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Robert S Fujinami

Publications and source records attributed to Robert S Fujinami.

29 records · Page 2Linked to original sources
PubMed2004

Distinct roles for IP-10/CXCL10 in three animal models, Theiler's virus infection, EAE, and MHV infection, for multiple sclerosis: implication of differing roles for IP-10.

Theiler's murine encephalomyelitis virus (TMEV) causes demyelination with inflammation of the central nervous system (CNS) in mice and is used as an animal model for multiple sclerosis (MS). Interferon-gamma inducible protein-10 kDa (IP-10) is a CXC chemokine and a chemoattractant for CXCR3+ T cells. IP-10 mRNA is expressed in the CNS during TMEV infection. However, administration of anti-IP-10 serum caused no difference in clinical signs, inflammation, demyelination, virus persistence or anti-virus antibody response in TMEV infection, while levels of virus specific and autoreactive lymphoproliferation increased. This likely reflects a difference in the pathogenesis of TMEV infection from that of two other animal models for MS, mouse hepatitis virus infection and experimental allergic encephalomyelitis (EAE), where blocking of IP-10 resulted in clinical and histological improvement with suppression of antigen specific lymphoproliferation. In this review, we compare and contrast the roles of IP-10 between the three animal models for MS, and discuss the relevance to MS patients with different clinical courses.

Animals↗
PubMed2003

Manganese superoxide dismutase induction during measles virus infection.

Measles virus infection of B-cells results in marked alterations in proliferation and immunoglobulin production. Very little is known about the changes of gene expression, if any, during acute measles virus infection. To elucidate cellular genes that are induced during measles virus infection, we carried out a subtraction technique, representational differential analysis. The mitochondrial protein, manganese superoxide dismutase (MnSOD), was upregulated in B-cells during measles virus infection. Although measles virus-infected B-cells did not secrete MnSOD into the environment, it was found, using an MnSOD mimetic, that intracellular MnSOD did inhibit proliferation of the B-cells. MnSOD also decreases the titer of virus produced from infected cells. Therefore, MnSOD seems to play a role in the alteration of immune function seen upon infection of B-cells with measles virus.

B-Lymphocytes↗
PubMed2003

Axonal injury heralds virus-induced demyelination.

Axonal pathology has been highlighted as a cause of neurological disability in multiple sclerosis. The Daniels (DA) strain of Theiler's murine encephalomyelitis virus infects the gray matter of the central nervous system of mice during the acute phase and persistently infects the white matter of the spinal cord during the chronic phase, leading to demyelination. This experimental infection has been used as an animal model for multiple sclerosis. The GDVII strain causes an acute fatal polioencephalomyelitis without demyelination. Injured axons were detected in normal appearing white matter at 1 week after infection with DA virus by immunohistochemistry using antibodies specific for neurofilament protein. The number of damaged axons increased throughout time. By 2 and 3 weeks after infection, injured axons were accompanied by parenchymal infiltration of Ricinus communis agglutinin I(+) microglia/macrophages, but never associated with perivascular T-cell infiltration or obvious demyelination until the chronic phase. GDVII virus infection resulted in severe axonal injury in normal appearing white matter at 1 week after infection, without the presence of macrophages, T cells, or viral antigen-positive cells. The distribution of axonal injury observed during the early phase corresponded to regions where subsequent demyelination occurs during the chronic phase. The results suggest that axonal injury might herald or trigger demyelination.

Animals↗
PubMed2003

Microorganisms and autoimmunity: making the barren field fertile?

Microorganisms induce strong immune responses, most of which are specific for their encoded antigens. However, microbial infections can also trigger responses against self antigens (autoimmunity), and it has been proposed that this phenomenon could underlie several chronic human diseases, such as type 1 diabetes and multiple sclerosis. Nevertheless, despite intensive efforts, it has proven difficult to identify any single microorganism as the cause of a human autoimmune disease, indicating that the 'one organism-one disease' paradigm that is central to Koch's postulates might not invariably apply to microbially induced autoimmune disease. Here, we review the mechanisms by which microorganisms might induce autoimmunity, and we outline a hypothesis that we call the fertile-field hypothesis to explain how a single autoimmune disease could be induced and exacerbated by many different microbial infections.

