scholarly journals Excessive Innate Immunity Steers Pathogenic Adaptive Immunity in the Development of Theiler’s Virus-Induced Demyelinating Disease

2021 ◽  
Vol 22 (10) ◽  
pp. 5254
Author(s):  
Byung S. Kim
Keyword(s):  
B Cells ◽  
Viral Infection ◽  
Cytokine Production ◽  
Viral Infections ◽  
Demyelinating Disease ◽  
Demyelinating Diseases ◽  
Viral Loads ◽  
Underlying Mechanisms ◽  
The Many ◽  
Antigen Presenting

Several virus-induced models were used to study the underlying mechanisms of multiple sclerosis (MS). The infection of susceptible mice with Theiler’s murine encephalomyelitis virus (TMEV) establishes persistent viral infections and induces chronic inflammatory demyelinating disease. In this review, the innate and adaptive immune responses to TMEV are discussed to better understand the pathogenic mechanisms of viral infections. Professional (dendritic cells (DCs), macrophages, and B cells) and non-professional (microglia, astrocytes, and oligodendrocytes) antigen-presenting cells (APCs) are the major cell populations permissive to viral infection and involved in cytokine production. The levels of viral loads and cytokine production in the APCs correspond to the degrees of susceptibility of the mice to the TMEV-induced demyelinating diseases. TMEV infection leads to the activation of cytokine production via TLRs and MDA-5 coupled with NF-κB activation, which is required for TMEV replication. These activation signals further amplify the cytokine production and viral loads, promote the differentiation of pathogenic Th17 responses, and prevent cellular apoptosis, enabling viral persistence. Among the many chemokines and cytokines induced after viral infection, IFN α/β plays an essential role in the downstream expression of costimulatory molecules in APCs. The excessive levels of cytokine production after viral infection facilitate the pathogenesis of TMEV-induced demyelinating disease. In particular, IL-6 and IL-1β play critical roles in the development of pathogenic Th17 responses to viral antigens and autoantigens. These cytokines, together with TLR2, may preferentially generate deficient FoxP3+CD25- regulatory cells converting to Th17. These cytokines also inhibit the apoptosis of TMEV-infected cells and cytolytic function of CD8+ T lymphocytes (CTLs) and prolong the survival of B cells reactive to viral and self-antigens, which preferentially stimulate Th17 responses.

scholarly journals Gammaherpesvirus infection licenses age-associated B cells for pathogenicity in MS and EAE

2021 ◽  
Author(s):  
Isobel C. Mouat ◽  
Jessica R. Allanach ◽  
Vina Fan ◽  
Anna M. Girard ◽  
Iryna Shanina ◽  
...  
Keyword(s):  
B Cells ◽  
Viral Infection ◽  
Viral Infections ◽  
Autoimmune Encephalomyelitis ◽  
Barr Virus ◽  
Ebv Infection ◽  
Latent Viral Infection ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Experimental Autoimmune

While age-associated B cells (ABCs) are known to expand and persist following viral infection and during autoimmunity, their interactions are yet to be studied together in these contexts. Epstein-Barr virus (EBV) infection has long been implicated in multiple sclerosis (MS), and it is not known whether ABCs could play a role in mediating viral contribution to autoimmunity. Here, we show that the circulating ABC population is expanded in people with MS and that EBV infection and MS status differentially impact the circulating ABC phenotype. We then directly compared ABCs during viral infection and autoimmunity using mouse models of EBV, gammaherpesvirus 68 (γHV68), and MS, experimental autoimmune encephalomyelitis (EAE). We observed that splenic ABCs are expanded in a sex-biased manner during both latent virus infection and EAE, and each event drives the ABC population to opposing phenotypes. We have previously shown that latent γHV68 infection exacerbates EAE and here we show that mice lacking ABCs fail to display γHV68-enhanced disease. Collectively, these findings indicate that latent viral infection and central nervous system autoimmunity differentially impact the ABC population and suggests that viral infections such as EBV prime ABCs to contribute pathogenically in MS.

scholarly journals Preexisting Virus-Specific T Lymphocytes-Mediated Enhancement of Adenovirus Infections to Human Blood CD14+ Cells

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 154
Author(s):  
Fengling Feng ◽  
Jin Zhao ◽  
Pingchao Li ◽  
Ruiting Li ◽  
Ling Chen ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Viral Infection ◽  
Viral Infections ◽  
Critical Role ◽  
Scavenger Receptor ◽  
Activation Markers ◽  
Gm Csf ◽  
Cell Responses ◽  
Underlying Mechanisms

