Sex bias in lymphocytes: Implications for autoimmune diseases

Abstract

Autoimmune diseases are characterized by a significant sex dimorphism, with women showing increased susceptibility to disease. This is, at least in part, due to sex-dependent differences in the immune system that are influenced by the complex interplay between sex hormones and sex chromosomes, with contribution from sociological factors, diet and gut microbiota. Sex differences are evident in the number and function of lymphocyte populations. Women mount a stronger pro-inflammatory response than males, with increased lymphocyte proliferation, activation and pro-inflammatory cytokine production, whereas men display expanded regulatory cell subsets. Ageing alters the immune landscape of men and women in differing ways, resulting in changes in autoimmune disease susceptibility. Here we review the current literature on sex differences in lymphocyte function, the factors that influence this, and the implications for autoimmune disease. We propose that improved understanding of sex bias in lymphocyte function can provide sex-specific tailoring of treatment strategies for better management of autoimmune diseases.

Keywords: B cells; T cells; estrogen; lymphocytes; sex; sex-bias; testosterone.

Figure 1

The effects of sex hormones on T cells. Sex hormones bind to nuclear receptors, leading to direct binding to HREs, or indirect effects on gene promotors through transcription factors. Oestrogen at pre-ovulatory concentrations upregulates T-bet and IRF5 to cause a Th1 shift, and downregulates AIRE and FoxP3 to reduce Tregs. High-dose estrogen during pregnancy leads to a Th2 shift, via GATA-3, and promotes Treg expression and PD-1 expression. Testosterone upregulates PPAR-α, and Ptpn-1 leading to reduced Th1 responses, but also suppresses Th2 cytokine production, and therefore the Th1/Th2 bias is less clear. Testosterone does increase Th17 production, as well as increasing expression of FoxP3 and AIRE to promote Treg differentiation and increased IL-10 production. AIRE, autoimmune regulator; AR, androgen receptor; ER, estrogen receptor; FoxP3, Forkhead-box-P3; HREs, hormone response elements; IFN, interferon; IL, interleukin; IRF, interferon regulatory factor; mAR, membrane androgen receptor; PPAR, proliferator-activated receptor; Ptpn, protein-tyrosine phosphatase; Th, T-helper; Treg, regulatory T cell.

Figure 2

Sex differences in B cells. AR signaling appears to upregulate caspases, and downregulate NF-κB and Bcl2, resulting in increased B cell apoptosis. Males also demonstrate reduced B cell lymphopoiesis in the bone marrow, reduced proliferation and differentiation of B cells, and lower antibody production, but higher Bregs. Oestrogen upregulates Bcl-2, SHP-2, Hox-C4, and AICDA, as well as surface expression of TLR7 and CD80. Female B cells demonstrate higher proliferation, survival and maturation, higher pro-inflammatory antibody production, leading to higher levels of autoreactive B cells. AICDA, Activation-induced cytidine deaminase; AR, androgen receptor; Bcl-2, B cell lymphoma 2; Bregs, regulatory B cells; Hox-C4, homeobox protein C4; IFN, interferon; IL, interleukin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; SHP-2, Src homology region 2 domain- containing protein tyrosine phosphatase; TLR, toll-like receptor.