Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis

Abstract

The study examined germinal centre (GC) reaction in lymph nodes draining inflamed joints and adjacent tissues (dLNs) in male and female Dark Agouti rat collagen type II (CII)-induced arthritis (CIA) model of rheumatoid arthritis. Female rats exhibiting the greater susceptibility to CIA mounted stronger serum CII-specific IgG response than their male counterparts. This correlated with the higher frequency of GC B cells in female compared with male dLNs. Consistently, the frequency of activated/proliferating Ki- 67+ cells among dLN B cells was higher in females than in males. This correlated with the shift in dLN T follicular regulatory (Tfr)/T follicular helper (Tfh) cell ratio towards Tfh cells in females, and greater densities of CD40L and CD40 on their dLN T and B cells, respectively. The higherTfh cell frequency in females was consistent with the greater dLN expression of mRNA for IL-21/27, the key cytokines involved in Tfh cell generation and their help to B cells. Additionally, in CII-stimulated female rat dLN cell cultures IFN-γ/IL-4 production ratio was shifted towards IFN-γ. Consistently, the serum IgG2a(b)/ IgG1 CII-specific antibody ratio was shifted towards an IgG2a(b) response in females. Thus, targeting T-/B-cell interactions should be considered in putative further sex-based translational pharmacology research.Rheumatoid arthritis (RA) is a chronic autoimmune systemic inflammatory disease characterized by synovial inflammation and the progressive destruction of joint cartilage and bones significantly reducing health-related quality of life 1 . The prevalence of RA is approximately threefold higher in women than in men, and the disease in women exhibits a more severe course 2 . Thus, research focused on sex as a determinant of disease severity could be important for further personalized management of patients with this autoimmune disease 3 .Collagen-induced arthritis (CIA) is a well-established experimental model mimicking many aspects of RA immunopathogenesis 4 . Differently from most of the mouse models of experimentally induced arthritis 5,6 , in several studies, female rats exhibited greater susceptibility to CIA compared with their male counterparts 7-10 . Thus, these rat CIA models seem to be suitable for research aimed to elucidate cellular and molecular mechanisms underlying sex differences in pathogenesis and clinical outcome of RA, as a base for designing efficient sex-specific therapies.Sex differences in susceptibility to autoimmune diseases have been related to sex-based differences in immunopathogenesis and susceptibility of the target tissue to damage caused by autoimmune or inflammatory burden 11,12 . These differences most likely arise from intricate interactions between circulating sex steroids, microbiota, genetic and environmental factors 11,13 .CIA is shown to be T helper (Th)1/Th17 mediated disease 14 . The main function of Th cells is to activate macrophages and fibroblasts and transform them into tissue-destructive cells 15 . Our previous studies in Dark Agouti (DA) rat CIA mo...

Therapeutic Cytokine Inhibition Modulates Activation and Homing Receptors of Peripheral Memory B Cell Subsets in Rheumatoid Arthritis Patients

“…Hence, we analyzed activation status and chemokine receptor expressions in different B cell subsets from RA patients during IL-6R (TCZ) and TNF-α (ADA) inhibition. Previous data from experimental arthritis have shown a gender-based differences in B cell signatures (34,35), however, in our cohort, we did not observe any gender-biased variation in B cell subsets (data not shown). We longitudinally analyzed patients undergoing treatment with these biologics for 24 weeks.…”

Implications of Sex Differences in Immunity for SARS-CoV-2 Pathogenesis and Design of Therapeutic Interventions

“…Other genes located on the X chromosome encoding for proteins that play an important role in the regulation of antibody responses, including CD40L and BTK, can also escape XCI ( Tukiainen et al., 2017 ) and might contribute to better induction and maintenance of antibody responses in women. This is further supported by studies demonstrating sex differences in T follicular helper (Tfh) cells that support B cell maturation, including higher interleukin-21 (IL-21) and IL-27 expression in females ( Dimitrijević et al., 2020 ), and an increase in circulating Tfh cells at the time of induction of plasma cells was recently described in a case study of a woman with nonsevere COVID-19 ( Thevarajan et al., 2020 ). Finally, the ability to induce or maintain antibody responses further decreases with age, in particular in men ( Márquez et al., 2020 ).…”

Human pregnancy levels of estrogen and progesterone contribute to humoral immunity by activating TFH/B cell axis

“…[81] Sex differences in T FH cells help B cells contribute to sexual dimorphism in severity of experimental model for rheumatoid arthritis. [82] Moreover, uncontrolled IgG production in animals lacking functional ERα on CD4 + T-cells [83] should also be related to a loss of functional T FH cells. Furthermore, an imbalance of T FR and T FH cells could result in abnormal GC response and contribute to progression of pathogenesis of autoimmune diseases, as observed in lupus [84].…”