Antigen-specific T lymphocytes play a critical role in controlling viral infections. However, we report here that preexisting virus-specific T cell responses also contribute to promoting adenovirus (Ad) infection. Previously, we found that CD14+ monocytes from Ad-seropositive individuals exhibited an increased susceptibility to Ad infection, when compared with that of Ad-seronegative individuals. But the underlying mechanisms for this enhancement of viral infection are not completely clarified. In this study, we found that the efficacy of Ad infection into CD14+ monocytes was significantly decreased after CD3+ T lymphocytes depletion from PBMC samples of Ad-seropositive individuals. In contrast, adding virus-specific CD3+ T lymphocytes into PBMC samples of Ad-seronegative individuals resulted in a significant increase of infection efficacy. CD3+ T lymphocytes in PBMC samples from Ad-seropositive individuals were more sensitive to be activated by adenovirus stimulus, characterized by upregulation of multiple cytokines and activation markers and also enhancement of cell proliferation. Further studies demonstrated that GM-CSF and IL-4 can promote Ad infection by up-regulating the expression of scavenger receptor 1 (SR-A) and integrins αVβ5 receptor of CD14+ cells. And taken together, these results suggest a novel role of virus-specific T cells in mediating enhancement of viral infection, and provide insights to understand the pathogenesis and complicated interactions between viruses and host immune cells.

scholarly journals Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+Macrophage Function during Viral Infection

2015 ◽  
Vol 89 (9) ◽  
pp. 4748-4759 ◽  
Author(s):  
Haifeng C. Xu ◽  
Jun Huang ◽  
Vishal Khairnar ◽  
Vikas Duhan ◽  
Aleksandra A. Pandyra ◽  
...  
Keyword(s):  
B Cells ◽  
Viral Infection ◽  
B Cell ◽  
Viral Infections ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Production ◽  
Immune Priming ◽  
Adaptive Immune ◽  
Deficient Mice

ABSTRACTThe B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169+macrophage compartment. Consequently,Baffr−/−mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells inBaffr−/−animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169+cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections.IMPORTANCEViruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169+macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.

scholarly journals Autoantibody-boosted T-cell reactivation in the target organ triggers manifestation of autoimmune CNS disease

2016 ◽  
Vol 113 (12) ◽  
pp. 3323-3328 ◽  
Author(s):  
Anne-Christine Flach ◽  
Tanja Litke ◽  
Judith Strauss ◽  
Michael Haberl ◽  
César Cordero Gómez ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Nervous Tissue ◽  
Immune Cell ◽  
Clinical Disease ◽  
Blood Brain Barrier Disruption ◽  
Cns Autoimmunity ◽  
Brain Barrier Disruption ◽  
Underlying Mechanisms ◽  
Antigen Presenting

Multiple sclerosis (MS) is caused by T cells that are reactive for brain antigens. In experimental autoimmune encephalomyelitis, the animal model for MS, myelin-reactive T cells initiate the autoimmune process when entering the nervous tissue and become reactivated upon local encounter of their cognate CNS antigen. Thereby, the strength of the T-cellular reactivation process within the CNS tissue is crucial for the manifestation and the severity of the clinical disease. Recently, B cells were found to participate in the pathogenesis of CNS autoimmunity, with several diverse underlying mechanisms being under discussion. We here report that B cells play an important role in promoting the initiation process of CNS autoimmunity. Myelin-specific antibodies produced by autoreactive B cells after activation in the periphery diffused into the CNS together with the first invading pathogenic T cells. The antibodies accumulated in resident antigen-presenting phagocytes and significantly enhanced the activation of the incoming effector T cells. The ensuing strong blood–brain barrier disruption and immune cell recruitment resulted in rapid manifestation of clinical disease. Therefore, myelin oligodendrocyte glycoprotein (MOG)-specific autoantibodies can initiate disease bouts by cooperating with the autoreactive T cells in helping them to recognize their autoantigen and become efficiently reactivated within the immune-deprived nervous tissue.

scholarly journals Emerging Respiratory Viruses: Challenges and Vaccine Strategies

2006 ◽  
Vol 19 (4) ◽  
pp. 614-636 ◽  
Author(s):  
Laura Gillim-Ross ◽  
Kanta Subbarao
Keyword(s):  
Avian Influenza ◽  
Viral Infection ◽  
Viral Infections ◽  
Vaccine Development ◽  
Respiratory Viruses ◽  
Lessons Learned ◽  
Influenza Viruses ◽  
Viral Pathogens ◽  
Current Vaccine ◽  
The Many

SUMMARY The current threat of avian influenza to the human population, the potential for the reemergence of severe acute respiratory syndrome (SARS)-associated coronavirus, and the identification of multiple novel respiratory viruses underline the necessity for the development of therapeutic and preventive strategies to combat viral infection. Vaccine development is a key component in the prevention of widespread viral infection and in the reduction of morbidity and mortality associated with many viral infections. In this review we describe the different approaches currently being evaluated in the development of vaccines against SARS-associated coronavirus and avian influenza viruses and also highlight the many obstacles encountered in the development of these vaccines. Lessons learned from current vaccine studies, coupled with our increasing knowledge of the host and viral factors involved in viral pathogenesis, will help to increase the speed with which efficacious vaccines targeting newly emerging viral pathogens can be developed.

