Uloga B stanica u patogenezi i terapiji multiple skleroze

Multiple sclerosis (MS) is an autoimmune disorder that targets myelin sheaths in the central nervous system. It is a chronic disorder and although the axonal damage is initially reversible, at later stages it eventually results in neuroaxonal loss. It has a wide range of symptoms including sensory, autonomic nervous system, motoric and cognitive problems. It affects over 2.5 million people in the world, and starts in most patients at 20 to 40 years of age. MS is a multifactorial disease, with both genetic and environmental factors playing a role in its pathogenesis. Based on its clinical course it is categorized into four types: relapse-remitting, secondary progressive, primary progressive, and progressive relapsing MS. There is still no definite cure for MS, and all current therapies work solely by alleviating symptoms and the severity of the disease. The immune system plays a key role in MS. Autoreactive CD4+ T cells in the periphery are accepted as the most likely cause of the disease, although the triggering mechanisms for their activation are still unclear. Microglia and macrophages have both pro- and antiinflammatory effects in MS, whereas the natural killer cells have been shown to have a regulatory role and could suppress the autoreactive CD4+ T cells. B cells have been extensively studied in MS in recent years, and were found to play an important role in its pathogenesis and course, thus presenting an attractive therapeutic target. Oligoclonal immunoglobulin bands in the cerebrospinal fluid are produced by B cells and are found in over 95% of MS patients. B cells also act as antigen-presenting cells to T cells, and secrete cytokines which can be either pro-inflammatory or anti-inflammatory. In this thesis we will elaborate on the pathogenesis of MS and review MS therapies, all of which target the immune system. Specifically, we will list and compare the traditional therapies such as interferon-β and glatiramer acetate, which are still the first-line therapy for MS, with second- and third-line therapies that include various B cell-targeting approaches. With a higher efficacy than older therapies and a smaller risk of serious side effects, B cell-focused therapies are proving to be the future of MS treatmentMultipla skleroza (MS) je kronični autoimuni poremećaj koji pogađa mijelinske ovojnice u središnjem živčanom sustavu. U ranijim stadijima aksonalna šteta je reverzibilna, ali u kasnijima dolazi do neuroaksonalnog gubitka. Ima širok spektar simptoma uključujući probleme u senzornom, autonomnom živčanom i motoričkom sustavu, kao i kognitivne poteškoće. Više od 2,5 milijuna ljudi u svijetu boluje od ove bolesti, a u većine pacijenata započinje u dobi od 20 do 40 godina. MS je multifaktorijalna bolest u čijoj patogenezi ulogu imaju i okolišni i genetski faktori. Na temelju kliničkog tijeka, MS je kategorizirana u četiri tipa: relapsno-remitirajuća, sekundarno progresivna, primarno progresivna i progresivno relapsirajuća. Još uvijek ne postoji definitivni lijek za MS i sve trenutno dostupne terapije samo umanjuju simptome. Imuni sustav igra ključnu ulogu u ovoj bolesti. Autoreaktivne CD4+ T stanice na periferiji su prihvaćene kao najvjerojatniji uzrok bolesti, iako mehanizmi njihove aktivacije još uvijek nisu jasni. Mikroglija i makrofagi imaju i proupalne i protuupalne učinke u MS-u. NK stanice imaju regulatornu ulogu i mogle bi utišati autoreaktivne CD4+ T stanice. Posljednih godina B stanice su opsežno istraživane i pokazalo se da igraju bitnu ulogu u patogenezi i tijeku MS-a te ih to čini dobrom terapijskom metom. B stanice proizvode oligoklonalne vrpce imuoglobulina koje se nalaze u preko 95% pacijenata. B stanice su također antigen-prezentirajuće stanice T stanicama, te proizvode citokine koji imaju ili proupalni ili protuupalni učinak. U ovom završnom radu bit će pojašnjena patogeneza MS-a i opisane terapije za MS. Sve terapije za MS djeluju na imunosni sustav. Tradicionalne terapije poput glatiramer acetata i interferona-β usporedit će se s novijim terapijama koje na neki način djeluju na B stanice. Zbog veće učinkovitosti od starijih terapija i manjeg rizika od ozbiljnih nuspojava, terapije fokusirane na B stanice su se pokazale kao budućnost tretiranja MS-a