Department of Neurology and Medicine
Beth Israel Deaconess Medical Center
E/CLS - 1005
330 Brookline Ave
Boston, MA 02215
Lab Members: 3 faculty, 3 post doctoral fellows, 1 PhD student, 4 research assistants, 1 college student
Immunopathogenesis of JC virus-associated brain diseases
Our laboratory is studying the immunopathogenesis of the polyomavirus JC in the central nervous system (CNS). Progressive Multifocal Leukoencephalopathy (PML) is a deadly demyelinating disease of the central nervous system caused by JC virus (JCV) in immunosuppressed individuals, including patients with AIDS, hematologic malignancies, transplant recipients, or individuals with autoimmune diseases treated with immunomodulatory medications. JCV infects most healthy adults without causing any disease, but its reactivation leads to a productive and lytic infection of oligodendrocytes, the myelin producing cells in the CNS. We are studying the cellular immune response against JCV in patients with PML and we have demonstrated that a JCV-specific response mediated by CD8+ cytotoxic T lymphocytes is associated with survival. We are now characterizing host and viral markers associated with a favorable clinical outcome. In addition we are trying to elucidate the mechanisms of the immune reconstitution inflammatory syndrome (IRIS) in patients with PML. IRIS is a frequent complication associated with antiretroviral treatment in HIV-infected patients with PML.
Our laboratory is also studying the determinants of JCV latency and reactivation in patients with multiple sclerosis treated with the immunomodulatory medication natalizumab (Tysabri). Natalizumab is a monoclonal antibody against a4b7 integrin receptors, which has been associated with more than 200 cases of PML in the world. We have also adapted a humanized mouse model for the study of the early events surrounding JCV infection, immune response and reactivation. Since there is no cure for PML, we are now developing a dendritic cell-based immunotherapy for this disease.
Although PML is a demyelinating disease of the CNS white matter, we have shown for the first time that JCV can also infect neurons in the grey matter. Our laboratory has characterized two novel brain diseases associated with infection of neurons by JCV variants, called JCV granule cell neuronopathy (JCV GCN) and JCV encephalopathy (JCVE). We are now studying the cellular immune response to JCV in the setting of neuronal infection.
Immunopathogenesis of BK virus infection in transplantation
Our laboratory is investigating the immunopathogenesis of the polyomavirus BK in the transplant setting. BK virus (BKV) infects most healthy adults without causing any disease, but it may reactivate and cause a severe nephritis in kidney transplant recipients, leading to the loss of the allograft. We are studying how the immune system recognizes BKV infection in HLA-mismatched kidney grafts. Finally, our laboratory is also investigating JCV latency and reactivation in patients with hematopoietic stem cell transplant.
1. Wüthrich C, Dang X, Westmoreland S, McKay J, Maheshwari A, Anderson M, Viscidi R, Ropper AH, Koralnik IJ. Fulminant JCV encephalopathy with infection of cortical pyramidal neurons. Ann Neurol 2009, 65:742-748. PMCID: PMC2865689
2. Chen Y, Bord E, Tompkins T, Miller J, Tan CS, Kinkel RP, Stein MC, Viscidi R, Ngo LH, Koralnik IJ. Asymptomatic reactivation of JC virus in patients treated with natalizumab. New Engl J Med 2009, 361:1067-74 . PMCID: PMC3077718
3. Marzocchetti A, Tompkins T, Clifford DB, Gandhi RT, Kesari S, Berger JR, Simpson DM, De Luca A, Koralnik IJ. Determinants of survival in Progressive Multifocal Leukoencephalopathy. Neurology 2009, 73:1551-8. PMCID: PMC2777072
4. Gheuens S, Pierone G, Peeters P, Koralnik IJ. Progressive Multifocal Leukoencephalopathy in individuals with minimal or occult immunosuppression. J Neurol Neurosurg Psychiatry 2010, 81:247-54. PMCID: PMC2889486
5. Gheuens S, Fellay J, Goldstein DB, Koralnik IJ. Role of HLA class I alleles in Progressive Multifocal Leukoencephalopathy. J NeuroVirol 2010, 16:41-7 PMCID: PMC2854537
6. Tan CS, Ellis LC, Wüthrich C, Ngo L, Broge T, Saint-Aubin J, Miller JS, Koralnik IJ. JC Virus latency in the brain and extraneural organs of patients with and without progressive multifocal leukoencephalopathy. J Virol 2010, 84:9200-9 PMCID: PMC2937633
7. Gheuens S, Bord E, Kesari S, Simpson D, Gandhi RT, Clifford DB, Berger RB, Ngo L, Koralnik IJ. Role of CD4+ and CD8+ T-Cell Responses against JC Virus in the Outcome of Patients with progressive multifocal leukoencephalopathy (PML) and PML-IRIS. J Virol 2011, 85:7256-63 PMCID: PMC3126613
8. Dang X, Vidal JE, Morgello S, Hecht JH, Koralnik IJ. JC virus granule cell neuronopathy is associated with VP1 c-terminus deletion variants. J Gen Virol 2012 93:175-83
9. Wüthrich C, Koralnik IJ. Frequent infection of cortical neurons by JC virus in patients with progressive multifocal leukoencephalopathy J Neuropath Exp Neurol 2012, 71:54-65
For a complete listing of publications click here.
Last Update: 1/6/2014