Inflammation, Gestation and Autoimmunity

 

Figure 1. Inflammation is a first-line defense against infections, but its dysregulations have many pathological consequences, including on immune and reproductive systems

We study the molecular and cellular mechanisms of inflammatory conditions, in pregnant and non-pregnant mice, in 2 different experimental models: Chlamydia trachomatis (CT) infection of the genital tract, and an auto-immune syndrome such as Systemic Erythematosus Lupus (SLE). Our results have led us to develop new therapeutic and preventive strategies in both models.

Main achievements

We have analyzed the leukocyte populations and cytokines present at the fetal-maternal interface. We have characterized an unknown cell subpopulation present in mouse placenta and uterus during pregnancy. These cells have several surface markers of dendritic cells. Our goal is to decipher their role in normal and pathological pregnancy, in infected or autoimmune mice.

Figure 2. Mouse uterine dendritic cells, stained for specific cell surface marker (green), nucleus (blue). Scale 10µm. Copyright CNRS/IJM M. Habbeddine

In 2007, we have shown that beta lactams (BL) do not induce the persistence of Chlamydia trachomatis (CT), but cause the expansion of bacterial bodies and their death from fusion with lysosomes. We have also shown that BL-treatment of vaginally infected mice protects them from genital tissue lesions and subsequent infertility (results patented in 2010).

Figure 3. Uterus from C. muridarum infected B6 mice, left untreated, treated with Doxycycline (Dox) or penicillin G (pG). Black arrows indicate pathological cysts due to tissue lesions. Copyright CNRS/IJM M. Habbeddine, P. Verbeke.

We have previously demonstrated that arsenic trioxide (As₂O₃) efficiently corrects or prevents autoimmune and lymphoproliferative syndromes (SLE) in MRL/lpr mice, by selectively inducing the death of pathogenic T cells responsible for the cutaneous, pulmonary and renal lesions, as well as lymphoproliferation (Bobé et al. 2006, European patent). As₂O₃ restores normal serum levels of TNF-α, Fas ligand, IL-18, IFN-γ, IL-10 and NO metabolites. It also inhibits the production of autoantibodies and prevents the onset of glomerulonephritis, which drastically extends the life of MRL/lpr mice. As₂O₃ also prevents mouse graft-versus-host disease after bone marrow transplant (European patent). Our current work aims at understanding how A₂O₃ specifically targets pathogenic T cells (patent pending), and whether the P2X7 purinergic receptor (P2X7R), absent on these T cells, plays a role in T-cell homeostasis.

Figure 4. Regression of skin and ear tissue lesions due to SLE in MRL/lpr mice treated with As₂O₃ (compared to PBS, same age and sex) for 2 months (Bobe et al., 2006). Copyright CNRS/I. A. Lwoff P. Bobé.

Our goal is to study:

• the role of uterine and placental cell populations and cytokines in the regulation of local inflammation, in normal and pathological (CT-infected and SLE) pregnancy,
• iin CT-infected cell lines and mice, the mechanisms of action of BL, and their consequences on inflammatory tissue lesions and reproduction,
• in SLE mice, the specificity of As₂O₃, for inflammatory cells, and the role of P2X7R in inflammatory T cell homeostasis.

 

Selection of Publications

Transplantation tolerance to a single noninherited MHC class I maternal alloantigen studied in a TCR-transgenic mouse model.
Akiyama Y*, Caucheteux SM*, Vernochet C, Iwamoto Y, Tanaka K, Kanellopoulos-Langevin C, Benichou G.
J Immunol. 2011;186 (3):1442-9. * equal contribution
Abstract

ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as TGFα, L-selectin, and TNFα.
Le Gall SM, Bobé P, Reiss K, Horiuchi K, Niu XD, Lundell D, Gibb DR, Conrad D, Saftig P, Blobel CP.
Mol Biol Cell. 2009;20 (6):1785-94.
Abstract

Tolerance induction to self-MHC antigens in fetal and neonatal mouse B cells.
Caucheteux SM, Vernochet C, Wantyghem J, Gendron MC, Kanellopoulos-Langevin C.
Int Immunol. 2008;20(1):11-20.
Abstract

Recruitment of BAD by the Chlamydia trachomatis vacuole correlates with host-cell survival.
Verbeke P, Welter-Stahl L, Ying S, Hansen J, Häcker G, Darville T, Ojcius DM.
PLoS Pathog. 2006 May;2(5):e45.
Full Text

Arsenic trioxide: A promising novel therapeutic agent for lymphoproliferative and autoimmune syndromes in MRL/lpr mice.
Bobé P, Bonardelle D, Benihoud K, Opolon P, Chelbi-Alix MK.
Blood. 2006 Dec 15;108(13):3967-75.
Abstract

Last modified 12/15/2011

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