Alterations in B- and circulating T-follicular helper cell subsets in immune thrombotic thrombocytopenic purpura

Abstract

T follicular helper (Tfh) cells regulate development of antigen-specific B-cell immunity. We prospectively investigated B-cell and cTfh subsets in 45 immune TTP patients at presentation and longitudinally after rituximab (RTX). B-cell phenotype was altered at acute iTTP presentation with decreased transitional cells and postgerminal centre (post-GC) memory B cells and increased plasmablasts compared to healthy controls. A higher percentage of plasmablasts was associated with higher anti-ADAMTS13 IgG and lower ADAMTS13 antigen levels. In asymptomatic patients with ADAMTS13 relapse, there were increased naïve B cells and a global decrease in memory subsets, with a trend to increased plasmablasts. Total circulating Tfh (CD4+CXCR5+) and PD1+ Tfh cells were decreased at iTTP presentation. CD80 expression was decreased on IgD+ memory cells and double negative memory cells in acute iTTP. Longitudinal analysis: at repopulation after B cell depletion in de novo iTTP, post-GC and double negative memory B cells were reduced compared to pre-RTX. RTX did not cause alteration in cTfh frequency. The subsequent kinetics of naïve, transitional, memory B cells and plasmablasts did not differ significantly between patients who went on to relapse vs those who remained in remission. In summary, acute iTTP is characterised by dysregulation of B- and cTfh-cell homeostasis with depletion of post-GC memory cells and cTfh cells and increased plasmablasts. Changes in CD80 expression on B cells further suggest altered interactions with T cells.

Pathological Mechanisms and Novel Testing Methods in Thrombotic Thrombocytopenic Purpura

“…iTTP is an autoantibody-mediated phenomenon that functions as a Type II immune reaction, and certain aspects of lymphocyte populations—although heretofore not well studied—are characteristic. Recent research indicates that T-follicular helper (Tfh) cells have a yet to be determined role in TTP pathogenesis, and that furthermore, there could be defined differences in these cell populations between new-onset and relapsed iTTP [ 52 ]. In effect, new-onset TTP is characterized by the overexpression of and hyperfunction of the memory capabilities of Tfh cells.…”

“…In contrast, during relapse, the primed immune system is less able to mount a response. This is especially evidenced by a decrease during relapse of double negative IgD - CD38 - memory B cells [ 52 ]. Similarly, activated plasmablasts are significantly higher in new-onset iTTP as compared to healthy controls but not in relapsed patients [ 52 , 53 ].…”

“…This is especially evidenced by a decrease during relapse of double negative IgD - CD38 - memory B cells [ 52 ]. Similarly, activated plasmablasts are significantly higher in new-onset iTTP as compared to healthy controls but not in relapsed patients [ 52 , 53 ]. Thus, it has been hypothesized that increased plasmablasts increase the clearance rate of ADAMTS13 in new TTP patients due to first-time antibody production [ 52 ].…”

“…Similarly, activated plasmablasts are significantly higher in new-onset iTTP as compared to healthy controls but not in relapsed patients [ 52 , 53 ]. Thus, it has been hypothesized that increased plasmablasts increase the clearance rate of ADAMTS13 in new TTP patients due to first-time antibody production [ 52 ]. While the use of rituximab in relapsed patients may partially explain the lack of memory B cells, the higher A-IPC in relapsed versus new-onset iTTP does suggest that there is a mechanistic difference between iTTP types across immune responses [ 8 , 52 , 53 ].…”

The differentiation courses of the Tfh cells: a new perspective on autoimmune disease pathogenesis and treatment

“…Patients with multiple sclerosis exhibited significantly elevated PD1 + cTfh cells frequencies; 36 months after autologous haematopoietic stem cell transplantation (AHSCT), PD1 + cTfh cells frequencies were significantly reduced, consistent with normal subjects, suggesting that AHSCT can control the disease by modulating PD1 + cTfh cells expression in patients with multiple sclerosis [ 109 ]. Patients with acute immune thrombotic thrombocytopenic purpura had decreased GC memory B cells, total cTfh cells, PD1 + cTfh cells, and increased frequency of circulating plasma cells, while dysregulation of B cell and cTfh cells homeostasis may be caused by hyperactivation of T and B cells leading to differentiation of memory B cells to antibody-producing plasmablast and migration of circulating Tfh cells into the GC [ 110 ]. Peripheral blood PD-1 + ICOS + Tfh cells in patients with primary SS (pSS) correlate strongly and positively with disease activity [ 111 ].…”