Granice Starenje, Pretilost I Upalne Bolesti Povezane S Godinama - Imunologija

20. 10. 2019.
Granice | Starenje, pretilost i upalne bolesti povezane s godinama | Imunologija
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Imunološki sistem starenja i zdravlje Pogledajte svih 23 članaka
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SADRŽAJ
Sažetak
Uvod
Veze pretilosti sa
inzulinskom
rezistencijom (IR) i
T2D
Pretilost i
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mehaničke veze
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Osteoartritis (OA),
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Kognitivna oštećenja,
demencija i odnos
prema bolestima i
pretilosti povezanih

sa godinama  
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Zaključne napomene
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20. 10. 2019. Granice | Starenje, pretilost i upalne bolesti povezane s godinama | Imunologija
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Prednji. Immunol., 07. decembra 2017. | https://doi.org/10.3389/ mmu.2017.01745 (https://doi.org/10.3389/ mmu.2017.01745)
Starenje, pretilost i upalne bolesti povezane sa

godinama
Daniela Frasca (http://www.frontiersin.org/people/u/449388)1 *, Bonnie B. Blomberg
(http://www.frontiersin.org/people/u/23614)1 i Roberto Paganelli
(http://www.frontiersin.org/people/u/40696)2
1
Katedra za mikrobiologiju i imunologiju, Univerzitet u Majamiju, Medicinski fakultet, Miami, FL, Sjedinjene Države
2
Dipartimento di Medicina e Scienze dell'Invecchiamento, Università degli Studi 'G. d'Annunzio 'Chieti-Pescara, Chieti, Italija
Porast učestalosti pretilosti predstavlja svjetsku pojavu u svim dobnim skupinama i patološki je i genetski
povezan s nekoliko metaboličkih i kardiovaskularnih bolesti, što predstavlja najčešće bolesti povezane s
godinama. Pretilost nanesena starenjem drastično povećava kroničnu nisku stupanj upale (upale), što je
važna veza između pretilosti, inzulinske rezistencije i bolesti povezanih sa starenjem. Imune ćelije i
urođenog i adaptivnog imunološkog sustava infiltriraju u masno tkivo (AT) i za vrijeme pretilosti
induciraju upalne reakcije povezane s metaboličkim prekidačima i promjenama fenotipa i funkcijom
podskupina imunoloških stanica. Gojaznost predstavlja nove zdravstvene probleme, posebno kada se
pojavljuje
SADRŽAJ u kontekstu drugih bolesti, a mnoge od njih često pogađaju starije osobe. Novi problem je
smanjeni
Sažetak udio bolesnika s pretilošću koji postižu klinički odgovor na terapiju. U ovom ćemo pregledu
raspravljati o recipročnim utjecajima imunoloških ćelija i AT upale u starenju i bolestima povezanim sa
Uvod
starenjem te složenom odnosu homeostatskih kontrolnih točaka koje se odnose na hranjive tvari i
Veze pretilosti sa
energije, a koje doprinose oblikovanju fenotipa AT. Posebno ćemo ispitati dijabetes tipa 2, reumatoidni
inzulinskom
artritis, osteoartritis, kognitivno oštećenje i demenciju, gdje pretilost igra značajnu ulogu, također u
T2D
oblikovanju nekih kliničkih aspekata. raspravljat ćemo o recipročnim utjecajima imunoloških stanica i AT
Pretilost i
upale u starenju i bolestima povezanim s godinama te složenom odnosu homeostatskih kontrolnih točaka
hranjivih
(RA): dokazi i tvari i energije, koji pridonose oblikovanju fenotipa AT. Posebno ćemo ispitati dijabetes tipa 2,
mehaničke veze
reumatoidni artritis, osteoartritis, kognitivno oštećenje i demenciju, gdje pretilost igra značajnu ulogu,
Osteoartritis
također u(OA),oblikovanju nekih kliničkih aspekata. raspravljat ćemo o recipročnim utjecajima imunoloških
stanica i AT upale u starenju i bolestima povezanim s godinama te složenom odnosu homeostatskih
kontrolnih točaka hranjivih tvari i energije, koji pridonose oblikovanju fenotipa AT. Posebno ćemo ispitati
demencija i odnos
dijabetes
prema tipai 2, reumatoidni artritis, osteoartritis, kognitivno oštećenje i demenciju, gdje pretilost igra
bolestima
značajnu ulogu, također u oblikovanju nekih kliničkih aspekata.
