The X-files in immunity: sex-based differences predispose immune responses

Abstract

Despite accumulating evidence in support of sex-based differences in innate and adaptive immune responses, in the susceptibility to infectious diseases and in the prevalence of autoimmune diseases, health research and clinical practice do not address these distinctions, and most research studies of immune responses do not stratify by sex. X-linked genes, hormones and societal context are among the many factors that contribute to disparate immune responses in males and females. It is crucial to address sex-based differences in disease pathogenesis and in the pharmacokinetics and pharmacodynamics of therapeutic medications to provide optimal disease management for both sexes.

Figure 1. Genes on the X chromosome with the potential to influence immunocompetence.

Several proteins encoded by genes that are found on the X chromosome might underlie sex-based differences in immune responses. The proteins listed were selected from more than 1,100 identified genes on the X chromosome, and have been grouped according to their associated function as receptors and associated proteins (a), proteins related to the immune response (b) or proteins involved in transcriptional and translational control (c). Proteins with their definition and/or known function are listed. The proteins marked with an asterisk indicate those encoded by genes also found on the Y chromosome.

Figure 2. The effects of 17β-oestradiol on immunocompetence.

The activation of oestrogen receptors expressed by T cells, B cells, dendritic cells (DCs), macrophages, neutrophils and natural killer (NK) cells influences immunocompetence. Oestrogens, such as 17β-oestradiol, exert a biphasic effect on T helper (T_H)-cell polarization: low levels promote T_H1-cell differentiation and higher levels promote T_H2-cell polarization, with consequent effects on the production of cytokines that are associated with each of the T_H-cell populations. Oestrogen increases the size of the T_Reg-cell population. In addition, oestrogen increases CC-chemokine receptor 1 (CCR1) and CCR5 expression and decreases tumour-necrosis factor (TNF) production by CD4⁺ T cells. Oestrogen decreases the negative selection of naive B cells, enhances the survival of autoreactive B cells and enhances polyclonal B-cell activation and immunoglobulin production. The inhibition of CD16 expression by oestrogen in monocytes and macrophages leads to the reduced production of the pro-inflammatory cytokines interleukin-1 (IL-1β), IL-6 and TNF. In neutrophils, oestrogen upregulates the production of nitric-oxide synthase and nitric oxide, thereby promoting their anti-inflammatory effects, and decreases their chemotactic activity. Oestrogen promotes the differentiation of conventional DCs (cDCs) from bone-marrow-derived DC precursors (BMDCs), and increases their IL-12 production, whereas exposure of mature splenic DCs to oestrogen results in the expansion of interferon-γ (IFNγ)-producing killer DCs. 17β-oestradiol treatment increases the secretion of IL-6, IL-8 and CC-chemokine ligand 2 (CCL2) by immature DCs (iDCs). Oestrogen also reduces the cytotoxicity of NK cells. ^* refer to Fig. 3.

Figure 3. Oestrogen and progesterone effects on T-cell responses during the menstrual cycle.

Variations in oestrogen and progesterone levels during the different phases of the menstrual cycle influence T helper 1 (T_H1)-, T_H2- and T regulatory (T_Reg)-cell populations. The upper panel illustrates fluctuations in the levels of oestrogen and progesterone during the different phases of the 28-day menstrual cycle. In the middle and lower panels, the corresponding changes in the size of the T_Reg-cell population and the T_H-cell bias, respectively, are shown.