Distinct phenotypic subpopulations of circulating CD4+CXCR5+ follicular helper T cells in children with active IgA vasculitis

Abstract

Background: Circulating follicular helper T (Tfh) cells are a heterogeneous population of CD4⁺ helper T cells that promotes pathogenic immune responses in autoimmune diseases. In this study, we examined the status of different subpopulations of Tfh cells in peripheral circulation and their associations with various clinical characteristics of IgA vasculitis (IgAV).

Methods: According to the phenotypic expressions of different molecules, focus was given on six subpopulations of Tfh cells: CD4⁺CXCR5⁺, CD4⁺CXCR5⁺ICOS⁺, CD4⁺CXCR5⁺ICOS⁺PD-1⁺, CD4⁺CXCR5⁺ICOS^highPD-1^high, CD4⁺CXCR5⁺ICOS^-PD-1⁺, and CXCR5⁺CD45RA^-IL-21⁺. The frequencies of these six subpopulations and the circulating level of Tfh-related cytokine interleukin 21 (IL-21) were measured from 27 patients with IgAV and 15 healthy controls (HC) by flow cytometry and flow cytometric bead array, respectively.

Results: Significantly higher frequencies of CD4⁺CXCR5⁺, CD4⁺CXCR5⁺ICOS⁺, CD4⁺CXCR5⁺ICOS⁺PD-1⁺, CD4⁺CXCR5⁺ICOS^highPD-1^high and CXCR5⁺CD45RA^-IL-21⁺ Tfh cells, as well as higher levels of plasma IL-21, were detected in IgAV patients compared to HC. The level of each Tfh subpopulation varied by the presenting symptoms of IgAV, but did not differ between patients treated or not treated with glucocorticoids. When the disease entered the remission stage following treatment, circulating levels of CD4⁺CXCR5⁺, CD4⁺CXCR5⁺ICOS⁺, CD4⁺CXCR5⁺ICOS⁺PD-1⁺, CD4⁺CXCR5⁺ICOS^highPD-1^high and CXCR5⁺CD45RA^-IL-21⁺ Tfh cells, as well as plasma IL-21 levels were reduced. Among the six subpopulations of Tfh cells, both CD4⁺CXCR5⁺ICOS⁺ and CXCR5⁺CD45RA^-IL-21⁺ significantly and positively correlated with serum IgA and plasma IL-21 levels, but only CXCR5⁺CD45RA^-IL-21⁺ significantly and negatively correlated with the serum C4 level.

Conclusions: Tfh cells may differentially contribute to the development of IgAV or predict disease progression. These findings provide novel insights in the pathogenesis of IgAV and may benefit treatment development targeting organ-specific presenting symptoms of IgAV.

Keywords: Follicular helper T cells; Glucocorticoid; IgA vasculitis; Interleukin 21; Remission; Symptoms.