Sex hormones modulate the immune response to Plasmodium berghei ANKA in CBA/Ca mice

Abstract

Susceptibility to malaria differs between females and males, and this sexual dimorphism may have important implications for the effects of vaccines and drugs. However, little is known about the mechanisms mediating these sexual differences. Because the main differences between sexes are dictated by sex hormones, we studied the effect of gonadal steroids on immune responses to malaria in CBA/Ca mice. We decreased sex hormones levels by gonadectomy and evaluated the splenic index and the cells involved in the immune response, including T cells (CD3(+), CD4(+), CD8(+) and NK(+)), B cells and macrophages (Mac-3(+)) in the spleens of female and male mice infected with Plasmodium berghei ANKA. In addition, we measured antibody and cytokine levels in blood. Gonadectomy increased T(+) and B(+) splenic cells in both sexes but increased Mac-3(+) cells only in male mice. By contrast, gonadectomy decreased the NK(+) cell population only in male mice. In general, female mice developed higher antibody levels than males. Contrary to our expectations, gonadectomy increased the synthesis of IgG1, IgG2b, IgG3, and total IgG in female mice, indicating negative regulation of antibody production by female sex hormones. Gonadectomy increased the synthesis of tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) only in female mice, suggesting that female sex hormones have anti-inflammatory properties. This work demonstrates that the levels of sex hormones affect the immune response and should be considered when designing malaria vaccines.

Sex Differences in Pain

“…After administration of group B streptococci, male animals had greater leukocyte influx, but there was no difference in cytokine activity in spite of greater macrophage numbers in female animals (Scotland et al, ). After exposure to malaria, male animals had a greater macrophage response than females but had lower levels of CD8 + T cells and CD19 + B cells (Legorreta‐Herrera et al, ). Ischemia with reperfusion resulted in greater microglia and neutrophil response in males as well as an upregulation of the chemokines CXCL1 and CXCL5 in mesentery or bone marrow (Madalli et al, ; Xiong et al, ).…”

Sex-Associated Differential mRNA Expression of Cytokines and Its Regulation by Sex Steroids in Different Brain Regions in aPlasmodium bergheiANKA Model of Cerebral Malaria

“…Ovariectomies were performed as we previously reported [ 17 ]. Briefly, four-week-old female mice were anaesthetised with ketamine (80 mg/kg body weight, Phoenix Pharmaceutical Inc., St. Joseph, MO, US), and incisions were made in the lower abdomen.…”

“…Notably, the severity and mortality of natural infections with Plasmodium are higher in males than females [ 13 – 15 ]. In experimental malaria models, gonadectomy and hormone replacement therapy show that the susceptibility of male mice is determined by gonadal steroids [ 16 , 17 ]. Furthermore, castration of male mice induces resistance to Plasmodium infection, while the administration of testosterone or oestradiol induces immunosuppression [ 16 , 18 , 19 ].…”

“…In previous studies, we have shown sexual dimorphism in the systemic immune responses of CBA/Ca mice infected with P. berghei ANKA [ 17 ]. Sex steroids are important modulators of the immune system; oestrogen, progesterone, and testosterone regulate different immune cell functions, such as growth, differentiation, and survival.…”

Endocrine Immune Interactions in the Host-Parasite Relationship: Steroid Hormones as Immune Regulators in Parasite Infections

“…Gonadectomy also induced an increase in the synthesis of IgG1, IgG2b, IgG3, and total IgG; the proinflammatory cytokines TNF-α and IL-6 and induced higher levesl of NO only in female mice. This suggest that female sex hormones have anti-inflammatory properties in malaria [131,132].…”