scholarly journals Differential Virus Replication, Cytokine Production, and Antigen-Presenting Function by Microglia from Susceptible and Resistant Mice Infected with Theiler's Virus

2007 ◽  
Vol 81 (21) ◽  
pp. 11690-11702 ◽  
Author(s):  
Young-Hee Jin ◽  
Mani Mohindru ◽  
Min H. Kang ◽  
Alyson C. Fuller ◽  
Bongsu Kang ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytokine Production ◽  
Demyelinating Disease ◽  
Costimulatory Molecule ◽  
Differential Susceptibility ◽  
Necrosis Factor Alpha ◽  
Underlying Mechanisms

ABSTRACT Infection with Theiler's murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) causes an immune system-mediated demyelinating disease similar to human multiple sclerosis in susceptible but not resistant strains of mice. To understand the underlying mechanisms of differential susceptibility, we analyzed viral replication, cytokine production, and costimulatory molecule expression levels in microglia and macrophages in the CNS of virus-infected resistant C57BL/6 (B6) and susceptible SJL/J (SJL) mice. Our results indicated that message levels of TMEV, tumor necrosis factor alpha, beta interferon, and interleukin-6 were consistently higher in microglia from virus-infected SJL mice than in those from B6 mice. However, the levels of costimulatory molecule expression, as well as the ability to stimulate allogeneic T cells, were significantly lower in TMEV-infected SJL mice than in B6 mice. In addition, microglia from uninfected naïve mice displayed differential viral replication, T-cell stimulation, and cytokine production, similar to those of microglia from infected mice. These results strongly suggest that different levels of intrinsic susceptibility to TMEV infection, cytokine production, and T-cell activation ability by microglia contribute to the levels of viral persistence and antiviral T-cell responses in the CNS, which are critical for the differential susceptibility to TMEV-induced demyelinating disease between SJL and B6 mice.

scholarly journals Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease

2020 ◽  
Vol 140 (4) ◽  
pp. 535-548 ◽  
Author(s):  
Sebastian Torke ◽  
Roxanne Pretzsch ◽  
Darius Häusler ◽  
Philipp Haselmayer ◽  
Roland Grenningloh ◽  
...  
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Demyelinating Disease ◽  
Cell Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Functionally Impaired ◽  
Anti Cd20 ◽  
Antigen Presenting

Abstract Anti-CD20-mediated B-cell depletion effectively reduces acute multiple sclerosis (MS) flares. Recent data shows that antibody-mediated extinction of B cells as a lasting immune suppression, harbors the risk of developing humoral deficiencies over time. Accordingly, more selective, durable and reversible B-cell-directed MS therapies are needed. We here tested inhibition of Bruton’s tyrosine kinase (BTK), an enzyme centrally involved in B-cell receptor signaling, as the most promising approach in this direction. Using mouse models of MS, we determined that evobrutinib, the first BTK inhibiting molecule being developed, dose-dependently inhibited antigen-triggered activation and maturation of B cells as well as their release of pro-inflammatory cytokines. Most importantly, evobrutinib treatment functionally impaired the capacity of B cells to act as antigen-presenting cells for the development of encephalitogenic T cells, resulting in a significantly reduced disease severity in mice. In contrast to anti-CD20, BTK inhibition silenced this key property of B cells in MS without impairing their frequency or functional integrity. In conjunction with a recent phase II trial reporting that evobrutinib is safe and effective in MS, our mechanistic data highlight therapeutic BTK inhibition as a landmark towards selectively interfering with MS-driving B-cell properties.

Viral Infection at the Blood-Brain Barrier in Multiple Sclerosis: – An Ultrastructural Study of Tissues from a Uk Regional Brain Bank

1996 ◽  
Vol 1 (4) ◽  
pp. 242-252 ◽  
Author(s):  
J Kirk ◽  
A-L Zhou
Keyword(s):  
Multiple Sclerosis ◽  
Viral Infection ◽  
Blood Brain Barrier ◽  
Viral Infections ◽  
Demyelinating Disease ◽  
Brain Barrier ◽  
Morphological Evidence ◽  
Blood Brain ◽  
Published Evidence

