CXCL13/CXCR5 axis facilitates TFH expansion and correlates with disease severity in adults with immune thrombocytopenia.

Background: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder defined by a diminished platelet count. ITP pathogenesis involves intricate changes to both cellular and humoral immunity. The pivotal roles of follicular helper T (TFH) cells in the maturations of B cells and the production of antibodies are well-established. However, the specific role of TFH to the immunopathogenesis of ITP remain incompletely understood. This study aimed to clarify the association of CXCL13/CXCR5 axis with TFH in adults with ITP.
Methods: A total of 97 ITP patients and 41 healthy controls were enrolled. CD4 ⁺ CXCR5 ⁺ TFH, CD4 ⁺ CXCR5 ⁺ PD-1 ⁺ TFH, CD4 ⁺ CXCR5 ⁺ Foxp3 ⁺ follicular regulatory T cells (TFR), and desialylated platelets in peripheral blood were measured by flow cytometry. Plasma cytokines were assessed by enzyme-linked immunosorbent assay. CD4 ⁺ T cells cocultured with chemokine CXCL13 in vitro was performed for the measurement of TFH proliferation. Intracellular production of reactive oxygen species (ROS) was examined by dichlorodihydrofluorescein diacetate (DCFH-DA) probe staining.
Results: We observed a significant increase in circulating TFH and a marked decrease in circulating TFR in the entire ITP cohort. The ratio of TFH/TFR was elevated, accompanied by heightened levels of platelet desialylation, cytokines BAFF, HMGB1, and IL-21, while levels of IL-10 were downregulated in adults with ITP. Notably, patients with ITP exhibiting platelet count below 50 × 10 ⁹ /L had dramatically elevated levels in both chemokine CXCL13 and its receptor CXCR5 ⁺ TFH compared to those with platelet count above 100 × 10 ⁹ /L. High frequencies of TFH correlated with poor therapeutic response. Furthermore, in vitro CD4 ⁺ T cell proliferation assay demonstrated a CXCL13 dose-dependent increase in the frequencies in both CD4 ⁺ CXCR5 ⁺ TFH and CD4 ⁺ CXCR5 ⁺ PD-1 ⁺ TFH from ITP patients. Intriguingly, DCFH-DA assay illustrated a significant enhancement in intracellular ROS generation in CXCR5 ⁺ T cell subsets, especially in CD4 ⁺ CXCR5 ⁺ PD-1 ⁺ TFH from 4 patients with ITP.
Conclusions: These results underscore the pivotal role of CXCL13/CXCR5 axis-drived TFH expansion in the pathogenesis of ITP, providing a potential disease severity biomarker.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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