A case for regulatory B cells in controlling the severity of autoimmune-mediated inflammation in experimental autoimmune encephalomyelitis and multiple sclerosis

Abstract

Multiple sclerosis (MS) is considered to be a T cell-mediated autoimmune disease that results in the presence of inflammatory lesions/plaques associated with mononuclear cell infiltrates, demyelination and axonal damage within the central nervous system (CNS). To date, FDA approved therapies in MS are thought to largely function by modulation of the immune response. Since autoimmune responses require many arms of the immune system, the direct cellular mechanisms of action of MS therapeutics are not definitively known. The mouse model of MS, experimental autoimmune encephalomyelitis (EAE), has been instrumental in deciphering the mechanism of action of MS drugs. In addition, EAE has been widely used to study the contribution of individual components of the immune system in CNS autoimmunity. In this regard, the role of B cells in EAE has been studied in mice deficient in B cells due to genetic ablation and following depletion with a B cell-targeted monoclonal antibody (mAb) (anti-CD20). Both strategies have indicated that B cells regulate the extent of EAE clinical disease and in their absence disease is exacerbated. Thus a new population of “regulatory B cells” has emerged. One reoccurring component of regulatory B cell function is the production of IL-10, a pleiotropic cytokine with potent anti-inflammatory properties. B cell depletion has also indicated that B cells, in particular antibody production, play a pathogenic role in EAE. B cell depletion in MS using a mAb to CD20 (rituximab) has shown promising results. In this review, we will discuss the current thinking on the role of B cells in MS drawing from knowledge gained in EAE studies and clinical trials using therapeutics that target B cells.

Regulatory B cells in autoimmune diseases

“…Importantly, in the absence of IL-10-producing B cells, mice are not able to recover from EAE. 60,64 In a recent study, fusokine GIFT15-induced Breg cells are shown to secrete IL-10 and express MHC I, MHC II, and surface IgM and IgD. Moreover, mice with EAE undergo complete remission after the intravenous transfer of GIFT15-Breg cells.…”

Role of B cells in the development of multiple sclerosis and experimental autoimmune encephalomyelitis

“…8,11,12 Rezultati ovog istraživanja su pokazali i da je intratekalna produkcija antitela relevantna za patofiziološke procese u razvoju MS, ali i da se obrasci oligoklonskih traka razlikuju među pacijentima. Taj podatak ukazuje da se kod obolelih razvija specifičan odgovor B limfocita ali jedinstven za svakog pacijenta.…”

“…Taj podatak ukazuje da se kod obolelih razvija specifičan odgovor B limfocita ali jedinstven za svakog pacijenta. 11,12 Oligoklonske trake nisu specifične za MS. Njihovo prisustvo se takođe može ustanoviti i kod infektivnih oboljenja CNS, kao što su neuroborelioza, herpes simplex enchephalitis, HIV infekcija ili subakutni sklerozirajući panencefalitis, pri čemu prisutna antitela specifično prepoznaju antigene koji učestvuju u nastanku bolesti. 8 Iako su intratekalna antitela predmet brojnih istraživanja već više decenija, njihov značaj u patogenezi, kao i njihova specifičnost, odnosno ciljni autoantigeni, još uvek nisu precizno definisani.…”

“…13 Među autoantigenima koji najverovatnije imaju ulogu u iniciranju i patogenezi bolesti, najznačajnije mesto zauzimaju proteini koji ulaze u sastav mijelinskog omotača: mijelinski oligodendrocitni glikoprotein (myelin oligodendrocyte glycoprotein, MOG), mijelinski bazni protein (myelin basic protein, MBP), proteolipid protein (proteolypid protein, PLP), glikoprotein udružen sa mijelinom (myelin-associated glycoprotein, MAG), fosfatidilholin i galaktocerebrozid (galactocerebroside, GalC), oligodendrocitni protein 2' , glijalni fibrilarni kiseli protein (glial fibrillary acidic protein, GFAP). 12,14,15 Ovoj grupi mogućih autoantigena treba dodati i molekule koji ne ulaze u sastav mijelinskog omotača kao što je αβ-kristalin, mali heatshock protein koji ima antiinflamatornu aktivnost. Antitela specifična za ovaj molekul su detektovana u likvoru pacijenata sa MS. 13 Intratekalno sintetisana antitela oligoklonskih traka u najvećoj meri pripadaju IgG klasi.…”

Humoral-Targeted Immunotherapies in Multiple Sclerosis

“…They also function as antigen-presenting cells, contribute to T-cell activation and produce effector cytokines that are considered modulators of the local immune environment. Recent evidence in MS also suggests a role in formation and maintenance of new lymphoid foci within the CNS [3].…”