Animals↗
PubMed2003

Modulation of immune system function by measles virus infection. II. Infection of B cells leads to the production of a soluble factor that arrests uninfected B cells in G0/G1.

Measles can result in a variety of immunologic defects. Previously we showed that an Epstein-Barr virus-transformed B cell line (B cells), when infected with measles virus, produced a soluble antiproliferative factor that inhibited proliferation of T and B cells. Here we explore the effects of infection by measles virus versus the virus-free soluble antiproliferative factor on B cells. The B cells showed no change in the amounts of interleukin (IL)-2, 10, 12, interferon (IFN)-gamma, or transforming growth factor (TGF)-beta when infected or exposed to the soluble factor. Similarly, B cells showed no change in the expression of class II major histocompatibility antigens, LFA-1, ICAM-1, CD19, CD40, CD80, CD86, CD95 (Fas), or CD178 (FasL). Cell cycle analysis showed that measles virus infection caused an accumulation of cells in S and G(2)/M phases with a "sub-G(1)" cell population, while incubation of cells with the soluble factor caused an accumulation in G(0)/G(1). These experiments provide evidence that measles virus causes a profound inhibition of B cell proliferation without distinguishable changes in cytokine profile or cell surface phenotype. Further, it appears that there are two populations of cells affected by infection: one population is growth arrested due to the influence of the immunosuppressive factor and is not infected; a second population that is infected progresses through S phase less efficiently. Alternatively, while both the soluble factor and live virus infection may affect cells in G(0)/G(1) phases, only live virus infection could selectively induce apoptosis of G(0)/G(1) cells, resulting in cell accumulation in S and G(2)/M phases with a build up of "sub-G(1)" cells.

B-Lymphocytes↗
PubMed2002

Altered cell growth and morphology in a BHK-21 cell mutant that lacks a receptor for Theiler's murine encephalomyelitis virus.

The receptor for Theiler's murine encephalomyelitis virus (TMEV) remains unknown. In vitro, BHK-21 cells are permissive to infection by TMEV. Selecting mutants of BHK-21 cells produced a cell line (BHKR-) resistant to infection by TMEV. Viral persistence was ruled out by immunofluorescent staining for viral antigens. BHKR- cells were nonpermissive to infection even at high multiplicities of infection. In contrast, cells were able to support one round of virus replication when transfected with infectious TMEV RNA. Binding studies indicated that TMEV was unable to attach to these cells. These data are consistent with the BHKR- cells lacking a receptor for TMEV. Interestingly, BHKR- cells were larger in size and had a significant lag in growth after subculture versus BHK-21 cells. This suggests that the TMEV receptor on BHK-21 cells could play an important role in cell growth and morphology under physiologic conditions. BHKR- cells should facilitate the search for TMEV receptors.

Animals↗
PubMed2002

Inside-Out versus Outside-In models for virus induced demyelination: axonal damage triggering demyelination.

The primary target in multiple sclerosis (MS) is believed to be either myelin itself (myelinopathy) or the myelin-forming cell, the oligodendrocyte (oligodendrogliopathy). Although axonal injury occurs in MS, it is regarded as a secondary event to the myelin damage. Here, the lesion develops from myelin (outside) to the axon (inside) (Outside-In model). Recently, gray matter lesions and axonal injury in normal-appearing white matter have also been reported in MS. This raises two questions. 1) Is axonal injury exclusively secondary to myelin damage or from a direct insult to the axon or neurons (axonopathy)? (2) Is the injured axon regarded as only an end result of pathology or disease, or can axonal injury contribute to the spread of secondary damage, including demyelination? The former is raised from the fact that axonal damage has been reported in several virus infections, including human immunodeficiency virus, human T-lymphotropic virus 1, herpes simplex virus and coronavirus, which also cause demyelination. The latter possibility where axonal injury leads to other changes is raised from the rather unexpected similarity between spinal cord injury (SCI) and MS where axonal injury, oligodendrocyte apoptosis and demyelination are all present. In SCI, transection of axons leads to delayed oligodendrocyte apoptosis with secondary demyelination. Neurofilament immunostaining of spinal cord sections demonstrates that axonal injury with oligodendrocyte apoptosis also precedes demyelination in an animal model for MS, Theiler's murine encephalomyelitis virus infection. This implies that axonal injury could trigger demyelination. In this instance, lesions develop from the axon (inside) to the myelin (outside) (Inside-Out model).

