Cyclooxygenase-2 is Essential for the Optimal Differentiation of Human Antibody Secreting Cells: Implications for Vaccination (84.11)

Abstract

Abstract Generation of optimal humoral immunity in response to vaccination is essential in order to protect the public from potentially devastating infectious agents. Cyclooxygenase inhibitors are amongst the most widely used and commonly prescribed medications. However, relatively little is understood about their influence on human immune responses. Herein, we report that non-steroidal anti-inflammatory drugs (NSAIDs) and small molecule Cox-2 selective inhibitors attenuated human B cell immunoglobulin production in a Cox-2-dependent manner. We further demonstrated that the Cox-2 selective inhibitors SC-58125 and NS-398 non-selectively blunt the production of human antibody isotypes including IgM, IgG1, IgG2, IgG3 and IgG4. This correlated with a significant reduction in the generation of CD38+ IgM+ and CD38+IgG+ antibody secreting plasma cell precursors. Interestingly, we discovered that inhibition of Cox-2 activity with SC-58125 severely reduced the mRNA and protein levels of the essential plasma cell transcription factors, Blimp-1 and Xbp-1 in normal human B cells. These new results demonstrate an essential role for Cox-2 in the terminal differentiation of human B lymphocytes to antibody secreting cells. Our findings suggest that the use of drugs that attenuate Cox-2 activity can reduce the generation of plasma cells and ultimately optimal antibody responses to vaccines and pathogenic infections. This research was supported by DE011390, ES01247, AI071064 and T32-DE007202.