B cells undergo unique compartmentalized redistribution in multiple sclerosis

Haas, Jürgen; Bekeredjian‐Ding, Isabelle; Milkova, Miriam; Balint, Bettina; Schwarz, Alexander; Korporal, Mirjam; Jarius, Sven; Fritz, Brigitte; Lorenz, Hanns‐Martin; Wildemann, Brigitte

doi:10.1016/j.jaut.2011.08.003

Cited by 67 publications

(85 citation statements)

References 44 publications

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“…This interpretation is consistent with the natalizumab-induced increase in marginal zone-like (early memory) B cells recently reported 28 and is in line with the increased proportions of B-memory subsets previously described in natalizumab-treated patients. 29 We observed a small increase in the proportion of circulating mature T lymphocytes during natalizumab, similarly to previously published data, 10 and potentially associated with protection from clinical reactivation postnatalizumab discontinuation. 30 In notable addition, we report a significant and persistent accumulation of the proportion of CD1031CD81 T cells, described as a regulatory population 15,16 and more pronounced among the mobilizer patients, thus suggesting a novel immune tolerizing mechanism, previously described after HSPC transplantation in patients with systemic lupus erythematosus 31 but not in Figure 5 CD1031CD81 regulatory T cells proportion significantly increases in natalizumab-treated patients to a different extent according to hematopoietic stem and progenitor cells mobilization status (A) The proportion of circulating CD1031CD81 T regulatory cells increased in patients with multiple sclerosis (MS) after 2, 6, and 12 natalizumab infusions (mean 6 SD 3.13 6 1.17%, 4.63 6 1.48%, and 4.31 6 1.66%, respectively) compared to pretreatment baseline (mean 6 SD 1.94 6 1.03%).…”

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confidence: 91%

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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confidence: 91%

Hematopoietic mobilization

et al. 2015

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“…Specifically, CXCL13 contributes to GC formation by recruiting activated B and follicular helper CD4 ϩ T (T FH ) cells expressing CXCR5 (15)(16)(17). CXCL13 is also associated with lymphoid neogenesis in nonlymphoid tissue, such as joints during rheumatoid arthritis (18) and CNS meninges during some neuroinflammatory diseases, including multiple sclerosis (MS) and Lyme disease (19)(20)(21)(22)(23). However, despite impaired GC formation, CXCL13 Ϫ/Ϫ mice infected with glial-tropic JHMV mounted effective peripheral ASC and serum Ab responses (24).…”

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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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“…In fact, the majority of these B cells consist of CD19 + CD27 + CD 138 À memory B cells. 23,24 Furthermore, besides being present in the CSF, B cells, plasma blasts, plasma cells and antibodies have been found in the brain parenchyma, white matter lesions and leptomeninges of patients with MS. Because these CSF/CNS B cells largely are antigenexperienced B cells, it has been questioned whether the activation and maturation of these cells occur within or outside the CNS, or perhaps even on both sides of the blood-brain barrier. Clonally related B cells in MS have been found both in the CNS and the peripheral blood compartment, implying that they are able to exchange across the blood-brain barrier.…”

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confidence: 99%

Illuminating vitamin D effects on B-cells - the multiple sclerosis perspective

et al. 2016

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SummaryVitamin D is associated with many immune-mediated disorders. In multiple sclerosis (MS) a poor vitamin D status is a major environmental factor associated with disease incidence and severity. The inflammation in MS is primarily T-cell-mediated, but increasing evidence points to an important role for B cells. This has paved the way for investigating vitamin D effects on B cells. In this review we elaborate on vitamin D interactions with antibody production, T-cell-stimulating capacity and regulatory B cells. Although in vitro plasma cell generation and expression of co-stimulatory molecules are inhibited and the function of regulatory B cells is promoted, this is not supported by in vivo data. We speculate that differences might be explained by the B-cell-Epstein-Barr virus interaction in MS, the exquisite role of germinal centres in B-cell biology, and/or in vivo interactions with other hormones and vitamins that interfere with the vitamin D pathways. Further research is warranted to illuminate this tube-versus-body paradox.

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B cells undergo unique compartmentalized redistribution in multiple sclerosis

Cited by 67 publications

References 44 publications

Hematopoietic mobilization

Hematopoietic mobilization

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

Illuminating vitamin D effects on B-cells - the multiple sclerosis perspective

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