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Robert S. Fujinami, Ph.D.

last modified 2009-02-06 15:01 — by Kathleen Borick

Professor of Pathology

Adjunct Professor of Neurology

Scholarly Emphasis: Neurovirology, Neuroimmunology
Robert S. Fujinami, Ph.D.

Robert S. Fujinami

Contact Info

Email Address: robert.fujinami {@} hsc.utah.edu

Office Phone Number: 801-585-3305

Location: 3R330 SOM School of Medicine

Research Lab: Fujinami Lab

Division: Cell Biology & Immunology

Supporting Staff:   Kathleen Borick  

 

About Robert S. Fujinami, Ph.D.

            Our first project is Theiler’s murine encephalomyelitis virus (TMEV) infection of mice is a relevant animal model for the human demyelinating disease multiple sclerosis (MS).  TMEV belongs to the Picornaviridae family and are in the Cardiovirus genus.  These viruses are small positive-sense single-stranded RNA viruses.  Infection of mice with the DA strain of TMEV causes an acute polioencephalomyelitis where mice survive and later develop a central nervous system (CNS) inflammatory demyelinating disease.  Once clinical signs (weight loss, spastic paralysis and gait disturbances) develop in these mice, there is disease progression without relapses or remissions.  This mirrors the progressive forms of MS.  Many reports have described the need for CD8+ and CD4+ T cells as well as antibodies in the pathogenesis of TMEV induced demyelinating disease.  CD8+ T cells have been reported to be responsible for viral clearance and protection from the chronic demyelinating disease in resistant mice.  Similarly, CD4+ T cells have been described to be responsible for the inflammatory CNS demyelination in infected susceptible mice.  Recently, CD8+ T cells have also been shown to influence demyelination in DA virus infected mice.  We have evidence that another cell type may also participate in TMEV infection and demyelinating disease.  This new cell type has cytotoxic activity on uninfected syngenic target cells but not allogenic target cells.  In preliminary studies, the cell is CD3+, CD8+ and B220+ and can cause inflammation in the CNS.  These cells are induced by TMEV infection but not vaccinia virus infection of susceptible SJL/J.  Our goals are to: 1) further characterize the phenotype of the autoreactive killer cells; 2) determine how these cells contribute to disease and define the mechanism of killing; 3) study the induction of the killer cells; and 4) define the determinant(s) in VP1 necessary for the induction of the autoreactive cells.  These findings are novel and may help explain differences between various reports stating that CD4+ or CD8+ T cells are exclusively involved in demyelination and viral clearance, respectively.  The studies not only are important to viral pathogenesis but also the pathogenesis of autoimmune disease.  As part of these studies we recently discovered that infection of a different mouse strain (C57BL/6) when infected with TMEV develop seizures during the acute phase of infection.  Interestingly, after day 10 post infection seizures stop.  After a variable latent period mice develop spontaneous seizures, epilepsy.  We are investigate how the innate immune response contribute to seizure development.

            The second project is to investigate why no one agent is responsible for exacerbations of multiple sclerosis.  Numerous reports indicate the important role infections may play in multiple sclerosis (MS) and other autoimmune diseases.  There are reports associating attacks and/or exacerbations of MS with viral infections.  These infections are thought to be involved in the disease by expanding autoreactive T cells in genetically susceptible individuals.  More than a dozen viruses have been isolated from MS in the past 50 years, but no single virus has been singled out as the “MS virus.”  We propose that infections having molecular mimicry with self central nervous system (CNS) proteins could prime genetically susceptible individuals; once priming has occurred, a non-specific immunologic challenge such as an infection could result in disease.  In theory, myelin specific Th1 CD4+ T cells mediate MS.  In an experimental animal model for MS, experimental allergic encephalomyelitis (EAE), myelin specific CD4+ T cells can adoptively transfer disease to naïve animals.  In conventional forms of EAE, mice are sensitized to myelin antigens by inoculation of myelin proteins or encephalitogenic peptides in powerful adjuvants generating these myelin specific Th1 CD4+ T cells.  This results in an inflammatory demyelinating disease of the CNS.  Lesions seen in EAE are very similar to early lesions of MS.  Mice with EAE also will develop a relapsing-remitting clinical course seen in about 80% of MS patients.  We are testing the hypothesis that viral infections having molecular mimicry with self-CNS proteins can prime animals for EAE, and whether an infection favoring bystander events and/or cross-reactivity will initiate an exacerbation.  We have shown that cDNAs or recombinant viruses encoding self-CNS proteins when used to inoculate or infect mice can prime for EAE.  These primed mice do not show any clinical or pathological changes indicative of EAE.  However, at a later time when these mice are challenged by infection, mice develop an acute attack of EAE.  This project will investigate the immunological basis for the initiation of disease and study factors involved in the priming and challenge phase.  This model could provide an explanation why no single virus has been identified as the MS agent.

