Preclinical stress originates in the rat optic nerve head during development of autoimmune optic neuritis

Abstract

Optic neuritis is a common manifestation of multiple sclerosis, an inflammatory demyelinating disease of the CNS. Although it is the presenting symptom in many cases, the initial events are currently unknown. However, in the earliest stages of autoimmune optic neuritis in rats, pathological changes are already apparent such as microglial activation and disturbances in myelin ultrastructure of the optic nerves. αB‐crystallin is a heat‐shock protein induced in cells undergoing cellular stress and has been reported to be up‐regulated in both multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Therefore, we wished to investigate the timing and localization of its expression in autoimmune optic neuritis. Although loss of oligodendrocytes was not observed until the later disease stages accompanying immune cell infiltration and demyelination, an increase in oligodendrocyte αB‐crystallin was observed during the preclinical stages. This was most pronounced within the optic nerve head and was associated with areas of IgG deposition. Since treatment of isolated oligodendrocytes with sera from myelin oligodendrocyte glycoprotein (MOG)‐immunized animals induced an increase in αB‐crystallin expression, as did passive transfer of sera from MOG‐immunized animals to unimmunized recipients, we propose that the partially permeable blood–brain barrier of the optic nerve head may present an opportunity for blood‐borne components such as anti‐MOG antibodies to come into contact with oligodendrocytes as one of the earliest events in disease development.

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

“…7d). Previous studies have also reported RGC loss prior to inflammatory infiltration, demyelination, or edema of the optic nerve [17, 55–57]. In line with reports by other authors [3], we found that early signs of RGC pathology precedes IRL thinning, suggesting that neuronal damage may occur, at least partially, independent of apparent inflammation.…”

“…Our study lacked a CFA-only control group to assess whether the effects of neuro-axonal degeneration observed are MOG-specific. However, previous studies assessing optic nerve and retinal pathology in autoimmune ON reported little to no difference between the CFA-only group and healthy controls in inflammatory pathology and neuro-axonal degeneration [2, 57]. Our results suggests that IRL changes in EAE are primarily influenced by pRNFL changes over time; yet previous OCT studies investigating pRNFL changes in EAE mice report contradictory findings [3, 32].…”

Matrine protects retinal ganglion cells from apoptosis in experimental optic neuritis

“…It has been shown that in ammatory responses play an important role in the development of ON (30), and optic nerve demyelination and in ltration have also been found to correlate with the severity of clinical disease in EAE mice (31). Among in ammatory cells, activated macrophages and microglia are the major cell types in ON that are closely associated with demyelination, axonal damage and loss of visual function (32).…”

Matrine protects retinal ganglion cells from apoptosis in experimental optic neuritis

“…It has been shown that inflammatory responses play an important role in the development of ON (29), and optic nerve demyelination and infiltration have also been found to correlate with the severity of clinical disease in EAE mice (30). Among inflammatory cells, activated macrophages and microglia are the major cell types in ON that are closely associated with demyelination, axonal damage and loss of visual function (31).…”