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

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

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.

Other informations


Publications

2018

Laffont, S; Blanquart, E; Guery, J C

[Sex-bias in allergic asthma: androgens and group 2 innate lymphoid cells] Journal Article

Med Sci (Paris), 34 (3), pp. 247-252, 2018, ISSN: 1958-5381 (Electronic) 0767-0974 (Linking).

Links | BibTeX

Souyris, M; Cenac, C; Azar, P; Daviaud, D; Canivet, A; Grunenwald, S; Pienkowski, C; Chaumeil, J; Mejia, J E; Guery, J C

TLR7 escapes X chromosome inactivation in immune cells Journal Article

Sci Immunol, 3 (19), 2018, ISSN: 2470-9468 (Electronic) 2470-9468 (Linking).

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2017

Basso, L; Garnier, L; Bessac, A; Boue, J; Blanpied, C; Cenac, N; Laffont, S; Dietrich, G

T-lymphocyte-derived enkephalins reduce Th1/Th17 colitis and associated pain in mice Journal Article

J Gastroenterol, 2017, ISSN: 1435-5922 (Electronic) 0944-1174 (Linking).

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Laffont, S; Blanquart, E; Savignac, M; Cenac, C; Laverny, G; Metzger, D; Girard, J P; Belz, G T; Pelletier, L; Seillet, C; Guery, J C

Androgen signaling negatively controls group 2 innate lymphoid cells Journal Article

J Exp Med, 214 (6), pp. 1581-1592, 2017, ISSN: 1540-9538 (Electronic) 0022-1007 (Linking).

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Laffont, S; Seillet, C; Guery, J C

Estrogen Receptor-Dependent Regulation of Dendritic Cell Development and Function Journal Article

Front Immunol, 8 , pp. 108, 2017, ISSN: 1664-3224 (Linking).

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Rosa, N; Triffaux, E; Robert, V; Mars, M; Klein, M; Bouchaud, G; Canivet, A; Magnan, A; Guery, J C; Pelletier, L; Savignac, M

The beta and alpha2delta auxiliary subunits of voltage-gated calcium channel 1 (Cav1) are required for TH2 lymphocyte function and acute allergic airway inflammation Journal Article

J Allergy Clin Immunol, 2017, ISSN: 1097-6825 (Electronic) 0091-6749 (Linking).

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2015

Griesbeck, M; Ziegler, S; Laffont, S; Smith, N; Chauveau, L; Tomezsko, P; Sharei, A; Kourjian, G; Porichis, F; Hart, M; Palmer, C D; Sirignano, M; Beisel, C; Hildebrandt, H; Cenac, C; Villani, A C; Diefenbach, T J; Le Gall, S; Schwartz, O; Herbeuval, J P; Autran, B; Guery, J C; Chang, J J; Altfeld, M

Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-alpha Production in Women Journal Article

J Immunol, 195 (11), pp. 5327-36, 2015, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).

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Laffont, S; Garnier, L; Lelu, K; Guery, J C

Estrogen-mediated protection of experimental autoimmune encephalomyelitis: Lessons from the dissection of estrogen receptor-signaling in vivo Journal Article

Biomed J, 38 (3), pp. 194-205, 2015, ISSN: 2320-2890 (Electronic) 2319-4170 (Linking).

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Lupar, E; Brack, M; Garnier, L; Laffont, S; Rauch, K S; Schachtrup, K; Arnold, S J; Guery, J C; Izcue, A

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction Journal Article

J Immunol, 195 (10), pp. 4742-52, 2015, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).

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2014

Laffont, S; Rouquie, N; Azar, P; Seillet, C; Plumas, J; Aspord, C; Guery, J C

X-Chromosome complement and estrogen receptor signaling independently contribute to the enhanced TLR7-mediated IFN-alpha production of plasmacytoid dendritic cells from women Journal Article

J Immunol, 193 (11), pp. 5444-52, 2014, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).

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Lucca, L E; Desbois, S; Ramadan, A; Ben-Nun, A; Eisenstein, M; Carrie, N; Guery, J C; Sette, A; Nguyen, P; Geiger, T L; Mars, L T; Liblau, R S

Bispecificity for myelin and neuronal self-antigens is a common feature of CD4 T cells in C57BL/6 mice Journal Article

J Immunol, 193 (7), pp. 3267-77, 2014, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).

