Research Topic

Immune Control of JC Virus Infection and Immune Failure during Progressive Multifocal Leukoencephalopathy

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Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease caused by replication of human JC polyomavirus (JCV) in the central nervous system (CNS). PML usually occurs in patients with immunodeficiencies, due to AIDS, leukemia/lymphoma, transplantation or idiopathic CD4 ...

Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease caused by replication of human JC polyomavirus (JCV) in the central nervous system (CNS). PML usually occurs in patients with immunodeficiencies, due to AIDS, leukemia/lymphoma, transplantation or idiopathic CD4 lymphopenia. However, numerous cases of PML have recently been reported following immunotherapy for autoimmune diseases or lymphoid malignancies based on monoclonal antibodies such as natalizumab, efalizumab, rituximab, infliximab, brentuximab and alemtuzumab. This recent increase in the incidence of PML raises numerous questions regarding the immunological mechanisms that control JCV replication in the CNS and thereby prevent PML.

These questions include:

-What is the possible role of CD8 T cells, CD4 T cells and brain-resident memory T cells, as well as B and NK cells, in controlling JCV replication within the central nervous system?
-In addition to preventing peripheral T cells from crossing the blood-brain barrier, does natalizumab have other effects on the anti-JCV immune response (functionality of JCV-specific T cells, antigen presentation of brain-derived antigens, brain-resident T cell memory, etc.)?
How does B cell depletion therapy (rituximab) trigger PML?
-Is there an immunological common denominator between natalizumab-induced PML and HIV-induced PML?
-What are the mechanisms of JCV immune tolerance in the kidney?
-Is there a genetic predisposition to PML, and does it involve immunological factors?
-What are the mechanisms of PML-IRIS?
-How to identify patients at risk for PML during natalizumab therapy (anti-JCV antibody testing, JCV-specific T cell response-based tests...) ?
-What immunotherapeutic approaches might be used to treat PML?

By drawing together the latest findings in this field, this series of reviews may provide deeper insights into how the immune system controls JCV replication in the CNS, how to identify patients at risk for PML, and how to treat PML.


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