Marc S Horwitz

Marc S Horwitz
University of British Columbia - Vancouver | UBC

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77
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Publications (77)
Article
Full-text available
Multiple sclerosis (MS) is caused by a combination of genetic and environmental factors. It is believed that previous infection with Epstein Barr Virus (EBV) plays an important role in the development of MS. Previously, we developed a murine model where latent infection with gamma herpesvirus 68 (γHV-68), a murine homolog to EBV, enhanced the sympt...
Article
Full-text available
Pancreatic beta-cells are selectively destroyed by the host immune system in type 1 diabetes. Thus, drugs that preserve beta-cell mass and/or function have the potential to prevent or slow the progression of this disease. We recently reported that the use-dependent sodium channel blocker, carbamazepine, protects beta-cells from inflammatory cytokin...
Article
Full-text available
Type 1 diabetes (T1D) has been associated with both genetic and environmental factors. Increasing incidence of T1D worldwide is prompting researchers to adopt different approaches to explain the biology of T1D, beyond the presence and activity of autoreactive lymphocytes. In this review, we propose inflammatory pathways as triggers for T1D. Within...
Article
As if the pathway of regulation leading islet cells toward dysfunction and diabetes was not difficult enough to grasp, here come viruses to further complicate matters. In the past few years, we have come to recognize that a class of small noncoding RNAs termed microRNAs (miRNAs) has a powerful ability to regulate most, if not all, of the key proces...
Article
Full-text available
Autoimmune destruction of the pancreatic islets in Type 1 diabetes is mediated by both increased proinflammatory (Teff) and decreased regulatory (Treg) T lymphocytes resulting in a significant decrease in the Treg:Teff ratio. The non-obese diabetic (NOD) mouse is an excellent in vivo model for testing potential therapeutics for attenuating the decr...
Data
TA1 therapy increased multiple toloerogenic cell supopulations (relative to control mice) in the pancreatic lymph node of both diabetic and non-diabetic NOD mice. Shown are representative flow cytometric data for Saline-Diabetic, TA1-Diabetic, Saline-NonDiabetic and TA1-NonDiabetic mice as presented in Fig 5. The saline-treated control NOD mouse gr...
Data
Putative Function(s) of Identified TA1 miRNA Species. U = Upregulated; D = Downregulated. (DOCX)
Data
TA1 therapy decreased multiple Teff cell subpopulations (relative to control mice) in the pancreatic lymph node of both diabetic and non-diabetic NOD mice. Shown are representative flow cytometric data for Saline-Diabetic, TA1-Diabetic, Saline-NonDiabetic and TA1-NonDiabetic mice as presented in Fig 5. The saline-treated control NOD mouse group con...
Article
Full-text available
The onset of multiple sclerosis (MS) is caused by both genetic and environmental factors. Among the environmental factors, it is believed that previous infection with Epstein–Barr virus (EBV) may contribute in the development of MS. EBV has been associated with other autoimmune diseases, such as systemic lupus erythematous, and cancers like Burkitt...
Article
Full-text available
Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS) by multiple groups working worldwide. Previously, we reported that when experimental autoimmune encephalomyelitis (EAE) was induced in mice latently infected with murine γ-herpesvirus 68 (γHV-68), the murine homolog to EBV, a disease more rem...
Article
Although it is widely accepted that Type 1 diabetes (T1D) is the result of the autoimmune destruction of insulin-producing beta cells in the pancreas little is known about the events leading to islet autoimmunity. Epidemiological and genetic data have associated virus infections and anti-viral type I interferon (IFN-I) response genes with T1D. Gene...
Article
Although genetic predisposition to type 1 diabetes (T1D) is a key risk factor, it does not explain the recent and rapid rise in incidence of the disease, particularly among children under the age of 5 (1). Changes in the environment and/or how individuals respond to these changes are now widely believed to be responsible for the recent increases in...
Article
Full-text available
The HIV/AIDS pandemic remains an enormous global health concern. Despite effective prevention options, 2.6 million new infections occur annually, with women in developing countries accounting for more than half of these infections. New prevention strategies that can be used by women are urgently needed. Topical microbicides specific for HIV-1 repre...
Data
JS4026 and JS4038 strains were compared side-by-side in the described viral blocking assay. Results represent mean with the range provided. Experiments were set up in quadruplicate and performed a minimum of 3 times. (PDF)
Article
Multiple sclerosis (MS) and systemic lupus erythematosus (SLE) are both chronic autoimmune diseases with unknown etiology. To date, EBV is the most closely implicated infectious agent to be associated with both MS and SLE. Epidemiological findings show a strong correlation between EBV infection and the risk of developing these diseases. The type an...
