myelin-oligodendrocyte-glycoprotein-(35-55) and Neuromyelitis-Optica

Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system (CNS) mediated by antibodies to the water channel protein AQP4 expressed in astrocytes. The contribution of AQP4-specific T cells to the class switch recombination of pathogenic AQP4-specific antibodies and the inflammation of the blood-brain barrier is incompletely understood, as immunogenic naturally processed T-cell epitopes of AQP4 are unknown. By immunizing Aqp4

Topics: Animals; Aquaporin 4; Astrocytes; Autoantibodies; Autoimmunity; B-Lymphocytes; Clonal Deletion; Clone Cells; Epitope Mapping; Histocompatibility Antigens Class II; Humans; Immunodominant Epitopes; Immunoglobulin Class Switching; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin-Oligodendrocyte Glycoprotein; Neuromyelitis Optica; Peptide Fragments; Receptors, Antigen, T-Cell; Retina; Self Tolerance; T-Lymphocytes

Neuromyelitis optica (NMO) is a devastating inflammatory disorder of the optic nerves and spinal cord characterized by frequently recurring exacerbations of humoral inflammation. NMO is associated with the highly specific NMO-IgG biomarker, an antibody that binds the aquaporin-4 water channel. Aquaporin-4 is present on glial endfeet in the central nervous system (CNS). In humans, the NMO-IgG portends more frequent exacerbations and a worse long-term clinical outcome.. We tested the longer-term outcome of mice with EAE injected with NMO-IgG and followed them for 60 days. Clinical exams and pathology of the spinal cord and optic nerves were compared to mice that received control human IgG.. Passively transferred human NMO-IgG leads to more severe neurology disability over two months after onset of disease. Clinical worsening is associated with an increased concentration of large demyelinating lesions primarily to subpial AQP4-rich regions of the spinal cord.. NMO-IgG is pathogenic in the context of EAE in mice.

Topics: Animals; Antigens, CD; Antigens, Ly; Aquaporin 4; Demyelinating Diseases; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Immunoglobulin G; Mice; Mice, Inbred C57BL; Myelin Sheath; Myelin-Oligodendrocyte Glycoprotein; Neuromyelitis Optica; Optic Nerve; Peptide Fragments; Spinal Cord; Time Factors

The pathology of neuromyelitis optica (NMO), in contrast to multiple sclerosis, comprises granulocyte infiltrates along extensive lengths of spinal cord, as well as optic nerve. Furthermore, IFN-β treatment worsens NMO. We recently found that experimental autoimmune encephalomyelitis (EAE) induced with Th17 cells is exacerbated by IFN-β, in contrast to disease induced with Th1 where treatment attenuated symptoms.. This study demonstrates the similarities between NMO and Th17 EAE and how neutrophils mediate pathology in Th17 disease.. Levels of blood biomarkers in NMO were assessed by Luminex and ELISA. Effects of IFN-β on neutrophils were assessed by culture assays and immunofluorescence. EAE was induced by transfer of myelin-specific Th1 or Th17 cells and treated with Sivelestat sodium hydrate, a neutrophil elastase inhibitor.. We show Th17 cytokines, granulocyte chemokines, type 1 interferon and neutrophil elastase are elevated in patients with definitive NMO. In culture, we find that IFN-β stimulates neutrophils to release neutrophil elastase. In Th17 EAE, we demonstrate neutrophilic infiltration in the optic nerve and spinal cord which was not present in Th1 EAE. Blockade of neutrophil elastase with Sivelestat had efficacy in Th17 EAE but not Th1 EAE.. The similarities between Th17 EAE and NMO indicate that this model represents several aspects of NMO. Neutrophils are critical in the pathologies of both Th17-EAE and NMO, and therefore blockade of neutrophil elastase is a promising target in treating NMO.

Topics: Adolescent; Adult; Animals; Cells, Cultured; Encephalomyelitis, Autoimmune, Experimental; Female; Glycine; Glycoproteins; Humans; Interferon-beta; Male; Mice; Mice, Inbred C57BL; Middle Aged; Myelin-Oligodendrocyte Glycoprotein; Neuromyelitis Optica; Pancreatic Elastase; Peptide Fragments; Serine Proteinase Inhibitors; Sulfonamides; Th1 Cells; Th17 Cells; Young Adult