Mice with targeted deletion of fibrinogen‐like protein 2 (fgl2) spontaneously developed autoimmune glomerulonephritis with increasing age, as did wild‐type recipients reconstituted with fgl2−/− bone marrow. These data implicate FGL2 as an important immunoregulatory molecule and led us to identify the underlying mechanisms. Deficiency of FGL2, produced by CD4+CD25+ regulatory T cells (Treg), resulted in increased T cell proliferation to lectins and alloantigens, T helper 1 (Th1) polarization, and increased numbers of antibody‐producing B cells following immunization with T‐independent antigens. Dendritic cells (DC) were more abundant in fgl2−/− mice and had increased expression of CD80 and MHCII following LPS stimulation. Treg cells were also more abundant in fgl2−/− mice, but their suppressive activity was significantly impaired. Antibody to FGL2 completely inhibited Treg cell activity in vitro. FGL2 inhibited DC maturation and induced apoptosis of B cells through binding to the low affinity FcγRIIB receptor. Collectively, these data suggest that FGL2 contributes to Treg cell activity and inhibits the development of autoimmune disease. This work was supported in part by grants from the Heart and Stroke Foundation of Canada and the Canadian Institutes for Health Research.

Historically, research databases have existed in isolation with no practical avenue for sharing or pooling medical data into high dimensional datasets that can be efficiently compared across databases. To address this challenge, the Ontario Brain Institute’s “Brain-CODE” is a large-scale neuroinformatics platform designed to support the collection, storage, federation, sharing and analysis of different data types across several brain disorders, as a means to understand common underlying causes of brain dysfunction and develop novel approaches to treatment. By providing researchers access to aggregated datasets that they otherwise could not obtain independently, Brain-CODE incentivizes data sharing and collaboration and facilitates analyses both within and across disorders and across a wide array of data types, including clinical, neuroimaging and molecular. The Brain-CODE system architecture provides the technical capabilities to support (1) consolidated data management to securely capture, monitor and curate data, (2) privacy and security best-practices, and (3) interoperable and extensible systems that support harmonization, integration, and query across diverse data modalities and linkages to external data sources. Brain-CODE currently supports collaborative research networks focused on various brain conditions, including neurodevelopmental disorders, cerebral palsy, neurodegenerative diseases, epilepsy and mood disorders. These programs are generating large volumes of data that are integrated within Brain-CODE to support scientific inquiry and analytics across multiple brain disorders and modalities. By providing access to very large datasets on patients with different brain disorders and enabling linkages to provincial, national and international databases, Brain-CODE will help to generate new hypotheses about the biological bases of brain disorders, and ultimately promote new discoveries to improve patient care.

Background— Xenografts ultimately fail as a result of acute vascular rejection (AVR), a process characterized by intravascular thrombosis, fibrin deposition, and endothelial cell activation. Methods and Results— We studied whether targeted deletion of Fgl-2, an inducible endothelial cell procoagulant, (Fgl-2 −/− ) in the donor prevents AVR in a mouse-to-rat cardiac xenotransplantation model. By 3 days after transplant, Fgl-2 +/+ grafts developed typical features of AVR associated with increased levels of donor Fgl-2 mRNA. Grafts from Fgl-2 −/− mice had reduced fibrin deposition but developed cellular rejection. Treatment with a short course of cobra venom factor and maintenance cyclosporine resulted in long-term acceptance of both Fgl-2 +/+ and Fgl-2 −/− grafts. On withdrawal of cyclosporine, Fgl-2 +/+ grafts developed features of AVR; in contrast, Fgl-2 −/− grafts again developed acute cellular rejection. Rejecting Fgl-2 +/+ hearts stained positively for IgG, IgM, C3, and C5b-9, whereas rejecting Fgl-2 −/− hearts had minimal Ig and complement deposition despite xenoantibodies in the serum. Furthermore, serum containing xenoantibodies failed to stain Fgl-2 −/− long-term treated hearts but did stain wild-type heart tissues. Treatment of Fgl-2 −/− xenografts with mycophenolate mofetil and tacrolimus, a clinically relevant immune suppression protocol, led to long-term graft acceptance. Conclusions— Deletion of Fgl-2 ameliorates AVR by downregulation of xenoantigens and may facilitate successful clinical heart xenotransplantation.

Background: A subset of juvenile myelomonocytic leukemia (JMML) patients harbor mutations in the E3 ubiquitin ligase CBL. Results: CBL mutations result in increased GM-CSFR phosphorylation, elevated JAK2 and LYN levels, and enhanced survival. Conclusion: CBL JMML mutants display hypersensitive GM-CSF signaling that can be modulated via inhibition of JAK2 and/or SRC kinases. Significance: Mutation of CBL in JMML is associated with altered GM-CSF function.