Connexin 43 Astrocytopathy Linked to Rapidly Progressive Multiple Sclerosis and Neuromyelitis Optica

• Published in: PloS one Vol. 8; no. 8; p. e72919
• Main Authors: Masaki, Katsuhisa, Suzuki, Satoshi O., Matsushita, Takuya, Matsuoka, Takeshi, Imamura, Shihoko, Yamasaki, Ryo, Suzuki, Makiko, Suenaga, Toshihiko, Iwaki, Toru, Kira, Jun-Ichi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.08.2013; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Aged, 80 and over; Analysis; Antibodies; Aquaporin 4; Aquaporins; Astrocytes - pathology; Autoantibodies; Autoimmune diseases; Autoimmunity; Autopsies; Blood-brain barrier; Connexin 32; Connexin 43; Connexin 43 - blood; Connexin 43 - metabolism; Demyelination; Disease; Disease Progression; Fatalities; Female; Fluorescent Antibody Technique, Indirect; Gap junctions; Glycoproteins; Hospitals; Humans; Immunoglobulins; Lesions; Macrophages; Male; Medical research; Microscopy, Confocal; Middle Aged; Multiple sclerosis; Multiple Sclerosis - blood; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Myelin; Myelin-associated glycoprotein; Neurological diseases; Neurology; Neuromyelitis; Neuromyelitis optica; Neuromyelitis Optica - blood; Neuromyelitis Optica - metabolism; Neuromyelitis Optica - pathology; Neuropathology; Paralysis; Pathology; Patients; Proteins; Rodents; Spinal cord
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0072919

Multiple sclerosis (MS) and neuromyelitis optica (NMO) occasionally have an extremely aggressive and debilitating disease course; however, its molecular basis is unknown. This study aimed to determine a relationship between connexin (Cx) pathology and disease aggressiveness in Asian patients with MS and NMO. Samples included 11 autopsied cases with NMO and NMO spectrum disorder (NMOSD), six with MS, and 20 with other neurological diseases (OND). Methods of analysis included immunohistochemical expression of astrocytic Cx43/Cx30, oligodendrocytic Cx47/Cx32 relative to AQP4 and other astrocytic and oligodendrocytic proteins, extent of demyelination, the vasculocentric deposition of complement and immunoglobulin, and lesion staging by CD68 staining for macrophages. Lesions were classified as actively demyelinating (n=59), chronic active (n=58) and chronic inactive (n=23). Sera from 120 subjects including 30 MS, 30 NMO, 40 OND and 20 healthy controls were examined for anti-Cx43 antibody by cell-based assay. Six NMO/NMOSD and three MS cases showed preferential loss of astrocytic Cx43 beyond the demyelinated areas in actively demyelinating and chronic active lesions, where heterotypic Cx43/Cx47 astrocyte oligodendrocyte gap junctions were extensively lost. Cx43 loss was significantly associated with a rapidly progressive disease course as six of nine cases with Cx43 loss, but none of eight cases without Cx43 loss regardless of disease phenotype, died within two years after disease onset (66.7% vs. 0%, P=0.0090). Overall, five of nine cases with Cx43 loss and none of eight cases without Cx43 loss had distal oligodendrogliopathy characterized by selective myelin associated glycoprotein loss (55.6% vs. 0.0%, P=0.0296). Loss of oligodendrocytic Cx32 and Cx47 expression was observed in most active and chronic lesions from all MS and NMO/NMOSD cases. Cx43-specific antibodies were absent in NMO/NMOSD and MS patients. These findings suggest that autoantibody-independent astrocytic Cx43 loss may relate to disease aggressiveness and distal oligodendrogliopathy in both MS and NMO.