Article
Full-text available
During the progression of autoimmune (type 1) diabetes, T cells and macrophages infiltrate the pancreas, disrupt islet function, and destroy insulin-producing beta cells. B-lymphocytes, particularly innate like B-cell populations such as marginal zone B cells and B-1 cells, have been implicated in many autoimmune diseases, and non-obese diabetic (N...
Data
γHV-68 EAE mice show increased amount of immune cells infiltrations in the spinal cords. Mice were infected with γHV-68 (right panels) or MEM only (left panels). Five weeks p.i. EAE was induced. At day 28 post EAE induction mice were perfused and spinal cords were harvested, fixed in formalin and paraffin embedded (similar results obtained at day 1...
Data
γHV-68 EAE mice show increased levels of CXCR3 on splenic T cells. Mice were infected i.p. with γHV-68 (black bars) or MEM only (open bars). Five weeks p.i., EAE was induced. At day 15 post EAE induction, spleens were harvested and the levels of CXCR3 were assessed through FACS analysis. The histograms show the numbers of CD4+CXCR3+ cells (left pan...
Data
γHV-68 EAE mice show increased T cell expression of IFN-γ accompanied by IL-17 suppression after MOG restimulation. Mice were infected with γHV-68 (black bars, shaded histograms) or MEM only (open bars, open histograms). Five weeks p.i. EAE was induced. At day 14–16 post EAE induction (mean clinical score of 3 for γHV-68 EAE mice, EAE mice were har...
Data
γHV-68 EAE mice show increased levels of pro-inflammatory cytokines in the serum. Mice were infected i.p. with γHV-68 (black bars) or MEM only (open bars). Five weeks p.i., EAE was induced. At day 10 (A) and 15 (B) post EAE induction blood was harvested through a cardiac puncture and the levels of cytokines were evaluated using BD Cytometric Bead A...
Data
γHV-68 EAE mice show increased levels of IFN-γ in CNS supernatants. Mice were infected i.p. with γHV-68 (black bars) or MEM only (open bars). Five weeks p.i., EAE was induced. At day 14–16 post EAE induction (mean score of 3 for γHV-68 EAE mice, EAE mice were harvested at the same time), mice were perfused and brains and spinal cords were homogeniz...
Article
Full-text available
Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS), yet EBV's role in MS remains elusive. We utilized murine gamma herpesvirus 68 (γHV-68), the murine homolog to EBV, to examine how infection by a virus like EBV could enhance CNS autoimmunity. Mice latently infected with γHV-68 developed more...
Article
Full-text available
P-selectin glycoprotein ligand-1 (PSGL-1), a heavily glycosylated sialomucin expressed on most leukocytes, has dual function as a selectin ligand for leukocyte rolling on vascular selectins expressed in inflammation and as a facilitator of resting T cell homing into lymphoid organs. In this article, we document disturbances in T cell homeostasis pr...
Article
Full-text available
Progression towards type 1 diabetes (T1D) in susceptible patients is linked to a progressive decline in the capacity of regulatory T cells (Treg) to maintain tolerance. As such, therapies aimed at redressing the failing Treg compartment have been the subject of intense investigation. Treg dysfunction in T1D has recently been linked to a reduced cap...
Data
MyD88 deficiency decreases the capacity of cellular effectors to activate in response to CB4 infection. Representative histograms of expression of activation or costimulatory marker (as indicated) on the surface of A) NK cells (Pan-NK+, TCRβ −), B) NK T cells (Pan-NK+, TCRβ +), C) macrophages (CD11b+CD11c−), D) dendritic cells (CD11c+), E) B cells...
Data
CB4 infection in the context of TGF-β does not affect the capacity of DCs to produce cytokines. Ex vivo production of A) TNF-α or B) IL-6 from CD11c+ DCs FACS sorted from CB4 infected NOD (black bar) or NODTGFβ (white bar) mice. Data represent mean + s.e.m of normalized cytokine levels from pooled mice in 3 separate experiments. (EPS)
Data
CD11b+CD11c− APCs from NODTGFβ mice do not express increased levels of PD-L1 compared NOD mice following CB4 infection. A) Representative histogram of surface PD-L1 expression on CD11b+CD11c− APCs from NOD (black line) or NODTGFβ (grey line) mice at day 7 following CB4 infection. B) Average mean fluorescence intensity of PD-L1 expression on the sur...
