Month Follow-Up Study

<div><p>Background and objective</p><p>The long term effects of fingolimod, an oral treatment for relapsing-remitting (RR) multiple sclerosis (MS), on blood circulating B and T cell subtypes in MS patients are not completely understood. This study describes for the first time the longitudinal effects of fingolimod treatment on B and T cell subtypes. Furthermore, expression of surface molecules involved in antigen presentation and costimulation during fingolimod treatment are assessed in MS patients in a 12 month follow-up study.</p><p>Methods</p><p>Using flow cytometry, B and T cell subtypes, and their expression of antigen presentation, costimulation and migration markers were measured during a 12 month follow-up in the peripheral blood of MS patients. Data of fingolimod-treated MS patients (n = 49) were compared to those from treatment-naive (n = 47) and interferon-treated (n = 27) MS patients.</p><p>Results</p><p>In the B cell population, we observed a decrease in the proportion of non class-switched and class-switched memory B cells (p<0.001), both implicated in MS pathogenesis, while the proportion of naive B cells was increased during fingolimod treatment in the peripheral blood (PB) of MS patients (p<0.05). The remaining T cell population, in contrast, showed elevated proportions of memory conventional and regulatory T cells (p<0.01) and declined proportions of naive conventional and regulatory cells (p<0.05). These naive T cell subtypes are main drivers of MS pathogenesis. B cell expression of CD80 and CD86 and programmed death (PD) -1 expression on circulating follicular helper T cells was increased during fingolimod follow-up (p<0.05) pointing to a potentially compensatory mechanism of the remaining circulating lymphocyte subtypes that could provide additional help during normal immune responses.</p><p>Conclusions</p><p>MS patients treated with fingolimod showed a change in PB lymphocyte subtype proportions and expression of functional molecules on T and B cells, suggesting an association with the therapeutic efficacy of fingolimod.</p></div

Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis.

Follicular regulatory T cells (TFR) have been extensively characterized in mice and participate in germinal center responses by regulating the maturation of B cells and production of (auto)antibodies. We report that circulating TFR are phenotypically distinct from tonsil-derived TFR in humans. They have a lower expression of follicular markers, and display a memory phenotype and lack of high expression of B cell lymphoma 6 and ICOS. However, the suppressive function, expression of regulatory markers, and FOXP3 methylation status of blood TFR is comparable with tonsil-derived TFR. Moreover, we show that circulating TFR frequencies increase after influenza vaccination and correlate with anti-flu Ab responses, indicating a fully functional population. Multiple sclerosis (MS) was used as a model for autoimmune disease to investigate alterations in circulating TFR. MS patients had a significantly lower frequency of circulating TFR compared with healthy control subjects. Furthermore, the circulating TFR compartment of MS patients displayed an increased proportion of Th17-like TFR. Finally, TFR of MS patients had a strongly reduced suppressive function compared with healthy control subjects. We conclude that circulating TFR are a circulating memory population derived from lymphoid resident TFR, making them a valid alternative to investigate alterations in germinal center responses in the context of autoimmune diseases, and TFR impairment is prominent in MS

Proportional B cell and T cell subtype changes in MS patients during fingolimod treatment.

<p>(A) CD19⁺ B cell subtype proportion and (B) CD4⁺ T cell subtype proportion within the PB of treatment-naive, IFN-β and fingolimod-treated MS patients. Results are presented as relative values within the CD19⁺ B cell or CD4⁺ T cell population. Subtype proportions were calculated as follows: (% subtype/100)×% CD19⁺ or CD4⁺ within the total lymphocyte population. Statistically significant differences compared to 0 m are shown in bold. For B cells: naive B cells; NCSM B cells  =  non class-switched memory B cells; CSM B cells  =  class-switched memory B cells and DN B cells  =  double negative B cells. For T cells: nTreg  =  naive Treg; mTreg  =  memory Treg; TransTreg  =  transitional Treg; nTconv  =  naive Tconv; mTconv  =  memory Tconv; TransTconv  =  transitional Tconv.</p

Total number of lymphocytes, CD4⁺ T cells and CD19⁺ B cells in the PB.

<p>Total number (×10³ cells/µl blood) of lymphocytes, T cells and B cells in treatment-naive, IFN-β treated MS patients at baseline and fingolimod-treated MS patients during 12 months follow-up. Mean and standard error of the mean are presented. • lymphocytes; ▪ CD4⁺ T cells; ▴ CD19⁺ B cells.</p

Percentage of T_FH and expression of CXCR5 and PD-1 during fingolimod treatment in MS patients.

<p>(A.) Percentage of PB follicular helper T cells (T_FH) in MS patients treated with fingolimod. Data are presented as percentage within the CD4⁺ T cell population. (B.) Expression of CXCR5 and (C.) expression of PD-1 within T_FH cell population.</p