Sex differences in immunity: mechanisms and pathophysiology
Coordinator : J.C. Guéry
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:
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.
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.
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.
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.
Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases Journal Article
Int J Mol Sci, 22 (3), 2021, ISSN: 1422-0067.
J Allergy Clin Immunol, 2021, ISSN: 1097-6825 (Electronic) 0091-6749 (Linking).
Separation of the CaV1.2-CaV1.3 calcium channel duo prevents type-2 allergic airway inflammation Journal Article
Allergy, In press , 2021.
TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women Journal Article
JCI Insight, 5 (12), 2020, ISSN: 2379-3708.
[Asthma and allergy: what about the differences between men and women?] Journal Article
Rev Prat, 70 (2), pp. 195-199, 2020, ISSN: 0035-2640.
Why is systemic lupus erythematosus more common in women? Journal Article
Joint Bone Spine, 86 (3), pp. 297-299, 2019, (invited editorial).
Semin Immunopathol, 41 (2), pp. 153-164, 2019, ISSN: 1863-2300 (Electronic); 1863-2297 (Linking), (review).
CD49d/CD29-integrin controls the accumulation of plasmacytoid dendritic cells into the CNS during neuroinflammation Journal Article
Eur J Immunol, 2019, ISSN: 0014-2980.
Deconstructing the sex bias in allergy and autoimmunity: From sex hormones and beyond Journal Article
Adv Immunol, 142 , pp. 35-64, 2019, ISSN: 0065-2776, (review).
Long-term immunity against yellow fever in children vaccinated during infancy: a longitudinal cohort study Journal Article
Lancet Infect Dis, 2019, ISSN: 1473-3099.
J Immunol, 201 (11), pp. 3218–3228, 2018, ISSN: 1550-6606 (Electronic); 0022-1767 (Linking).
J Allergy Clin Immunol, 142 (3), pp. 892-903, 2018, ISSN: 1097-6825 (Electronic) 0091-6749 (Linking).
Involvement of ion channels in allergy Journal Article
Current Opinion in Immunology, 52 , pp. 60 - 67, 2018, ISSN: 0952-7915, (review).
TLR7 escapes X chromosome inactivation in immune cells Journal Article
Sci Immunol, 3 (19), 2018, ISSN: 2470-9468 (Electronic) 2470-9468 (Linking), (In the top 5% of all research outputs scored by Altmetric. http://www.altmetric.com/details/32261033).
Med Sci (Paris), 34 (3), pp. 247-252, 2018, ISSN: 1958-5381 (Electronic) 0767-0974 (Linking), (review).
Rev Fr Allergol, 5991 (4), pp. 297-357, 2018, ISSN: 1877-0320, (review).
J Gastroenterol, 2017, ISSN: 1435-5922 (Electronic) 0944-1174 (Linking).
J Exp Med, 214 (6), pp. 1581-1592, 2017, ISSN: 1540-9538 (Electronic) 0022-1007 (Linking).
Front Immunol, 8 , pp. 108, 2017, ISSN: 1664-3224 (Linking).
Frontiers in Immunology, 8 , pp. 1069, 2017, ISSN: 1664-3224.
J Immunol, 195 (11), pp. 5327-36, 2015, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).
Biomed J, 38 (3), pp. 194-205, 2015, ISSN: 2320-2890 (Electronic) 2319-4170 (Linking).
J Immunol, 195 (10), pp. 4742-52, 2015, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).
J Immunol, 193 (11), pp. 5444-52, 2014, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).
J Immunol, 193 (7), pp. 3267-77, 2014, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).
Mol Cell Biol, 34 (5), pp. 877-87, 2014, ISSN: 1098-5549 (Electronic) 0270-7306 (Linking).
J Invest Dermatol, 134 (7), pp. 1961-1970, 2014, ISSN: 1523-1747 (Electronic) 0022-202X (Linking).
Front Immunol, 4 , pp. 150, 2013, ISSN: 1664-3224 (Print) 1664-3224 (Linking).
Singularities of calcium signaling in effector T-lymphocytes Journal Article
Biochim Biophys Acta, 1833 (7), pp. 1595-602, 2013, ISSN: 0006-3002 (Print) 0006-3002 (Linking).
J. Immunol., 190 (11), pp. 5459-70, 2013, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).
Pain, 153 (2), pp. 485-93, 2012, ISSN: 1872-6623 (Electronic) 0304-3959 (Linking).