Although viral infections are often invoked as environmental factors in the aetiology and pathogenesis of multiple sclerosis (MS) it is only recently that a specific, indirect, cytokine-mediated mechanism for triggering of relapses during viral infections has been demonstrated. It is not yet clear however whether this indirect mechanism can account for all reported viral associations with the aetiopathogenesis of MS. A direct causal role of central nervous system (CNS) viral infection in MS has largely been discounted following repeated failures to demonstrate virus within the oligodendrocyte-myelin unit In the light of increasing evidence of blood-brain barrier (BBB) dysfunction in MS and to further explore the issue of possible viral involvement in MS, an ultrastructural search for viruses was undertaken in the CNS microvasculature, in autopsy and biopsy tissue from human CNS primary demyelinating diseases, including MS (20 cases), idiopathic monophasic CNS demyelinating disease (Mdemy, four cases) and metabolic or immunopathological demyelinating disease (two cases). For comparison, tissues from CNS viral disease in which demyelination is a major feature (nine cases) were examined in the same way. Control CNS tissues (nine cases) from a range of other neurological and non-neurological diseases were also examined. Outside the MS and Mdemy groups, morphological evidence of virus associations with the BBB were found only in the acute and subacute viral encephalitides (three cases subacute sclerosing panencephalitis, one case of Herpes encephalitis) and in one case of disseminated Cytomegalovirus infection. In a small proportion of MS and Mdemy cases, particles resembling either adenovirus (one case of MS) or paramyxovirus (one case of MS, one case of Mdemy) were found in the vicinity of microvessels. In each case a different cell type or extracellular compartment was involved and an exact correlation between the virus particles and the demyelinating lesions could not be demonstrated. Furthermore, corroborative clinical or laboratory evidence of current CNS infection in these primary demyelinating disease cases was available only from the single positive Mdemy case and not from the two cases of MS. This and other previously published evidence from MS (which implicated a Coronavirus) and other diseases highlights the potential vulnerability to viral infection of cells associated with the BBB. Furthermore it is concluded that the detection rate of such infections in pathological tissue could underestimate their true frequency. A possible role of transient virus-BBB interactions in triggering focal inflammation, BBB breakdown and demyelination in some cases of MS and parainfectious demyelinating disease cannot be discounted.

scholarly journals The Level of Viral Infection of Antigen-Presenting Cells Correlates with the Level of Development of Theiler's Murine Encephalomyelitis Virus-Induced Demyelinating Disease

2014 ◽  
Vol 89 (3) ◽  
pp. 1867-1878 ◽  
Author(s):  
Young Hee Jin ◽  
Hyun Seok Kang ◽  
Wanqiu Hou ◽  
Liping Meng ◽  
Byung S. Kim
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Viral Infection ◽  
Demyelinating Disease ◽  
Antigen Presenting Cells ◽  
Cell Types ◽  
Innate Immune ◽  
Mhc Genes ◽  
Encephalomyelitis Virus ◽  
Antigen Presenting

ABSTRACTIntracerebral infection with Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelinating disease in susceptible SJL/J mice but not in resistant C57BL/6 mice. Previous studies have indicated that the major histocompatibility complex (MHC) genes play the most prominent role in the development of TMEV-induced demyelinating disease. In this study, we used C57BL/6.S (B6.S) congenic mice, which carryH-2sMHC genes instead ofH-2bMHC genes in conjunction with the C57BL/6 (B6) background genes. Our data show that virus-infected B6.S mice are free from disease and have significantly lower viral loads than susceptible SJL mice, particularly in the spinal cord. A strong protective Th1-type T helper response with virtually no pathogenic Th17 response was detected in B6.S mice, in contrast to the reduced Th1- and robust Th17-type responses in SJL mice. Notably, lower levels of viral infectivity in B6.S antigen-presenting cells (APCs) correlated with the disease resistance and T-cell-type response.In vitrostudies using APCs from B6.S and SJL mice show that TLR2, -3, -4, and -7, but not TLR9, signaling can replace viral infection and augment the effect of viral infection in the differentiation of the pathogenic Th17 cell type. Taken together, these results strongly suggest that the viral replication levels in APCs critically affect the induction of protective versus pathogenic Th cell types via the signaling of pattern recognition receptors for innate immune responses. Our current findings further imply that the levels of viral infectivity/replication and TLR-mediated signaling play critical roles in the pathogenesis of chronic viral diseases.IMPORTANCEThis study indicates that innate immune cytokines produced in antigen-presenting cells stimulating the T cell immune responses during early viral infection play a critical role in determining the susceptibility of mice to the development of demyelinating disease. The level of innate immune cytokines reflects the level of initial viral infection in the antigen-presenting cells, and the level determines the development of T cell types, which are either protective or pathogenic. The level of initial viral infection to the cells is controlled by a gene or genes that are not associated with the major histocompatibility antigen complex genes. This finding has an important implication in controlling not only chronic viral infections but also infection-induced autoimmune-like diseases, which are closely associated with the pathogenic type of T cell responses.

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