sa godinama
Zaključne napomene
Uvod
Prilozi autora
Izjava o sukobu
interesa
Finansiranje
Porast učestalosti prekomjerne težine i pretilosti predstavlja svjetsku pojavu, koja je povezana s nekoliko kroničnih
Reference
bolesti poput dijabetesa tipa 2 (T2D), raka, reumatoidnog artritisa i osteoartritisa (OA), kognitivnih oštećenja i
demencije i onih koji utječu na kardiovaskularni (CV) sistem.
Globalna pandemija gojaznosti pogađa sve starosne grupe. Nedavne studije koje su ispitivale podatke o indeksu
tjelesne mase (BMI) kod 68 miliona ljudi u 195 zemalja pokazale su i povećanu prevalenciju i opterećenje bolesti kod
visokih BMI subjekata u globalu tokom posljednjih 20 godina ( 1 ). Iako je prevalenca gojaznosti među djecom niža
nego kod odraslih, njegova stopa porasta prevazilazi onu odraslih ( 2). Globalni teret bolesti povezanih s visokim BMI
izračunava se kod pojedinaca bez osnovnih uvjeta, a kod odraslih raste sporije, uglavnom zbog smanjenja ostalih
faktora rizika za bolesti CV-a i učinkovite kliničke intervencije. Međutim, pokazalo se da je povećani BMI
patogenetički povezan sa nekoliko bolesti. Među njima su otpornost na inzulin (IR) i T2D snažnu vezu s pretilošću, a
metabolički sindrom predstavlja skup rizičnih faktora za teške događaje s CV-om (koronarna bolest, moždani udar).
Gojaznost nanesena starenjem predstavlja dodatni faktor rizika za starije starosne grupe u kojima raste prevalenca
hronične bolesti kao i pojava komplikacija ( 3 - 5). Opterećenje bolesti visokog BMI u djece (≤18 godina) nije bavljeno
istim detaljima.
Proces starenja karakterizira stanje kronične upale, poznato kao upala. Nekoliko faktora doprinosi upali, uključujući
polimorfizme u promotornim regijama pro-upalnih gena, kroničnu stimulaciju imunoloških stanica virusima poput
citomegalovirusa, promjene u mikrobiomu crijeva i povećanu propustljivost iz crijeva [pregledano u Ref. ( 6 )].
Nedavno je predloženo da kontinuirano uključivanje urođenih receptora endogenim signalima poput molekularnih
obrazaca povezanih s oštećenjem dovodi do hroničnog stanja pozadinske upale, što je potrebno uravnotežiti
protuupalnim mehanizmima. Stanična starenje i stjecanje sekretornog fenotipa (SASP) vezanog za starenje (FASP)
pomoću fibroblasta ( 7 ) i endotela (8 ) i imunološke ćelije ( 9 - 11 ) također su istaknute kao značajan doprinos upali.
Starenje ćelije inducira akumulaciju terminalno diferenciranih B, T i NK ćelija s disreguliranom funkcijom
aktivacijom puteva integrirajući signale starenja i osjetljivosti energije.
Upala je važna karika između gojaznosti, infracrvenog porekla, starenja i bolesti povezanih sa starenjem kao što su
kognitivno oštećenje, ateroskleroza, rak i autoimunost. Povišani protuupalni citokini povezani su sa smanjenom
osjetljivošću na inzulin. Hronična (sterilna) upala niske stupnjeve uzrokuje IR, što dovodi do prelaska iz metabolički
normalne pretilosti u metabolički sindrom. To se događa i kroz sistemsku upalu i metaflamiranje ( 12 ), proces u
kojem višak hranljivih sastojaka potiče kroničnu upalu niskog stupnja, a čiji su metabolički značajci visoki nivoi lipida,
slobodnih masnih kiselina (FFA), glukoze i reaktivnih vrsta kisika (ROS) .