Estrogens and inflammatory autoimmune diseases Journal Article
Joint, bone, spine : revue du rhumatisme, 79 (6), pp. 560-2, 2012, ISSN: 1778-7254 (Electronic) 1297-319X (Linking).
J Invest Dermatol, 132 (6), pp. 1741-3, 2012, ISSN: 1523-1747 (Electronic) 0022-202X (Linking).
Br J Dermatol, 167 (1), pp. 210-2, 2012, ISSN: 1365-2133 (Electronic) 0007-0963 (Linking).
[Calcium signaling in T lymphocytes] Journal Article
Med Sci (Paris), 28 (8-9), pp. 773-9, 2012, ISSN: 0767-0974 (Print) 0767-0974 (Linking).
Blood, 119 (2), pp. 454-64, 2012, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).
Impact on the society
The knowledge of the biological mechanisms underlying the sex differences in immunity is of fundamental importance with potential significant impacts for the management of patients suffering from autoimmune, infectious diseases, or allergy.
This research area has been largely under-studied for many years despite societal demand and the numerous clinical, epidemiological and experimental observations highlighting a major role of sex in the susceptibility, severity and magnitude of numerous immuno- pathological, whether in autoimmune (MAI) and infectious diseases, allergy and anti-tumor immunity.
In recent years, this area has gained increasing interest, particularly following the recommendations of the NIH in 2015, prompting recognition of sex as a biological variable in preclinical studies in order to improve the rigor and reproducibility of research.
- Gilles Foucras, diplôme de Doctorat en Immunologie, Université Paul Sabatier, 1997-2000.
Now Full Professor at Ecole Nationale Vétérinaire de Toulouse, France
- Jérôme Coudert, diplôme de Doctorat en Immunologie, Université Paul Sabatier, 1998-2002
Now Research Officer, Lions Eyes Institute, Perth, Australia
- Lucile Garidou, diplôme de Doctorat en Immunologie, Université Paul Sabatier, 2002-2005
Now Research Officer, Pierre Fabre, Toulouse
- Sophie Laffont, diplôme de Doctorat en Immunologie, Université Paul Sabatier, 2003-2007
Now post-doctoral fellow, University of Geneva, Switzerland
- Abdallah Badou, diplôme de Doctorat en Immunologie, Université Paul Sabatier, 1994-1998
Now assistant Professor at the University of Safi, Marocco
- Bruno Gomes diplôme de de Doctorat en Immunologie, Université Paul Sabatier, 2003-2005
Head, Tumor Immunology, ITEOS THERAPEUTICS, Gosselies, Belgium
- Marilena Djata Cabral diplôme de Doctorat en Immunologie, Université Paul Sabatier, 2004-2008
Teaching Organizer Université Virtuelle Africaine, Nairobi, Kenya
- Karine Lélu, diplôme de Doctorat en Immunologie, Université Paul Sabatier, 2006-2010
Now Research Officer, Transgene, Illkirch, France
- Cyril Seillet, diplôme de Doctorat en Immunologie, Université Paul Sabatier, 2007-2011
Now post-doctoral fellow, WEHI, Melbourne, Australia
- Virginie Robert- Gavioli Diplôme de Doctorat en Immunologie, Université Paul Sabatier, 2008-2012
Now post-doctoral fellow at Stromalab, Toulouse
- Emily Triffaux, diplôme de Doctorat en Immunologie, Université Paul Sabatier, 2010-2013
Now Medical Science Liaison Thrombosis Benelux, LEO Pharma, Belgium
- Pascal Azar, diplôme de Doctorat en Immunologie, Université Paul Sabatier, 2012-2016
Now assistant Professor at the University of Lebanon
- Laure Garnier, diplôme de Doctorat en Immunologie, Université Paul Sabatier, 2012-2016
Now post-doctoral fellow, University of Geneva, Switzerland
- Nicolas Rosa, diplôme de Doctorat en Immunologie, Université Paul Sabatier, 2014-2017
- Laurent Delpy, INSERM U563, CPTP, Toulouse (2002-2006)
Now DR2 CNRS, CNRS UMR7276 CRIBL, Limoges, France
- Victorine Douin, INSERM U563, CPTP, Toulouse (2003-2004)
Now assistant Professor (MCU-PH) at the University of Toulouse, France