Abstract
Previous work from our group has shown that Cd38−/− mice develop a milder pristane-induced lupus disease than WT or Art2−/− counterparts, demonstrating a new role for CD38 in promoting aberrant inflammation and lupus-like autoimmunity via a Transient Receptor Potential Melastatin 2 (TRPM2)-dependent apoptosis-driven mechanism. In this study we asked whether CD38 may play a role in the expression and function of regulatory B cells (IL-10-producing B cells or B10 cells). In pristane-treated mice the frequency of spleen CD19+CD1dhiCD5+ B cells, which are highly enriched in B10 cells, was significantly increased in Cd38−/− splenocytes compared to WT, while the frequency of peritoneal plasmacytoid dendritic cells (pDCs), which are major type I Interferon (IFN) producers, was greatly diminished. The low proportion of pDCs correlated with lower amounts of IFN-α in the peritoneal lavage fluids of the Cd38−/− mice than of WT and Art2−/− mice. Functional ex vivo assays showed increased frequencies of IL-10-producing B cells in Cd38−/− splenocytes than in WT upon stimulation with an agonist anti-CD40 mAb. Overall these results strongly suggest that Cd38−/− mice are better suited than WT mice to generate and expand regulatory B10 cells following the appropriate stimulation.
Highlights
CD38 is a transmembrane glycoprotein with receptor-mediated signaling capabilities and is an enzyme that catalyzes nicotinamide adenine dinucleotide (NAD+) or nicotinamide adenine dinucleotide phosphate (NADP+) to produce molecules involved in Ca2+ messenger signaling (cyclic ADPR, adenosine diphosphate ribose (ADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP)
The functional ex vivo assays showing increased frequencies of IL-10-producing B cells in Cd38−/− splenocytes than in WT upon stimulation with an agonist anti-CD40 mAb are in agreement with the in vivo experiments in the pristane-induced lupus model
Since this does not occur under steady-state conditions, or short-term pharmacological stimulation (LPS + PMA + Ionomycin), these results strongly suggest that Cd38−/− mice are better suited than WT mice to generate regulatory B10 cells under strong inflammatory conditions, or under the appropriate agonist stimulation
Summary
CD38 is a transmembrane glycoprotein with receptor-mediated signaling capabilities and is an enzyme that catalyzes nicotinamide adenine dinucleotide (NAD+) or nicotinamide adenine dinucleotide phosphate (NADP+) to produce molecules involved in Ca2+ messenger signaling (cyclic ADPR (cADPR), adenosine diphosphate ribose (ADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP). Previous studies of our group in Systemic Lupus Erythematosus (SLE) patients show increased CD38 surface expression in T cells and low levels of anti-CD38 autoantibodies in clinically active patients. In a kinase-dead mutant of PI3Kp110δ mice, Patton et al [4] reported that PI3Kp110δ kinase regulates expression of CD38 on regulatory T cells (Treg). These studies, combined with the observations that continuous administration of anti-IL-10 demonstrated a delay in onset of autoimmunity in NZB/W F1 mice [5], and anti-IL-10 mAb administered to six steroid-dependent patients with SLE was shown to have a beneficial effect on disease activity [6], suggest that this cytokine may promote disease. The positive and negative regulatory roles of IL-10 are likely to differ depending on the cell source of IL-10, as well as the timing of its production, duration, and levels of IL-10 expression [8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
