Gabriela Gutiérrez

Neuroendocrine–immune disequilibrium and endometriosis: an interdisciplinary approach

Endometriosis, a chronic disease characterized by endometrial tissue located outside the uterine cavity, affects one fourth of young women and is associated with chronic pelvic pain and infertility. However, an in-depth understanding of the pathophysiology and effective treatment strategies of endometriosis is still largely elusive. Inadequate immune and neuroendocrine responses are significantly involved in the pathophysiology of endometriosis, and key findings are summarized in the present review. We discuss here the role of different immune mechanisms particularly adhesion molecules, protein–glycan interactions, and pro-angiogenic mediators in the development and progression of the disease. Finally, we introduce the concept of endometrial dissemination as result of a neuroendocrine-immune disequilibrium in response to high levels of perceived stress caused by cardinal clinical symptoms of endometriosis.

Role of regulatory and angiogenic cytokines in invasion of trophoblastic cells.

Citation Dubinsky V, Poehlmann TG, Suman P, Gentile T, Markert UR, Gutierrez G. Role of regulatory and angiogenic cytokines in invasion of trophoblastic cells. Am J Reprod Immunol 2010; 63: 193–199

Interleukin Regulation of Asymmetric Antibody Synthesized by Isolated Placental B Cells

Canellada A, Färber A, Zenclussen AC, Gentile T, Dokmetjian J, Keil A, Blois S, Miranda S, Berod L, Gutiérrez G, Markert UR, Margni RA. Interleukin regulation of asymmetric antibody synthesized by isolated placental B cells. AJRI 2002; 48: 275–282

The placental regulatory factor involved in the asymmetric IgG antibody synthesis responds to IL-6 features.

Pregnancy success is attributed to the joint action of several factors such as regulatory placental molecules and components of the mothers immune system, among others. Asymmetrical glycosilated and functionally univalent IgG antibodies are suggested to influence the immune balance between the mother and foetus, playing a meaningful role on the foetal survival in the maternal uterus. Placental secretory factors might be responsible for the increase of these molecules during gestation. Since placental factors appeared to be the inducers of these high Concanavaline A-affinity (Con-A) IgG molecules our work was focused on the identification of such factors. The chromatographic separation of placental culture supernatants (PCS) allowed the detection of fractions capable of increasing the high Con-A affinity monoclonal antibody (Mab) ratio synthesised by a hybridoma. The presence of multimeric placental forms of interleukin 6 (IL-6) could be identified in these fractions. Considering that IL-6 modulates protein glycosylation we decided to investigate its effect on the monoclonal IgG glycosylation. When placental IL-6 containing fractions or rIL-6h were added to hybridoma cultures, the proportion of asymmetric IgG antibodies increased substantially.

Regulation of Interleukin-6 Fetoplacental Levels could be Involved in the Protective Effect of Low-molecular Weight Heparin Treatment on Murine Spontaneous Abortion

Problem:  CBA/J × DBA/2 abortion rate could be the consequence of a deficient local production of T helper (Th2) cytokines, which cause fetal wastage via fgl2 prothrombinase. Heparin reduces significantly the abortion rate in mice and recurrent spontaneous abortion (RSA) patients. We proposed to determine the effect of enoxaparin on the levels of local interleukin (IL)‐6 during murine pregnancy.

Ovarian stimulation affects the levels of regulatory endometrial NK cells and angiogenic cytokine VEGF.

Citation Junovich G, Mayer Y, Azpiroz A, Daher S, Iglesias A, Zylverstein C, Gentile T, Pasqualini S, Markert UR, Gutiérrez G. Ovarian stimulation affects the levels of regulatory endometrial NK cells and angiogenic cytokine VEGF. Am J Reprod Immunol 2011; 65: 146–153

Asymmetric Antibodies:A Protective Arm in Pregnancy

In normal conditions, a simple change in the pattern of cytokines towards a Th2 response is associated with the production of aggressive antibodies. This fact could not completely explain phenomena such as the fetal survival or the chronicity of certain infections. However, it has been demonstrated that Th2 cytokines increase the proportion of asymmetric antibodies, which are unable to activate effector immune mechanisms (complement fixation, clearance of antigens and phagocytosis). Investigations of asymmetrically glycosylated antibodies demonstrated that these IgG molecules have an extracarbohydrate in one of the Fab regions. This glycosylation affects their antigen interaction turning them into a functionally univalent and blocking antibodies. It has been established that their synthesis is increased under different physiopathological situations involving Th2 responses: chronic infections by extracellular microorganisms, pregnancy and allergic processes. In this review we summarize the experiments performed by our research group over the last years as well as the advances made concerning the role and mechanism of asymmetric antibodies.

Implication of RANTES in the Modulation of Alloimmune Response By Progesterone During Pregnancy

Several studies indicate that RANTES (regulated on activation, normal T cell expressed and secreted) is able to downregulate T‐cell responses which suggest it might be relevant for fetal tolerance induction. However, the role of RANTES in pregnancy had not been established. Here we investigate RANTES regulation during early pregnancy and potential failures leading to losses of pregnancies.

ORIGINAL ARTICLE: Role of Regulatory and Angiogenic Cytokines in Invasion of Trophoblastic Cells

Citation Dubinsky V, Poehlmann TG, Suman P, Gentile T, Markert UR, Gutierrez G. Role of regulatory and angiogenic cytokines in invasion of trophoblastic cells. Am J Reprod Immunol 2010; 63: 193–199

IL-6 as a regulatory factor of the humoral response during pregnancy.

Problem  Regulatory factors seem to be essential to achieve transition from implantation window to placental vascularization. A novel function of interleukin (IL)‐6 in the promotion of Th2 differentiation and inhibition of Th1 polarization has been demonstrated. Considering that Th2 response promotes antibody synthesis, we postulate that IL‐6 could be modulating the quality of this response during pregnancy by increasing the proportion of blocking asymmetric antibodies.