            The third project is to investigate different forms of MS.  MS can be divided into four clinical forms:  relapsing-remitting (RR), primary progressive (PP), secondary progressive (SP) and progressive relapsing (PR).  The pathogenesis of the progressive forms of MS remains unclear, partly due to the lack of animal models that have these clinical patterns of disease.  Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)92-106, we have established animal models that mimic the different forms of MS in two strains of MHC identical H-2s mice, SJL/J and A.SW.  We induce experimental allergic encephalomyelitis (EAE) with MOG92-106 in the presence or absence of supplemental Bordetella pertussis (BP).  SJL/J mice develop RR-EAE whether BP was administered or not.  Interestingly, A.SW mice develop PP-EAE without BP and SP-EAE with BP supplementation.  Histologically, SJL/J mice develop a mild demyelinating disease with extensive T cell infiltration, while A.SW mice develop large plaque-like demyelinating lesions with immunoglobulin deposition and neutrophil infiltration, associated with very minimal T cell infiltration.  In A.SW mice without BP, high titer serum anti-MOG antibody is detected and the anti-MOG IgG2a/IgG1 ratio correlated with survival times of the mice.  We hypothesize that, in A.SW mice, a Th2 response favors the production of myelinotoxic antibodies, leading to progressive forms of EAE with early death, while a Th1 response in SJL mice favors a RR form with longer survival.  To test this hypothesis, four approaches or studies are in progress.  The first will study the role of NK1.1+ T cells in progressive disease.  The second will determine whether IL-4 is responsible for the T helper (Th) 2 phenotype and progressive EAE seen in A.SW mice sensitized with MOG92-106.  The third will be to investigate the role of anti-myelin antibodies in disease progression and contribution to lesion formation.  The last study will investigate other factors involved in progressive disease such as environmental and genetic contributions.  These new models could help explain the transition from RR disease to progressive disease often observed in MS patients.

            The last project investigates the etiology and pathogenesis of autism.  This developmental disease is acknowledged as a syndrome having a broad range of symptoms.  It appears that genetics play a major role in the development of this disease.  Two lines of evidence support this.  First, twin studies have shown concordance rates between 36% to 91% for monozygotic twins and 0% to 30% for dizygotic twins, depending on the criteria used to define autism.  Second, there is evidence for an association with autism and a region on human chromosome 6 encompassing the major histocompatibility complex (MHC) that includes HLA class I and class II, and some of the complement components, including C4B.  Since concordance rates in monozygotic twins are not 100%, this implies that other factors play a role in the development of autism or are responsible for different subtypes of this disease.  Elevated serotonin levels are a consistent finding in autism.  Similarly, it appears that the immune response and/or immune regulation in autistic subjects is altered versus control subjects.  These immune aberrations often present as a decreased lymphoproliferative response to mitogens and immune reactivity to central nervous system (CNS) proteins.  Genetic predisposition (elevated serotonin levels) and/or environmental agents such as viral infections or exposure to toxins in utero or early in life could be responsible for the immune dysregulation.  Immune responses against CNS proteins during development could lead to CNS changes that affect behavior and social development later in life.  First, we are investigating the role of serotonin in inducing dysregulation of the immune response.  Second, we are examining the specificity and autoreactivity of T cells and antibodies present in children with autism.  Third, we are determining whether immune effector cells and antibodies induce or mimic CNS features often observed in autistic subjects such as hippocampal and mammillary body changes.  Lastly, we are performing microarray analyses on RNA isolated from peripheral blood mononuclear cells (PBMC) of autistic children versus control subjects.  Determining what genes are altered and identifying their chromosomal positions may lead to additional loci that contribute to this disease.

