Team 01 – J.C. Guéry - Institut Toulousain des Maladies Infectieuses et Inflammatoires

Sex differences in immunity: mechanisms and pathophysiology

Coordinator : J.C. Guéry

Scientific objectives

The nature and strength of the immune response differ between women and men, resulting in sex-based differences in the prevalence, manifestations and outcome of autoimmune and infectious diseases. While women are able to mount a more vigorous immune response to infections, they also suffer more from autoimmune diseases and inflammation-induced tissue damages.

Growing data indicate that common biological pathways leading to inflammation and immune activation are involved in the pathophysiology of autoimmune and infectious diseases, and that these pathways are regulated by sex-linked factors, including sex hormones and sex-chromosome loci.

Our team is interested in understanding the mechanisms by which sex-specific factors regulate the immune responses. Our current research objectives focus on three main areas:

Intro

Our projects

AXIS 1: Protective effect of estrogens on CNS autoimmunity

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease characterized by the infiltration of inflammatory leukocytes into the central nervous system resulting in myelin damages.

Clinical remissions in MS patients are frequent during pregnancy suggesting that hormones such as 17ß-estradiol (E2) could be protective. Indeed, beneficial effects of estrogen therapy have mainly been documented in experimental autoimmune encephalomyelitis (EAE) in mice and in MS patients.
Using genetic mouse models, we discovered that the anti-inflammatory action of E2 in EAE relies on ERa-, but not ERß-expression in T lymphocytes.
Using new genetic mouse models, the group is investigating the underlying mechanisms responsible for the anti-inflammatory effect of estrogens in EAE. This may lead to the development of innovative therapies in an effort to mimic the protective effect of pregnancy in women with MS.

AXE 2: Role of sex-linked factors in the regulation of innate immunity

In recent studies, the laboratory provided evidence that estrogen-mediated activation of ER signaling is a key regulator of dendritic cell biology, which may account for the sex-based differences in autoimmune and infectious diseases.

Fig2

In particular, we discovered that the TLR-dependent type I IFN response of plasmacytoid dendritic cells is positively regulated by estrogens both in human and mouse.

Using genetic and cellular approaches, the group is investigating the underlying mechanisms by which sex hormones and X-linked factors could contribute to regulate innate and adaptive immunity in the context of autoimmune and infectious diseases.

AXIS 3: Understanding sex bias in infectious and allergic respiratory diseases

Sexual dimorphism is observed in the susceptibility to asthma, which is more frequent and more severe in women than in men. Likewise, women are more prone than men to develop a severe form of influenza virus infection.

Fig3

In vivo models and genetic approaches using tissue-specific inhibition of candidate signaling pathways are being applied to dissect the cellular and molecular mechanisms involved.
In this context, the group recently established that androgen signaling is a potent negative regulator of group 2 innate lymphoid cells thereby attenuating type 2 lung inflammation in vivo. These results indicate that targeting androgen signaling or their downstream pathways may represent a new avenue for the treatment of allergic disorders.

Fig4

In a second line of expertise, the team is also investigating the role of Cav1 calcium channels in Th2 cell biology and their implication in asthma. The group contributed to demonstrate the key role of some Cav1 channel isotypes in the regulation Th2 cell effector functions in mouse and human. Insights from the lab’s research may lead to the development of small molecule therapeutics for inflammatory diseases through the selective targeting of Cav1 channel family members.