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Estrogens and calcium channels in the pathophysiology of autoimmune and allergic diseases

Heads : Jean Charles Guéry / Lucette Pelletier

Scientific objective :

The main focus of laboratory has been for the past 5 years to study the regulation of T helper cell activation and differentiation, particularly Th2 cells, in experimental models of allotransplantation and allergic diseases. In allotransplantation we demonstrated that cytotoxic lymphocytes (CTL, NK cells) have important regulatory functions through their capacity to eliminate donor-derived dendritic cells in lymphoid organs. Regarding Th2-cell mediated immune disorders, we identified molecules, specifically expressed by Th2-cells and implicated in Ca2+ signaling and therefore in Th2 effector functions. We then demonstrated that they represent potential therapeutic targets for the treatment of allergic diseases.

Our aims :

Our current projects focus on the two following themes:
1) the impact of estrogens on adaptive and innate immune responses and its potential implication in the pathogenesis of autoimmune diseases.
2) the understanding of the mechanisms involved in the control of Th2 effector functions and its implication in the treatment of allergic asthma.

Main publications :

Seillet C, Rouquié N, Foulon E, Douin-Echinard V, Krust A, Chambon P, Arnal JF, Guéry JC, Laffont S.
Estradiol promotes functional responses in inflammatory and steady-state dendritic cells through differential requirement for activation function-1 of estrogen receptor.
J Immunol. 2013 Jun 1;190(11):5459-70.

Seillet C, Laffont S, Trémollières F, Rouquié N, Ribot C, Arnal JF, Douin-Echinard V, Gourdy P, Guéry JC.
The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor a signaling.
Blood. 2012 Jan 12;119(2):454-64. Epub 2011 Nov 16.

Cabral MD, Paulet PE, Robert V, Gomes B, Renoud ML, Savignac M, Leclerc C, Moreau M, Lair D, Langelot M, Magnan A, Yssel H, Mariamé B, Guéry JC, Pelletier L.
Knocking down Cav1 calcium channels implicated in Th2 cell activation prevents experimental asthma.
Am J Respir Crit Care Med., 2010 Jun 15;181(12):1310-7.

Laffont S, Seillet C, Ortaldo J, Coudert JD, Guéry JC.

Natural killer cells recruited into lymph nodes inhibit alloreactive T-cell activation through perforin-mediated killing of donor allogeneic dendritic cells.
Blood., 2008 Aug 1;112(3):661-71.

Douin-Echinard V, Laffont S, Seillet C, Delpy L, Krust A, Chambon P, Gourdy P, Arnal JF, Guéry JC.

Estrogen receptor alpha, but not beta, is required for optimal dendritic cell differentiation and [corrected] CD40-induced cytokine production.
J Immunol., 2008 Mar 15;180(6):3661-9.

Last updated December 3, 2013

Version française

French version

Key words

Autoimmunity and allergy
Estrogen and estrogen receptors
T lymphocytes
Cellular differentiation
Calcium signaling

Expected health effects

Despite the obvious impact of estrogens on the pathophysiology of autoimmune diseases, the cellular and the molecular mechanisms responsible fo the immuno-stimulatory or anti-inflammatory effects of 17ß-estradiol (E2) are still unclear. Our project will help to define the cellular targets responsible of the paradoxical effects of estrogens in autoimmunity. This could open new perspectives regarding the modulation of adaptive or innate immune responses by using selective estrogen receptor modulators (SERMs). Finally, the identification of key components proper to the regulation of intracellular calcium concentration in Th2 cells would allow to propose them as potential targets for the treatment of allergic diseases as asthma that affects more than 10% of people living in Western countries.
Centre de physiopathologie de Toulouse Purpan - CHU Purpan - BP 3028 31024 Toulouse Cedex 3
Inserm University of Toulouse Université Toulouse III - Paul Sabatier