Data
Adoptive transfer of CD11b+CD11c− APCs from CB3-infected NODTGFβ mice is not sufficient to increase Treg levels in uninfected NOD mice. Average percentage of CD4+ T cells expressing Foxp3 in the PLNs of 10–12 week uninfected NOD recipients mock transferred with DMEM (grey bars) or adoptively transferred with CD11b+CD11c− APCs FACS sorted from CB3 i...
Article
Full-text available
Innovative methods of prevention are needed to stop the more than two million new HIV-1 infections annually, particularly in women. Local application of anti-HIV antibodies has been shown to be effective at preventing infection in nonhuman primates; however, the concentrations needed are cost prohibitive. Display of antibodies on a particulate plat...
Article
Multiple sclerosis (MS) is an inflammatory neurological disease that is widely regarded as the outcome of complex interactions between a genetic predisposition and an environmental trigger. Epstein-Barr virus (EBV) has recently been associated with the onset of MS, yet understanding how it elicits autoimmunity remains elusive. Neuroinflammation, in...
Article
Development of viral-induced chronic myocarditis is thought to involve both environmental and genetic factors. However, to date, no susceptibility genes have been identified. We sought to identify loci that confer susceptibility to viral-induced chronic myocarditis with the use of chromosome substitution strain mice that are composed of 1 chromosom...
Article
Full-text available
The development of alternative strategies to prevent HIV infection is a global public health priority. Initial efforts in anti-HIV microbicide development have met with poor success as the strategies have relied on a non-specific mechanism of action. Here, we report the development of a microbicide aimed at specifically blocking HIV entry by displa...
Article
Interleukin (IL)-6 is a pleiotropic cytokine that plays a key role in a wide variety of diseases. Based on a number of adjuvant-induced experimental models, IL-6 is critical to the development of autoimmune diseases including experimental autoimmune encephalomyelitis, adjuvant-induced arthritis, and experimental autoimmune myocarditis. However, whe...
Article
The development of type 1 diabetes is, in part, dictated by the failure of regulatory T cells to maintain peripheral tolerance. As such, therapies aimed at correcting the declining function of regulatory T cells have been the subject of intense investigation. In this review, we discuss the potential of regulatory T cells to suppress autoreactive re...
Data
IL-6KO mice have decreased regulatory T cells. (A) Representative flow cytometry analysis of splenocyte regulatory T cells 3 days post DMEM, LPS, CB3 or CB3/LPS treatment. Treg cells were identified by immunostaining for expression of CD4 and the transcription factor Foxp3. IL-6KO mice contained a significantly lower percentage of CD4+ Foxp3+ cells...
Data
rIL-6 injection in IL-6KO mice increased the number of innate and adaptive immune cells infiltrating in the heart at 10 days post infection. (A) Heart infiltrate was measured by flow cytometry analysis at 10 days post treatment with CB3/LPS with or without rIL-6 treatment. Cardiac infiltrate was immunostained to determine innate and adaptive immune...
Data
IL-6KO mice have an increased number of monocyte/macrophage cells in the heart at 7 days post infection. Heart infiltrate was measured by flow cytometry analysis at 7 days post treatment with CB3/LPS. Cardiac infiltrate was determined based on forward and side scatter as well as CD11b and CD11c immunostaining. IL-6KO mice had significantly increase...
Data
IL-6KO mice have increased expression of the early activation marker CD69 at 3 days PI. (A) Representative flow cytometry analysis of splenocyte T cell activation at 3 days post DMEM, LPS, CB3 or CB3/LPS treatment. Activated T cells were identified by immunostaining to the surface markers CD4, CD8 and CD69. CD69 expression was significantly increas...
Article
To protect against viral infection, the immune response is critically dependent on innate sensing mechanisms to provide rapid detection of pathogens and allow for the development of an appropriate adaptive immune response. Mounting evidence suggests that mechanistic differences in the sensing of viruses by the innate immune response can contribute...
Article
Susceptibility to type 1 diabetes (T1D) is dictated by a complex interplay between genetic determinants and environmental influences. Accumulating evidence strongly supports viral infection as an important factor in the etiology of T1D. To this effect, several viruses have been associated with the capacity to induce or exacerbate T1D in both humans...
