Experimental intracerebral vaccination protects mouse from a neurotropic virus by attracting antibody secreting cells to the CNS

Lee, Hyunkyoung; Sunden, Yuji; Ochiai, Kenji; Umemura, Takashi

doi:10.1016/j.imlet.2011.05.008

Cited by 9 publications

(10 citation statements)

References 54 publications

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“…The data represent the means and SEM of transcript levels relative to gapdh mRNA of individual mice from 2 or 3 separate experiments, each comprising 2 to 6 individual mice per time point and group. Statistically significant differences between WT and CD19 Ϫ/Ϫ mice, determined by unpaired t test, are denoted by asterisks: *, P Ͻ 0.05; **, P Ͻ 0.01; ***, P Ͻ 0.001. infections established by Sindbis, rabies, and neurotropic coronaviruses (3,11,46,(66)(67)(68)(69)(70). Sustained Ab output by local ASC provides a potent nonlytic mechanism of immune control potentially beneficial for a variety of neurotropic infections that are prone to persist.…”

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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“…Furthermore, oligoclonal IgG in the CSF during chronic infection as well as MS is consistent with local ASC enrichment (12,(73)(74)(75). B cells, including ASC, are also prominent in the CNS during experimental murine infections (2,10,20,76,77), where they appear to play a protective role (24,(76)(77)(78)(79). While CNS-resident ASC may also provide local immunity during human CNS infections (80)(81)(82)(83), the influence of other B cell subsets on disease progression in distinct neuroinflammatory infections is unclear.…”

Section: Discussionmentioning

confidence: 99%

Progression From IgD⁺IgM⁺to Isotype-Switched B Cells Is Site Specific during Coronavirus-Induced Encephalomyelitis

Phares

DiSano

Stohlman

et al. 2014

J Virol

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Various infections in the central nervous system (CNS) trigger B cell accumulation; however, the relative dynamics between viral replication and alterations in distinct B cell subsets are largely unknown. Using a glia-tropic coronavirus infection, which is initiated in the brain but rapidly spreads to and predominantly persists in the spinal cord, this study characterizes longitudinal changes in B cell subsets at both infected anatomical sites.

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“…IT immunization also increases the permeability of the blood‐brain barrier (BBB) and allows for the migration of effector cells into the CNS . The B lymphocytes infiltrating the CNS via up‐regulation of the chemokine CXCL12 are the source of locally produced antibodies important in the clearance RABV from the CNS . In addition, effector T lymphocytes infiltrating the CNS permit the clearance of RABV by inducing apoptosis of infected neurons in the presence of antibodies .…”

Section: Discussionmentioning

confidence: 99%

Survival of rabid rabbits after intrathecal immunization

et al. 2014

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Rabies is a fatal zoonotic disease for which no effective treatment measures are currently available. Rabies virus (RABV) has anti-apoptotic and anti-inflammatory properties that suppress nerve cell damage and inflammation in the CNS. These features imply that the elimination of RABV from the CNS by appropriate treatment could lead to complete recovery from rabies. Ten rabbits showing neuromuscular symptoms of rabies after subcutaneous (SC) immunization using commercially available vaccine containing inactivated whole RABV particles and subsequent fixed RABV (CVS strain) inoculation into hind limb muscles were allocated into three groups. Three rabbits received no further treatment (the SC group), three rabbits received three additional SC immunizations using the same vaccine, and four rabbits received three intrathecal (IT) immunizations, in which the vaccine was inoculated directly into the cerebrospinal fluid (the SC/IT group). An additional three naïve rabbits were inoculated intramuscularly with RABV and not vaccinated. The rabbits exhibited neuromuscular symptoms of rabies within 4–8 days post-inoculation (dpi) of RABV. All of the rabbits died within 8–12 dpi with the exception of one rabbit in the SC group and all four rabbits in SC/IT group, which recovered and started to respond to external stimuli at 11–18 dpi and survived until the end of the experimental period. RABV was eliminated from the CNS of the surviving rabbits. We report here a possible, although still incomplete, therapy for rabies using IT immunization. Our protocol may rescue the life of rabid patients and prompt the future development of novel therapies against rabies.

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Experimental intracerebral vaccination protects mouse from a neurotropic virus by attracting antibody secreting cells to the CNS

Cited by 9 publications

References 54 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

Progression From IgD⁺IgM⁺to Isotype-Switched B Cells Is Site Specific during Coronavirus-Induced Encephalomyelitis

Survival of rabid rabbits after intrathecal immunization

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Experimental intracerebral vaccination protects mouse from a neurotropic virus by attracting antibody secreting cells to the CNS

Cited by 9 publications

References 54 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

Progression From IgD+IgM+to Isotype-Switched B Cells Is Site Specific during Coronavirus-Induced Encephalomyelitis

Survival of rabid rabbits after intrathecal immunization

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Progression From IgD⁺IgM⁺to Isotype-Switched B Cells Is Site Specific during Coronavirus-Induced Encephalomyelitis