CC BY
15mediterranean journal
of RHEUMATOLOGY
EAAHNIKH PEYMATQAOriA
26 1
2015
BPAXEIA ANAXKOnHIH REViEW
Ta PuÖMiöTiKa B XeMQoKUTiapa avoiyouv veeq oipainYiKSQ öepaneiaq oe auioavooa voonMaia
AaZapoq I. laKKäq, MD, DM, PhD, ABavaoioq MaupönouXoq, PhD, AnMHipioq n. MnöYÖavoq, MD, PhD PeuMaToXoYiKn KXiviKn, laipiKö TpHMa, ZxoXn EnioinM^v Yyelaq, navenioirpo OeooaXlaq
nEPIAHYH
Ta puBpiöTiKa B XeMQoKUTiapa naiZouv onpaviiKö pöXo oinv KaiaoioXn QXeYMovüöouQ
avooiaKHQ aviiöpaonQ Kai oinv avaoioXn auioavoonQ vöoou. Ze avBpünouQ pe ouoinpaiira epuBnMaiwön Xuko Kai ANCA aYYeimöa, n XeiToupYia iwv pu0MiöTiKÜv B XeMQoKuiiapwv eivai Meiwpevn. Ze neipaMaiiKa povieXa, n ex vivo avaniu^n pu0MiöTiKÜv B XeMQoKuiiapwv Kai n enavaxopnYnon oia neipaMaiöZwa KaiaoieiXe eYKaieoinpevn auioavoon vöoo. Auiö avoiYei to öpöpo Yia veeq BepaneuiiKSQ oipainYiKSQ oe avBpüniveQ auioavooeq vöoouq.
Mediterr J Rheumatol 2015; 26(1): 64-67
Ynsu8uvoq aAAr|Aoypa0iac;
Ka8nvnTnQ AäZapoQ I laKKäq
PeupaxoAoyiKn KAiviKii, laTpiKÖ TMHMa,
ZxoAq EniCTTHM^v YyeiaQ,
naveniCTTHMio QeaaaAiaq
BiönoAiQ 41110, AäpiCTa
TnA +241350 2813, Fax: +2413501016,
email:lsakkas@med.uth.gr
Corresponding author:
Professor Lazaros I. Sakkas
Department of Rheumatology
Faculty of Medicine, School of Health Sciences,
University of Thessaly and University
General Hospital of Larissa
Biopolis 41110, Larissa
Tel:+241350 2813, Fax:+241350 1016,
email:lsakkas@med.uth.gr
Ae^eiQ-KXeiöiä: PuGmiotikö B XeMQoKUTiapo, B XeMQoKUTiapo, auioavooia
Regulatory B cells open new therapeutic strategies for autoimmune diseases
Lazaros I. Sakkas, MD, DM, PhD, Athanasios Mavropoulos, PhD, Dimitrios P. Bogdanos, MD, PhD Department of Rheumatology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Greece
ABSTRACT
Regulatory B cells (Bregs) play a significant role in suppressing proinflammatory immune responses and preventing autoimmunity. In human systemic lupus erythematosus and ANCA vascuitis, Bregs may be defective. Ex vivo expansion of Bregs and readministration to experimental animals suppressed experimental autoimmune diseases. This opens the way for new therapeutic strategies in human autoimmune diseases.
