Treatment with IgM-enriched intravenous immunoglobulins (IgM-IVIg) enhances clearance of stroke-associated bacterial lung infection

McCulloch, Laura; Harris, A.J.; Malbon, Alexandra; Daniels, Michael J.; Younas, Mehwish; Grainger, John; Allan, Stuart M.; Smith, Craig J.; McColl, Barry W.

doi:10.1101/2021.12.16.472965

Cited by 3 publications

(3 citation statements)

References 68 publications

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“…Their reconstitution with intravenous immunoglobulins (IgM-IVIg) experimentally prevents SAP and has no negative effect on neurological outcome. 195…”

Section: Long-term Sequelaementioning

confidence: 99%

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

Endres

Moro

Nolte

et al. 2022

Circulation Research

149

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Inflammation and immune mechanisms are crucially involved in the pathophysiology of the development, acute damage cascades, and chronic course after ischemic stroke. Atherosclerosis is an inflammatory disease, and, in addition to classical risk factors, maladaptive immune mechanisms lead to an increased risk of stroke. Accordingly, individuals with signs of inflammation or corresponding biomarkers have an increased risk of stroke. Anti-inflammatory drugs, such as IL (interleukin)-1β blockers, methotrexate, or colchicine, represent attractive treatment strategies to prevent vascular events and stroke. Lately, the COVID-19 pandemic shows a clear association between SARS-CoV2 infections and increased risk of cerebrovascular events. Furthermore, mechanisms of both innate and adaptive immune systems influence cerebral damage cascades after ischemic stroke. Neutrophils, monocytes, and microglia, as well as T and B lymphocytes each play complex interdependent roles that synergize to remove dead tissue but also can cause bystander injury to intact brain cells and generate maladaptive chronic inflammation. Chronic systemic inflammation and comorbid infections may unfavorably influence both outcome after stroke and recurrence risk for further stroke. In addition, stroke triggers specific immune depression, which in turn can promote infections. Recent research is now increasingly addressing the question of the extent to which immune mechanisms may influence long-term outcome after stroke and, in particular, cause specific complications such as poststroke dementia or even poststroke depression.

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“…Their reconstitution with intravenous immunoglobulins (IgM-IVIg) experimentally prevents SAP and has no negative effect on neurological outcome. 195…”

Section: Long-term Sequelaementioning

confidence: 99%

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

Endres

Moro

Nolte

et al. 2022

Circulation Research

149

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“…Mouse cytokines from microglial supernatants were measured using MILLIPLEX® multiplex assays as described previously (McCulloch et al , 2022). Briefly, MILLIPLEX MAP Mouse Cytokine/Chemokine Magnetic Bead Panel (MCYTOMAG-70K, Merck) was used to measure GM-CSF, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-12(p40), IL-33 and TNF-α.…”

Section: Methodsmentioning

confidence: 99%

Cystatin F(Cst7)drives sex-dependent changes in microglia in an amyloid-driven model of Alzheimer’s Disease

Daniels

Lefèvre

Szymkowiak

et al. 2022

Preprint

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Microglial endolysosomal (dys)function is strongly implicated in neurodegeneration. Transcriptomic studies show that a microglial state characterised by a set of genes involved in endolysosomal function is induced in both mouse Alzheimer's Disease (AD) models and in human AD brain and that the onset of this state is emphasized in females.Cst7(encoding protein Cystatin F) is among the most highly upregulated genes in these microglia. However, despite such striking and robust upregulation, the sex-specific function ofCst7in neurodegenerative disease is not understood. Here, we crossedCst7-/-mice with theAppNL-G-Fmouse to test the role ofCst7in a model of amyloid-driven AD. Surprisingly, we found thatCst7plays a sexually dimorphic role regulating microglia in this model. In females,Cst7-deficient microglia had greater endolysosomal gene expression, lysosomal burden, and amyloid beta (Aβ) burdenin vivoand were more phagocyticin vitro. However, in males,Cst7-deficient microglia were less inflammatory and had a reduction in lysosomal burden but had no change in Aβ burden. This study has important implications for AD research, confirming the functional role of a gene which is commonly upregulated in disease models, but also raising crucial questions on sexual dimorphism in neurodegenerative disease and the interplay between endolysosomal and inflammatory pathways in AD pathology.

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“…In the mouse model of stroke, this can improve the clearance of bacteria in SAP in the lungs. 105 Besides immunomodulation, preventive antibiotic therapy is an obvious approach to prevent SAP. In experimental stroke, this therapeutic approach reveals no difference in survival compared with standard treatment (initiation of antibiotic therapy after SAP diagnosis) but improves long-term functional outcome.…”

Section: Immunomodulatory Approaches To Prevent Stroke-associated Inf...mentioning

confidence: 99%

Immunodepression, Infections, and Functional Outcome in Ischemic Stroke

Westendorp

Dames

Nederkoorn

et al. 2022

Stroke

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Stroke remains one of the main causes of mortality and morbidity worldwide. Immediately after stroke, a neuroinflammatory process starts in the brain, triggering a systemic immunodepression mainly through excessive activation of the autonomous nervous system. Manifestations of immunodepression include lymphopenia but also dysfunctional innate and adaptive immune cells. The resulting impaired antibacterial defenses render patients with stroke susceptible to infections. In addition, other risk factors like stroke severity, dysphagia, impaired consciousness, mechanical ventilation, catheterization, and older age predispose stroke patients for infections. Most common infections are pneumonia and urinary tract infection, both occur in ≈10% of the patients. Especially pneumonia increases unfavorable outcome and mortality in patients with stroke; systemic effects like hypotension, fever, delay in rehabilitation are thought to play a crucial role. Experimental and clinical data suggest that systemic infections enhance autoreactive immune responses against brain antigens and thus negatively affect outcome but convincing evidence is lacking. Prevention of poststroke infections by preventive antibiotic therapy did not improve functional outcome after stroke. Immunomodulatory approaches counteracting immunodepression to prevent stroke-associated pneumonia need to account for neuroinflammation in the ischemic brain and avoid further tissue damage. Experimental studies discovered interesting targets, but these have not yet been investigated in patients with stroke. A better understanding of the pathobiology may help to develop optimized approaches of preventive antibiotic therapy or immunomodulation to effectively prevent stroke-associated pneumonia while improving long-term outcome after stroke. In this review, we aim to characterize epidemiology, risk factors, cause, diagnosis, clinical presentation, and potential treatment of poststroke immunosuppression and associated infections.

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Treatment with IgM-enriched intravenous immunoglobulins (IgM-IVIg) enhances clearance of stroke-associated bacterial lung infection

Cited by 3 publications

References 68 publications

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

Cystatin F(Cst7)drives sex-dependent changes in microglia in an amyloid-driven model of Alzheimer’s Disease

Immunodepression, Infections, and Functional Outcome in Ischemic Stroke

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