Selected Publications

  • 1. Tsunoda I, Lane TE, Blackett J, Fujinami RS. Distinct roles for IP-10/CXCL10 in three animal models, Theiler’s virus infection, EAE, and MHV infection, for multiple sclerosis: implications of differing roles for IP-10 among the subtypes of multiple sclerosis. Mult Scler 10:26-34, 2004.
  • 2. Sweeten TL, Fujinami RS. A potential link between measles virus and autism: age-matched control groups are essential. (Letter to the editor.) Pediat Neurol 30:78, 2004.
  • 3. Tsunoda I, Kuang L-Q, Igenge IZM, Fujinami RS. Converting relapsing remitting to secondary progressive experimental allergic encephalomyelitis (EAE) by ultraviolet B irradiation. J Neuroimmunol 160:122-34, 2005.
  • 4. Libbey JE, Sweeten TL, McMahon WM, Fujinami RS. Autistic disorder and viral infections. J NeuroVirol 11:1-10, 2005.
  • 5. Fujinami RS. A tax on luxury: HTLV-1 infection of CD4+CD25+ regulatory T cells. J Clin Invest 115:1144-6, 2005.
  • 6. Tsunoda I, Kuang L-Q, Kobayashi-Warren M, Fujinami RS. Central nervous system pathology caused by autoreactive CD8+ T cell clones following virus infection. J Virol 79:14640-6, 2005.
  • 7. Tsunoda I, Libbey JE, Kuang L-Q, Terry EJ, Fujinami RS. Massive apoptosis in lymphoid organs in animal models for primary and secondary progressive multiple sclerosis. Am J Pathol 167:1631-46, 2005.
  • 8. Tsunoda I, Fujinami RS. TMEV and neuroantigens: Myelin genes and proteins, molecular mimicry, epitope spreading and autoantibody-mediated remyelination. In Experimental Models of Multiple Sclerosis. E Lavi, CS Constantinescu (Eds.), Springer, New York, 2005, pp. 593-616.
  • 9. Fujinami RS, von Herrath MG, Christen U, Whitton JL. Molecular mimicry, bystander activation or viral persistence: Infections and autoimmune disease. Clin Microbiol Rev 19:80-94, 2006.
  • 10. McCoy L, Tsunoda I, Fujinami RS. Multiple sclerosis and virus induced immune responses: Autoimmunity can be primed by molecular mimicry and augmented by bystander activation. Autoimmunity 39:9-19, 2006.
  • 11. Tsunoda I, Libbey JE, Kobayashi-Warren M, Fujinami RS. IFN- production and astrocyte killing by autoreactive T cells induced by Theiler’s virus infection: Role of viral strains and capsid proteins. J Neuroimmunol 172:85-93, 2006.
  • 12. Rentz AC*, Libbey JE*, Fujinami RS, Whitby FG, Byington CL. Investigation of treatment failure in neonatal echovirus 7 infection. Ped Infect Dis J 25:259-262, 2006 (*equal contribution). [Figures printed online Ped Infect Dis J 25:e5-e6, 2006].
  • 13. Libbey JE, Peterson LK, Tsunoda I, Fujinami RS. Monoclonal MOG-reactive autoantibody from progressive EAE has the characteristics of a natural antibody. J Neuroimmunol 173:135-45, 2006.
  • 14. Carlson NG, Hill KE, Tsunoda I, Fujinami RS, Rose JW. The pathologic role for COX-2 in apoptotic oligodendrocytes in virus induced demyelinating disease: Implications for multiple sclerosis. J Neuroimmunol 174:21-31, 2006.
  • 15. Fujinami RS. Neurons tame T cells. Nat Med 12:503-4, 2006.
  • 16. Burgess NK, Sweeten TL, McMahon WM, Fujinami RS. Hyperserotoninemia and altered immunity in autism. J Autism Dev Disord 36:697-704, 2006.
  • 17. Libbey JE, Tsunoda I, Fujinami RS. Autologous hematopoietic stem cell transplantation: A cure for multiple sclerosis? Future Neurol 1:403-8, 2006.
