The effect of sex on the prevalence and severity of parasitic diseases is an emerging area of research. Several factors underlie sex-based differences, including sociocultural influences that affect exposure to parasites, and physiological disparities linked to biological sex. Hence, human studies must be interpreted cautiously; however, studies conducted under controlled laboratory conditions are important to validate findings in humans. Such research can more effectively elucidate the role of sex-determining physiological factors (particularly their impact on immune responses), as well as the role of sex-specific differences in resistance to, or severity of, parasitic diseases. This review focuses on the overarching impact of biological sex variables on immunity. Both human and rodent experimental data are discussed, with a focus on selected protozoan and helminth infections.

Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed upregulation of retinoic acid (RA) signaling in ILC2s during adaptation to the small intestinal microenvironment, and RA signaling mediated reprogramming of kidney effector ILC2s toward the small intestinal phenotype in vitro and in vivo. Inhibition of intestinal ILC2 adaptation by blocking RA signaling impaired worm expulsion during Strongyloides ratti infection, indicating functional importance of ILC2 tissue imprinting. In conclusion, this study highlights that effector ILC2s retain the ability to adapt to changing tissue-specific microenvironments, enabling them to exert tissue-specific functions, such as promoting control of intestinal helminth infections.

Basophils are innate effector cells that contribute to allergic reactions and provide protection against parasites. Using basophil-deficient Mcpt8-cre mice, we have previously shown that these granulocytes contributed to the immune mediated early control of the gastrointestinal helminth Strongyloides ratti in mice. In this study, we analyze the impact of basophils on the immune response and defense against the tissue-dwelling filarial helminth parasite Litomosoides sigmodontis. Although basophils and IgE increased at the site of infection, the absence of basophils did not change the outcome of L. sigmodontis infection. Worm burden in the thoracic cavity and microfilaremiae in the peripheral blood were alike in L. sigmodontis–infected Mcpt8-cre mice compared with Mcpt8 wild type littermates during the entire course of infection. Analysis of the cytokine and Ab response to L. sigmodontis revealed no consistent alterations in the absence of basophils. Furthermore, basophil-deficient and -competent mice were protected to the same extent during a secondary infection with L. sigmodontis. In summary, our findings suggest that basophils are dispensable for the initiation of the appropriate immune response and host defense against L. sigmodontis infection in mice.

Immunoglobulin E (IgE) antibodies play a key role in allergy and its most dangerous and life-threatening manifestation, anaphylaxis. Anti-IgE monoclonal antibodies (mAbs) have been developed to treat IgE-dependent diseases such as allergic asthma, food allergy, and chronic spontaneous urticaria. However, their use is still restricted to a minority of patients suffering from the most severe symptoms because treatment is costly and requires repeated administration. Therefore, we developed a conjugate vaccine against human IgE as a potential alternative therapy for long-term protection from IgE-dependent diseases. The IgE conjugate vaccine was generated by coupling a mutated fragment containing the Cε3-4 domains of human IgE with the carrier protein diphtheria cross-reactive material 197 (CRM ₁₉₇ ) using kinoid technology to raise autoantibodies against a self-antigen by engrafting it onto the highly immunogenic CRM ₁₉₇ carrier. To assess the efficacy of IgE-kinoid (IgE-K) vaccination, we generated a mouse model humanized for IgE and its high-affinity receptor FcεRI. IgE-K vaccination induced long-term production of anti–human IgE neutralizing antibodies without any detectable adverse effect. Anti-IgE antibodies were detected in the sera of IgE-K–immunized mice for up to 12 months postvaccination with a similar avidity as the approved anti-IgE mAb omalizumab. Furthermore, IgE-K vaccination protected against both IgE-mediated cutaneous and severe systemic anaphylaxis in IgE/FcεRI-humanized mice. Our results demonstrate that long-term reduction in IgE activity can be achieved through vaccination with human kinoids and can protect against anaphylaxis in humanized mice. This may represent a cost-effective, long-term therapeutic strategy for the treatment of IgE-mediated diseases.

Strongyloides ratti is a parasitic nematode that naturally infects wild rats. However, most laboratory rat and mouse strains are fully susceptible to infection. Immunocompetent BALB/c and C57BL/6 mice terminate S. ratti infections within a month in the context of a canonical type 2 immune response and remain semi-resistant to a re-infection. The course of infection can be divided into three phases: (a) the tissue migration phase of the infective third-stage larvae during the first two days; (b) the early intestinal phase, including the molting to the adult parasites and embedding in the mucosa of the intestine in days 3 to 6 post-infection with reproduction starting by day 5 to 6 post-infection; (c) the later intestinal phase ending with the complete clearance of the parasites. Experimental infections of mice with S. ratti enable the precise study of host-parasite interactions throughout the whole life cycle at the different sites of infection, as well as immune evasion strategies employed by the parasite. The protocol presented here describes the maintenance of the parasite in Wistar rats, the infection of laboratory mice, and the detection and quantification of S. ratti parasites in the tissue migrating phase and during the intestinal phase.

Helminths infect a quarter of the human population and are controlled in the frame of a canonical type-2 immune response. Interleukin-9 is a cytokine with pleiotropic functions during type-2 immunity that can be produced by many different cells. Accumulating evidence suggest that IL-9 is of particular relevance in controlling intestinal helminth infections. Using mice infected with the parasitic nematode Strongyloides ratti, we showed previously that ejection from the intestine depends on IL-9 and IL-9-mediated activation of mucosal mast cells. Here we use IL-9 reporter mice to identify the relevant cellular sources of IL-9 in vivo. We report that predominantly CD4⁺ T cells and group 2 innate lymphoid cells (ILC2s) produced IL-9 in S. ratti-infected or IL-33-treated mice. Interestingly, the IL-33-mediated induction of IL-9 and subsequent mast cell degranulation was modulated by concurrent S. ratti infection. While the IL-33-mediated expansion of IL-9-producing ILC2s was supressed by S. ratti infection, IL-9-producing CD4⁺ T cells were proportionally increased. Finally, we show that S. ratti-derived E/S products interfered with IL-9 production by BM-derived ILC2 in vitro. In conclusion, we have identified that ILC2 and CD4⁺ T cells produce IL-9 during S. ratti infection, and that ILC2 responses are suppressed by S. ratti products.