Mediterr J Rheumatol 2015; 26(1): 64-67
Keywords: Systemic sclerosis, treatment, methotrexate, bosentan, digital ulcer, scleroderma renal crisis
TA PY0MITIKA B AEMOOKYTTAPA ANOIROYN NEEI ITRATHRIKEX QERAnElAI IE AYTOANOIA NOIHMATA REGULATORY B CELLS OPEN NEW THERAREUTiC STRATEGiES FOR AUTOiMMUNE DiSEASES
ElZAmrH
Ta B Aep^oKuirapa (B KuTTapa) onwQ Kai Ta T Aep-0OKUTTapa exouv Tnv iKavoTnTa va avaYvwpiZouv avTiYova Ka9eva xwpioTa peow eiSiKou unoSoxea tou avTiYovou (B cell receptor, BCR), Kai anoTeAouv pepoQ tou eniKTHTou avooiaKou ouoTHpaToQ. napa-Youv avTiowpaTa, KuTTapoKiveQ aAAa Kai exouv Tnv iKavoTHTa va napouoiaZouv avTiYova oe T Aep0oKuT-Tapa, SnAaSH va Spouv wq avTiYovonapouoiaoTiKa KUTTapa. Me Tr|v e^eAi^n oe nAaopaTOKuirapa Kai Tnv napaYwYH avTiowpaTwv, Ta B KuTTapa naiZouv Ka9opioTiKo poAo oTnv apuva tou opYaviopou oe na-9oy6vouq piKpo-opYaviopouQ. 'OpwQ pnopei va oup-Pei uneppeTpn SieYepon twv B Aep^oKuirapwv ano auToavTiYovo Kai napaYwYH avTiowpaTwv evavTi tou iSiou tou opYaviopou (auToavTiowpaTa). Auto ovo-paZeTai auToavooia Kai pnopei va oSnYHoei oe iotikh PAaPn (auToavoon vooo). ria Ta T Aep0oKuTTapa yvw-piZope 6Ti unapxouv opiopeva T KuTTapa nou ovopa-ZovTai pu9pioTiKa T KuTTapa (T regulatory cells, Tregs) Ta onoia KaTaoTeAAouv Tnv uneppeTpn evepYonoinon twv auToSpaoTiKwv T Aep0oKuTTapwv. Ta TeAeuTaia xpovia exouv avaYvwpio6ei pu9pioTiKa B Aep0oKuT-Tapa (regulatory B cells, Bregs) Ta onoia exouv onpa-vtiko poAo oTnv KaTaoToAH 0AeYpovwSouQ avooiaKHQ anavTnonQ Kai npoAn^nQ auToavooiaQ.
PuGpioTiKd B AeM^OKurxapa
Ta Bregs anoTeAouv piKpo nooooTo twv B Aep0o-KuTTapwv oto nepi0epiK6 aipa oe av9pwnouQ Kai novTiKia Kai KaTaoTeAouv Tnv 0AeYpovwSn avooi-aKH anavTnon peow napaYWYHQ ivTepAeuKivnQ 10 (interleukin-10, IL10) Kai YiauTo exouv to ovopa B10 cells 1. THpepa, to xapaKTnpioTiKo nou opiZei Ta Bregs eivai n evSoKuTTapia napaYwYH IL-10. Ta Bregs nou napaYouv IL-10 otouq av9pwnouQ exouv KupiwQ to 0aivoTuno CD19+CD24hiCD38hi Kai eivai YvwoTa wq immature/transitional B cells (transitional Bregs), Kai to 0aivoTuno CD19+CD24hiCD27+ Kai eivai YvwoTa wq memory Bregs 1-5. (EiKova). H avanTu^n twv B10 KuTTapwv eniTuYxaveTai pe SieYepTeQ TnQ eniKrnTnQ avooiaQ. Te novTiKia, exei onpaoia n onpaToSoTnon peow tou BCR, a0ou eAAei^n tou CD19, nou au^a-vei Tn onpaToSoTnon peow tou BCR, exouv peYaAn eAaTTwon twv B10 KuTTapwv. Bregs pe napaYwYH IL-10 avanTuooovrai Kai pe aAAa epe9iopaTa tou eniKTnTou avooiaKou ouoTHpaToQ, onwQ CD40- and IL-21-SiapeooAaPoupeva oHpaTa ano CD4+ T KuTTapa. B10 KuTTapa avanTuooovTai Kai ano epe9i-opaTa tou ep0uTou avooiaKou ouoTHpaToQ, onwQ lipopolysaccharide (LPS) Kai oAiYovouKAeoTiSia CpG (peow tou toll-like receptor 9, TLR9) 6-8. H napaYwYH IL-10 ano Ta B KuTTapa uoTepa ano CpG SieYep-TeQ anaiTei ev noAAoiQ Tnv evepYonoinon TnQ oSou p38MAPK 9 Kai STAT3 10.
