Premature birth (PTB) is estimated to affect 5?18% pregnancies worldwide. Despite extensive public health efforts, PTL has remained an insidious and intractable cause of infant death and long-term illnesses, suggesting that we do not completely understand PTL pathogenesis. Indeed, the prediction, prevention and treatment of PTL have been very challenging. Intrauterine and systemic infection and/or inflammation are recognized pathophysiologic mechanisms that account for 30?40% of PTL, and ~85% of spontaneous PTB cases at <28 weeks and ~65% of those before 37 weeks showed evidences of intrauterine inflammation. To this end, we have focused on B cells, where our expertise lies, in pregnancy and PTL, because B cells are critical effectors and regulators of innate and adaptive immunity that protects the host against infection, and B cell dysfunction crucially contributes to many autoimmune and inflammatory conditions that predispose women to PTL. Our preliminary studies showed that human choriodeciduas harbored B cells, but B cells in PTL choriodeciduas were functionally altered. B cell-deficient mice were markedly more susceptible than wild-type (WT) mice to PTL after systemic inflammation, but B cells conferred interleukin (IL)-10-independent protection against PTL. B cell deficiency in mice diminished the level of uterine progesterone-induced blocking factor 1 (Pibf1), a progesterone-inducible molecule that carries out many effector functions of progesterone in pregnancy. A lower serum and urine PIBF1 concentration in late pregnancy was strongly associated with an increased risk of PTL. More importantly, therapeutic administration of PIBF1 mitigated PTL and uterine inflammation in B cell-deficient mice, and the protective activity resided in the amino (N) terminal part of PIBF1 (nPIBF1). Interestingly, PIBF1 expression by uterine B cells in late gestation was dependent on the mucosal alarmin IL-33, and PTL patients had diminished expression of the ?-chain of IL-33 receptor, ST2L, on choriodecidual B cells and a lower level of active PIBF1 in late gestation choriodecidua. However, the mechanisms by which PIBF1 protects against PTL and the causes of the intriguing B cell defect in PTL are unknown. As we work to develop PIBF1 into a therapeutic agent to prevent PTL, we want to know the answers to these key questions. Employing computational modelling, biochemical methods and mouse models, studies in Aim 1 will determine the mechanism of PIBF1-mediated protection against PTL. Studies in Aim 2 will use molecular and biochemical approaches to determine the causes of the diminished IL-33R? expression that underlies the functional defects of B cell in PTL patients. Our studies will not only catalyze the preclinical and clinical development of nPIBF1 as a therapeutic agent to prevent or treat PTL, but also offer novel and specific targets to predict and mitigate the B cell defects in this prevalent, devastating and intractable condition. Beside the apparent translational value, the work could reveal novel mechanisms of regulation of type 2 immunity by B cells, tissue danger signals and PIBF1 at the nexus of inflammation, tissue homeostasis and endocrinology.
Preterm birth is prevalent, complex, and causes heavy social and economic burdens. This project builds upon our recent breakthrough on the function of B cells in pregnancy to explore the immunologic causes of B cells defects in preterm labor and harness the protective function of B cells to prevent preterm birth. The novel scientific idea and the clinical and translational implications could advance the prediction and prevention of preterm labor.
