The mission of the Neuroimmunological Diseases Section of the National Institute of Allergy and Infectious Diseases that I lead is to understand, diagnose, prognosticate, and cure neuroimmunological diseases. Through understanding of the mechanisms that participate in central nervous system (CNS) injury and those that have neuroprotective functions, we aim to develop effective therapies for neuroimmunological diseases. Because observational studies cannot determine causal relationships, we use interventional trials supported by biomarker/mechanistic studies to investigate major hypotheses about the pathophysiology of MS. Our guiding principle is methodological rigor, including independent validation cohorts, to assure reproducibility of our results.
Our studies revealed that relapsing-remitting MS (RRMS) and progressive MS are categorical descriptions of early versus evolved stages of the identical continuous disease process characterized by aberrant activation of adaptive but also innate immunity in CNS tissue, which evolves by progressive intrathecal compartmentalization and terminal differentiation of lymphocytes to a treatment-resistant stage. The multiplicity of potential pathogenic processes in evolved MS makes high efficacy of a single therapy unlikely. Analogous to cardiovascular diseases, effective therapy will require combinations of therapeutics that target patient-specific drivers of disability. We believe that the development of such combination treatments requires the ability to reliably measure the diverse CNS pathophysiological processes in living people and thereby define process-specific biomarkers for identification of therapeutic targets and to use as outcomes in Phase II trials. Indeed, using CSF biomarkers and systems biology methodology we have defined (and validated in independent cohorts) molecular signature(s) that differentiate MS from other CNS diseases and those that can reliably measure the levels of intrathecally compartmentalized inflammation and CNS tissue destruction. Our goal is to formulate (and validate) a framework where a combinatorial CSF biomarker(s) can provide reliable diagnostic, prognostic, and therapeutically predictive information that will empower neurologists to practice precision medicine.