Imune
SADRŽAJ ćelije urođenog i adaptivnog imunološkog sustava infiltriraju tkiva koja reagiraju na inzulin, poput visceralnog
masnog tkiva (PDV) i s pretilošću potiču upalne reakcije. Imune ćelije (makrofagi, T, B, NK, stanice NKT i neutrofili)
Sažetak
uključene su u upalu masnog tkiva (AT) i infracrvenu bolest ( 13 - 17 ). Upala dovodi do lokalnog i sistemskog
Uvod
povećanja pro-upalnih molekula, kao što su faktor nekroze tumora (TNF) -α, interleukin (IL) -1β, IL-6, interferon
Veze pretilosti
(IFN) sa
-γ, upalni adipokini, hemokini i FFAs [ recenzirano u ref. ( 16 )].
inzulinskom
T2D
Veze pretilosti sa inzulinskom rezistencijom (IR) i T2D
Pretilost i
IR je nedostatak odgovarajućeg odgovora na cirkulirajući inzulin u nekoliko tkiva, uključujući jetru, mišiće i AT ( 18 ).
(RA): dokazi i
Često se povezuje
mehaničke veze s pretilošću, hipertenzijom (integrišući karakteristike metaboličkog sindroma) i CV bolesti te obično
prethodi nastanku T2D. U gušterači se β-ćelije prilagođavaju hiperglikemiji ekspanzijom ukupne β-ćelijske mase i
Osteoartritis (OA),
povećanim
starenje lučenjem inzulina (hiperinzulinemija), koji je u stanju ne samo da kontrolira normalne nivoe glikemije, već
i gojaznost
također može izazvati stres β-ćelija, izazivajući neuspjeh β-stanica, a zatim T2D ( 19 ). Loša kontrola glikemije kod
osoba sai T2D
demencija odnosrezultira teškim komplikacijama, poput bubrežnog zatajenja, sljepoće, neuropatije i poremećaja CV-a (
prema
20 ). bolestima i
saNije potpuno jasno kako pretilost uzrokuje razvoj IR-a. Iako su predloženi mnogi molekularni mehanizmi, uključujući
godinama
ER stres,
Zaključne oksidativni stres, disregulaciju lipidne homeostaze, disfunkciju mitohondrija, hipoksiju i oštećenje
napomene
inzulinskog signala u stanicama koje reagiraju na inzulin, postoje dokazi da upala izazvana pretilošću može biti
Prilozi autora
ključna faktor za IR ( 21 ). Slika 1 sažima glavne putove koji vode do upale u pretilih AT.
Izjava o sukobu
interesa
Finansiranje
Reference
SLIKA 1
(https://www.frontiersin.org/files/Articles/324042/fimmu-08-01745-HTML/image_m/fimmu-08-01745-
g001.jpg)
Slika 1. Model za regulaciju upalnih putova u pretilom masnom tkivu (AT). Adipociti (AD) kod gojaznih AT su
izrazito upalni i luče nekoliko protuupalnih citokina i hemokina koji regrutuju imunološke ćelije i tako doprinose
uspostavljanju i održavanju lokalne i sistemske upale. Među tim posrednicima upale, faktor nekroze tumora (TNF) -
a oslobođen i od AD i imunoloških ćelija inducira lipolizu i oslobađanje slobodnih masnih kiselina (FFAs), koje
aktiviraju makrofage rezidencijalne u tkivima (MΦ) da oslobađaju citokine i hemokine. FFA se također oslobađaju u
krvi te uzrokuju i inzulinsku rezistenciju i upale u glavnim ciljanim tkivima inzulina. Imune ćelije regrutovane do gojaznih AT diferenciraju se u
upalne podskupove i izdvajaju dodatne pro-upalne posrednike. Pretpostavljamo da bi ove ćelije stvorile suboptimalne imunološke odgovore kod
gojaznih pojedinaca cirkulirajući do perifernih limfoidnih organa. Patogena antitela mogu se izlučiti B ćelijama u AT. Ova antitela mogu formirati
imune komplekse sa „samo“ antigenima, koji zauzvrat aktiviraju komplement i Fc receptore na imunološkim ćelijama, što dovodi do pojačane
lokalne upale, remodeliranja AT, poremećaja funkcije adipocita i metabolizma hranljivih materija i pogoršanja povezanosti sa pretilošću. uslova.
