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Role of T cells in neuromyelitis optica

Neuromyelitis Optica (NMO), although previously characterized as a variant of multiple sclerosis (MS), is now recognized as a distinct central nervous system (CNS) autoimmune disease that primarily affects the optic nerve and spinal cord and is caused by autoantibodies directed against aquaporin-4 (AQP4). AQP4 is a CNS water channel that is abundantly expressed on astrocytes, and the distribution of NMO lesions in the optic nerve and spinal cord, where AQP4-Ig is deposited, can partly be explained by the anatomic localization of AQP4. AQP4 antibodies not only serve a pathogenic role but provide a sensitive biomarker by which NMO is diagnosed. Binding of AQP4-immunoglobulin (Ig) is associated with damage to astrocytes, and adoptive transfer of APQ4-IgG causes disease in animal models. The treatment of NMO consists of immune-based therapy that includes removal of pathogenic antibodies via plasma exchange and nonspecific immunosuppression with drugs such as azathioprine and mycophenolic acid. In addition, rituximab, a B cell-depleting antibody, has been reported to be of benefit in NMO. NMO may thus be considered an antibody-mediated autoimmune disease of the nervous system, analogous conceptually to myasthenia gravis, the classic autoimmune disease of the neuromuscular junction. The immune system acts in a coordinated fashion with the cooperation of cellular and humoral limbs. The APQ4 antibodies in NMO serum are IgG1, a subclass of IgG that requires help from T cells. This raises the question of the role of T cells in NMO, where antibodies appear to be pathogenic. In the current issue, Varrin-Doyer et al systematically examine T-cell reactivity to the AQP4 protein and identify a naturally processed immunodominant determinant of AQP4 (p61–80) that is recognized by CD4þ T cells from NMO patients. Furthermore, these cells have a Th17 polarization that is consistent with pathological findings in NMO, in which neutrophil infiltrates are increased. Interleukin-17 promotes neutrophil accumulation. What are the implications of finding T-cell reactivity to AQP4 in NMO? One of the major goals for treatment of autoimmune diseases is antigen-specific therapy, which is considered by some to be the holy grail of treating autoimmunity. The specificity of therapy would directly target pathogenic cells and would have little if any side effects, a major problem with chronic immunosuppressive therapy. The pathologic agent in an autoimmune disease is an autoreactive antibody or T cell. Although antibodies play a major role in NMO, these antibodies are dependent on T cells. T-cell reactivity to AQP4 has been described, but the current study for the first time provides a basis for antigen-specific therapy in NMO that targets T cells. The major current clinical use of antigen-specific therapy is allergy in which patients are desensitized to the offending allergen by parental injections. Is it possible to tolerize T cells by administering the autoantigen and affect an antibody-mediated disease? This indeed has been shown in the animal model of myasthenia gravis in which an orally administered peptide of the acetylcholine receptor ameliorated disease. Antigen-specific therapy to tolerize autoreactive T cells for the treatment of autoimmune disease in humans is being investigated, although it has yet to reach clinical practice. In addition to mucosal tolerance, there are multiple methods to induce antigen-specific tolerance. Examples include DNA vaccination, and a DNA vaccine encoding myelin basic protein has been tested in MS. Myelin basic protein peptides have also been administered epicutaneously in MS. Other methods include injection of antigencoupled cells and T-cell vaccination in which T cells specific for the autoantigen are injected. Furthermore, antigen-specific therapy is a major goal in type 1 diabetes, and initial results suggest there may be a benefit of oral insulin in delaying diabetes, presumably by tolerizing insulin-reactive T cells. The findings of Varrin-Doyer et al raise the possibility that one could use either the AQP4 protein or the AQP4 immunodominant peptide as a treatment for NMO. Treatment could be monitored by demonstrating a reduction in anti-AQP4 antibodies and a decrease in the Th17 immune response to AQP4. An important feature of NMO is that unlike MS, NMO is made worse by administration of beta interferon, a first-line drug for the treatment of MS. This may be related to the Th17 bias reported for NMO T cells, as Th17 responses are not well controlled by beta interferon. Of note, treatment of MS with rituximab, a B cell-depleting agent, is very effective in relapsing– remitting disease and appears to act not by affecting antibody levels, but by secondarily affecting T-cell responses