Figure 8
Schematic presentation of mechanisms underlying sex differences in germinal centre (GC) reaction leading to the greater magnitude and more pathogenic profile of IgG response in female compared with male rats immunized with collagen type II (CII). The greater magnitude of the serum CII-specific IgG response in female compared with male rats could be associated with the greater number of GC B cells in lymph nodes draining inflamed joints and adjacent tissue (dLNs) from females reflecting most likely the greater number of CII-specific B cells, their augmented proliferation, and increased IRF4 expression. This was consistent with the greater proliferation of Th cells and a more efficient generation of Tfh cells in female dLNs expressing a more favourable cytokine milieu [mirrored in greater and less expression of cytokines supporting (IL-21 and IL-27) and inhibiting (IL-2) Tfh-cell differentiation, respectively] followed by comparable number of Tfr cells exerting suppressive action on B cells either directly or indirectly acting on Tfh cells. Hence, in female rats, Tfr/Tfh and Tfr/B-cell ratios were shifted towards Tfh and GC B cells, respectively. Additionally, to the greater serum total CII-specific IgG response in female compared with male rats contributed a more efficient T-cell to B-cell communication trough CD40L/CD40 interactions (judging by their surface densities), and increased IL-21/IL-27 expression in dLN cells. The shift in the serum CII-specific IgG2a/IgG1 antibody ratio to the side of IgG2a antibody in female compared with male rats reflected the shifted INF-γ/IL-4 production ratio toward INF-γ, and possibly sex difference in the total Tfr-cell suppressive capacity in female rats. Red arrows (inhibition); green arrows (stimulation).
