JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis

Chalkias, Spyridon; Dang, Xin; Bord, Evelyn; Stein, Marion C.; Kinkel, R. Philip; Sloane, Jacob A.; Donnelly, Maureen; Ionete, Carolina; Houtchens, Maria K.; Buckle, Guy J.; Batson, Stephanie; Koralnik, Igor J.

doi:10.1002/ana.24148

Cited by 45 publications

(46 citation statements)

References 47 publications

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“…In contrast, CD19-independent accumulation of early-recruited IgD ϩ B cells in the CNS suggests that independent activation mechanisms drive the emergence of early versus more differentiated, isotypeswitched B cells accumulating in the CNS as GCs are formed in the periphery. A better understanding of distinct B cell subsets in the CNS is essential to preempt reactivation of persistent viruses in the CNS during immune-suppressive therapies (87,88), as well as to combat susceptibility to acute encephalitic arboviral infections.…”

Section: Discussionmentioning

confidence: 99%

Protective Humoral Immunity in the Central Nervous System Requires Peripheral CD19-Dependent Germinal Center Formation following Coronavirus Encephalomyelitis

Atkinson

Bergmann

2017

J Virol

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B cell subsets with phenotypes characteristic of naive, non-isotypeswitched, memory (B mem ) cells and antibody-secreting cells (ASC) accumulate in various models of central nervous system (CNS) inflammation, including viral encephalomyelitis. During neurotropic coronavirus JHMV infection, infiltration of protective ASC occurs after T cell-mediated viral control and is preceded by accumulation of non-isotype-switched IgD ϩ and IgM ϩ B cells. However, the contribution of peripheral activation events in cervical lymph nodes (CLN) to driving humoral immune responses in the infected CNS is poorly defined. CD19, a signaling component of the B cell receptor complex, is one of multiple regulators driving B cell differentiation and germinal center (GC) formation by lowering the threshold of antigen-driven activation. JHMV-infected CD19 Ϫ/Ϫ mice were thus used to determine how CD19 affects CNS recruitment of B cell subsets. Early polyclonal ASC expansion, GC formation, and virus-specific ASC were all significantly impaired in CLN of CD19 Ϫ/Ϫ mice compared to wild-type (WT) mice, consistent with lower and unsustained virus-specific serum antibody (Ab). ASC were also significantly reduced in the CNS, resulting in increased infectious virus during persistence. Nevertheless, CD19 deficiency did not affect early CNS IgD ϩ B cell accumulation. The results support the notion that CD19-independent factors drive early B cell mobilization and recruitment to the infected CNS, while delayed accumulation of virus-specific, isotype-switched ASC requires CD19-dependent GC formation in CLN. CD19 is thus essential for both sustained serum Ab and protective local Ab within the CNS following JHMV encephalomyelitis. IMPORTANCE CD19 activation is known to promote GC formation and to sustain serum Ab responses following antigen immunization and viral infections. However, the contribution of CD19 in the context of CNS infections has not been evaluated. This study demonstrates that antiviral protective ASC in the CNS are dependent on CD19 activation and peripheral GC formation, while accumulation of early-recruited IgD ϩ B cells is CD19 independent. This indicates that IgD ϩ B cells commonly found early in the CNS do not give rise to local ASC differentiation and that only antigen-primed, peripheral GC-derived ASC infiltrate the CNS, thereby limiting potentially harmful nonspecific Ab secretion. Expanding our understanding of activation signals driving CNS migration of distinct B cell subsets during neuroinflammatory insults is critical for preventing and managing acute encephalitic infections, as well as preempting reactivation of persistent viruses during immune-suppressive therapies targeting B cells in multiple sclerosis (MS), such as rituximab and ocrelizumab.

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Section: Discussionmentioning

confidence: 99%

Protective Humoral Immunity in the Central Nervous System Requires Peripheral CD19-Dependent Germinal Center Formation following Coronavirus Encephalomyelitis

Atkinson

Bergmann

2017

J Virol

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“…Two other studies have demonstrated that natalizumabmobilized CD341 HSPC are not a relevant reservoir for the virus. 18,20 Technical reasons and different number of patients and of natalizumab infusions may account for the discrepancies among the studies, as discussed also in Chalkias et al, 21 and it remains controversial whether CD341 HSPC mobilization takes part in the development of PML.…”

