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

Mirjana Dimitrijević,Ivan Pilipović,Biljana Bufan,Mirjana Nacka-Aleksić,Duško Kosec,Gordana Leposavić,Nevena Arsenović-Ranin

doi:10.1038/s41598-020-58127-y

Mirjana Dimitrijević, Ivan Pilipović + Show 5 more

Open Access

https://doi.org/10.1038/s41598-020-58127-y

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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 higher Tfh 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.

Highlights

The study examined germinal centre (GC) reaction in lymph nodes draining inflamed joints and adjacent tissues in male and female Dark Agouti rat collagen type II (CII)-induced arthritis (CIA) model of rheumatoid arthritis
The present study extended our earlier findings on sexual dimorphism in susceptibility to CIA9,10 recapitulating female predominance observed in Rheumatoid arthritis (RA) by showing that female rats mount quantitatively greater and qualitatively different CII-specific IgG response compared with their male counterparts
This was associated with the more efficient generation of T follicular helper (Tfh) cells and most likely CD40L/CD40-mediated interactions between Th cells and B cells, and the shift in Th1/Th2 signature cytokine production ratio towards the former in females compared with males

Summary

Introduction

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 Ki67+ cells among dLN B cells was higher in females than in males. 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[7,8,9,10] 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. Our previous studies in Dark Agouti (DA) rat CIA model showed more robust Th1/17 responses in female rats

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