Distinctive sphingolipid patterns in chronic multiple sclerosis lesions

Abstract

Multiple sclerosis (MS) is a polyphasic immune-mediated disorder characterized by multifocal inflammatory infiltrates (T cells, B cells, and macrophages) within the CNS, with concomitant degradation of the myelin sheath, oligodendrocytes, and axons, along with reactive astrogliosis and activated microglia (1).Multiple areas of myelin loss within the CNS called "plaques" or "lesions" are the pathologic hallmark of MS.It is evident that MS lesions evolve differently during the early/acute versus the chronic phase of the disease, and within each phase, different plaque types occur in particular stages of activity (2).Furthermore, it is well-known that degradation of minor myelin proteins (myelin oligodendrocyte glycoprotein, myelin-associated glycoprotein, 2,3-cyclic-nucleotide 3-phosphodiesterase) denotes early active plaques, whereas the presence of major myelin proteins (proteolipid protein, myelin basic protein) indicates late active lesions.Inactive lesions are infiltrated by macrophages that lack myelin debris but may still contain empty vacuoles or periodic acid-Schiff-positive degradation products, the results of the macrophages' inability to digest the myelin neutral lipid components (2).As the plaque progresses from acute/active to chronic/inactive, its edema resolves, inflammation decreases, and macrophages and microglia gradually disappear.Astrocytes produce glial scars that fill the demyelinated plaque.These characteristics prompted Charcot to name these lesions as sclerotic plaques (3), appearing as a major autopsy finding in MS subjects.MS-related damage to CNS tissues has been found to include two main pathological processes: inflammatory myelin destruction (demyelination) and progressive irreversible axonal loss (neurodegeneration).The underlying pathology of the inflammatory component is generally believed to be associated with an autoimmune attack upon myelin antigens.However, extensive studies have not yet established the predominant target antigenic structures Abstract Multiple sclerosis (MS) is a CNS disease characterized by immune-mediated demyelination and progressive axonal loss.MS-related CNS damage and its clinical course have two main phases: active and inactive/progressive. Reliable biomarkers are being sought to allow identification of MS pathomechanisms and prediction of its course.The purpose of this study was to identify sphingolipid (SL) species as candidate biomarkers of inflammatory and neurodegenerative processes underlying MS pathology.We performed sphingolipidomic analysis by HPLC-tandem mass spectrometry to determine the lipid profiles in post mortem specimens from the normal-appearing white matter (NAWM) of the normal CNS (nCNS) from subjects with chronic MS (active and inactive lesions) as well as from patients with other neurological diseases.Distinctive SL modification patterns occurred in specimens from MS patients with chronic inactive plaques with respect to NAWM from the nCNS and active MS (Ac-MS) lesions.Chronic inactive MS (In-MS) lesions were characterized by decreased levels of dihydroceramide (dhCer), ceramide (Cer), and SM subspecies, whereas levels of hexosylceramide and Cer 1-phosphate (C1P) subspecies were significantly increased in comparison to NAWM of the nCNS as well as Ac-MS plaques.In contrast, Ac-MS lesions were characterized by a significant increase of major dhCer subspecies in comparison to NAWM of the nCNS.These results suggest the existence of different SL metabolic pathways in the active versus inactive phase within progressive stages of MS.Moreover, they suggest that C1P could be a new biomarker of the In-MS progressive phase, and its detection may help to develop future prognostic and therapeutic strategies for the disease.Supplementary key words brain lipids

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