2006 Rare Neuroimmunological Disorders Symposium; Sheraton Inner Harbor, Baltimore, MD, July 20-23, 2006

This conference on Rare Neuroimmunologic Disorders provided participants with a selective, yet broad, overview of research topics relevant to the understanding and treatment of a variety of neuroimmunologic disorders. The organizers insightfully chose to organize the presentations not by disease system, but according to mechanisms and stages of the disease process. These are the key issues to be elucidated in understanding the pathogenesis of each of the many diseases considered. The current paradigm of autoimmunity postulates that an initiating target antigen, exogenous or endogenous, is recognized by the immune system and triggers a cascade of effector mechanisms. New antigenic targets have been identified in the last 2 years, particularly those with associated autoantibodies. It is clear that some autoantibodies will be ultimately relegated to marker antibodies useful in diagnosis but not directly to the pathogenesis of the disease, but others may have led investigators to critical targets of the immune response. Certain cell surface receptors and channels, such as NMDA receptors in the case of paraneoplastic encephalitis, and aquaporin-4 for neuromyelitis optica, are promising as critical instigators of pathogenic immune responses. Detection of specific antibodies has identified a subgroup of patients with limbic encephalitis and NMO who are highly responsive to antibody depletion by plasma exchange. However, more work is required to establish these molecular targets as critical and pathogenically significant. Ultimately, identification of such specific antigens will provide the critical test for the success of antigen-tolerizing vaccines including plasmid-based DNA vaccination. Recognition is possible only in the context of appropriate presentation, and the genetic basis of immune recognition in terms of HLA has become increasingly recognized and is being fine mapped with enormous effort necessary to find informative individuals (e.g. African Americans with MS) that have broken the impasse generated by linkage disequilibrium that has confounded and obscured the understanding of HLA-antigen interaction; using these methods, DR and not DQ is becoming established as the critical class II HLA restriction element in MS. Effector responses lead to a variety of cellular reactions that cause direct or indirect tissue injury via soluble products. In addition to the known importance of cellular and antibody-based adaptive immunity, recent discoveries have increased our appreciation of the importance of the innate immune system, as manifest by the dominant cell in inflammatory infiltrates in MS, the microglia/macrophage. Furthermore, in both MS and HTLV-1 infection, the role of CD8 cells, dominant numerically over CD4 cells in MS and HTLV-1 associated myelopathy lesions is now established, as is the role of some of the mediators of tissue damage, including perforins, granzymes and cytokines. While many cytokines may cause tissue injury, the role of some seems to be greater than that of others. In some cases, selective immunodepletion of certain cytokines, such as of IL-6 in transverse myelitis, is effective; blockade of its downstream mediator, nitrous oxide, may be similarly effective. Blockade of effector pathways remains a promising treatment strategy, if the mechanism of immune injury is sufficiently specific. However, another emerging and important theme is the pleiotropic and often conflicting roles of immune mediators the final effects of which are dependent on dose, location and context. This has been known for TNF α, and was highlighted at this meeting for MMP-9 which is toxic to neurons and is correlated with increased gadolinium enhancement in MS, yet cleaves chemokines and is necessary for remyelination and neural stem cell function. Although previously recognized, much greater appreciation and effort have been placed in characterizing the endogenous compensatory mechanisms that downregulate the inflammatory response. Innate immune system activation may lead to downregulation of inflammation by generating neurotropic factors and otherwise downregulating inflammation. Another critical aspect of disease pathogenesis is the attempt of the host to compensate for the tissue injury, for example by spread of sodium channels in demyelinated axons. However, the inefficiency and lack of efficacy of repair was highlighted by defective mitochondrial function that may ultimately result in failure to control calcium influx with its attendant toxicity to neurons. Finally, another major theme that has emerged is heterogeneity in disease process between individuals depending on the dose and context of action of a mediator of inflammation. Sometimes, this heterogeneity has immunological correlates that may explain the pathogenesis, such as the emerging classification of inflammatory demyelinating polyneuropathies based in part on anti-ganglioside specificity. For some diseases such as MS, the heterogeneity is very complex; although the heterogeneity is not understood at a genetic level, the heterogeneity can be characterized immunopathologically such that, in some instances, the heterogeneity may predict response to treatment; for example, the immunopathologic detection of immunoglobulin and activated complement in brain tissue predicts a favorable response to plasma exchange in patients with acute attacks of MS. While the future is difficult to predict, elucidating targets of the immune response and characterizing the complexity of the immune processes will continue to dominate neuroimmunologic research. Molecular techniques will facilitate both approaches, though undoubtedly with increasing degrees of complexity mirroring the complexity of neuroimmunological disease. Continued interaction between scientists who study common mechanisms for disease and learn from one another will facilitate progress.