A study of classical and novel markers of disease in multiple sclerosis

[摘要] Multiple sclerosis (MS) is a chronic inflammatory and degenerative condition of the Central Nervous System. Focal demyelinating lesions are its neuropathological hallmark, but widespread abnormalities found in otherwise “normal-appearing” tissue are better associated with disability outcomes. HMGB1 is a promiscuous sensor of cellular stress, acting as a link between sterile damage and innate immune mechanisms, with its extra-nuclear release producing diverse outcomes.We report novel findings of significantly increased HMGB1 expression throughout the brain tissue of MS vs. non-MS patients, particularly in macrophages/microglia and oligodendrocytes (OGD). In addition, cerebrospinal fluid HMGB1 levels were increased in early-stage MS patients compared to non-inflammatory control patients. HMGB1 stimulation in-vitro upregulates expression of its receptors in an OGD cell line, potentially propagating chronic inflammation. Expression of the Leucine Rich Repeat and Ig-domain-containing molecules, AMIGO-3 and LINGO-1 is also significantly increased by HMGB1 stimulation in-vitro. These molecules demonstrate particularly intense immunoreactivity in human brain tissue taken at biopsy, at an early disease stage. Thus, exogenous HMGB1 may influence neurodegenerative processes via AMIGO-3 and LINGO-1 and blocking their function could have therapeutic value. Increased expression of HMGB1 in OGD, however, may highlight endogenous neuroprotective mechanisms in response to an unknown trigger.

[发布机构] University:University of Birmingham;Department:Institute of Immunology and Immunotherapy

[关键词] R Medicine;RC Internal medicine