Qotooo, o aKpiPHQ opiopoQ twv KaTaoTaATiKwv B KuTTapwv eivai ZHTnpa e^eAiooopevo. Etoi, exouv nepiYpa-0ei Bregs nou napaYouv IL-10 oe KuTTapa pe to 0aivo-Tuno CD25hiCD71hiCD73- 11, H CD19+CD1dhiCD5+ 12 13, H CD25hiCD27hiCD86hiCD1dhiTGFphi 14. H kut-TapoKivn 35 (IL-35) enionQ npoKaAeoe Tnv avanTu^n Kai noAAanAaoiaopo Bregs (IL-35+Bregs), nou napaYouv IL-35 Kai IL-10 8 15.
KaTaoTaATiKn Spdon twv PUGMIOTIKWV B Aep^o-KUTTdpwv
Ta Bregs, poAovoTi anoTeAouv piKpo nooooTo twv B KuTTapwv oe av9pwnouQ Kai novTiKouQ, naiZouv onpavTiKo avooopu9pioTiK6 poAo oTnv auToavooia. Ta Bregs KaTaoTeAAouv Tn 0AeYpovH Kai auToavooia oe ZwiKa povTeAa, KaTaoTeAAovTaQ tiq Th1 Kai Th17 avooiaKeQ anavTHoeiQ 16. Ta B10 eivai enionQ ioxupoi pu6pioTeQ TnQ AeiToupYiaQ twv SevSpiTiKwv KuTTapwv Kai twv paKpo0aYwv oe novTiKia Kai av-6pwnouQ 5. H ex vivo avanTu^n (pe napaYwYH IL-10) Kai o noAAanAaoiaopoQ B10 KuTTapwv Kai oTn ouve-xeia n enavaxopHYnon touq oe novTiKouQ pe neipa-paTiKH auToavoon eYKe0aAopueAiTi6a (experimental autoimmune encephalomyelitis, EAE) KaTaoTeiAe on-pavTiKa Ta oupnTwpaTa touq 7. Te novTiKouQ, B10 KuTTapa nou napaYouv IL-10 KaTaoTeAAouv Tnv npo-KaAoupevn pe KoAAaYovo ap9piTi5a, KaTaoTeAAovTaQ Tn avanTu^n Th17 KuTTapwv 17. TTn xpovia vooo pooxeupaToQ evavTi ^evioTH (chronic graft-versus host disease, cGVHD), eva Zwiko povTeAo ouoTnpa-tikhq oKAHpuvonQ, H npwipn enavep^avion B10 KuTTapwv KaTaoTeiAe Tn cGVHD 18. Te av6pwnouQ, Ta transitionsl CD19+CD24hiCD38hi Bregs Kai memory CD19+CD27+ Bregs KaTaoTeAAouv pe Soooe^apTw-pevo Tpono Tnv napaYwYH ivTep0epovnQ-Y ano Ta CD4+ TKuTTapa peow IL-10 Kai peow SiaKuTTapiKHQ ena0HQ 19.
