IgM-Dependent Phagocytosis in Microglia Is Mediated by Complement Receptor 3, Not Fcα/μ Receptor

Weinstein, Jonathan R.; Quan, Yi; Hanson, Josiah F.; Colonna, Lucrezia; Iorga, Michael; Honda, Shinichi; Shibuya, Kazuko; Shibuya, Akira; Elkon, Keith B.; Möller, Thomas

doi:10.4049/jimmunol.1401195

Cited by 35 publications

(20 citation statements)

References 59 publications

(75 reference statements)

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“…GAP43 is important for the glutamate uptake activity in reactive astrocytes following LPS challenge [109] or ischemic conditions [21,69,107]. Additionally, TLR3 expression in astrocytes appears to be critical to the astrocytic response to IPC [110]. Thus, many of the molecular pathways implicated in LPS studies of astrocytic activation and response may overlap with findings in IPC-mediated astrocytic activation.…”

Section: Astrocytesmentioning

confidence: 99%

Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2016

Neurotherapeutics

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Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon in which a brief period of cerebral ischemia confers transient tolerance to subsequent ischemic challenge. Research on IPC has implicated cellular, molecular, and systemic elements of the immune response in this phenomenon. Potent molecular mediators of IPC include innate immune signaling pathways such as Toll-like receptors and type 1 interferons. Brain ischemia results in release of proand anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammtory response, resolution of inflammation, and transition to neurological recovery and regeneration. Cellular mediators of IPC include microglia, the resident central nervous system immune cells, astrocytes, and neurons. All of these cell types engage in cross-talk with each other using a multitude of signaling pathways that modulate activation/ suppression of each of the other cell types in response to ischemia. As the postischemic neuroimmune response evolves over time there is a shift in function toward provision of trophic support and neuroprotection. Peripheral immune cells infiltrate the central nervous system en masse after stroke and are largely detrimental, with a few subtypes having beneficial, protective effects, though the role of these immune cells in IPC is largely unknown. The role of neural progenitor cells in IPC-mediated neuroprotection is another active area of investigation as is the role of microglial proliferation in this setting. A mechanistic understanding of these molecular and cellular mediators of IPC may not only facilitate more effective direct application of IPC to specific clinical scenarios, but also, more broadly, reveal novel targets for therapeutic intervention in stroke.

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Section: Astrocytesmentioning

confidence: 99%

Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2016

Neurotherapeutics

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“…While this function was initially attributed to Fca/mR, it was recently shown that any phagocytosis may result as an extension of the complement cascade (via the opsonin C3 and complement receptor 3 on phagocytes). 21,99 Excluding the IgG class, IgM has the most extensive history of clinical use. One IgM antibody, nebacumab, was approved by several European countries in the early 1990s for the treatment of gram-negative sepsis, but it was subsequently withdrawn because of a variety of factors including high toxicity, high cost, and an inability to diagnose which cases of sepsis would be suitable for nebacumab use.…”

Section: Immunoglobulin Mmentioning

confidence: 99%

Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

184

154

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Keywords: antibody(s) antibody drug(s) antibody drug conjugate(s) (ADC) physicochemical properties pharmacokinetics monoclonal antibody(s) immunotherapy IgG antibody(s) drug design developability a b s t r a c t Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not only have the inherent ability to bind both antigens and endogenous immune receptors but also have proven extremely amenable to protein engineering. Thus, several derivatives of the monoclonal antibody format, including bispecific antibodies, antibody-drug conjugates, and antibody fragments, have demonstrated efficacy for treating human disease, particularly in the fields of immunology and oncology. Reviewed here are considerations for the design of antibody-based therapeutics, including immunological context, therapeutic mechanisms, and engineering strategies. First, characteristics of antibodies are introduced, with emphasis on structural domains, functionally important receptors, isotypic and allotypic differences, and modifications such as glycosylation. Then, aspects of therapeutic antibody design are discussed, including identification of antigen-specific variable regions, choice of expression system, use of multispecific formats, and design of antibody derivatives based on fragmentation, oligomerization, or conjugation to other functional moieties. Finally, strategies to enhance antibody function through protein engineering are reviewed while highlighting the impact of fundamental biophysical properties on protein developability.

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“…The complement system regulates the activation of mononuclear phagocytes. The binding of C1q or cleavage products of C3 with the complement receptors on mononuclear phagocytes produce inflammatory cytokines [126,127], and promote phagocytosis of pathogens or apoptotic cells [128][129][130][131].…”

Section: Inflammation Versus Resolutionmentioning

confidence: 99%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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IgM-Dependent Phagocytosis in Microglia Is Mediated by Complement Receptor 3, Not Fcα/μ Receptor

Cited by 35 publications

References 59 publications

Neuroimmune Response in Ischemic Preconditioning

Neuroimmune Response in Ischemic Preconditioning

Considerations for the Design of Antibody-Based Therapeutics

Microglia and Monocyte-Derived Macrophages in Stroke

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