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

Abstract

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

Imbalanced immune homeostasis in immune thrombocytopenia

“…Similarly, elevated levels of CD4 + T-cell subset, T H 22 cells [10], and their associated cytokines IL-22 and tumor necrosis factor (TNF)-α, were reported in ITP [9,11]. With respect to pathogenic effector T cells that drive autoantibody production, both splenic and peripheral of T-follicular helper (T FH ) cell frequencies were elevated in ITP [12]. This CD4 + T-cell subset, characterized by expression of the surface expression of chemokine (C-X-C motif) receptor 5 (CXCR5) and production of B-cell–promoting cytokine IL-21, provides help to B cells to generate the initial wave of antibody response as well as in promoting B-cell differentiation into high-affinity antibody-producing cells and long-lasting IgG antibody [13].…”

“…This CD4 + T-cell subset, characterized by expression of the surface expression of chemokine (C-X-C motif) receptor 5 (CXCR5) and production of B-cell–promoting cytokine IL-21, provides help to B cells to generate the initial wave of antibody response as well as in promoting B-cell differentiation into high-affinity antibody-producing cells and long-lasting IgG antibody [13]. In ITP patients, the frequency of splenic T FH cells correlated with both with germinal center and plasma cell percentages in the spleens of ITP patients [12]. Furthermore, in vitro, simulation of T FH signaling through provision of IL-21 and CD40 engagement led to the differentiation of splenic B cells into plasma cells and to the secretion of antiplatelet antibodies in ITP patients [12].…”

“…In ITP patients, the frequency of splenic T FH cells correlated with both with germinal center and plasma cell percentages in the spleens of ITP patients [12]. Furthermore, in vitro, simulation of T FH signaling through provision of IL-21 and CD40 engagement led to the differentiation of splenic B cells into plasma cells and to the secretion of antiplatelet antibodies in ITP patients [12]. Altogether, these data suggest the involvement of T FH in ITP pathogenesis.…”

Altered circulating T follicular helper cells in patients with chronic immune thrombocytopenia

“…In addition, it has been recognized that IL-21 may be a master cytokine that promotes the expression of Bcl-6 in CD4 + T cells (21–23). TFH cells produce high levels of IL-21, a cytokine that is critical for GC formation and also for the generation of TFH cells (24).…”

A distinct plasmablast and naive B-cell phenotype in primary immune thrombocytopenia

“…9 High-affinity autoantibody production is facilitated by T follicular helper cells (TFH), a subset recently reported to be expanded proportional to germinal center and plasma cell numbers within the spleens of ITP patients. 10 This study sought to extend existing knowledge of immune dysregulation in ITP by performing detailed flow cytometry-based immunophenotyping of the B-and T-cell compartments. An interest in the therapeutic potential of belimumab, an anti-BAFF humanized monoclonal antibody, led us to focus on BAFF and its receptors in B cells.…”