To Glatiramar acetate (copaxone) nou xpnoiponoi-eiTai Yia Tn 9epaneia TnQ oKAnpuvonQ KaTa nAaKaQ (multiple sclerosis, MS) pnopei va Spa peow evepYo-noinonQ twv Bregs 20. Eva povoKAwviKo avTiowpa evavTi TIM-1 nou eK0paZeTai oTa Bregs avaoTeiAe twv anoppi^n navKpeaTiKou aAAopooxeupaToQ 21 . A^iZei va onpeiw9ei oti Ta Bregs pnopei va exouv Ka-TaoTaATiKH Spaon peow pnxaviopou ave^apTnTou TnQ IL-10, onwQ peow tou TGFP 22, 23. H xopHYnon IL-35 pe Tnv avanTu^n IL-35+Bregs KaTaoTeiAe Tnv neipapaTi-kh auToavoon paYoeiSiTiSa (experimental autoimmune uveitis, EAU), evw n xopHYnon twv IL-35+Bregs nou avanTuxQnKav ex-vivo avaoTeiAe eYKaTeoTnpevn EAU. AvTi9eTa, novTiKoi xwpiQ to YoviSio TnQ IL-35 avanTu-£av Papia EAU 8i 15. AuTa Ta eupHpaTa KaTaSeiKvuouv Tn onpaoia twv Bregs oTnv auToavooia Kai auToavo-oeQ vooouQ.
npoo0aTa, exouv peAeTn9ei Bregs oe peupaTiKeQ
mediterranean journal 26
of RHEUMATOLOGY 1
EAAHNIKH PEYMATQAOriA 2015
na6noeiQ. Zto ouoTnjaTiKo epu9njaTw5n AUKO, Ta CD19+CD24hiCD38hi Bregs eivai SuoAeiToupYiKa a0ou Sev napaYouv enapKii IL-10 4. Itfi oxeTiZojevn je ANCA aYYeiiTiSa, |jia jeAeTn eSei^e jeiwjevo api9-jo aAAa AeiToupYiKWQ enapKii CD19+CD24hiCD27+ memory Bregs 24, evw jia aAAn jeAeTn eSei^e jeiwje-vo api9jo aAAa AeiToupYiKWQ enapKii CD24hiCD38hi Bregs oe PR3-ANCA+ ao6eveiQ 25. TeAoq, jia TpiTn jeAeTn, eSei^e avenapKii napaYWYH IL-10 oTnv oxeTiZojevn je ANCA aYYeiinSa 26. MeTa ano jeTajo-oxeuon aAAoYevwv oTeAexiaiwv KuTTapwv, Bregs ano ao6eveiQ je cGVHD, nou joipaZeTai KAiviKa Kai avo-ooAoYiKa eupHjaTa je Tn ouoTnjaTiKH oKAHpuvon, eivai jeiwjeva Kai napaYouv AiYOTepo ouxva IL-10 19. MeiwjevoQ api6joQ Bregs Kai napaYWYH IL-10 exei enionQ napaTnpnQei oTn vooo Graves 27.
nponxiKn GepaneuxiKHQ XPH^HQ PU6MICTTIKWV B A£M0OKUTrapuv
Oi napanavw jeAeTeQ unoSnAwvouv oti 9a jnopou-oe va e0apjoo9ei jia vea 9epaneuTiKii oTpaTnYiKH oTn 9epaneia auToavoowv peujaTiKwv voowv. Aoyw xapiv, Bregs 9a jnopouoav va avanTux9ouv ex vivo Kai va enavaxopnYn9ouv oe ao9eveiQ je avenapKeia Bregs. TeToia oTpaTnYiKH e<t>apjoo9nKe oe novTiKia. Bregs nou avanTux9nKav ex vivo jeow eniSpaonQ IL-21 Kai CD40L ano Ta T Aej0oKUTTapa KaTaoTeiAe neipajaTiKH auToavoon eYKe0aAiTi5a 7. napojoiwQ, ex vivo avanTu^n IL-35+Bregs KaTaoTeiAe eYKaTeoTn-jevn neipajaTiKH auToavoon paYoeiSmSa 15.
EiKova. AneiKovion Transitional B regs Kai CD38(opiZovTioq a^ovaq). Ito eyKAeioTO R2 eivai o nAriQuajoq rav transitional Bregs je CD24highCD38high.
TA RY0MIITIKA B AEMOOKYTTARA ANOIROYN NEEI ITRATHRKEI QERAnEIA! IE AYTOANOIA NOIHMATA REGULATORY B CELLS OPEN NEW THERAREUTiC STRATEGiES FOR AUTOiMMUNE DiSEASES
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