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^hi 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^high 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.

Cross-linking of CD38 on hematopoietic cells induces activation, proliferation and differentiation of mature T and B cells and mediates apoptosis of myeloid and lymphoid progenitor cells. In addition to acting as a signaling receptor, CD38 is also an enzyme capable of producing several calcium-mobilizing metabolites, including cyclic adenosine diphosphate ribose (cADPR). It has been previously postulated that the calcium-mobilizing metabolites produced by CD38 may regulate its receptor-based activities. To test this hypothesis, we examined whether the enzyme activity of CD38 controls the apoptosis of an anti-CD38-stimulated leukemic B cell. We show that anti-CD38-induced apoptosis of Ba/F3 cells, a murine pro-B cell line, is not affected by blocking the calcium-mobilizing activity of cADPR or by inhibiting intracellular or extracellular calcium mobilization. In addition, we demonstrate that blocking CD38 enzyme activity with 2′-deoxy-2′-fluoro-nicotinamide arabinoside adenine dinucleotide has no effect on apoptosis and that Ba/F3 cells expressing catalytically inactive mutant forms of CD38 still undergo apoptosis upon CD38 cross-linking. Instead, we find that anti-CD38-induced apoptosis is dependent on tyrosine kinase and caspase activation, and that this process appears to be potentiated by the presence of membrane microdomains. Thus, the receptor-mediated functions of CD38 can be separated from its enzyme activity in a murine leukemic cell line, suggesting that CD38 plays multiple, but independent, biologic roles.

CD38 is a transmembrane glycoprotein expressed by T-cells. It has been reported that patients with systemic lupus erythematosus (SLE) showed increased CD38⁺CD25⁺ T-cells correlating with immune activation and clinical signs. Contrariwise, CD38 deficiency in murine models has shown enhanced autoimmunity development. Recent studies have suggested that CD38⁺ regulatory T-cells are more suppressive than CD38⁻ regulatory T-cells. Thus, we have suggested that CD38 overexpression in SLE patients could play a role in regulating immune activation cells instead of enhancing it. This study found a correlation between CD38 with FoxP3 expression and immunosuppressive molecules (CD69, IL-10, CTLA-4, and PD-1) in T-cells from lupus-prone mice (B6.MRL-Fas^lpr/J). Additionally, B6.MRL-Fas^lpr/J mice showed a decreased proportion of CD38⁺ Treg cells regarding wild-type mice (WT). Furthermore, Regulatory T-Cells (Treg cells) from CD38-/- mice showed impairment in expressing immunosuppressive molecules and proliferation after stimulation through the T-cell receptor (TCR). Finally, we demonstrated an increased ratio of IFN-γ/IL-10 secretion in CD38-/- splenocytes stimulated with anti-CD3 compared with the WT. Altogether, our data suggest that CD38 represents an element in maintaining activated and proliferative Treg cells. Consequently, CD38 could have a crucial role in immune tolerance, preventing SLE development through Treg cells.

Summary: CD38 is a 45 000 molecular weight transmembrane protein that is expressed in immature and mature lymphocytes. However, the expression and function of CD38 during B‐cell differentiation in mice is poorly understood. Here, we report that CD38 is expressed from the earliest stages of B‐cell development. Pre‐pro‐B, pro‐B, pre‐B and immature B cells from murine bone marrow all stained positive for CD38. Interestingly, CD38 expression increases with B‐cell maturation. To assess the role of CD38 during B‐cell maturation, CD38‐deficient mice were analysed. CD38^−/− mice showed a significant increase in both the frequency of B‐lineage cells and the absolute numbers of pre‐pro‐B cells in bone marrow; however, no other differences were observed at later stages. CD38 cross‐linking in Ba/F3 cells promoted apoptosis and marked extracellular signal‐regulated kinase (ERK) phosphorylation, and these effects were reduced by treatment with the mitogen‐activated protein kinase/ERK kinase inhibitor PD98059, and similar effects were observed in B‐cell precursors from bone marrow. These data demonstrate that B‐cell precursors in mouse bone marrow express functional CD38 and implicate the early ligation of CD38 in the ERK‐associated regulation of the B‐lineage differentiation pathway.

Colostrum is the primary source of maternal immunoglobulin A (IgA) for the newborn. IgA participates in protection and regulation mechanisms of the immune response at the neonate’s mucosa. Several studies have evaluated infectious diseases and vaccine protocols effects during pregnancy on maternal milk IgA levels, with the aim to understand lactation protecting effect on newborn. However, most of their results demonstrated that there were no differences in the total IgA levels. In humans, IgA has two subclasses (IgA1 and IgA2), they have an anatomical distribution among mucosal compartments, their levels vary after antigen stimulation and are also seen to describe differential affinities in colostrum. Although there are differences between IgA subclasses in several compartments, these studies have excluded specific colostrum IgA1 and IgA2 determination. We analyzed data from 900 women in Mexico City. With Pearson correlation, we compared the number of infectious episodes during their pregnancy that was associated with mucosal compartments (skin, respiratory and gastrointestinal tracts) and colostrum IgA subclasses. We show a correlation between increased colostrum IgA1 levels and the number of infectious episodes at respiratory tract and the skin. In contrast, infections at the gastrointestinal tract correlated with increased IgA2 amounts. Infections present during pregnancy at certain mucosal site increase specific IgA subclasses levels in human colostrum. These results will help in understanding infections and immunizations effects on maternal IgA at the mammary gland, and their impact on the development and protection of the newborn.