Follicular helper and follicular regulatory T cell subset imbalance is associated with higher activated B cells and abnormal autoantibody production in primary anti-phospholipid syndrome patients

Abstract

Primary anti-phospholipid antibody syndrome (pAPS) is a multi-organ autoimmune disease, and autoantibodies are involved in its pathogenesis. Follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr) are critical for B cell maturation and antibody production, but their roles in pAPS remain unknown. We enrolled 32 pAPS patients and 23 healthy controls (HCs) and comprehensively analyzed circulating Tfh and Tfr, as well as their subsets, using flow cytometry. Clinical data including autoantibody levels were collected and their correlations with Tfh and Tfr subsets were analyzed. In addition, correlation analyses between B cell functional subsets and Tfh and Tfr were performed. Changes and potential effects of serum cytokines on Tfr and Tfh were further explored. We found the circulating Tfr was significantly decreased while Tfh and Tfh/Tfr ratios were increased in pAPS patients. Tfh2, inducible T cell co-stimulator (ICOS) + programmed cell death 1 (PD-1) + Tfh and Ki-67 + Tfh percentages were elevated, while CD45RA − forkhead box protein 3 (FoxP3) hi , Helios + , T cell immunoglobulin and ITIM (TIGIT) + and Ki-67 + Tfr percentages were decreased in pAPS patients. New memory B cells and plasmablasts were increased and altered B cell subsets and serum autoantibodies were positively correlated with Tfh, Tfh2, ICOS + PD-1 + Tfh cells and negatively associated with Tfr, CD45RA − FoxP3 hi Tfr and Helios + Tfr cells. In addition, pAPS with LA/aCL/β2GPI autoantibodies showed lower functional Tfr subsets and higher activated Tfh subsets. Serum interleukin (IL)-4, IL-21, IL-12 and transforming growth factor (TGF)-β1 were up-regulated and associated with Tfh and Tfr subset changes. Our study demonstrates that imbalance of circulating Tfr and Tfh, as well as their functional subsets, is associated with abnormal autoantibody levels in pAPS, which may contribute to the pathogenesis of pAPS.

B-Cells and BAFF in Primary Antiphospholipid Syndrome, Targets for Therapy?

“…Transitional (CD24+CD38+) and double negative (CD27-IgD-) B-cells were found to be increased [33,43] or unaltered [34] in patients with PAPS and interleukin-10 producing regulatory B-cells (Bregs) were found decreased in patients with PAPS [42]. Transitional B-cells may develop into naïve B-cells, an increase in these cells may therefore be in line with the increase in naïve B-cells reported by others as outlined earlier.…”

“…Three studies measured the frequency of plasmablasts in the peripheral blood of patients with PAPS of which two reported an increase [42,43] and the other no statistically significant difference [34] in the number of plasmablasts between patients with PAPS versus healthy controls, although a similar trend was seen in this latter study. In one study, plasmablasts were identified as producers of aPL since omitting plasmablasts (by depletion of CD20 negative B-cells) from peripheral blood mononuclear cells from patients with PAPS that were stimulated ex vivo with IL-6, IL-21, CD40L, and APRIL resulted in an abrogation of the production of aPL.…”

“…Although SLE is similarly associated with an increase in plasmablasts [34,42], in SLE increased numbers of plasmablasts do correlate with anti-dsDNA antibodies and disease activity [44]. Although no clinical associations between plasmablasts numbers and clinical features were reported in patients with PAPS, a link between increased plasmablast numbers and increased activation of the type I IFN signature [42] and changes in the number of circulating regulatory and follicular helper T-cells [43] in patients with PAPS was noted.…”

Update on pathomechanisms and treatments in allergic rhinitis

“…Tfr cells represent a specialized subpopulation of Tfh cells with signatures from Treg and are present in B cell follicles. Accumulating evidence has highlighted a heterogeneity of Tfr cells in humans and mice, 35–37 of which Tfr (CD4 + CXCR5 + CD45RA low Foxp3 + ) cells with IL‐10‐deficient secretion have been shown to be inadequate in suppressing memory B cells in AR patients 38,39 …”

“…34 Tfr cells represent a specialized subpopulation of Tfh cells with signatures from Treg and are present in B cell follicles. Accumulating evidence has highlighted a heterogeneity of Tfr cells in humans and mice, [35][36][37] of which Tfr (CD4 + CXCR5 + CD45RA low Foxp3 + ) cells with IL-10-deficient secretion have been shown to be inadequate in suppressing memory B cells in AR patients. 38,39 Restoring Treg function in AR is one of the therapeutic targets, which is mainly dependent on the regulation of FOXP3 and inhibitory cytokines such as IL-10 and transforming growth factorβ (TGFβ).…”