Ova antitela takođe mogu da imaju dodatne štetne efekte kako lokalno, tako i sistemski ciljajući različite nakupine samoproteina. Jedan
mehanizam za oslobađanje "samo" -antigena u gojaznom AT je smanjena opskrba kisikom, što rezultira područjima hipoksije, što dovodi do
daljnjeg oslobađanja proupalnih citokina,
Proizvodnja proupalnih posrednika u prekomorskoj AT

Visoka razina TNF-α u AT povezana je s kronično povišenom bazalnom lipolizom, procesom hidrolize triglicerida do
oslobađanja FFA i lipida ( 22 ). Oni omogućavaju hroničnu stimulaciju makrofazima što dovodi do stvaranja TNF-α
izazvanog FFA, uzrokujući IR. Predloženo je da TNF-α koji potiče iz adipocita doprinosi povišenom nivou FFA u krvi
gojaznih pojedinaca ( 22 ), a neutralizacija TNF-a in vivo u pretilih miševa smanjuje cirkulacijsku razinu FFA ( 23 ).
Pokazalo se da i TNF-α smanjuje ekspresiju proteina stabilizirajući kapljica lipida (perilipini) ( 24), što dovodi do
ektopičnog taloženja lipida u tkivima osjetljivim na inzulin. Lipidi i molekuli koji potiču iz lipida imaju direktan efekat
na tkiva osjetljiva na inzulin i induciraju IR ( 25 ).
Ostali glavni protuupalni citokini koje oslobađa gojazni AT su IFN-γ izlučeni CD8 + T ćelijama ( 26 ) i NK ćelijama ( 27
) i IL-17 izlučene CD4 + T ćelijama ( 28 ).
Hipoksija i oslobađanje "samo" antigena u pretiloj AT

Tijekom
SADRŽAJ razvoja gojaznosti, opskrba kisika rastućim AT postaje nedovoljna, što rezultira područjima hipoksije ( 29 ,
30 ). Ovaj fenomen slabo oksigeniranog AT ne samo da aktivira faktor transkripcije hipoksiju-inducirajući faktor-1α
Sažetak
(HIF-1α) i daljnje oslobađanje proupalnih citokina ( 31 ), već i inducira staničnu smrt i oslobađanje "samo" antigena,
Uvod
koji stimulišu klasu prebacivanje i proizvodnju IgG patogenih antitijela. Hipoksija u AT-u jedini je mehanizam koji je
Veze pretilosti
do sada sa
predložen za oslobađanje „samo“ antigena u pretilih AT.
inzulinskom
T2D
In ltracija imune ćelije u prekomorskoj AT
Pretilost i
Podaci pretilih
reumatoidni artritis miševa i ljudi pokazuju da hipertrofirani AT postaje jako infiltriran raznim imunološkim ćelijama koje
pokazuju
(RA): dokazi ipro-upalni fenotip, karakteriziran izlučivanjem SASP markera ( 32 ), a njihov broj obrnuto je u korelaciji s
mehaničke veze
osjetljivošću na inzulin. Ćelije sa protuupalnim fenotipom prijavljene su i kod gojaznih AT, ali ove ćelije su prisutne na
Osteoartritis (OA),
niskim frekvencijama. To su stanice B1 B koje proizvode IL-10 ( 15 , 33 ) i urođene limfoidne ćelije tipa 2, koje
proizvode velike količine Th2 citokina poput IL-4, IL-5 i IL-13 ( 34 ). Objavljeni su i tregovi, ali samo u mršavoj AT (
Kognitivna
35 ). oštećenja,
demencija i odnos
Infiltracija
prema makrofaga
bolestima i unutar AT-a smatra se glavnim pokretačem upale zbog izlučivanja proupalnih citokina i
hemokina koji su uključeni u regrutovanje imunoloških ćelija na AT. Međutim, adipociti izlučuju i proupalne
sa godinama
posrednike (citokini, hemokini i adipokini) i u većim količinama u usporedbi s imunološkim ćelijama ( 36 ). Stoga, s
Zaključne napomene
pretilošću, ukrštanje adipocita i imunoloških stanica koje infiltriraju AT doprinosi uspostavljanju kronične upale,
Prilozi autora IR-a. Makrofagi u AT-u gotovo su isključivo M1, oni ovise o glikolizi zbog svoje upalne funkcije, a njihova
preduvjeta
stimulacija
Izjava o sukobuu AT-u inducira ekspresiju transportera glukoze i unos i korištenje glukoze ( 37). Hipoksija (putem HIF-
interesa
Finansiranje
1α) potencira glikolizu i stabilizira upalni fenotip ( 38 ). U M1 makrofagovima, inflamatorni NLRP3 aktivira kaspazu 1
Reference
i lučenje IL-1β ( 39 ), koji je direktno toksičan za β-stanice gušterače i inducira IR ( 40 ). Zabilježeno je povećano
upalno delovanje kod makrofaga koji potiču iz monocita kod T2D bolesnika ( 41 ).
