Water Deprivation Leads to Impaired Immune Responses to Vaccination

Background: The production of an effective immune response is a complex endeavor that is sensitive to disturbances in the extracellular milieu including hormones, cytokines, glucose and lipids. One factor whose effects on the immune response are incompletely understood is the concentration of the main extracellular ion sodium ([Na+]), which is regulated by the kidneys. Disorders of sodium homeostasis, hyponatremia (low serum [Na+]) and hypernatremia (high serum [Na+]) are highly prevalent , especially in hospitalized patients. Prior work in autoimmunity has shown that increased [Na+] can lead to T cells differentiating toward more proinflammatory subsets in vitro and our work in lupus has shown that hypernatremia after water deprivation can lead to the depletion of pathogenic intrarenal B cells. However, little is known about how sodium stress affects immune responses in non-autoimmune contexts. Methods: We compared the immune response between mice that were water deprived for 48h to induce hypernatremia and controls. Unimmunized cohorts were analyzed at t=48h without restoring access to free water. Immunized animals received a protein-based vaccine (NP-OVA) at d0, were water deprived d0-2 and w ere analyzed at days 7 and 14 after receiving antigen, when serum [Na+] had normalized. We used antigen-specific flow cytometry and ELISA to track immune responses. Results: Mice subjected to water deprivation for 48h had smaller spleens (70.6mg vs 109.6mg, p<0.0001) and decreased splenic B cell numbers (1.1x10^7 cells vs 2.9x10^7 cells, p 0.0009), compared to littermate controls. Supporting in vitro studies showed that B cells have decreased survival and impaired differentiation to antibody-secreting cells when exposed to high [Na+]. When mice were immunized with NP-OVA at d0, water deprived d0-2 and then analyzed on day 7, total splenic B cell numbers were unchanged but antigen-specific (NP+) B cells were decreased by 2.5-fold in water deprived animals as compared to controls (10^4 vs 2.5x10^4 cells, p 0.048). Antigen-specific antibodies were also decreased 2-fold as measured by ELISA. Conclusion: We show that even transient dysnatremia can negatively influence immune responses to antigen. We believe this work provides key insights on the intersection of ion homeostasis and immunity and has implications for dysnatremia treatment in populations at high risk for infection such as hospitalized patients. Funding: NIDDK Support