Under the influence: environmental factors as modulators of neuroinflammation through the IL-10/IL-10R axis

The IL-10/IL-10 receptor (IL-10R) axis plays an important role in attenuating neuroinflammation in animal models of Multiple Sclerosis (MS) and increased IL-10 has been associated with a positive response to MS disease modifying therapy. Because environmental factors play an important role in MS susceptibility and disease course, identification of environmental factors that impact the IL-10/IL-10R axis has therapeutic potential. In this review, we provide historical and updated perspectives of how IL-10R signaling impacts neuroinflammation, discuss environmental factors and intestinal microbes with known impacts on the IL-10/IL-10R axis, and provide a hypothetical model for how B cells, via their production of IL-10, may be important in conveying environmental “information” to the inflamed central nervous system

An “outside-in” and “inside-out” consideration of complement in the multiple sclerosis brain: lessons from development and neurodegenerative diseases

The last 15 years have seen an explosion of new findings on the role of complement, a major arm of the immune system, in the central nervous system (CNS) compartment including contributions to cell migration, elimination of synapse during development, aberrant synapse pruning in neurologic disorders, damage to nerve cells in autoimmune diseases, and traumatic injury. Activation of the complement system in multiple sclerosis (MS) is typically thought to occur as part of a primary (auto)immune response from the periphery (the outside) against CNS antigens (the inside). However, evidence of local complement production from CNS-resident cells, intracellular complement functions, and the more recently discovered role of early complement components in shaping synaptic circuits in the absence of inflammation opens up the possibility that complement-related sequelae may start and finish within the brain itself. In this review, the complement system will be introduced, followed by evidence that implicates complement in shaping the developing, adult, and normal aging CNS as well as its contribution to pathology in neurodegenerative conditions. Discussion of data supporting “outside-in” vs. “inside-out” roles of complement in MS will be presented, concluded by thoughts on potential approaches to therapies targeting specific elements of the complement system

Homeodomain-Interacting Protein Kinase (HIPK)-1 Is Required for Splenic B Cell Homeostasis and Optimal T-Independent Type 2 Humoral Response

The homeodomain-interacting protein kinase (HIPK) family is comprised of four highly related serine/threonine kinases originally identified as co-repressors for various homeodomain-containing transcription factors. The HIPKs have been shown to be involved in growth regulation and apoptosis, with numerous studies highlighting HIPK regulation of the tumor suppressor p53. In this study, we have discovered a B cell homeostatic defect in HIPK1-deficient (HIPK1−/−) mice. Lymphopoietic populations within the thymus and bone marrow of HIPK1−/− mice appeared normal based upon FACS analysis; however, the spleen exhibited a reduced number of total B cells with a significant loss of transitional-1 and follicular B cell populations. Interestingly, the marginal zone B cell population was expanded in HIPK1−/− mice, yielding an increased frequency of these cells. HIPK1−/− B cells exhibited impaired cell division in response to B cell receptor cross-linking in vitro based upon thymidine incorporation or CFSE dilution; however, the addition of CD40L rescued HIPK1−/− proliferation to wild-type levels. Despite the expanded MZ B cell population in the HIPK1−/− mice, the T-independent type 2 humoral response was impaired. These data identify HIPK1 as a novel kinase required for optimal B cell function in mice

Expression of lymphotoxin-αβ on antigen-specific T cells is required for DC function

During an immune response, activated antigen (Ag)-specific T cells condition dendritic cells (DCs) to enhance DC function and survival within the inflamed draining lymph node (LN). It has been difficult to ascertain the role of the tumor necrosis factor (TNF) superfamily member lymphotoxin-αβ (LTαβ) in this process because signaling through the LTβ-receptor (LTβR) controls multiple aspects of lymphoid tissue organization. To resolve this, we have used an in vivo system where the expression of TNF family ligands is manipulated only on the Ag-specific T cells that interact with and condition Ag-bearing DCs. We report that LTαβ is a critical participant required for optimal DC function, independent of its described role in maintaining lymphoid tissue organization. In the absence of LTαβ or CD40L on Ag-specific T cells, DC dysfunction could be rescued in vivo via CD40 or LTβR stimulation, respectively, suggesting that these two pathways cooperate for optimal DC conditioning

Metabolomics based markers predict type 2 diabetes in a 14-year follow-up study

Chemical probes are key components of the bioimaging toolbox, as they label biomolecules in cells and tissues. The new challenge in bioimaging is to design chemical probes for three-dimensional (3D) tissue imaging. In this work, we discovered that light scattering of metal nanoparticles can provide 3D imaging contrast in intact and transparent tissues. The nanoparticles can act as a template for the chemical growth of a metal layer to further enhance the scattering signal. The use of chemically grown nanoparticles in whole tissues can amplify the scattering to produce a 1.4 million-fold greater photon yield than obtained using common fluorophores. These probes are non-photobleaching and can be used alongside fluorophores without interference. We demonstrated three distinct biomedical applications: (a) molecular imaging of blood vessels, (b) tracking of nanodrug carriers in tumors, and (c) mapping of lesions and immune cells in a multiple sclerosis mouse model. Our strategy establishes a distinct yet complementary set of imaging probes for understanding disease mechanisms in three dimensions

