This application is submitted in response to an RFA that requested applications to identify and characterize differences in the innate and adaptive immune response between genders, with a specific call for interdisciplinary clinical and basic research studies that may be important in the understanding and treatment of autoimmune diseases. Neutrophils are key cells in the development of homeostatic as well as pathologic inflammatory responses. These cells play a central role in the generation of tissue damage in autoimmune diseases (i.e., rheumatoid arthritis) as well as in infectious diseases, including sepsis. The studies outlined in this application are designed to study the differences in neutrophil function in non-pregnant women, pregnant women, and men. Studies conducted in our laboratory have established that neutrophils of normal pregnant women have a unique immunological state, which has not been previously recognized. This state exhibits the simultaneous expression of activated and inhibited neutrophil properties as reflected in cell calcium signaling, metabolism, and oxidant production. We have demonstrated that these properties reverse shortly after delivery and, thus, may account for the increase in postpartum disease activity in some autoimmune disorders. Our preliminary studies have identified biochemical bases for the changes in neutrophil physiology observed in normal pregnancy and implicated the hexose monophosphate shunt (HMS) and lipid rafts in the regulation of calcium signaling, metabolism and oxidant production. Strikingly, we have identified that trophoblast cells (which are in direct contact with maternal neutrophils in the intervillous space) have the capacity to reverse neutrophil activation upon contact. Using ultra-fast microscopy, we have been able to demonstrate interference with normal calcium signaling and reactive oxygen metabolite (ROM) production upon cell-to-cell contact. More importantly, we have determined that this property of trophoblasts resides in the glycocalyx and can be released in soluble form. This factor may account for the clinical improvement of some autoimmune diseases during pregnancy and their worsening after delivery. Moreover, our findings and proposed strategy may offer a unique opportunity for the identification of endogenous mechanisms affecting women's health. We propose that studying neutrophil biology during pregnancy will result in a mechanistic understanding of factors responsible for clinical improvement in certain autoimmune diseases during pregnancy and will also lead to the development of novel therapeutic approaches to control inflammation and autoimmunity.
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