Analysis of the Systemic and Intrathecal Humoral Immune Response in Progressive Multifocal Leukoencephalopathy

Abstract

Progressive multifocal leukoencephalopathy (PML) is a subacute viral infection of oligodendrocytes by JC virus occurring almost exclusively in immunocompromised patients. By use of partially purified recombinant VP1 as antigen, the IgG response was analyzed by a quantitative ELISA of paired cerebrospinal fluid (CSF) and serum samples. An intrathecal immune response to VP1, defined as an antibody-specificity index of CSF to serum antibody titers > or =1.5, was found in 76% of PML patients (47/62) but in only 3.2% of controls (5/155) (P < .001). Intra-blood-brain barrier synthesis of VP1-specific IgG antibodies is 76% sensitive and 96.8% specific for the diagnosis of PML. Furthermore, the excellent correlation (r = .985) between the plasma cell count in brain tissue and the humoral intrathecal immune response to VP1 in PML patients suggests a role for B cells in this disorder.

Association of Prolonged Survival in HLA-A2+ Progressive Multifocal Leukoencephalopathy Patients with a CTL Response Specific for a Commonly Recognized JC Virus Epitope

“…Although IgG Abs specific for JCV can be detected in 90% of the normal adult population by a hemagglutination inhibition assay or ELISA (8), this humoral immune response is unable to prevent the development of PML. This disease occurs in patients with AIDS, cancer, or in organ transplant recipients, and is usually fatal in less than 1 year.…”

Progressive multifocal leukoencephalitis in a patient with sarcoidosis on hydroxychloroquine with negative cerebrospinal fluid testing for the John Cunningham virus

“…Approximately 86% of adults have antibodies to the JC virus, believed to be secondary to an asymptomatic childhood infection [1] . When a patient becomes immunosuppressed, the JC virus can spread to the central nervous system, and cause a life-threatening severe neurological illness.…”

Immunology of progressive multifocal leukoencephalopathy

“…PML survivors in the context of AIDS show significant increases in JCV-specific T cells and IgG responses in the peripheral blood, which are positively correlated with peripheral CD4 + T cell counts (Khanna et al, 2009). PML patients show generally JCV-specific oligoclonal IgG bands in the CSF and elevated intrathecal JCV VP1-specific antibodies with further increase at onset of IRIS (Aly et al, 2011;Sindic et al, 1997;Warnke et al, 2014;Weber et al, 1997). This goes in line with the observation that plasma cells are prominent -4-among the brain immune infiltrates in PML-IRIS (Aly et al, 2011;Metz et al, 2012).…”

“…Interestingly, a recent proof-of-concept study demonstrated that 29% of sera from MS patients lack anti-JCV neutralizing activity despite the presence of anti-JCV VP1 antibodies (Diotti et al, 2014). The fact that PML patients often show strong antibody responses within the serum and the CNS compartment at onset of PML and during the course of PML (Warnke et al, 2014;Weber et al, 1997) questions the role of JCV-specific antibodies in the prevention of PML development and clearance of symptomatic JCV infection from brain. Interestingly, JCV variants with mutations in VP1 are often found in addition to prototype Mad-1 sequences in the CNS of PML patients (Gorelik et al, 2011;Reid et al, 2011).…”