New roles for Fc receptors in neurodegeneration-the impact on Immunotherapy for Alzheimer's Disease - PubMed (original) (raw)

Review

New roles for Fc receptors in neurodegeneration-the impact on Immunotherapy for Alzheimer's Disease

James P Fuller et al. Front Neurosci. 2014.

Abstract

There are an estimated 18 million Alzheimer's disease (AD) sufferers worldwide and with no disease modifying treatment currently available, development of new therapies represents an enormous unmet clinical need. AD is characterized by episodic memory loss followed by severe cognitive decline and is associated with many neuropathological changes. AD is characterized by deposits of amyloid beta (Aβ), neurofibrillary tangles, and neuroinflammation. Active immunization or passive immunization against Aβ leads to the clearance of deposits in transgenic mice expressing human Aβ. This clearance is associated with reversal of associated cognitive deficits, but these results have not translated to humans, with both active and passive immunotherapy failing to improve memory loss. One explanation for these observations is that certain anti-Aβ antibodies mediate damage to the cerebral vasculature limiting the top dose and potentially reducing efficacy. Fc gamma receptors (FcγR) are a family of immunoglobulin-like receptors which bind to the Fc portion of IgG, and mediate the response of effector cells to immune complexes. Data from both mouse and human studies suggest that cross-linking FcγR by therapeutic antibodies and the subsequent pro-inflammatory response mediates the vascular side effects seen following immunotherapy. Increasing evidence is emerging that FcγR expression on CNS resident cells, including microglia and neurons, is increased during aging and functionally involved in the pathogenesis of age-related neurodegenerative diseases. Therefore, we propose that increased expression and ligation of FcγR in the CNS, either by endogenous IgG or therapeutic antibodies, has the potential to induce vascular damage and exacerbate neurodegeneration. To produce safe and effective immunotherapies for AD and other neurodegenerative diseases it will be vital to understand the role of FcγR in the healthy and diseased brain. Here we review the literature on FcγR expression, function and proposed roles in multiple age-related neurological diseases. Lessons can be learnt from therapeutic antibodies used for the treatment of cancer where antibodies have been engineered for optimal efficacy.

Keywords: ARIAs; Alzheimer's Disease; Fc receptors; auto-antibodies; cytokines; immunotherapy; neuroinflammation.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Activation or inhibition of a cell by Fc receptor ligation of IgG immune complexes. (A) Cross linking of activating FcγRs by IgG immune complexes results in the phosphorylation of cytoplasmic ITAM motifs. This allows the recruitment of SH2 domain containing kinases of the SYK family. These kinases activate pathways such as the RAS and PI3K pathways resulting in increased cellular calcium and activation of the cell. (B) The cross linking of an inhibitory receptor to an activating receptor results in the phosphorylation of an ITIM, leading to the recruitment of the phosphatase SHIP1. SHIP1 removes the 5'phopshate from PiP345 inhibiting downstream PI3K signaling, and also interacts with other adaptor proteins to inhibit other pathways. (C) Aβ binds with high affinity to the inhibitory FcγRIIb (_K_D = 5.67 × 10−8 M). Through an unknown signaling pathway, the ligation of Aβ causes the loss of FcγRIIb expressing neurons. (D) FcγRI possesses an extra immunoglobulin like domain compared to other FcγRs. This allows the high affinity binding of monomeric IgG, ligation of monomeric IgG by FcγRI expressing neurons, facilitating antibody uptake.

Figure 2

Figure 2

Mechanisms of Fc receptor mediated tissue damage in the CNS. (A) The proposed mechanism for inflammatory tissue damage to CNS vasculature and neurons after Anti-Aβ immunotherapy. Therapeutic antibodies penetrate the CNS and bind to deposits of Aβ in the parenchyma and around the blood vessels. Microglia express activating FcγR, and the antibody-Aβ immune complexes cause cross linking and FcγR activation. This results in a localized inflammatory response causing the vascular side effects observed in mice and humans. Furthermore soluble inflammatory mediators produced by this reaction may interfere with neuronal function or induce damage. (B) There is an emerging role for Fcγ receptors in neurodegeneration, with 3 different proposed mechanisms of Fc receptor mediated damage to neurons. (1) Inhibitory Fcγ receptor (FcγRIIb) expression has been detected on neurons, and FcRIIb binds Aβ with high affinity. The ligation of Aβ by neuronal FcRIIb results in neuronal death. (2) Autoantibodies against neurons are present in the sera of AD patients and also observed binding to neurons. This could lead to FcγR dependant neuronal loss through antibody dependent cellular cytotoxicity, caused by the ligation of activating Fcγ receptors on microglia. (3) Activating FcγR expression has been detected in certain models with neurodegenerative disease. Ligation of IgG by neuronal Fc receptors in mice results in neuronal loss.

Similar articles

Cited by

References

    1. Adolfsson O., Pihlgren M., Toni N., Varisco Y., Buccarello A. L., Antoniello K., et al. (2012). An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J. Neurosci. 32, 9677–9689 10.1523/JNEUROSCI.4742-11.2012 - DOI - PMC - PubMed
    1. Allsop D., Wong C. W., Ikeda S., Landon M., Kidd M., Glenner G. G. (1988). Evidence for the origin of cerebral amyloid in Alzheimer's disease drom A Beta protein precursor. Neuropathol. Appl. Neurobiol. 14, 254–255
    1. Andoh T., Kuraishi Y. (2004). Primary sensory neurons express the high affinity IgG Fc gamma RI receptor and responds to IgG-antigen complex. J. Pharmacol. Sci. 94, 74P 10.1096/fj.02-1169fje - DOI
    1. Bacskai B. J., Kajdasz S. T., McLellan M. E., Games D., Seubert P., Schenk D., et al. (2002). Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J. Neurosci. 22, 7873–7878 - PMC - PubMed
    1. Bard F., Cannon C., Barbour R., Burke R. L., Games D., Grajeda H., et al. (2000). Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916–919 10.1038/78682 - DOI - PubMed

Publication types

LinkOut - more resources