Uloga azot-monoksida u regulaciji ekspresije CXCL12 u eksperimentalnom autoimunskom encefalomijelitisu u pacova

Abstract

Multipla skleroza (MS) je hronična, inflamatorna, demijelinizirajuća i degenerativnabolest centralnog nervnog sistema (CNS), koja se najčešće javlja kod mlañih osoba.Smatra se da imunski sistem ima ključnu ulogu u patogenezi MS, odnosno da bolest nastajeusled autoimunskog odgovora usmerenog prema proteinima mijelinskog omotača. MS jeveoma raznolika bolest u svom kliničkom ispoljavanju, što je najverovatnije posledicarazličitih molekulskih mehanizama koji su uključeni u njenu patogenezu. Usled destrukcijemijelinskog omotača i degeneracije aksona neurona, dolazi do deficita u motornim,senzornim i kognitivnim funkcijama obolelih, koji mogu biti prolaznog ili trajnogkaraktera. Trenutnim terapijskim pristupima može se uticati na odlaganje pojave novihneuroloških ispada i može se usporiti hronično pogoršavanje stanja kod pacijenata, ali se neomogućava njihovo izlečenje.Eksperimentalni autoimunski encefalomijelitis (EAE) je najčešće korišćenieksperimentalni model za proučavanje patofiziologije MS. Upotreba ovog modela, kojioponaša autoimunsku patogenezu MS, dovela je do mnogih saznanja o mehanizmimaneuroimunoloških procesa, to jest, o prelasku imunskih ćelija iz krvotoka u CNS, onjihovoj interakciji sa lokalnim ćelijama glije i neuronima i o sledstvenoj inflamaciji, kaoistaknutom aspektu MS.Hemokini su citokini koji imaju ključnu ulogu u regulaciji migracije imunskih ćelijana mesto inflamacije prilikom odbrane organizma od patogena ili tokom patološkihimunskih procesa, poput MS. Hemokini najčešće stimulišu imunski odgovor privlačenjemćelija imunskog sistema na efektorska mesta, meñutim neki od njh ispoljavaju i regulatorneili antiinflamatorne uloge, poput CXCL12. CXCL12 deluje antiinflamatorno sprečavanjemprelaska autoreaktivnih imunskih ćelija iz perivaskularnog prostora u parenhim CNS-a,izazivanjem apoptoze autoreaktivnih T ćelija i stimulisanjem promene proinflamatornogkaraktera ovih ćelija u antiinflamatorni...

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating and degenerativedisease of the central nervous system (CNS) that occurs preferentially in young adults.Immune system plays a key role in its pathogenesis. It is considered that MS develops dueto an autoimmune response directed against myelin sheet components. MS is a veryheterogeneous disease in its clinical manifestations, which is most probably a consequenceof diverse molecular mechanisms involved in its pathogenesis. As a consequence of myelinsheet destruction and axonal degeneration, transient or permanent deficits in motor, sensoryand cognitive functions appear in MS patients. Therapies which are currently in usedecrease the frequency and the severity of acute attacks and slow down the rate ofneurological deterioration, but do not cure the patients.Experimental autoimmune encephalomyelitis (EAE) is the most widely usedexperimental model for studying pathophysiology of MS. The use of this model, whichmimics autoimmune pathogenesis of MS, led to many discoveries aboutneuroimmunological processes, such as egression of immune cells from the blood streaminto the CNS, immune cell interaction with resident glial cells and neurons and subsequentinflammation, as an important aspect of MS.Chemokines are cytokines with a central role in regulation of immune cell migrationat the site of inflammation during pathogen invasion and during pathological immuneprocesses, such as MS. Most often, chemokines boost immune response by attractingimmune cells at the effector sites. However, some chemokines, including CXCL12, exertregulatory or antiinflammatory roles. CXCL12 prevents egress of autoreactive immunecells from the perivascular space into the CNS parenchyma, induces autoreactive T cellapoptosis and stimulates shifting of proinflammatory phenotype of these cells towardsantiinflammatory phenotype...