Differential requirement of MALT1 for BAFF-induced outcomes in B cell subsets

B cell activation factor of the TNF family (BAFF) activates noncanonical nuclear factor κB (NF-κB) heterodimers that promote B cell survival. We show that although MALT1 is largely dispensable for canonical NF-κB signaling downstream of the B cell receptor, the absence of MALT1 results in impaired BAFF-induced phosphorylation of NF-κB2 (p100), p100 degradation, and RelB nuclear translocation in B220+ B cells. This corresponds with impaired survival of MALT1−/− marginal zone (MZ) but not follicular B cells in response to BAFF stimulation in vitro. MALT1−/− MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor–mediated signaling, and TRAF3 was found to interact with MALT1. Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numbers, elevated serum immunoglobulin titers, and spontaneous germinal center formation, were found to be dependent on B cell–intrinsic MALT1 expression. Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction

An analysis of steel factor-stimulated receptor trafficking, survival signals and mitogenesis, understanding the role of c-Kit-associated signaling proteins

grantor: University of TorontoReceptor tyrosine kinases, upon binding to their respective ligands, undergo dimerization, activation of intrinsic kinase domains and phosphorylation of intrinsic tyrosine residues. This results in the recruitment and activation of a number of intracellular signaling molecules. In the case of the receptor tyrosine kinase c-Kit, activation by its ligand Steel Factor (SLF) is important for a number of developmental systems including hematopoiesis, gametogenesis and germ cell formation. SLF stimulation of c-Kit induces the recruitment of a number of SH2-containing proteins including Phosphatidylinositol-3-kinase (PI3-kinase) and Phospholipase C gamma (PLC-ã). PI3-kinase generates D3 phosphoinositide second messengers. In the case of PLC-ã activation, hydrolysis of phosphatidylinositol bisphosphate into inositol trisphosphate and diacylglycerol leads to Ca2+ mobilization and activation of Protein Kinase C. In this thesis, using c-Kit positive mast cells and myelomonocytic cell lines I have examined the involvement of these two signaling enzymes in SLF-stimulated survival and mitogenic signals as well as SLF-stimulated receptor internalization. The mechanism of SLF-stimulated c-Kit internalization is examined and a requirement for both Ca2+ influx and PI3-kinase activity in this process is identified. In addition, I have determined that mitogenic stimulation of c-Kit positive cells by membrane-bound SLF requires the activity of PLC-ã. Finally, I have identified an important role for PLC-ã-mediated Ca2+ influx in c-Kit-mediated survival signals and characterized a SLF-mediated apoptotic mechanism involving Ca2+ influx blockade. Therefore, the use of both c-Kit receptor mutants as well as specific inhibitors has allowed the identification of important roles for these signaling proteins and their second messengers in SLF-stimulated cellular processes. The relevance of these c-Kit associated signaling molecules 'in vivo' will be discussed.Ph.D

Guardians of the oral and nasopharyngeal galaxy: IgA and protection against SARS-CoV-2 infection

In early 2020, a global emergency was upon us in the form of the coronavirus disease 2019 (COVID‐19) pandemic. While horrific in its health, social and economic devastation, one silver lining to this crisis has been a rapid mobilization of cross‐institute, and even cross‐country teams that shared common goals of learning as much as we could as quickly as possible about the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and how the immune system would respond to both the virus and COVID‐19 vaccines. Many of these teams were formed by women who quickly realized that the classical model of “publish first at all costs” was maladaptive for the circumstances and needed to be supplanted by a more collaborative solution‐focused approach. This review is an example of a collaboration that unfolded in separate countries, first Canada and the United States, and then also Israel. Not only did the collaboration allow us to cross‐validate our results using different hands/techniques/samples, but it also took advantage of different vaccine types and schedules that were rolled out in our respective home countries. The result of this collaboration was a new understanding of how mucosal immunity to SARS‐CoV‐2 infection vs COVID‐19 vaccination can be measured using saliva as a biofluid, what types of vaccines are best able to induce (limited) mucosal immunity, and what are potential correlates of protection against breakthrough infection. In this review, we will share what we have learned about the mucosal immune response to SARS‐CoV‐2 and to COVID‐19 vaccines and provide a perspective on what may be required for next‐generation pan‐sarbecoronavirus vaccine approaches