mentioning

confidence: 99%

Hematopoietic mobilization

et al. 2015

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Objective: To ascertain the mobilization from the bone marrow and the functional relevance of the increased number of circulating hematopoietic stem and progenitor cells (HSPC) induced by the anti-a-4 integrin antibody natalizumab in patients with multiple sclerosis (MS).Methods: We evaluated CD45 low CD341 HSPC frequency by flow cytometry in blood from 45 natalizumab-treated patients (12 of whom were prospectively followed during the first year of treatment as part of a pilot cohort and 16 prospectively followed for validation), 10 untreated patients with MS, and 24 healthy donors. In the natalizumab-treated group, we also assessed sorted HSPC cell cycle status, T-and B-lymphocyte subpopulation frequencies (n 5 29), and HSPC differentiation potential (n 5 10).Results: Natalizumab-induced circulating HSPC were predominantly quiescent, suggesting recent mobilization from the bone marrow, and were capable of differentiating ex vivo. Circulating HSPC numbers were significantly increased during natalizumab, but heterogeneously, allowing the stratification of mobilizer and nonmobilizer subgroups. Nonmobilizer status was associated with persistence of disease activity during treatment. The frequency of B cells and CD1031CD81 regulatory T cells persistently increased, more significantly in mobilizer patients, who also showed a specific naive/memory B-cell profile. Conclusions:The data suggest that natalizumab-induced circulating HSPC increase is the result of true mobilization from the bone marrow and has clinical and immunologic relevance. HSPC mobilization, associated with clinical remission and increased proportion of circulating B and regulatory T cells, may contribute to the treatment's mode of action; thus, HSPC blood counts could represent an early biomarker of responsiveness to natalizumab. Multiple sclerosis (MS) is thought to be initiated by inflammatory blood-derived leukocytes entering the CNS. a4b1 integrin plays a key role in leukocyte trafficking 1 ; its a4 subunit is targeted by the MS treatment natalizumab, which suppresses brain MRI lesion formation and reduces relapse rate.2-4 Improvement of neurologic function in treated patients has also been observed.5-7 Natalizumab's anti-inflammatory effect in CNS is mirrored by a radical decrease of lymphocyte number in the CSF 8,9 and by T-cell sequestration in the periphery, 10,11 yet less is known about its effects on B cells and on hematopoietic stem and progenitor cells (HSPC) recirculation, both cell types expressing a4b1. Natalizumab treatment induces a significant and protracted peripheral HSPC increase in the blood of patients with MS.12,13 The mechanism and the functional significance of the observed increase, however, remain poorly understood.

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“…It has been shown that most normal individuals have circulating cytotoxic T lymphocytes specific for JCV, which are crucial for PML containment [185]. Following natalizumab treatment, the drug alters T-cell-mediated immune surveillance, therefore allowing reactivation of JCV infection and PML development [186]. It has been shown that the CSF of patients treated with natalizumab contains not only reduced numbers of CD4+ and CD8+ T cells, but also reduced numbers of CD10+ B lymphocytes and CD138+ plasma cells compared with controls [182].…”

Section: Progressive Multifocal Leukoencephalopathymentioning

confidence: 99%

Immunotherapies for Neurological Manifestations in the Context of Systemic Autoimmunity

et al. 2016

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Neurological involvement is relatively common in the majority of systemic autoimmune diseases and may lead to severe morbidity and mortality, if not promptly treated. Treatment options vary greatly, depending on the underlying systemic pathophysiology and the associated neurological symptoms. Selecting the appropriate therapeutic scheme is further complicated by the lack of definite therapeutic guidelines, the necessity to differentiate primary neurological syndromes from those related to the underlying systemic disease, and to sort out adverse neurological manifestations caused by immunosuppressants or the biological agents used to treat the primary disease. Immunotherapy is a sine qua non for treating most, if not all, neurological conditions presenting in the context of systemic autoimmunity. Specific agents include classical immune modulators such as corticosteroids, cyclophosphamide, intravenous immunoglobulin, and plasma exchange, as well as numerous biological therapies, for example antitumor necrosis factor agents and monoclonal antibodies that target various immune pathways such as B cells, cytokines, and co-stimulatory molecules. However, experience regarding the use of these agents in neurological complications of systemic diseases is mainly empirical or based on small uncontrolled studies and case series. The aim of this review is to present the state-of-the-art therapies applied in various neurological manifestations encountered in the context of systemic autoimmune diseases; evaluate all treatment options on the basis of existing guidelines; and compliment these data with our personal experience derived from a large number of patients.

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JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis

Cited by 45 publications

References 47 publications

Protective Humoral Immunity in the Central Nervous System Requires Peripheral CD19-Dependent Germinal Center Formation following Coronavirus Encephalomyelitis

Protective Humoral Immunity in the Central Nervous System Requires Peripheral CD19-Dependent Germinal Center Formation following Coronavirus Encephalomyelitis

Hematopoietic mobilization

Immunotherapies for Neurological Manifestations in the Context of Systemic Autoimmunity

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