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Absence of mouse cell surface receptor CD38 in Cd38-/- mice suggests that this receptor acts as positive regulator of inflammatory and autoimmune responses. Here we report that in the setting of a chronic graft versus host disease (cGVHD) lupus model induced by the transfer of B6.C-H2bm12/KhEg (bm12) spleen cells into co-isogenic Cd38-/- B6 mice causes milder lupus-like autoimmunity with lower levels of anti-ssDNA autoantibodies than the transfer of bm12 spleen cells into WT B6 mice. I In addition, significantly lower percentages of Tfh cells, as well as GC B cells, plasma cells and T-bet+CD11chi B cells are observed in Cd38-/- mice than in WT mice, while the expansion of Treg cells, and Tfr cells is normal, suggesting that the ability of Cd38-/- B cells to respond to allogeneic help from bm12 CD4+ T cells is greatly diminished. The frequencies of T-bet+CD11chi B cells, which are considered the precursors of the autoantibody secreting cells, correlate with anti-ssDNA autoantibody serum levels, with IL-27, and sCD40L. Proteomics profiling of spleens from WT cGVHD mice reflects a STAT1-driven type I IFN-signature, which is absent in Cd38-/- cGVHD mice. Kidney, spleen and liver inflammation was mild and resolved faster in Cd38-/- cGVHD mice than in WT cGVHD mice. We conclude that in B cells CD38 functions as a modulator receptor that controls autoimmune responses.

In CD38-deficient (Cd38-/-) mice intraperitoneal injection of pristane induces a lupus-like disease, which is milder than that induced in WT mice, showing significant differences in the inflammatory and autoimmune processes triggered by pristane. Extracellular vesicles (EV) are present in all body fluids. Shed by cells, their molecular make-up reflects that of their cell of origin and/or tissue pathological situation. The aim of this study was to analyze the protein composition, protein abundance, and functional clustering of EV released by peritoneal exudate cells (PECs) in the pristane experimental lupus model, to identify predictive or diagnostic biomarkers that might discriminate the autoimmune process in lupus from inflammatory reactions and/or normal physiological processes. In this study, thanks to an extensive proteomic analysis and powerful bioinformatics software, distinct EV subtypes were identified in the peritoneal exudates of pristane-treated mice: 1) small EV enriched in the tetraspanin CD63 and CD9, which are likely of exosomal origin; 2) small EV enriched in CD47 and CD9, which are also enriched in plasma-membrane, membrane-associated proteins, with an ectosomal origin; 3) small EV enriched in keratins, ECM proteins, complement/coagulation proteins, fibrin clot formation proteins, and endopetidase inhibitor proteins. This enrichment may have an inflammation-mediated mesothelial-to-mesenchymal transition origin, representing a protein corona on the surface of peritoneal exudate EV; 4) HDL-enriched lipoprotein particles. Quantitative proteomic analysis allowed us to identify an anti-inflammatory, Annexin A1-enriched pro-resolving, neutrophil protein signature, which was more prominent in EV from pristane-treated Cd38-/- mice, and quantitative differences in the protein cargo of the ECM-enriched EV from Cd38-/- vs WT mice. These differences are likely to be related with the distinct inflammatory outcome shown by Cd38-/- vs WT mice in response to prista

Systemic Lupus Erythematous (SLE) is a complex autoimmune disease, characterized by increased cellular death by apoptosis and defective clearance of apoptotic bodies and nuclear fragments, resulting in increased antinuclear antibody production. We have used the inducible bm12 lupus model, where an abnormal chronic graft versus host disease (cGvHD) is induced in non-autoimmune C57BL6 mice (WT) by the adoptive transfer of MHC Class II IA-incompatible bm12 spleen cells. In the absence of CD38 in the host (CD38KO mice), we have observed a significant decrease in the severity of the disease (doi: 10.3389/fimmu.2021.713697). Objectives: Analyze the protein composition and function of EVs released in the peritoneal cavity of cGvHD mice, to identify predictive or diagnostic biomarkers of the disease Methods: EVs were isolated by qEV size-exclusion-chromatography (SEC) from peritoneal exudates of cGVHD lupus-mice, two weeks after the adoptive transfer of bm12 cells. Protein extracts from isolated EVs were analyzed by LC-MS/MS. Protein identification was performed with ProteinScape, and MASCOT data searching using Swiss-Prot database. To quantify protein abundance, the emPAI-based method was used. We used ClueGO and CluePedia apps within the Cytoscape software for functional analysis.

