Uloga B-stanica u etiopatogenezi i liječenju multiple skleroze

master's thesis

• Title (english): B cells in etiopathogenesis and treatment of multiple sclerosis
• Author: Tena Magovac
• Mentor: Tereza Gabelić (mentor)
• Committee member: Darija Mahović Lakušić (predsjednik povjerenstva)
• Committee member: Mario Habek (član povjerenstva)
• Committee member: Tereza Gabelić (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Neurology); Zagreb
• Defense date and country: 2020-09-11, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Neurology

Abstract

Multipla skleroza je tradicionalno bila smatrana bolešću posredovanoj T-stanicama. Imunomodulacijska terapija razvijena na ovoj osnovi utječe na smanjenje stope relapsa, ali ne može u potpunosti spriječiti pojavu relapsa i progresiju invalidnosti, te je uglavnom zanemarive djelotvornosti u primarno progresivnom obliku multiple skleroze. B-stanice ključna su sastavnica u patogenezi autoimunih neuroloških poremećaja i imaju važnu ulogu u regulaciji procesa aktivacije T-stanica, sekrecije citokina i stvaranja ektopičnih germinalnih centara u središnjem živčanom sustavu. Meningealne B-stanične strukture koje nalikuju germinalnim centrima važno su mjesto aktivacije B-stanica i njihova širenja u kroničnoj bolesti. Nakon prelaska krvno-moždane barijere, memorijske B-stanice podložne su stimulaciji antigenima, klonalnoj ekspanziji i diferencijaciji u plazma stanice koje izlučuju protutijela. Osim što je ciljni organ imunopatološkog procesa, središnji živčani sustav (SŽS) u bolesnika s neuroinflamacijom pruža jedinstvenu okolinu koja podržava dugotrajno preživljenje B stanične linije, osobito dugoživućih plazma stanica te lokalno stvaranje protutijela. Koncept deplecije B-stanica monoklonskim protutijelima koja prepoznaju specifični ciljni
CD20 antigen predstavlja potentno terapijsko riješenje, sa snažnim učinkom na progresiju bolesti i dokazanom učinkovitošću u primarno progresivnom obliku bolesti za koji do sada nije nađena adekvatna terapije. Klinička istraživanja nedvojbeno su pokazala da anti-CD20 monoklonska protutijela dovode do brze i trajne supresije upalne aktivnosti bolesti čak i nakon rekonstitucije B-stanica. Zabilježeno je smanjenje broja i stvaranja novih lezija SŽS-a i pridruženih kliničkih relapsa te je smanjena progresija onesposobljenosti. Osim toga, ranije uvođenje terapije može odgoditi razvoj progresivnih oblika bolesti. Terapija dodatno pokazuje obećavajući učinak u bolesnika s primarno progresivnim oblikom bolesti u kojih se primjećuje
značajno i produženo smanjenje progresije invalidnosti. Sigurnosni profil se s obzirom na dosadašnja ispitivanja čini povoljnim, međutim potrebno je dugotrajno praćenje kako bi se utvrdio rizik od neželjenih nuspojava, uključujući povećanu podložnost infekcijama ili povećan rizik obolijevanja od malignih bolesti.

Abstract (english)

Multiple sclerosis has traditionally been considered a T-cell mediated disease. Immunomodulatory therapy based on this theory reduces relapse rate but cannot completely prevent relapses or progression of disability and has generally negligible effect in the primary progressive form of the disease. B cells are crucial components of the pathogenesis of various autoimmune neurological disorders and play an important role in regulation of T cell activation, cytokine secretion and
formation of ectopic germinal centres in the central nervous system. B cell follicle-like structures in the cerebral meninges represent an important site of B cell activation and expansion in chronic disease. After crossing the blood-brain barrier, memory B cells are susceptible to stimulation by antigens, clonal expansion, and differentiation in plasma cells that secrete antibodies. Besides being the target of the immunopathological process, central nervous system in patients with inflammatory disease provides a unique environment that supports the long-term survival of B-lineage cells, notably long-lived plasma cells, and local antibody production. Concept of B cell depletion by monoclonal antibodies that recognize specific target, CD20 antigen, represents potent therapeutic solution, with a strong influence on disease progression and proven efficacy in progressive form of multiple sclerosis, currently treated unsatisfactorily. Clinical trials have undoubtedly showed that anti-CD20 monoclonal antibodies elicit prompt and sustained suppression of inflammatory disease activity even after B cell reconstitution. The clinical impact was reflected in a substantial reduction in number and formation of new CNS lesion, and associated clinical relapses; also, a reduction of disability progression is reported. Transition to progressive phase of the disease can be reaped by an early therapy initiation. Additionally, promising effect on primary progressive
multiple sclerosis was noted in terms of significant and sustained reduction of disability progression. Although the short-term safety profile appears favourable, long-term assessment of the safety profile of anti-CD20 monoclonal antibodies treatment is required in order to determine the risk of uncommon adverse effects, including PML or malignancies.

• Keywords: multipla skleroza; B-stanice; anti-CD20 monoklonska protutijela
• Keywords (english): multiple sclerosis; B cells; anti-CD20 monoclonal antibodies
• Language: croatian
• URN:NBN: urn:nbn:hr:105:908171
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2021-03-19 13:28:41