  • 18. Peterson LK, Fujinami RS. Molecular mimicry. In Autoantibodies, Second Edition. Y Shoenfeld, ME Gershwin, P-L Meroni (Eds.), Elsevier Press, Philadelphia, 2006, pp. 13-20.
  • 19. Tsunoda I, Tanaka T, Saijoh Y, Doyle SE, Terry EJ, Fujinami RS. Axonal damage targets inflammatory demyelinating lesions to sites of Wallerian degeneration: Inside-Out model for multiple sclerosis. In Proceedings of the 8th International Conference of Neuroimmunology (ISNI 2006), T. Tabira, T. Yamamura, J. Kira (Eds.), Medimond, Bologna, Italy, 2006, pp. 37-40.
  • 20. Tsunoda I, Tanaka T, Terry EJ, Fujinami RS. Contrasting roles for axonal degeneration in an autoimmune versus viral model of multiple sclerosis: When can axonal injury be beneficial? Am J Pathol 170:214-26, 2007.
  • 21. Tsunoda I, Terry EJ, Marble BJ, Lazarides E, Woods C, Fujinami RS. Modulation of experimental allergic encephalomyelitis by VLA-2 blockade. Brain Pathol 17:45-55, 2007.
  • 22. Peterson LK, Tsunoda I, Masaki T, Fujinami RS. Polyreactive myelin oligodendrocyte glycoprotein antibodies: Implications for systemic autoimmunity in progressive experimental autoimmune encephalomyelitis. J Neuroimmunol 183:69-80, 2007.
  • 23. Libbey JE, Tsunoda I, Whitton JL, Fujinami RS. Infectious RNA isolated from the spinal cords of mice chronically infected with Theiler’s murine encephalomyelitis virus. J Virol 81:3009-11, 2007.
  • 24. Peterson LK, Fujinami RS. Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis. J Neuroimmunol (Special Issue on Neurodegeneration) 184:37-44, 2007.
  • 25. Libbey JE, McCoy LL, Fujinami RS. Molecular mimicry in multiple sclerosis. In The Neurobiology of Multiple Sclerosis. Series: International Review of Neurobiology, Vol. 79. A. Minagar (Ed.), Elsevier, San Diego, CA, 2007, pp. 127-47.
  • 26. Libbey JE, Coon HH, Kirkman NJ, Sweeten TL, Miller JN, Lainhart JE, McMahon WM, Fujinami RS. Are there altered antibody responses to measles, mumps or rubella viruses in autism? J NeuroVirol 13:252-9, 2007.
  • 27. Welsh RM, Fujinami RS. Pathogenic epitopes, heterologous immunity, and vaccine design. Nat Rev Microbiol 5:555-63, 2007.
  • 28. Tsunoda I, Libbey JE, Fujinami RS. Sequential polymicrobial infections lead to CNS inflammatory disease: Possible involvement of bystander activation in heterologous immunity. J Neuroimmunol 188:22-33, 2007.
  • 29. Tsunoda I, Libbey JE, Fujinami RS. TGF-β1 suppresses T cell infiltration and VP2 puff B mutation enhances apoptosis in acute polioencephalitis induced by Theiler’s virus. J Neuroimmunol 190:80-9, 2007.
  • 30. Tsunoda I, Tanaka T, Saijoh Y, Fujinami RS. Targeting inflammatory demyelinating lesions to sites of Wallerian degeneration. Am J Pathol 171:1563-75, 2007.
  • 31. Libbey JE, Fujinami RS. Autoimmunity and immunology of autism. In: New Autism Research Developments, BS Mesmere (Ed.), Nova Sciences Publishers, Inc., 2007, pp. 87-107.
  • 32. Wang X, Ma Y, Yoder A, Crandall H, Zachary JF, Fujinami RS, Weis JH, Weis JJ. T cell infiltration is associated with increased Lyme arthritis in TLR2/ mice. FEMS Immunol Med Microbiol 52:124-33, 2008.
  • 33. Kirkman NJ*, Libbey JE*, Sweeten TL, Coon HH, Miller JN, Stevenson EK, Lainhart JE, McMahon WM, Fujinami RS. How relevant are GFAP autoantibodies in autism and Tourette syndrome? J Autism Dev Disord 38:333-41, 2008 (*equal contribution).