T ćelije u AT su Th1 CD4 + i CD8 + T stanice koje stvaraju IFN-y ( 26 ). One potiču izlučivanje proupalnih citokina iz
M1 makrofaga što dovodi do lokalnog i sistemskog IR-a ( 42 ). Slično makrofagovima, skeniranje podskupina T ćelija
u AT nastaje modulacijom metabolizma supstrata reguliranog hormonima (leptin) i intracelularnim kinazama
osjetljivim na hranjive tvari, poput AMPK / mTOR ( 43 ). Th1 CD4 + T ćelije izražavaju visoku razinu membranskih
transportera glukoze i visoko su glikolitičke ( 44 ), osobina koja podržava upalne reakcije.
Interferon-γ, potpis Th1 citokina, inducira makrofage i T ćelije da luče hemokine koji regrutuju imune ćelije do
gojaznih AT ( 45 , 46 ). Nadalje, IFN-γ olakšava polarizaciju M2 do M1 ( 47 ) i smanjuje signalizaciju receptora za
inzulin smanjujući ekspresiju inzulinskih receptora i transportera glukoze ( 48 ). Proizvodnju IFN-γ regulira T-bet,
faktor transkripcije porodice T-box koji je prvo identificiran kao induktor transkripcije IFN-γ u CD4 + T ćelijama ( 49
). T-bet igra kritičnu ulogu u razvoju IR-a u životinjskim modelima gojaznosti, a miševi s manjkom T-bet-a koji su
hranjeni dijetom s visokim udjelom masti otporni su na indukciju IR ( 50). Ovi miševi pokazuju poboljšanu
osjetljivost na inzulin i toleranciju na glukozu, smanjeni broj imunoloških stanica u AT-u (CD4 + / CD8 + T stanice,
NK stanice i makrofagi), te smanjenu proizvodnju proupalnih citokina po gramu masti (IFN-γ , TNF-α, IL-1β i IL-6).
Gojazni i gojazni i T2D imaju promjene u sastavu svog mikrobioma, s smanjenim udjelima bakterioida (korisnih
bakterija) u pretilih u odnosu na mršave jedinke ( 51 ). Nadalje, zabilježeno je da mikroflora crijeva regulira razvoj
pretilosti u životinjskim modelima ( 52 ). T-bet reguliše aktivaciju mukoznih T ćelija ( 53 ), a deficit T-betsa mijenja
sastav mikroflore ( 54 ). Manjak T-beta takođe može izmijeniti mikrobiom kod pojedinaca s pretilošću, što dovodi do
upalnih i metaboličkih procesa koji reguliraju T2D.
B ćelije se takođe nakupljaju u gojaznim AT ( 15 , 55 , 56 ). Regrutovanje iz B ćelije može pokrenuti T-stanicu izazvanu
M1 polarizaciju i IR. Pretilost i hiperglikemija direktno utječu na proizvodnju antitijela, a izlučivanje IgG iz upaljenog
PDV-a modulira funkciju rezidentnih makrofaga. Zabilježeno je da se B stanice u AT induciraju da stvaraju patogena
IgG autoantitijela, zbog disregulirane ekspresije autoantigena od strane hipoksičnih adipocita. B ćelije također
podržavaju aktiviranje upalnih T-stanica koje su glavni pokretači patogena u sistemskoj upali i IR-u.
Nedavno je identificirano novo limfoidno tkivo koje se naziva masnoća povezana s limfoidima (FALC) u
mezenterijskom AT miševa i ljudi. FALC se brzo induciraju nakon upalnih podražaja i podržavaju proliferaciju B
stanica i diferencijaciju koja regulira proizvodnju antitijela unutar AT ( 57 ).
