Final Report Summary - ACIGDSLE (Regulation and function of IgD in systemic lupus erythematosus) IgD emerged at the time of the inception of the adaptive immune system some 470 million years ago. Despite this striking evolutionary perpetuation, the role of IgD in health and disease remains unknown. Human B cells release IgD antibodies in the blood as well as respiratory, salivary, lachrymal and mammary secretions. The regulation and function of these antibodies are unclear. Recent research from our group shows that IgD is an important immunomodulator that orchestrates an ancestral surveillance system at the interface between immunity and inflammation. In the past 50 years numerous clinical and immunological observations of IgD, including its increased production in systemic lupus erythematosus (SLE), its frequent and intense reactivity to many SLE-associated autoantigens and its strong potential to induce inflammatory responses, suggest that IgD is an important but neglected component of autoimmune disorders.In the initial two years of this MC reintegration grant, we characterized the regulation of IgD production in human B cells. SLE is associated with dysregulated expression and release of various IgD-inducing factors. In addition, SLE patients often have an insufficiency of vitamin D (VD3), an immunoregulatory molecule that derives from the cholesterol biosynthetic pathway. This pathway is critical for the control of IgD production, because mutations of the gene encoding mevalonate kinase (MvK), an enzyme required for cholesterol and VD3 synthesis, cause hyper-IgD syndrome, an autoinflammatory disorder associated with hyper-IgD production and inflammation. Our work generated highly novel and significant results supporting the hypothesis that IgD is functionally linked to VD3. Indeed, we found that VD3 analogues such as calcitriol, calcipotriol and farnesol inhibited IgD induction in B cells exposed to cytokines such as BAFF, which is dysregulated in SLE. This inhibition was associated with the activation of VDR and farnesol receptor (FXR) at an intronic DNA region that governs switching from IgM to IgD. Thus, decreased VD3 availability, as observed in both SLE and HIDS patients, may exaggerate IgD production by removing the negative control imposed on non-canonical IgM-to-IgD class switching by VD3-VDR interaction in B cells. A corollary of this conclusion is that VD3 and VD3-like compounds may be used to attenuate inflammation in SLE and HIDS.In the second two years of this MC reintegration grant, we characterized the function of IgD in mouse models. Our results indicate that systemic or mucosal immunization under Th2 conditions, including papain administration, triggers an antigen-specific IgD response that amplifies pro-inflammatory IgG1 and IgE production through a mechanism involving the activation of basophils and Tfh cells expressing Th2 cytokines such as IL-4. Deletion of either IgD or basophils impairs IgG1 and IgE responses, including IgG1 affinity maturation. Of note, IgD binds to basophils ad its engagement by antigen activates basophil release of IL-4. Furthermore, IgD crosstalks with TSLP, an epithelial cytokine involved in basophil activation and Th2 immunity. Obverall, our findings indicate that IgD enhances primary Th2 responses by interacting with basophils and perhaps other effector cells of the innate immune system, including TSLP-responsive group 2 innate lymphoid cells. Whether IgD exacerbates or mitigates Th2-mediated inflammation remains to be established. Data that could not be included in this final progress report demonstrate that IgD interacts with the soluble lectin galectin-9 and that the resulting IgD-galectin-9 complex further interacts with the transmebrane protein CD44. This novel pathway may become dysregulated in SLE and other autoimmune disorders, thereby promoting the induction of pathogenic IgD as well as IgG1 and IgE autoantibodies. Ongoing studies are testing this possibility in autoimmune-prone mice.