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Mellstrom, B; Sahun, I; Ruiz-Nuno, A; Murtra, P; Gomez-Villafuertes, R; Savignac, M; Oliveros, J C; Gonzalez, P; Kastanauskaite, A; Knafo, S; Zhuo, M; Higuera-Matas, A; Errington, M L; Maldonado, R; DeFelipe, J; Jefferys, J G; Bliss, T V; Dierssen, M; Naranjo, J R

DREAM controls the on/off switch of specific activity-dependent transcription pathways Journal Article

Mol Cell Biol, 34 (5), pp. 877-87, 2014, ISSN: 1098-5549 (Electronic) 0270-7306 (Linking).

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Savignac, M; Simon, M; Edir, A; Guibbal, L; Hovnanian, A

SERCA2 dysfunction in Darier disease causes endoplasmic reticulum stress and impaired cell-to-cell adhesion strength: rescue by Miglustat Journal Article

J Invest Dermatol, 134 (7), pp. 1961-1970, 2014, ISSN: 1523-1747 (Electronic) 0022-202X (Linking).

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2013

Pelletier, L; Savignac, M

Ca(2+) signaling in T-cell subsets with a focus on the role of cav1 channels: possible implications in therapeutics Journal Article

Front Immunol, 4 , pp. 150, 2013, ISSN: 1664-3224 (Print) 1664-3224 (Linking).

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Robert, V; Triffaux, E; Savignac, M; Pelletier, L

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).

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Seillet, C; Rouquie, N; Foulon, E; Douin-Echinard, V; Krust, A; Chambon, P; Arnal, J F; Guery, J C; Laffont, S

Estradiol Promotes Functional Responses in Inflammatory and Steady-State Dendritic Cells through Differential Requirement for Activation Function-1 of Estrogen Receptor alpha Journal Article

J. Immunol., 190 (11), pp. 5459-70, 2013, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).

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2012

Boue, J; Blanpied, C; Djata-Cabral, M; Pelletier, L; Vergnolle, N; Dietrich, G

Immune conditions associated with CD4+ T effector-induced opioid release and analgesia Journal Article

Pain, 153 (2), pp. 485-93, 2012, ISSN: 1872-6623 (Electronic) 0304-3959 (Linking).

Links | BibTeX

Guery, J C

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).

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Pendaries, V; Gasc, G; Titeux, M; Tonasso, L; Mejia, J E; Hovnanian, A

siRNA-mediated allele-specific inhibition of mutant type VII collagen in dominant dystrophic epidermolysis bullosa Journal Article

J Invest Dermatol, 132 (6), pp. 1741-3, 2012, ISSN: 1523-1747 (Electronic) 0022-202X (Linking).

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Pernet, C; Bessis, D; Savignac, M; Tron, E; Guillot, B; Hovnanian, A

Genitoperineal papular acantholytic dyskeratosis is allelic to Hailey-Hailey disease Journal Article

Br J Dermatol, 167 (1), pp. 210-2, 2012, ISSN: 1365-2133 (Electronic) 0007-0963 (Linking).

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Robert, V; Triffaux, E; Savignac, M; Pelletier, L

[Calcium signaling in T lymphocytes] Journal Article

Med Sci (Paris), 28 (8-9), pp. 773-9, 2012, ISSN: 0767-0974 (Print) 0767-0974 (Linking).

Links | BibTeX

Seillet, C; Laffont, S; Tremollieres, F; Rouquie, N; Ribot, C; Arnal, J F; Douin-Echinard, V; Gourdy, P; Guery, J C

The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor alpha signaling Journal Article

Blood, 119 (2), pp. 454-64, 2012, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).

Links | BibTeX

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.

Alumni

PhD

  • 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

 

Post-doc

  • 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

INSERM

INSERM

CNRS

CNRS

Université de Toulouse

Université de Toulouse

Région Occitanie

Région Occitanie

ARSEP

ARSEP

ARTHRITIS

ARTHRITIS

Fondation de recherche médicale

Fondation de recherche médicale

Société Française d’Allergologie

Société Française d’Allergologie

CSL Behring

CSL Behring

ANRS

ANRS

Sidaction

Sidaction