SADRŽAJ
Sažetak
Pretilost i reumatoidni artritis (RA): dokazi i mehaničke veze
Uvod
RA pretilosti
Veze je oslabljujuća
sa hronična autoimuna bolest koja uzrokuje sinovijalnu upalu i uništavanje zglobova uključujući
hrskavicu i susjednu kost. Obično se javlja između četvrte i šeste decenije života i pogađa više žena nego muškaraca.
inzulinskom
Karakteriziraju ga krutost zgloba, bol i oticanje te su praćeni vanartikularnim manifestacijama i sistemskim upalama.
T2D
RA je povezan s gubitkom mišića i kaheksijom zbog nekontrolirane upale pokretane TNF-α, koji potiče
Pretilost i
hiperkatabolizam ( 58 ). Međutim, BMI rijetko pada ispod normalnog, jer se gubitak vitkog tkiva nadoknađuje
povećanim
(RA): dokazi i AT, a to karakterizira reumatoidnu kaheksiju, koja se još naziva i "kahektična pretilost" ( 59 , 60).
mehaničke
Primijećenovezeje da se u bolesnika s RA, usprkos adekvatnom unosu hranjivih sastojaka, ali upalnoj dominaciji citokina
i smanjenoj
Osteoartritis aktivnosti uslijed bola, deformacije zglobova i smanjene mišićne snage ( 61 ), čini da je kaheksija slična
(OA),
onoj koja se javlja kod starijih osoba s invaliditetom. Nenormalni sastav tijela u RA može se definirati kao
sarkopenična
Kognitivna gojaznost ( 62 ) s karakterističnim promjenama koje u starijih osoba pridonose krhkosti ( 63 , 64 ).
oštećenja,
demencija i odnos
Pored toga, procenat pretilih bolesnika s RA povećao se ( 65 ), a utjecaj pretilosti na RA postao je relevantan problem,
prema bolestima i
ne mnogo
pretilosti za zanemarivi rizik razvoja RA ( 66)), ali zbog negativnih utjecaja na aktivnost bolesti, odgovor na terapiju i
povezanih
sarizik od CV-a. Gojazni RA bolesnici doista imaju manje vjerojatnosti da će postići održivu remisiju kao odgovor na
godinama
terapijunapomene
Zaključne konvencionalnim hemijskim ( 4 ) ili biološkim (TNF-α inhibitorima) agensima ( 67 ). Uprkos suprotnim
rezultatima s nekim tretmanima ( 68 ), pretilost smanjuje stopu remisije RA i negativno utječe na aktivnost bolesti (
Prilozi autora
69 ) i na rezultate koje je izvijestio pacijent tijekom terapije ( 70 ).
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„Paradoks gojaznosti“ u RA
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Reference
Pretilost predstavlja važnu vezu sa komorbiditetima kao što su metabolički sindrom ( 71 ) i CV bolesti ( 72 ); međutim,
u nekim studijama povećani BMI imao je suprotan efekat smanjene smrtnosti ( 70 , 73 ), što je opisano kao "paradoks
gojaznosti" ( 74 ). Štoviše, kod bolesnika s RA prekomjernom težinom smanjena je progresija uništavanja kostiju ( 75 ,
76 ), broj natečenih zglobova se ne povećava, a zabilježen je i bolji kvalitet života ( 77 ). Gubitak kilograma i kaheksija
predstavljaju glavne odrednice za veći rizik od smrti ( 78 ) i lošiju kvalitetu života ( 77)) i tako jača paradoksalno
promatranje niže smrtnosti kod pretilih pacijenata. Međutim, naknadne studije pokazale su da je kod pacijenata s RA
s poviješću smanjene BMI snažno povezan sa smrću. Stoga „paradoks gojaznosti“ ne uključuje biološki zaštitnu ulogu
pretilosti ( 73 ), postavljajući pitanje je li upotreba BMI-a valjano sredstvo za procjenu pretilosti u RA ( 65 ).
Visoki BMI doprinosi aktivnosti bolesti u RA utječući i na biomehaniku i na metabolički status, a pretili bolesnici s RA
pokazuju lošiju subjektivnu procjenu simptoma ( 79 ). Hiperglikemija, kao dio metaboličkog sindroma, češća je u
ranom RA ( 80 ), dok aktivni RA pokazuje smanjenu razinu lipida ( 81 ), unatoč povećanom riziku od nastanka CV-a,
zbog efekta sistemske upale na smanjenje lipida ( 82) ). Povećanje PDV-a, npr., Epikardijalna mast ( 83 ), i obilniji
infiltrat makrofaga povezani su sa sistemskom upalom, metaboličkim sindromom i infracrvenom reakcijom ( 84)).
