Adrenergic-mediated loss of splenic marginal zone B cells contributes to infection susceptibility after stroke

McCulloch, Laura; Smith, Craig J.; McColl, Barry W.

doi:10.1038/ncomms15051

Cited by 58 publications

(108 citation statements)

References 68 publications

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“…As concerns BAFF, it is interesting to note that its secretion by splenic neutrophils can contribute to the activation of splenic MZ B cells and the acceleration of plasma cell generation (51,55). Moreover, BAFF administration to mice increases both the frequency of MZ B cells and antibody production (56,57) and constitutes a signal for both MZ B cell survival and differentiation into plasmablasts (47,(58)(59)(60)(61). Together with the fact that MZ B cells can favor the generation of plasma cells upon microbial infection (49), it is reasonable to speculate that BAFF induction in neutrophils of infected/treated mice may also favor the MZ B cell response and the subsequent generation of plasma cells.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils are essential for induction of vaccine-like effects by antiviral monoclonal antibody immunotherapies

Naranjo-Gómez¹,

Lambour²,

Piechaczyk³

et al. 2018

JCI Insight

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Using a mouse retroviral model, we have shown that mAb-based immunotherapy can induce life-long endogenous protective immunity (vaccine-like effects). This observation has potentially important consequences for treating life-threatening human viral infections. Here, we investigated the role of neutrophils in this effect. Neutrophils are innate immunity effector cells with well-established microbe-killing activities that are rapidly mobilized upon infection. They are also emerging as orchestrators of innate and adaptive immunities. However, their immunomodulatory activity during antiviral mAb immunotherapies has never been studied. Our data reveal that neutrophils have an essential role in immunotherapy-induced immune protection of infected mice. Unexpectedly, neutrophils have a limited effect in controlling viral propagation upon passive immunotherapy administration, which is mostly mediated by NK cells. Instead, neutrophils operate as essential inducers of a potent host humoral antiviral response. Thus, neutrophils play an unexpected key role in protective immunity induction by antiviral mAbs. Our work opens approaches to improve antiviral immunotherapies, as it suggests that preserving neutrophil functions and counts might be required for achieving mAb-induced protective immunity.

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Section: Discussionmentioning

confidence: 99%

Neutrophils are essential for induction of vaccine-like effects by antiviral monoclonal antibody immunotherapies

Naranjo-Gómez¹,

Lambour²,

Piechaczyk³

et al. 2018

JCI Insight

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“…Chemical ablation of hepatic catecholaminergic signals alleviates bacterial infection in this stroke mouse model (81). Catecholaminergic signaling also causes significant loss of splenic marginal zone B cells, which results in impaired IgM production and spontaneous bacterial infection in mice with stroke (82). Selective blocking of the β-adrenergic receptor signaling reverses the loss of the marginal zone B cells and suppression of circulating IgM levels, and significantly lowers bacterial burden (82).…”

Section: Functional Neuroanatomy For Communication With the Immune Symentioning

confidence: 99%

“…Catecholaminergic signaling also causes significant loss of splenic marginal zone B cells, which results in impaired IgM production and spontaneous bacterial infection in mice with stroke (82). Selective blocking of the β-adrenergic receptor signaling reverses the loss of the marginal zone B cells and suppression of circulating IgM levels, and significantly lowers bacterial burden (82). These findings have major implications for understanding the neural mechanisms of post-stroke immune dysregulation and increased susceptibility to bacterial infection (83–85).…”

Section: Functional Neuroanatomy For Communication With the Immune Symentioning

confidence: 99%

Molecular and Functional Neuroscience in Immunity

Pavlov

Chavan

Tracey

2018

Annu. Rev. Immunol.

333

320

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The nervous system regulates immunity and inflammation. The molecular detection of pathogen fragments, cytokines, and other immune molecules by sensory neurons generates immunoregulatory responses through efferent autonomic neuron signaling. The functional organization of this neural control is based on principles of reflex regulation. Reflexes involving the vagus nerve and other nerves have been therapeutically explored in models of inflammatory and autoimmune conditions, and recently in clinical settings. The brain integrates neuro-immune communication, and brain function is altered in diseases characterized by peripheral immune dysregulation and inflammation. Here we review the anatomical and molecular basis of the neural interface with immunity, focusing on peripheral neural control of immune functions and the role of the brain in the model of the immunological homunculus. Clinical advances stemming from this knowledge within the framework of bioelectronic medicine are also briefly outlined.

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“…Immunoglobulin M (IgM) is the predominant immunoglobulin isotype associated with early B cell antibody responses to infection by innate-like B cells which we have previously shown to be depleted after experimental stroke in mice 6, 8, 9 . Lower minimum concentrations of IgM were measured after stroke in comparison to non-stroke controls, and no difference was found between placebo and IL-1Ra treated patients.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown deficits in early antibody responses, particularly IgM, associated with innate-like B cells in both experimental animals and stroke patients that may contribute to post-stroke infection susceptibility 6 . Il-1β is reported to induce IgM production in innate-like B cells 7 , therefore treatment with IL-1Ra may inhibit these important anti-microbial effects.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1 receptor antagonist treatment in acute ischaemic stroke does not alter systemic markers of anti-microbial defence

McCulloch

Allan

Smith

et al. 2019

Preprint

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AimBlockade of the cytokine interleukin-1 (IL-1) with IL-1 receptor antagonist (IL-1Ra) is a candidate treatment for stroke entering phase II/III trials, which acts by inhibiting harmful inflammatory responses. Infection is a common complication after stroke that significantly worsens outcome and is related to stroke-induced deficits in systemic immune function thought to be mediated by the sympathetic nervous system. Therefore, immunomodulatory treatments for stroke, such as IL-1Ra, carry a risk of aggravating stroke-associated infection. Our primary objective was to determine if factors associated with antibody-mediated antibacterial defences were further compromised in patients treated with IL-1Ra after stroke.MethodsWe assessed plasma concentrations of immunoglobulin isotypes and complement components in stroke patients treated with IL-1Ra or placebo and untreated non-stroke controls using multiplex protein assays. Activation of the SNS was determined by measuring noradrenaline, a major SNS mediator.ResultsThere were significantly lower plasma concentrations of IgM, IgA, IgG1 and IgG4 in stroke-patients compared to non-stroke controls, however there were no differences between stroke patients treated with placebo or IL-1Ra. Concentrations of complement components associated with the classical pathway were increased and those associated with the alternative pathways decreased in stroke patients, neither being affected by treatment with IL-1Ra. Noradrenaline concentrations were increased after stroke in both placebo and IL-1Ra-treated stroke patients compared to non-stroke controls.ConclusionThese data show treatment with IL-1Ra after stroke does not alter circulating immunoglobulin and complement concentrations, and is therefore unlikely to further aggravate stroke-associated infection susceptibility through reduced availability of these key anti-microbial mediators.

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Adrenergic-mediated loss of splenic marginal zone B cells contributes to infection susceptibility after stroke

Cited by 58 publications

References 68 publications

Neutrophils are essential for induction of vaccine-like effects by antiviral monoclonal antibody immunotherapies

Neutrophils are essential for induction of vaccine-like effects by antiviral monoclonal antibody immunotherapies

Molecular and Functional Neuroscience in Immunity

Interleukin-1 receptor antagonist treatment in acute ischaemic stroke does not alter systemic markers of anti-microbial defence

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