B cells and progressive multifocal leukoencephalopathy: search for the missing link.

Deniz Durali,Yassine Taoufik,Marie-Ghislaine De Goã«R De Herve,Jacques Gasnault

doi:10.3389/fimmu.2015.00241

Abstract

Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to JC virus (JCV) replication in the brain. PML classically occurs in patients with severe immunodepression, and cases have recently been linked to therapeutic monoclonal antibodies such as natalizumab and also rituximab, which depletes B cells. B cells appear to play a complex role in the pathogenesis of PML. They may act as a viral reservoir and as a vector for viral dissemination in the central nervous system. Anti-JCV antibody responses appear to have a limited effect on JCV replication in the brain. However, accumulating evidence suggests that B cells may considerably influence T cell responses through their cytokine secretion. This immunomodulatory function of B cells may play an important role in the control of JCV infection and in the pathogenesis of PML, including rituximab-induced PML.

Highlights

Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to JC virus (JCV) replication in the brain
Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease caused by replication in the brain of the opportunistic polyomavirus JC virus (JCV), which asymptomatically infects a large proportion of the adult population worldwide
Specific CD4 and CD8 T cell responses appear to play a critical role in the control of JCV infection: for instance, the beneficial effect of highly active antiretroviral therapy (HAART) on AIDS-related PML is largely due to restoration of anti-JCV T cell immunity [3,4,5]

Summary

B Cells are a Potential JCV Reservoir and a Vector for CNS Dissemination

JC virus infection usually occurs in childhood and persists throughout life. It generally remains clinically silent, despite active virus replication in the kidneys and urinary virus excretion in a. Severe, prolonged immunosuppression may lead to JCV dissemination to the central nervous system (CNS) from sites of persistence (kidney, bone marrow, lymphoid organs), or to reactivation of dormant virus already present in the CNS. In both cases, this may lead to productive infection of oligodendrocytes, followed by demyelination and development of PML [2, 8]. Natalizumab has been reported to inhibit VLA-4-dependent retention of CD34+ hematopoietic precursor cells, B cell precursors, and B cells in bone marrow and lymphoid tissues, leading to increased circulation of pre-B and B cells [17, 43] It remains unclear how much its effects on B cells may contribute to natalizumab-associated PML. A longitudinal study of an HIV-seronegative PML patient showed that the anti-VP1 antibody response increased with time, yet neurological status deteriorated and the patient died [45]

B Cells Modulate the Differentiation and Functions of CD4 and CD8 T Cells

B Cells as Regulators of Cellular Immune Responses to Viral Infections

Findings

Conclusion