Critical role of JC virus-specific CD4 T-cell responses in preventing progressive multifocal leukoencephalopathy

Grill, Jacques; Kahraman, Mufide; Herve, Marie de Goër de Ghislaine; Duralı, Deniz; Delfraissy, Jean‐François; Taoufik, Yassine

doi:10.1097/00002030-200307040-00004

Cited by 116 publications

(96 citation statements)

References 32 publications

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“…A disconcerting issue, however, is the long-term safety of B cell-depleting agents. Fatal progressive multifocal leukoencephalopathy after JC virus reactivation is associated with suppression of T cell-mediated immunity (45,46) and has been reported in five rituximab-treated autoimmune disease patients (including two with SLE) (47), and clinical trials of ocrelizumab, a next-generation version of rituximab, were recently halted because of unacceptable serious and fatal infections.…”

Section: Discussionmentioning

confidence: 99%

Antibody-Mediated Coengagement of FcγRIIb and B Cell Receptor Complex Suppresses Humoral Immunity in Systemic Lupus Erythematosus

Horton

Chu

Ortiz

et al. 2011

The Journal of Immunology

124

111

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Engagement of the low-affinity Ab receptor FcγRIIb downregulates B cell activation, and its dysfunction is associated with autoimmunity in mice and humans. We engineered the Fc domain of an anti-human CD19 Ab to bind FcγRIIb with high affinity, promoting the coengagement of FcγRIIb with the BCR complex. This Ab (XmAb5871) stimulated phosphorylation of the ITIM of FcγRIIb and suppressed BCR-induced calcium mobilization, proliferation, and costimulatory molecule expression of human B cells from healthy volunteers and systemic lupus erythematosus (SLE) patients, as well as B cell proliferation induced by LPS, IL-4, or BAFF. XmAb5871 suppressed humoral immunity against tetanus toxoid and reduced serum IgM, IgG, and IgE levels in SCID mice engrafted with SLE or healthy human PBMC. XmAb5871 treatment also increased survival of mice engrafted with PBMC from a unique SLE patient. Unlike anti-CD20 Ab, coengagement of FcγRIIb and BCR complex did not promote B cell depletion in human PBMC cultures or in mice. Thus, amplification of the FcγRIIb inhibitory pathway in activated B cells may represent a novel B cell-targeted immunosuppressive therapeutic approach for SLE and other autoimmune diseases that should avoid the complications associated with B cell depletion.

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Section: Discussionmentioning

confidence: 99%

Antibody-Mediated Coengagement of FcγRIIb and B Cell Receptor Complex Suppresses Humoral Immunity in Systemic Lupus Erythematosus

Horton

Chu

Ortiz

et al. 2011

The Journal of Immunology

124

111

View full text Add to dashboard Cite

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“…Several studies in animal models demonstrated that virus-specific CD4 + T cells are critical for the expansion of virus-specific CD8 + T cells, their differentiation to memory cells, their recruitment to sites of infection, and their secondary expansion during reinfection (1-7), as well as for efficient neutralizing-Ab-mediated virus clearance (8). In humans, the importance of virus-specific CD4 + T cells in control of viral infections has been shown for different viruses such as HIV (9,10), hepatitis C virus (11), and also for JC polyoma virus (JCV) (12). JCV is a ubiquitous virus that infects between 60 and 80% of the population worldwide.…”

Section: Irus-specific Cd4mentioning

confidence: 99%

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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“…Natalizumab does not affect antibody production. Most adults are seropositive for JC virus, and although the humoral immune response cannot prevent a reactivation of JC virus and the development of PML, we and others have found that the cellular immune response plays a crucial role in the containment of JC virus [20][21][22][23][24] and is mediated by CD8+ cytotoxic T cells. The BK virus, a polyomavirus related to JC virus, may be reactivated in patients with multiple sclerosis who are treated with natalizumab.…”

mentioning

confidence: 78%

Asymptomatic Reactivation of JC Virus in Patients Treated with Natalizumab

2009

N Engl J Med

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Critical role of JC virus-specific CD4 T-cell responses in preventing progressive multifocal leukoencephalopathy

Abstract: JCV-specific CD4 T-cell responses appear to play a critical role in the control of JCV infection, preventing PML development. Such responses can be restored in PML survivors following effective and prolonged antiretroviral therapy.

Cited by 116 publications

References 32 publications

Antibody-Mediated Coengagement of FcγRIIb and B Cell Receptor Complex Suppresses Humoral Immunity in Systemic Lupus Erythematosus

Antibody-Mediated Coengagement of FcγRIIb and B Cell Receptor Complex Suppresses Humoral Immunity in Systemic Lupus Erythematosus

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

Asymptomatic Reactivation of JC Virus in Patients Treated with Natalizumab

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