Different antibody-associated autoimmune diseases have distinct patterns of T follicular cell dysregulation

Abstract

Autoantibodies are produced within germinal centers (GC), in a process regulated by interactions between B, T follicular helper (Tfh), and T follicular regulatory (Tfr) cells. The GC dysregulation in human autoimmunity has been inferred from circulating cells, albeit with conflicting results due to diverse experimental approaches. We applied a consistent approach to compare circulating Tfr and Tfh subsets in patients with different autoimmune diseases. We recruited 97 participants, including 72 patients with Hashimoto’s thyroiditis (HT, n = 18), rheumatoid arthritis (RA, n = 16), or systemic lupus erythematosus (SLE, n = 32), and 31 matched healthy donors (HD). We found that the frequency of circulating T follicular subsets differed across diseases. Patients with HT had an increased frequency of blood Tfh cells (p = 0.0215) and a reduced Tfr/Tfh ratio (p = 0.0338) when compared with HD. This was not observed in patients with systemic autoimmune rheumatic diseases (RA, SLE), who had a reduction in both Tfh (p = 0.0494 and p = 0.0392, respectively) and Tfr (p = 0.0003 and p = 0.0001, respectively) cells, resulting in an unchanged Tfr/Tfh ratio. Activated PD-1+ICOS+Tfh and CD4+PD-1+CXCR5–Tph cells were raised only in patients with SLE (p = 0.0022 and p = 0.0054), without association with disease activity. Our data suggest that GC dysregulation, assessed by T follicular subsets, is not uniform in human autoimmunity. Specific patterns of dysregulation may become potential biomarkers for disease and patient stratification.

Children with extended oligoarticular and polyarticular juvenile idiopathic arthritis have alterations in B and T follicular cell subsets in peripheral blood and a cytokine profile sustaining B cell activation

“… 46 58 59 Furthermore, lower levels of PD1+Tfh cells, PD1+ICOS+Tfh cells and Tph cells were found in JIA patients when compared with controls. Although the frequencies observed of Tfh and Tph cells are not consistent among distinct immune-mediated diseases, 60 some studies described an increased frequency of these T cell subpopulations in peripheral blood and synovial fluid from JIA patients. 48–50 In particular, it was observed that Tph cells are enriched in the joints of oligo JIA patients and in the synovial fluid of ANA+ JIA patients, where they express many B cell helper-associated markers and have the capacity to induce B cell differentiation and antibody production.…”

Gut-joint axis: Gut dysbiosis can contribute to the onset of rheumatoid arthritis via multiple pathways

“…In another study, Ribeiro et al reported that the frequency of circulating Tfh and Tfr cells was decreased in patients with RA and that the Tfr/Tfh ratio was similar to HCs (Ribeiro et al, 2022). These results show inconsistent results on the role of the Tfr/Tfh ratio in the pathogenesis of RA.…”

“…B cells produce antibodies against extracellular pathogens and toxins. Antibodies are produced within germinal centers, regulated by interactions between B, Tfh, and Tfr cells (Ribeiro et al, 2022). Tfh cells are a CD4 T cell lineage that interacts with B cells to form germinal centers, promote differentiation into plasma cells, promote class-switching, somatic hypermutation, and the generation of high-affinity antigen-specific memory B cells and antibody-producing cells (Diamanti et al, 2016;Wang et al, 2019b;Zeng et al, 2022).…”

Exploring the Role of PD-1 in the Autoimmune Response: Insights into Its Implication in Systemic Lupus Erythematosus

“…The absence of CXCR5 leads them to exit germinal centers and position themselves within inflamed tissues by expressing other chemokine receptors such as CCR2 and CCR5, where Tph cells induce B cell differentiation through the production of IL-21 [14]. Increased numbers of Tph cells have also been observed in SLE (59)(60)(61)(62), RA [58][59][60][61], and pSS [54,67,68].…”