Article
Full-text available
Toll-like receptor 3 (TLR3) has been proposed to play a central role in the early recognition of viruses by sensing double stranded RNA, a common intermediate of viral replication. However, several reports have demonstrated that TLR3 signaling is either dispensable or even harmful following infection with certain viruses. Here, we asked whether TLR...
Article
Full-text available
Chronic myocarditis is often initiated by viral infection, the most common of which is coxsackievirus infection. The precise mechanism by which viral infection leads to chronic autoimmune pathology is poorly understood, however it is clear that the early immune response plays a critical role. Previous results have shown that the inflammatory cytoki...
Data
Type 1 interferon production is reduced following CB4 infection in both TLR3KO and MyD88KO mice. Serum levels of IFNα from WT NOD (black bars), TLR3KO (white bars) and MyD88KO (grey bars) mice were measured with a VeriKine Elisa Kit at 48 hours following infection with 400 pfu of N = at least 7 for each group. Pooled data from at least 2 independen...
Data
TLR3 deficiency does not affect T cell activation following LCMV or CB4 infection. Representative histograms of CD44 expression on the surface of (A, C) CD4 and (B, D) CD8 T cells from WT NOD (left panels) and TLR3KO (right panels) mice at 7 days post-infection with (A,B) 400 pfu of CB4 (solid black lines) or (C,D) 1×105 pfu of LCMV (solid black li...
Article
Full-text available
Coxsackievirus infections have long been associated with the induction of type 1 diabetes. Infection with coxsackievirus B4 (CB4) enhances type 1 diabetes onset in NOD mice by accelerating the presentation of beta-cell antigen to autoreactive T-cells. It has been reported that a progressive defect in regulatory T-cell (Treg) function is, in part, r...
Article
Susceptibility to autoimmune diseases is dictated by a complex interplay of genetic determinants and environmental factors. Viral infections have long been suspected to be involved in the etiology of several autoimmune disorders. In particular, the incidence of type 1 diabetes worldwide is increasing at a yearly rate that cannot be solely attribute...
Article
Full-text available
The Ras-guanyl nucleotide exchange factor RasGRP1 is an important link between TCR-mediated signaling and the activation of Ras and its downstream effectors. RasGRP1 is especially critical for the survival and differentiation of developing thymocytes whereas negative selection of thymocytes bearing an autoreactive TCR appears to be RasGRP1 independ...
Article
Coxsackievirus infections are a major cause of chronic autoImmune myocarditis, a known precursor to dilated cardiomyopathy. Dilated cardiomyopathy leads to heart failure and is responsible for nearly half of all heart transplant cases. The induction of chronic autoimmunity following coxsackievirus infection is governed by the interplay of several g...
Article
Coxsackie B virus (CBV) infections are a leading cause of autoimmune myocarditis associated with inflammatory heart disease and sudden death in young adults. Previously, we demonstrated that transgenic expression of the immunosuppressive cytokine, transforming growth factor-beta (TGF-beta), specifically in the pancreas protected otherwise susceptib...
Article
Clinical myocarditis is a precursor to dilated cardiomyopathy and a principal cause of heart failure. Nearly 30% of all recently diagnosed cases of myocarditis are attributable to infection with coxsackie B virus (CBV), the most frequently associated pathogen. CBV initially replicates in the pancreas and quickly spreads to the heart, inducing chron...
Article
Chronic myocarditis often progresses to dilated cardiomyopathy resulting in heart failure or cardiac transplantation. Viral infection is the most common cause of myocarditis and coxsackie B viruses (CBV) are the most frequently cited etiologic agents associated with myocarditis and cardiomyopathy. Additionally, CBV infections of genetically suscept...
Article
Full-text available
The wide diversity of the T and B Ag receptor repertoires becomes even more extensive postneonatally due to the activity of TdT, which adds nontemplated N nucleotides to Ig and TCR coding ends during V(D)J recombination. In addition, complementarity-determining region 3 sequences formed in the absence of TdT are more uniform due to the use of short...
Article
Epidemiological studies have associated coxsackie B virus (CBV) with the development of insulin-dependent diabetes mellitus (IDDM) in humans. Infections of genetically susceptible mice with CBV strain 4 (CB4) induce autoimmune diabetes. Herein, we demonstrate that in mice, CB4 infection of insulin-producing pancreatic beta cells does not directly c...
Article
The induction of autoimmunity by viruses has been hypothesized to occur by a number of mechanisms. Coxsackievirus B4 (CB4) induces hyperglycemia in SJL mice resembling diabetes in humans. While virus is effectively cleared within 2 weeks, hyperglycemia does not appear until about 8-12 weeks postinfection at a time when replicative virus is no longe...
