Recurrent Pregnancy Loss through the Lens of Immunology

Evolutionary development of the immune system dates back to the emergence of life in the universe. Immune system emerges early in the course of embryogenesis; immune-restricted progenitor cells appear very early during development in the yolk sac and contribute later to the emergence of lymphoid and myeloid components of the immune system (1). Immune system consists of biological structures, entities, players and processes with a multiplex and intricate interaction with other body systems. It inspects and senses every subtle change in the expression level, stereochemical composition and conformation of the molecules and accordingly mounts regulatory responses. In physiological condition, immune system remains steady and delicately balanced; a small change in the normal physiological processes is concomitantly followed by immediate counter-regulatory mechanisms of the immune system leading to establishment of a new level of immunological balance. Pregnancy, as the most prominent physiological condition associated with a new level of immunological balance, is preceded by vaginal insemination. Seminal plasma contains large amounts of transforming growth factor β and prostaglandin E capable of induction of regulatory T cells (Treg). Seminal fluid initiates a series of events leading to induction of tolerogenic dendritic cells competent to prime Tregs (2). Treg deficiency is associated with such pregnancy-related complications as unexplained infertility, miscarriage, and pre-eclampsia. Within hours after fertilization and in order to adapt to such an immune-stimulatory condition as pregnancy , immune system deliberately creates early pregnancy factor (EPF) with potent immunomodulatory properties (3), a very early sign of pre-implantation immune adaptation to antigenically dissimilar embryo. For successful implantation, extensive modification of endometrium at the cellular and molecular levels and intricate bidirectional communication between implanting blastocyst and the endometrium are required. Such communication is orchestrated by a complex and multilayer network of immune cells, chemokines, cytokines, growth factors and adhesion molecules. In this context, a set of pro-inflammatory TH1 cytokines work in concert in a tightly-regulated manner to establish endometrial receptivity and window of implanta-tion. Chemokines and adhesion molecules mediate blastocyst apposition and adhesion to endometrium. And finally decidual immune cells, mainly uterine natural killer cells (uNK), dendritic cells, TH1 and Treg cells play an eminent role not only in mediating immune tolerance, but also in vascular remodeling and decidual development (4). During pregnancy, the composition of decidual immune cells and cytokine profile gradually undergoes extensive modification and new functional synapses between fetal trophoblast and maternal immune cells are formed, supporting the fourth piece of …