Type I Interferons and anti-DNA Antibodies in Neuromyelitis Optica

Neuromyelitis optica (NMO) is a severe devastating disease of the central nervous system (CNS). The dominating cell type in fresh NMO lesions are neutrophilic granulocytes, which by far outnumber other inflammatory cells like macrophages/activated microglia cells and T cells. Damage in NMO lesions is characterized by the deposition of aquaporin 4 (AQP4)-specific autoantibodies (found in the serum of up to 80% of all NMO patients) and of complement on astrocytes. This initiates a complement-mediated destruction of these cells, which forms the basis for secondary damage to myelin sheaths and axons. To date, a number of observations have been made, the relevance of which is currently completely unclear: 1. Although the AQP4-antibodies are highly specific and predictive for NMO, there is only a moderate/poor correlation between anti-AQP4 antibody titres and disease severity. 2. Several case reports suggest that NMO patients may deteriorate under treatment with the type I interferon IFN- beta. Unfortunately, these data are not backed up by controlled clinical studies, and the mechanisms responsible for the interferon beta effects are essentially unknown. 3. More than 40% of all AQP4-antibody positive NMO patients also have anti-DNA/anti-nuclear antibodies (ANAs, ENAs) in the serum, and the relevance of this finding for the disease process is currently completely unclear. We hypothesize that type I interferons and anti-DNA antibodies could further activate the granulocytes in NMO lesions and induce them to form neutrophilic extracellular traps consisting of potential tissue-destructive proteases and DNA, and that these neutrophilic products could initiate and propagate a vicious cycle of further granulocyte activation and tissue destruction. We propose to study this hypothesis in an animal model of NMO. Our results will clarify the interrelationship between type I interferons, anti-DNA antibodies and tissue destruction in an animal Model of NMO. They will reveal the underlaying mechanisms involved, and pave the way for better therapies of this disease.

Neuromyelitis optica (NMO) is a severe disease of the central nervous system (CNS). In the course of NMO, pathogenic antibodies against the water channel aquaporin 4 (AQP4) bind to astrocytes in the CNS and initiate their destruction, predominantly in spinal cord and optic nerves. We planned to clarify the significance of two observations for the disease process: Several different case reports suggested that treatment of NMO patients with type I interferons might be problematic. We addressed this point in experimental NMO and could show that it is a matter of timing whether treatment with type I interferons is harmful or beneficial. At the time when the spinal cord is affected by inflammation and astrocyte destruction, type I interferons are locally produced in this tissue and induce the production of protective interferon-stimulated proteins. When additional type I interferon injections were made, this protective effect was further enhanced, and the tissue damage in the spinal cord significantly reduced. More than 40% of all AQP4-antibody positive NMO patients have additional serum antibodies against DNA/nuclear material, and the relevance of this finding for the NMO-typical tissue destruction in the CNS was unclear. We addressed this point in experimental NMO and could show that the antibodies against DNA/nuclear material have no effect on the extent of tissue destruction. In the course of our project, an additional observation in the NMO field became important: It has been repeatedly described that AQP4 antibody positive NMO patients have also defects in the retina, and it was assumed that these defects are secondary consequences of the AQP4-antibody dependent tissue damage in the optic nerve. We also addressed this point in experimental NMO and showed that retinal damage can also occur independently from the AQP4-antibody-mediated astrocyte destruction in the optic nerve, and that T cells play an important role in this process.