The absence of the mouse cell surface receptor CD38 in Cd38−/− mice suggests that this receptor acts as a positive regulator of inflammatory and autoimmune responses. Here, we report that, in the context of the chronic graft-versus-host disease (cGVHD) lupus inducible model, the transfer of B6.C-H2bm12/KhEg(bm12) spleen cells into co-isogenic Cd38−/− B6 mice causes milder lupus-like autoimmunity with lower levels of anti-ssDNA autoantibodies than the transfer of bm12 spleen cells into WT B6 mice. In addition, significantly lower percentages of Tfh cells, as well as GC B cells, plasma cells, and T-bet+CD11chi B cells, were observed in Cd38−/− mice than in WT mice, while the expansion of Treg cells and Tfr cells was normal, suggesting that the ability of Cd38−/− B cells to respond to allogeneic help from bm12 CD4+ T cells is greatly diminished. The frequencies of T-bet+CD11chi B cells, which are considered the precursors of the autoantibody-secreting cells, correlate with anti-ssDNA autoantibody serum levels, IL-27, and sCD40L. Proteomics profiling of the spleens from WT cGVHD mice reflects a STAT1-driven type I IFN signature, which is absent in Cd38−/− cGVHD mice. Kidney, spleen, and liver inflammation was mild and resolved faster in Cd38−/− cGVHD mice than in WT cGVHD mice. We conclude that CD38 in B cells functions as a modulator receptor that controls autoimmune responses.

Introduction: Systemic Lupus Erythematous (SLE) is a complex autoimmune disease, characterized by increased cellular death by apoptosis and defective clearance of apoptotic bodies and nuclear fragments, resulting in increased antinuclear antibody production. In this study, we have used the inducible bm12 lupus model, where an abnormal chronic graft versus host disease (cGvHD) is induced in non-autoimmune C57BL6 mice (WT) by the adoptive transfer of MHC Class II Ia-incompatible bm12 spleen cells. In the absence of CD38 in the host (CD38KO mice), we have observed a significant decrease in the severity of the disease (doi: 10.3389/fimmu.2021.713697). Objectives: Analyze the protein composition and function of EVs released by specific cell types in the peritoneal cavity of cGvHD mice, to identify predictive or diagnostic biomarkers of the disease that may help to discriminate the role of CD38 in the cGVHD lupus-like autoimmunity process. Methods: EVs were isolated by qEV size-exclusion-chromatography (SEC) from peritoneal exudates of cGVHD lupus-mice, two weeks after the adoptive transfer of bm12 cells. Protein extracts from isolated EVs were analyzed by LC-MS/MS. Protein identification was performed with ProteinScape, and MASCOT data searching using Swiss-Prot database. To quantify the protein abundance, the emPAI-based method was used. ClueGO and CluePedia apps within the Cytoscape software environment were used for functional enrichment analysis of the lists of identified proteins. Results: Data showed that peritoneal exudate EVs can be isolated by SEC in 2 distinct EV subsets, which differ in size, protein composition and functional potential. Functional enrichment analyses indicated that a significant proportion of the identified proteins were related with EVs. In cGvHD CD38KO mice, among the unique and highly abundant proteins, there were phagocytosis inductors and apoptosis inhibitors, such as CD5L and LSP1. In cGvHD WT mice were identified proteins like CD24, a