Animals↗
PubMed2002

Mutation in loop I of VP1 of Theiler's virus delays viral RNA release into cells and enhances antibody-mediated neutralization: a mechanism for the failure of persistence by the mutant virus.

The DA strain of Theiler's murine encephalomyelitis viruses (TMEV) causes a central nervous system (CNS) demyelinating disease with viral persistence despite the presence of high serum anti-TMEV antibody titers. The DA virus mutant, T81D, was created to have a mutation at position 81 in loop I of VP1, close to the putative virus receptor binding site. T81D showed slower replication in vitro and in vivo. T81D-infected mice developed anti-TMEV antibody responses with no virus persistence. We tested whether the differences between the viruses were due to alteration in virus-cell interactions, or in the resistance to neutralization by anti-TMEV antibody. Using radiolabeled viruses, we found no difference in binding to permissive cell lines between the mutant and wild-type viruses. In a semipermissive cell line, DA virus bound more efficiently than T81D. During the uncoating step, both viruses decapsidated without the production of stable intermediates and 80% of viruses were eluted or decapsidated after 45 minutes. At the final step of uncoating, however, T81D showed a slower rate of RNA release than DA virus into cells using a photoinactivation assay. Anti-TMEV monoclonal and polyclonal antibodies neutralized T81D virus more efficiently than DA virus in suspension. Further, these anti-TMEV antibodies were able to neutralize viruses that had already attached to cells but not internalized (postadsorption neutralization [PAN]). However, DA virus showed significant resistance to PAN after cells were incubated at 37 degrees C compared with T81D-infected cells. The development of resistance to PAN appeared to correlate with the rate of RNA release from virions into cells. In T81D virus infection, the slow RNA release and high susceptibility to neutralization by antibodies would result in a failure to establish virus persistence in vivo. Conversely, rapid RNA release and resistance to neutralization could favor virus persistence in DA virus infection.

Animals↗
PubMed2002

Induction of autoreactive CD8+ cytotoxic T cells during Theiler's murine encephalomyelitis virus infection: implications for autoimmunity.

Theiler's murine encephalomyelitis virus (TMEV) belongs to the family Picornaviridae and causes demyelinating disease in the spinal cords of infected mice. Although immune responses have been shown to play an important role in demyelination, the precise effector mechanism(s) is unknown. Potentially autoreactive cytotoxic cells could contribute to the destruction. We tested whether an autoreactive cell induced by TMEV infection mediated cytotoxicity by using a 5-h (51)Cr release assay in SJL/J mice. Spleen cells from TMEV-infected mice were stimulated with irradiated TMEV antigen-presenting cells and used as effector cells. The effector cells differed from conventional cytotoxic T cells since these cells could kill both TMEV-infected and uninfected syngeneic or semisyngenic cell lines (PSJLSV and BxSF11gSV) but could not kill an allogeneic cell line (C57SV). The TMEV-induced autoreactive cells were also different from conventional natural killer (NK) cells or lymphokine-activated killer (LAK) cells, because they could kill neither NK cell-sensitive YAC-1 nor NK cell-resistant P815 and EL4 cells. Induction of autoreactive cells was not detected in vaccinia virus infection. The autoreactive killing required direct cell-to-cell contact and was mediated by a Fas-FasL pathway but not by a perforin pathway. The phenotype of the killer cells was CD3(+) CD4(-) CD8(+). Intracerebral inoculation of the effector cells into naive mice caused meningitis and perivascular cuffing not only in the brain parenchyma but also in the spinal cord, with no evidence of viral antigen-positive cells. This is the first report demonstrating that TMEV can induce autoreactive cytotoxic cells that induce central nervous system pathology.

Adoptive Transfer↗