Measuring autoantigen-specific T cells as new diagnostic sensors and therapeutic targets in neuromyelitis optica (AspecT-NMO)

Abstract

Neuromyelitis optica spectrum disorders (NMOSD) form a rare group of severe antibody-mediated autoimmune diseases (AID) of the central nervous system, requiring lifelong therapy with potentially severe side effects. Aquaporin-4 (AQP4) has been identified as a specific target of autoantibodies in most NMOSD patients. AQP4-specific T cells are centrally involved in disease pathogenesis and chronification. They support the formation of anti-AQP-4-antibody-producing plasma cells and are required for disease transfer in animal models. Dynamic changes in autoreactive CD4 T cell activity in NMOSD may therefore explain why autoantibody levels do not correlate with clinical disease activity. Thus, autoreactive T cell characteristics should provide fundamental insight into disease etiology and allow for refined diagnosis, prognosis as well as personalized therapy of NMOSD. However, technical limitations so far prevented the characterization of AQP4-specific T cells and their NMOSD-associated quantitative, phenotypic or functional alterations. We have developed powerful technologies for the characterization of human effector- and regulatory autoantigen-specific CD4 T cells. In a proof of principle experiment we identified a unique and discriminative phenotype of AQP4-specific T cells in AQP4 antibody-positive but not -negative NMOSD patients. Our consortium also provides unique expertise to study T:B cell interaction, to determine the full spectrum of peptides recognized by selected TCR and to characterize patients microbiota. We propose to molecularly and functionally characterize autoreactive T cells and their interaction with B cells, as well as to define their self and foreign, e.g. microbiota-associated, peptide/MHC antigens as potential trigger of the pathogenic response. Integration of a biotech company will allow developing optimized analysis tools for their rapid application in basic research and clinical routine. Our project on autoreactive lymphocyte characteristics will thus make a pioneer contribution to the understanding of human AIDs, which will provide the basis for the future development of refined diagnostics, beyond mere antibody analysis, and for disease prognosis, monitoring as well as autoantigen-specific therapeutics. We anticipate that the results on disease-relevant T cell characteristics, which will be obtained using this human AID with well-characterized target autoantigens, will also reach out to other more frequent autoimmune diseases with less well-defined autoantigen targets, such as multiple sclerosis, type 1 diabetes or rheumatoid arthritis.