Article
The induction of autoimmunity by viruses has been attributed to numerous mechanisms. In mice, coxsackievirus B4 (CB4) induces insulin-dependent diabetes mellitus (IDDM) resembling the final step of disease progression in humans. The immune response following the viral insult clearly precipitates IDDM. However, the molecular pathway between viral in...
Article
The induction of autoimmunity by viruses has been attributed to numerous mechanisms. Coxsackievirus B4 (CB4) induces insulin-dependent diabetes mellitus (IDDM) in mice resembling the final step of disease progression in humans. Following viral infection, autoreactive lymphocytes are activated through exposure to damaged islets consequently precipit...
Article
Coxsackieviral infections have been linked etiologically to multiple diseases. The serotype CB4 is associated with acute pancreatitis and autoimmune type 1 diabetes. To delineate the mechanisms of host survival after an acute infection with CB4 (strain E2), we have investigated the role of nitric oxide (NO), generated by the inducible form of nitri...
Article
Cardiovascular disease is one of the leading causes of death worldwide, and has been associated with many environmental risk factors. Recent evidence has indicated the involvement of pathogens such as viruses as causative agents, and specifically identified the coxsackievirus B serogroup as the leading culprit. Not only has coxsackievirus B3 (CB3)...
Article
Conceptually, the initiation of autoimmune disease can be described as a three-stage process involving both genetic and environmental influences. This process begins with the development of an autoimmune cellular repertoire, followed by activation of these autoreactive cells in response to a localized target and, finally, the immune system's failur...
Article
Coxsackievirus infection causes severe pancreatitis and myocarditis in humans, often leading to death in young or immunocompromised individuals. In susceptible strains of mice, coxsackievirus strain CB4 causes lethal hypoglycemia. To investigate the potential of gamma interferon (IFN-gamma) in protection and clearance of the viral infection, IFN-ga...
Article
To recognize and respond immunologically to foreign antigens, T lymphocytes require the presentation of foreign peptides by MHC molecules. To determine which cells of the central nervous system (CNS) are capable of expressing MHC molecules, we used confocal microscopy and dual immunofluorescence with cell-specific and MHC-specific antibodies to stu...
Article
Viral induction of autoimmunity is thought to occur by either bystander T-cell activation or molecular mimicry. Coxsackie B4 virus is strongly associated with the development of insulin-dependent diabetes mellitus in humans and shares sequence similarity with the islet autoantigen glutamic acid decarboxylase. We infected different strains of mice w...
Article
Full-text available
Ever since the use of interferon-gamma to treat patients with multiple sclerosis resulted in enhanced disease, the role of IFN-gamma in demyelination has been under question. To address this issue directly, transgenic mice were generated that expressed the cDNA of murine IFN-gamma in the central nervous system by using an oligodendrocyte-specific p...
Article
The HIV-1-specific cytotoxic T lymphocyte (CTL) response is temporally associated with the decline in viremia during primary HIV-1 infection, but definitive evidence that it is of importance in virus containment has been lacking. Here we show that in a patient whose early CTL response was focused on a highly immunodominant epitope in gp 160, there...
Article
One hypothesis for the etiology of central nervous system (CNS) autoimmune disease is that infection by a virus sharing antigenic epitopes with CNS antigens (molecular mimicry) elicits a virus-specific immune response that also recognizes self-epitopes. To address this hypothesis, transgenic mice were generated that express the nucleoprotein or gly...
Article
Les virus sont depuis longtemps associés aux maladies auto-immunes. Plusieurs mécanismes ont été proposés pour expliquer comment une infection virale peut annuler la tolérance immunitaire et initier un processus autoréactif spécifique d'organe. Nous discutons deux mécanismes potentiels d'initiation virale de l'autoimmunité, le mimétisme moléculaire...
Article
Viruses have often been associated with autoimmune diseases. One mechanism by which self-destruction can be triggered is molecular mimicry. Many examples of cross-reactive immune responses between pathogens and self-antigens have been described. This review presents two transgenic models of autoimmune disease induced by a virus through activation o...
Article
Transgenic technology has been used by virologists for two main purposes. One has been to evaluate cell-specific expression and function in vivo of specific viral proteins. Of the many such studies performed, one prominent example is the work of Levine and colleagues (MARKS et al. 1989) on the expression of SV40 T antigen that resulted in choroid p...