  • 34. Libbey JE, Coon HH, Kirkman NJ, Sweeten TL, Miller JN, Stevenson EK, Lainhart JE, McMahon WM, Fujinami RS. Are there enhanced MBP autoantibodies in autism? J Autism Dev Disord 38:324-32, 2008.
  • 35. Fujinami RS, Oldstone MBA. Immunopathology of virus infection. In Encyclopedia of Virology, Third Edition, B Mahy, MHV van Regenmortel (Eds.), Elsevier, Oxford, UK, 2008, pp. 78-83.
  • 36. Libbey JE, Kirkman NJ, Smith MCP, Tanaka T, Wilcox KS, White HS, Fujinami RS. Seizures following picornavirus infection. Epilepsia 49(6):1066-74, 2008.
  • 37. Peterson LK, Tsunoda I, Fujinami RS. Role of CD5+ B-1 cells in EAE pathogenesis. Autoimmunity, 41(5):353-62, 2008.
  • 38. Peterson LK, Tsunoda I, Libbey JE, Fujinami RS. Role of B:T cell ratio in suppression of clinical signs: A model for silent MS. Exp Mol Path 85(1):28-39, 2008.
  • 39. Tsunoda I, Tanaka T, Fujinami RS. Regulatory role of CD1d in neurotropic virus infection. J Virol 82(20):10279-89, 2008.
  • 40. Peterson LK, Masaki T, Wheelwright SR, Tsunoda I, Fujinami RS. Cross-reactive myelin antibody induces renal pathology. Autoimmunity 41(7):526-36, 2008.
  • 41. Theil DJ, Libbey JE, Rodriguez F, Whitton JL, Tsunoda I, Derfuss TJ, Fujinami RS. Targeting myelin proteolipid protein to the MHC class I pathway by ubiquitination modulates the course of experimental allergic encephalomyelitis. J Neuroimmunol 204:92-100, 2008.
  • 42. Bale JF Jr., Fujinami RS. Subacute sclerosing panencephalitis. In Neurotropic Viral Infections, CS Reiss (Ed.), Cambridge University Press, Cambridge, UK, 2008, pp. 26-34.
  • 43. Tsunoda I, Kobayashi-Warren M, Libbey JE, Fujinami RS. Central nervous system degeneration caused by autoimmune cytotoxic CD8+ T cell clones and hybridomas. In Encyclopedia of Neuroscience. MD Binder, N Hirokawa, U Windhorst (Eds.), Springer, New York, 2008, pp. 619-25.
  • 44. Tsunoda I, Libbey JE, Fujinami RS. Theiler’s murine encephalomyelitis virus attachment to the gastrointestinal tract is associated with sialic acid binding. J NeuroVirol, epub December 28, 2008.
  • 45. Tsunoda I, Tanaka T, Taniguchi M, Fujinami RS. Contrasting roles for V14+ NKT cells in a viral model for multiple sclerosis. J NeuroVirol, epub December 28, 2008.
  • 46. Libbey JE, Fujinami RS. Potential triggers of MS. In Molecular Basis of Multiple Sclerosis. The Immune System. Series: Results and Problems in Cell Differentiation. R Martin, A Lutterotti (Eds.), Springer-Verlag, Berlin, 2009, epub January 8, 2009.
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Honors and Awards

  • 1968, Japanese American Citizens League Scholarship, Salt Lake City, Utah Chapter
  • 1968, University of Utah Presidential Scholarship
  • 1981-1983, National Institutes of Health, New Investigator Award
  • 1982-1986, National Multiple Sclerosis Society Harry M. Weaver Neuroscience Scholar, National Multiple Sclerosis Society (Career Development Award)
  • 1988, Nobel Medica Research Forum, Honorary Lecturer
  • 1989-1996, National Institutes of Health, Javits Neuroscience Scholar Award

Professional Education

  • 1968-1972, B.A., University of Utah, Salt Lake City, Utah (Microbiology)
  • 1972-1977, Ph.D., Northwestern University, Chicago, Illinois (Immunology/Microbiology)
  • 1977-1980, Postdoctoral, The Scripps Research Institute [formerly Scripps Clinic and Research Foundation], LaJolla, California (Immunology)