Chronic inhibition of cyclooxygenase-2 attenuates antibody responses against vaccinia infection

Abstract

Generation of optimal humoral immunity to vaccination is essential to protect against devastating infectious agents such as the variola virus that causes smallpox. Vaccinia virus (VV), employed as a vaccine against smallpox, provides an important model of infection. Herein, we evaluated the importance cyclooxygenase-2 (Cox-2) in immunity to VV using Cox-2 deficient mice and Cox-2 selective inhibitory drugs. The effects of Cox-2 inhibition on antibody responses to live viruses such as vaccinia have not been previously described. Here, we used VV infection in Cox-2 deficient mice and in mice chronically treated with Cox-2 selective inhibitors and show that the frequency of VVspecific B cells was reduced, as well as the production of neutralizing IgG. VV titers were approximately 70 times higher in mice treated with a Cox-2 selective inhibitor. Interestingly, Cox-2 inhibition also reduced the frequency of IFN-γ producing CD4 + T helper cells, important for class switching. The significance of these results is that the chronic use of NSAIDs, and other drugs that inhibit Cox-2 activity or expression, blunt the ability of B cells to produce anti-viral antibodies, thereby making vaccines less effective and possibly increasing susceptibility to viral infection. These new findings support an essential role for Cox-2 in regulating humoral immunity.

A Cyclooxygenase-2/Prostaglandin E2 Pathway Augments Activation-Induced Cytosine Deaminase Expression within Replicating Human B Cells

“…This is indicated by the presence of IgG Ab, albeit at lower levels, in immunized COX-2-deficient mice (8,9) and by the inability of COX-2 inhibitors to fully abrogate AID mRNA and protein expression in this study. Nevertheless, it remains unclear whether PGE 2 , or a related prostanoid acting through similar G-protein-coupled receptors, might play a critical role.…”

“…This study's finding that AID is positively influenced by PGE 2 is consistent with a past report that PGE 2 levels were high in mouse strains characterized by the production of high-affinity Abs (80), and furthermore, that Ab affinity was reduced when antigenic challenge was accompanied by indomethacin (an inhibitor of COX-2 and COX-1) (80). Moreover, these findings may provide an additional mechanism for the augmented switching to IgG and IgE in LPS + IL-4-stimulated mouse B cell cultures supplemented with PGE 2 (10,11,81) and the reduced isotype switching previously noted in immunized COX-2-deficient and mPGES-1-deficient mice (8,9,63).…”

“…Within nontransformed human B cell clones generated by surrogate C3dg-coated Ag, IL-4, and BAFF (5), the latter cytokine upregulates COX-2 protein within replicating progeny (6). B cell-expressed COX-2 appears to be functionally relevant because pharmacologic inhibitors of the enzyme can ablate B cell Ab synthesis (7)(8)(9), as well as reduce the viability of progeny (6). This inhibition is reversible by exogenous PGE 2 -a downstream product of the COX-2 pathway (6).…”

“…Interestingly, mice deficient in COX-2 have significantly impaired IgG Ab responses to vaccination, whereas they exhibit normal or even heightened IgM responses (8,9). Although diminished viability of replicating progeny may, in part, explain these findings, there is also evidence that COX-2 influences B cell Ig class-switch recombination.…”

Effect of antipyretic analgesics on immune responses to vaccination

“…[57][58][59] Inhibition of COX-2 leads to reduced interferon-g producing T cells and reduced antibody production by B cells in mice infected with vaccinia virus. 60 COX-1 and COX-2 inhibitors have been shown to markedly reduce antibody production. [61][62][63] Human B cells strongly express COX mRNA and protein and produce prostaglandins upon activation 61 suggesting a potential target for antipyretic analgesics in antibody producing cells.…”