Immunobiology of Gestational Diabetes Mellitus in Post-Medawar Era

Abstract

Although the concepts related to fetal immune tolerance proposed by Sir Peter Medawar in the 1950s have not withstood the test of time, they revolutionized our current understanding of the immunity at the maternal-fetal interface. An important extension of the original Medawar paradigm is the investigation into the underlying mechanisms for adverse pregnancy outcomes, including recurrent spontaneous abortion, preterm birth, preeclampsia and gestational diabetes mellitus (GDM). Although a common pregnancy complication with systemic symptoms, GDM still lacks understanding of immunological perturbations associated with the pathological processes, particularly at the maternal-fetal interface. GDM has been characterized by low grade systemic inflammation that exacerbates maternal immune responses. In this regard, GDM may also entail mild autoimmune pathology by dysregulating circulating and uterine regulatory T cells (Tregs). The aim of this review article is to focus on maternal-fetal immunological tolerance phenomenon and discuss how local or systemic inflammation has been programmed in GDM. Specifically, this review addresses the following questions: Does the inflammatory or exhausted Treg population affecting the Th17:Treg ratio lead to the propensity of a pro-inflammatory environment? Do glycans and glycan-binding proteins (mainly galectins) contribute to the biology of immune responses in GDM? Our understanding of these important questions is still elementary as there are no well-defined animal models that mimic all the features of GDM or can be used to better understand the mechanistic underpinnings associated with this common pregnancy complication. In this review, we will leverage our preliminary studies and the literature to provide a conceptualized discussion on the immunobiology of GDM.

Lower HLA-G levels in extravillous trophoblasts of human term placenta in gestational diabetes mellitus than in normal controls

“…NK cells generally destroy cells which do not express HLA class-la molecules, but HLA-G protects the extravillous cells through cytolysis of NK cells (Rajagopalan and Long 1999). Therefore, our data could provide a possible link between the enhanced inflammation often associated with GDM and an altered immune response by a consequent loss of HLA-G expression (Sharma et al 2021).…”

Lower HLA-G levels in Extravillous Trophoblasts of Human Term Placenta in Gestational Diabetes Mellitus than in normal controls

“…NK cells generally destroy cells which do not express HLA class-la molecules and, but HLA-G protects the extravillous cells by cytolysis of NK cells (Rajagopalan and Long 1999). Therefore, our data could provide a possible link between enhanced in ammation often associated with GDM and an altered immune response by a consequent loss of HLA-G expression (Sharma, Banerjee et al 2021).…”

Evaluation of first and second trimester maternal thyroid profile on the prediction of gestational diabetes mellitus and post load glycemia

“…This decline is due to the physiological immunosuppression that occurs in normal pregnancy to tolerate the fetus and placenta [41]. That process is disrupted in GDM [42], which could explain why the levels of aTG do not decrease amidst trimesters in the GDM group as they do in the NGT group. These results indicate that, when considered individually, the main differential variables between the two study groups are non-thyroid in the first trimester of pregnancy, and thyroid in the second trimester of pregnancy.…”