Progressive multifocal leukoencephalopathy in a patient with idiopathic CD4+T lymphocytopenia

Puri, Vinita; Chaudhry, Neera; Gulati, Parveen; Patel, Nisheeth; Tatke, Medha; Sinha, Shalini

doi:10.4103/0028-3886.60423

Cited by 24 publications

(19 citation statements)

References 16 publications

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“…JCV is a ubiquitous virus that only causes PML under circumstances of immunocompromise and especially impaired CD4 + T cell function (13)(14)(15). The lack of PML development in immunocompetent healthy individuals, who are persistently infected with JCV, implies the existence of very efficient JCV-specific immunity.…”

Section: Discussionmentioning

confidence: 99%

“…JCV is a ubiquitous virus that infects between 60 and 80% of the population worldwide. Under circumstances of immunocompromise and especially impaired CD4 + T cell function such as late-stage HIV infection, hematological malignancies, organ transplantation, but also in clinically inconspicuous idiopathic CD4 + lymphopenia (13)(14)(15), JCV is able to cause an opportunistic infection of the brain called progressive multifocal leukoencephalopathy (PML) (13,16,17). Because PML often runs a fatal course, it is an important medical concern.…”

Section: Irus-specific Cd4mentioning

confidence: 99%

“…Proliferation was measured in daughter plates, and VP1-responsive cultures were identified in mother plates. TCCs were established from these VP1-responsive cultures by limiting dilution, and fine specificity was determined using 64 (13)(14)(15)(16) Nucleotide sequencing of PCR products was performed by incubating 5 ml PCR product with 10 U exonuclease I (no. EN0581; Fermentas) and 1 U FastAP Thermosensitive alkaline phosphatase (no.…”

Section: Brain-infiltrating Vp1-specific Tccs and Apcsmentioning

confidence: 99%

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TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection

Yousef

Planas

Chakroun

et al. 2012

The Journal of Immunology

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Virus-specific CD4+ T cells play a central role in control of viral pathogens including JC polyoma virus (JCV) infection. JCV is a ubiquitous small DNA virus that leads to persistent infection of humans with no clinical consequences. However, under circumstances of immunocompromise, it is able to cause an opportunistic and often fatal infection of the brain called progressive multifocal leukoencephalopathy (PML). PML has emerged as a serious adverse event in multiple sclerosis patients treated with the anti–VLA-4 mAb natalizumab, which selectively inhibits cell migration across the blood–brain barrier and the gut’s vascular endothelium thus compromising immune surveillance in the CNS and gut. In a multiple sclerosis patient who developed PML under natalizumab treatment and a vigorous immune response against JCV after Ab washout, we had the unique opportunity to characterize in detail JCV-specific CD4+ T cell clones from the infected tissue during acute viral infection. The in-depth analysis of 14 brain-infiltrating, JCV-specific CD4+ T cell clones demonstrated that these cells use an unexpectedly broad spectrum of different strategies to mount an efficient JCV-specific immune response including TCR bias, HLA cross-restriction that increases avidity and influences in vivo expansion, and a combination of Th1 and Th1-2 functional phenotypes. The level of combinatorial diversity in TCR– and HLA–peptide interactions used by brain-infiltrating, JCV-specific CD4+ T cells has not, to our knowledge, been reported before in humans for other viral infections and confirms the exceptional plasticity that characterizes virus-specific immune responses.

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Section: Discussionmentioning

confidence: 99%

Section: Irus-specific Cd4mentioning

confidence: 99%

Section: Brain-infiltrating Vp1-specific Tccs and Apcsmentioning

confidence: 99%

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TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection

Yousef

Planas

Chakroun

et al. 2012

The Journal of Immunology

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“…ϩ T cell reduction due to idiopathic CD4 ϩ T lymphocytopenia has been associated with a number of cases of PML (179,396). Other studies have implicated an impairment of T cell responses in the development of PML (526), while a cytotoxic T lymphocyte (CTL) response has been associated with greater control of JCV and longer PML survival rates (129,249,250,278,321).…”

Section: Immune Control Of Jcv: Humoral and Cellular Responses To Infmentioning

confidence: 99%

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

et al. 2012

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SUMMARY Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.

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“…Thus, pronounced lymphopenia together with fumarate and additional treatments might be operating in concert. In support of the general role of lymphopenia, PML has also been diagnosed in patients with idiopathic CD4+ lymphocytopenia or without (identified) immunological deficits (160,(177)(178)(179)(180)(181)(182)(183).…”

Section: Jcpyv Diseasementioning

confidence: 99%

The human JC polyomavirus (JCPyV): virological background and clinical implications

Hirsch

Kardas

Kranz

et al. 2013

APMIS

141

169

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JC polyomavirus (JCPyV) was the first of now 12 PyVs detected in humans, when in 1964, PyV particles were revealed by electron microscopy in progressive multifocal leukoencephalopathy (PML) tissues. JCPyV infection is common in 35–70% of the general population, and the virus thereafter persists in the renourinary tract. One third of healthy adults asymptomatically shed JCPyV at approximately 50 000 copies/mL urine. PML is rare having an incidence of <0.3 per 100 000 person years in the general population. This increased to 2.4 per 1000 person years in HIV‐AIDS patients without combination antiretroviral therapy (cART). Recently, PML emerged in multiple sclerosis patients treated with natalizumab to 2.13 cases per 1000 patients. Natalizumab blocks α4‐integrin‐dependent lymphocyte homing to the brain suggesting that not the overall cellular immunodeficiency but local failure of brain immune surveillance is a pivotal factor for PML. Recovering JCPyV‐specific immune control, e.g., by starting cART or discontinuing natalizumab, significantly improves PML survival, but is challenged by the immune reconstitution inflammatory syndrome. Important steps of PML pathogenesis are undefined, and antiviral therapies are lacking. New clues might come from molecular and functional profiling of JCPyV and PML pathology and comparison with other replicative pathologies such as granule cell neuronopathy and (meningo‐)encephalitis, and non‐replicative JCPyV pathology possibly contributing to some malignancies. Given the increasing number of immunologically vulnerable patients, a critical reappraisal of JCPyV infection, replication and disease seems warranted.

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Progressive multifocal leukoencephalopathy in a patient with idiopathic CD4+T lymphocytopenia

Cited by 24 publications

References 16 publications

TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection

TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

The human JC polyomavirus (JCPyV): virological background and clinical implications

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