. The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination. Nat Neurosci. 2004 Jul;7(7):736-44. PubMed.

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  1. The idea that damage to axons might be prevented and/or repaired by augmenting the activity of myelin-derived inhibitors of neurite outgrowth is exciting. It opens the door to the development of new molecular targets. The contribution of an aberrant immune system has been the hallmark of several human diseases, such as systemic lupus erythematosus, autoimmune diabetes, myasthenia gravis, Alzheimer’s disease (AD), multiple sclerosis (MS), etc. Autoantibodies plague the host in a battle where the “good guys” end up doing more harm than good. This is especially true in cases where the autoantigen resembles an unrelated antigen through molecular mimicry or epitope spreading (intramolecular and intermolecular).

    Much excitement has arisen from the discovery of Nogo and its receptor, NgR. A quick literature search brings up several hundred publications on this topic since their discovery in 2000 and 2001, respectively. Nogo is an inhibitor of axonal outgrowth, and its receptor is widely expressed in the cells of the CNS. In this report, Karnezis et al. show that blocking the actions of Nogo A blunts clinical signs, demyelination, and axonal damage associated with experimental autoimmune encephalomyelitis (EAE), a model of MS. [It is interesting to note that Nogo B has a similar effect on PDGF-induced smooth muscle migration.] These workers suggestworkers suggest that Nogo A is an important determinant of the development of EAE, and that its blockade may help to maintain and/or restore the neuronal integrity of the CNS after autoimmune insult in diseases such as MS.

    First, the authors immunized EAE-susceptible mice with the CNS-specific Nogo (623-640) peptide and observed beneficial results by reducing the time of disease onset as well as the severity of the disease symptoms. Then they targeted Nogo A through vaccination of EAE mice and were able to suppress EAE. This effect may have occurred through the modulation of the auto-reactivity to MOG, which has been reported as a primary CNS-specific target antigen promoting primary demyelination, and which is highly auto-antigenic in MS.

    Therefore, antibodies against Nogo not only decrease the incidence and severity of EAE but also block disease progression and, hence, should be considered a potent therapeutic agent for EAE. Axon loss is an early and continuous feature of the MS pathological process. The presence of antimyelin antibodies in the serum has been suggested as a predictor of clinically defined MS after the first demyelinating event. In fact, anti-Nogo antibodies are present in patients with MS, but is more frequent and in greater amounts in individuals with mild disability status.

    Somewhere in the clinical plan, one will need to characterize 1) the antibody’s affinity and avidity, and 2) the integrity of the blood-brain barrier (BBB) of the patient. Immunologically targeting a single epitope or protein could be an exhaustive task when considering the extensive intra- and intermolecular epitope spreading reported in chronic EAE. Such extensive diversity and spreading not only suggests considerably broader autoimmune responses, but also hat the design for antigen-specific, "tolerizing" therapies may be difficult. Unfortunately, the diversity of autoimmune responses poses a huge challenge to the development of antigen-specific neutralizing therapies. Despite this, new approaches are certainly needed.

    The integrity of the BBB in the patient also deserves consideration to allow antibody passage into the CNS. Experimental models of CNS neurodegeneration typically studies whichuse pertussis toxin—the virulence factor of Bordella pertussis that causes the childhood disease whooping cough—to disrupt the integrity of the BBB and allow antibodies to penetrate into the CNS. (Interestingly, group B streptococcal infection can also thwart the normal protective role of the BBB, leading to serious CNS infection.) It is important to note that other recent studies have determined that some human antibodies derived from patient serum can promote myelin repair in disease models of demyelination. In fact, in immunohistochemical studies, the labeling pattern of these antibodies suggests that they co-localize with anti-MOG antibody, a known marker of oligodendrocytes. Although this study did not comment on the BBB, one must concede that the BBB must be compromised for vascular-derived antibodies to have CNS effects.

    I believe that molecular mimicry and a dysfunctional BBB may be common factors in several CNS diseases including MS and AD. Overall, this is exciting data. For a single antibody regimen to be successful in treating MS, one must consider epitope expansion and the BBB.

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