CD38 protein deficiency induces autoimmune characteristics and its activation enhances IL‐10 production by regulatory B cells

Abstract

CD38 is a transmembrane protein expressed in B lymphocytes, and is able to induce responses as proliferation, differentiation or apoptosis. Several reports propose that CD38 deficiency accelerates autoimmune processes in murine models of autoimmune diabetes, lymphoproliferation and rheumatoid arthritis. Other reports have shown elevated CD38 expression in B and T cells from patients with autoimmunity; however, the role of CD38 is still unclear in the development of autoimmunity. Recently, it has been characterized as CD1d CD5 regulatory B cell subpopulation able to produce IL-10, and the loss of these cells exacerbates the autoimmunity in murine models. Here, we report that CD38 mice exhibited elevated titres of ANAS, anti-dsDNA autoantibodies from 12 months of age and were higher by 16 months of age and mice presented kidney damage. Interestingly, there is a reduction in the survival of CD38 mice compared to the WT. Furthermore, CD38 is highly expressed by CD1d CD5 regulatory B cells, and the agonistic anti-CD38 stimulus plus LPS was able to increase the percentage of this cell subset and its ability to induce IL-10 production. Together, these results suggest that CD38 could play a role in the control of autoimmune diseases through their expression on regulatory B cells.

The Role of CD38 on the Function of Regulatory B Cells in a Murine Model of Lupus

“…As shown in Figure 2 , CD38 expression was significantly higher in the CD1d hi subsets, either CD5 + or CD5 − than in the other two subsets. Note that the highest CD38 expression resides in the CD1d hi CD5 + subset; as these differences are statistically significant they confirm and extend previous results obtained by others [ 23 ].…”

“…Increased CD38 surface expression is a hallmark of regulatory B cells in both human and mice [ 9 , 23 ]. Therefore, we tested CD38 surface expression in the four major B cells subsets (CD19 + cells) defined by the CD1d and CD5 markers.…”

CD38, a Receptor with Multifunctional Activities: From Modulatory Functions on Regulatory Cell Subsets and Extracellular Vesicles, to a Target for Therapeutic Strategies

“…Another study has addressed the crucial role of CD38 for the modulatory functions of Bregs in pre-clinical models. CD38 −/− mice develop autoimmunity, displaying high levels of anti-nuclear antibodies, anti-double strand DNA auto-antibodies and a reduced survival, and such effects have been related to a defective function of Bregs [36].…”

Is There a Future for Anti-CD38 Antibody Therapy in Systemic Autoimmune Diseases?

“…Therefore, it could be argued that the depletion of immunosuppressive and regulatory subtypes may limit the efficacy of anti-CD38 therapies, or, in worst cases, induce a flare of the autoimmune disease. Indeed, in murine models the loss of CD38 was able to induce autoimmune features such as autoantibodies and end-organ damage [69]. However, the role of CD38 in the development of autoimmunity and its implications are still controversial, as is the role of regulatory B cells in patients with established autoimmune diseases, in which they have been shown to be already reduced and functionally impaired [28,29,47,70].…”