New roles for Fc receptors in neurodegeneration-the impact on immunotherapy for Alzheimer's disease

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 (A?), neurofibrillary tangles, and neuroinflammation. Active immunization or passive immunization against A? leads to the clearance of deposits in transgenic mice expressing human A?. 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-A? antibodies mediate damage to the cerebral vasculature limiting the top dose and potentially reducing efficacy. Fc gamma receptors (Fc?R) 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 Fc?R by therapeutic antibodies and the subsequent pro-inflammatory response mediates the vascular side effects seen following immunotherapy. Increasing evidence is emerging that Fc?R 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 Fc?R 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 Fc?R in the healthy and diseased brain. Here we review the literature on Fc?R 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

Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases

Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases

4- and 5-level anterior fusions of the cervical spine: review of literature and clinical results

In the future, there will be an increased number of cervical revision surgeries, including 4- and more-levels. But, there is a paucity of literature concerning the geometrical and clinical outcome in these challenging reconstructions. To contribute to current knowledge, we want to share our experience with 4- and 5-level anterior cervical fusions in 26 cases in sight of a critical review of literature. At index procedure, almost 50% of our patients had previous cervical surgeries performed. Besides failed prior surgeries, indications included degenerative multilevel instability and spondylotic myelopathy with cervical kyphosis. An average of 4.1 levels was instrumented and fused using constrained (26.9%) and non-constrained (73.1%) screw-plate systems. At all, four patients had 3-level corpectomies, and three had additional posterior stabilization and fusion. Mean age of patients at index procedure was 54 years with a mean follow-up intervall of 30.9 months. Preoperative lordosis C2-7 was 6.5° in average, which measured a mean of 15.6° at last follow-up. Postoperative lordosis at fusion block was 14.4° in average, and 13.6° at last follow-up. In 34.6% of patients some kind of postoperative change in construct geometry was observed, but without any catastrophic construct failure. There were two delayed unions, but finally union rate was 100% without any need for the Halo device. Eleven patients (42.3%) showed an excellent outcome, twelve good (46.2%), one fair (3.8%), and two poor (7.7%). The study demonstrated that anterior-only instrumentations following segmental decompressions or use of the hybrid technique with discontinuous corpectomies can avoid the need for posterior supplemental surgery in 4- and 5-level surgeries. However, also the review of literature shows that decreased construct rigidity following more than 2-level corpectomies can demand 360° instrumentation and fusion. Concerning construct rigidity and radiolographic course, constrained plates did better than non-constrained ones. The discussion of our results are accompanied by a detailed review of literature, shedding light on the biomechanical challenges in multilevel cervical procedures and suggests conclusions