We study NMO, a severe inflammatory disease of the central nervous system (CNS), which is characterized by the formation of large astrocyte-destructive lesions, mostly in the spinal cord and in the optic nerves of affected patients. Most patients harbor pathogenic auto-antibodies, the so-called NMO-IgGs, in their serum. These antibodies are directed against the water channel aquaporin 4 (AQP4), which is found on astrocytes in the CNS. When these antibodies gain access to the brain, they bind to AQP4 on the surface of astrocytes and initiate complement-mediated, antibody-dependent destruction of these cells. We already know a lot about the mechanisms causing tissue injury, but we are essentially ignorant about the many little steps before the disease becomes clinically overt. We know that in both diseases, T cells and antibodies are found in the CNS, but we do not know what the T cells recognize, and why they became activated to enter the CNS. Likewise, in NMO, we know that most autoantibodies recognize the water channel aquaporin 4 in the CNS, but we do not know how they escaped from tolerance and are formed in the first place. We also do not know why these antibodies prefer certain sites of the CNS for entry. These are the questions my group tries to resolve.
We recently found a way to 'trick' the immune system with mimicking peptides and could establish experimental models which produce aquaporin 4-specific autoantibodies ? the pathogenic antibodies causing astrocyte damage in NMO. With these models we now study the events in the immune system prior to disease outbreak
In NMO patients and in experimental models, aquaporin 4-specific autoantibodies have predilection sites for entry. We currently study the mechanisms underlying this observation in more detail.
To address these questions, we use archival tissue sections from patients which have died decades ago, at a time when there were no treatments available yet to modify or improve their disease. We currently use next generation sequencing to identify the antibody molecules found in these brain sections, reconstruct functional antibodies from this information, and test antigen recognition and pathogenicity of the resulting antibodies.
Some patients develop NMO years after they have been diagnosed with myastenia gravis (MG). This is a very interesting coincidence, since NMO is a disease of the CNS, while MG is an autoimmune disease of the PNS affecting the neuromuscular end plate. However, in some circumstances, also muscles of patients with NMO or of experimental NMO models are targeted by antibodies and T cells. We currently analyze whether muscle inflammation leads to the liberation and/or better presentation of proteins which may serve as additional targets for the immune system, and whether this mechanism causes the ?switch? between these two different autoimmune diseases.