Anti-TNF-α terapija poboljšava osjetljivost na inzulin kod RA rezistentnih pacijenata, ali uprkos kontroliranju upale
ne postiže isti stupanj poboljšanja kod pretilih bolesnika s RA ( 85 ). Uz to, čak i kad terapija uspije kontrolirati
aktivnost bolesti, ne uspijeva vratiti izmijenjeni sastav tijela i poboljšati fizičku funkciju ( 86 ). Adipokini (leptin,
adiponektin, visfatin, rezistentin i chemerin) su postulirani kao posrednici koji povezuju AT i RA aktivnost ( 87 ).
Neravnoteža adipokina može biti podložna većem stepenu upale ( 88)), razine autoantitijela (leptin i adiponektin
različito reguliraju stvaranje Treg ćelija koje obiluju normalnim PDV-om), a također i manju količinu resorpcije kosti
koja se opaža kod pretilih bolesnika ( 89 ). Na drugoj razini, povezanost RA s metaboličkim sindromom i
aterosklerozom vjerovatno je također posredovana PDV-om kroz izmjenjenu sekreciju adipokina. Stoga adipokini
presudno doprinose sistemskoj upali koja je u osnovi RA, što predstavlja neovisni faktor rizika za CV bolesti.
Budući da smanjenje tjelesne težine može imati moguće kontraindikacije (niži BMI povezan s ubrzanom smrtnošću od
RA), a procjena upalnog stanja PDV-a kod pacijenata s RA još uvijek nije potpuna, mnogo je istraživanja posvećeno
otkrivanju metaboličkih promjena koje se javljaju u razvoju i hronizacija RA. Ovo je polje nedavno pregledano ( 90 ) i
može se sumirati u dvije različite faze rane i kronične RA. U prvoj fazi postoji velika metabolička potražnja u svim
uključenim tipovima stanica, zbog proliferativne signalizacije, angiogeneze, stanične de-diferencijacije i
neuravnoteženog prometa kostiju. Međutim, u RA T ćelijama, za razliku od drugih tipova upalnih metaboličkih
promjena, glikolitički put se smanjuje u korist šentu pentoz fosfatnog šanta ( 91), smanjena generacija ROS-a i
smanjena AMPK funkcija. U ranim fazama aktiviranje AMPK (npr. Metformin) može biti atraktivan cilj jer je njegova
SADRŽAJ
aktivnost smanjena u nekoliko tkiva pretilih ili infarkta. U kasnom (erozivnom) stadijumu RA, upalni zglob je
Sažetak
hipermetabolička lezija ( 90 ), T ćelije prolaze metabolički prelazak na aerobnu glikolizu zbog hipoksičnih stanja, a
disfunkcija mitohondrija uz povećanu proizvodnju laktata uzrokuje zakiseljavanje sinovije. Reprogramiranje T ćelija
Uvod
predstavlja
Veze pro-upalni Th1 / Th17 fenotip i prerano starenje T ( 92 ). Nađeno je da su nekoliko aspekata
pretilosti sa
imunosenescencije relevantni u patogenezi RA ( 93 - 96)), a pomlađivanje imunološkog sistema je predloženo kao
inzulinskom
terapija, uključujući mTOR inhibitore ( 97 , 98 ).
T2D
Pretilost i
Uloga B ćelija u patogenezi RA
(RA): dokazi i
Ključna uloga
mehaničke veze koju imaju autoreaktivne B ćelije istaknuta je prisutnošću dijagnostičkih autoantitijela, a reumatoidni
faktor (RF)
Osteoartritis ( 99 ) i anticiklično-citrulinirani peptidna antitijela (ACPA) ( 100 ) dobro su utvrđeni pokazatelji bolesti i
(OA),
težine ibolesti
starenje gojaznosti mogu biti prethodi nastanku bolesti. Uloga B ćelija u patogenezi RA u kontekstu prekomjerne težine /
pretilostioštećenja,
Kognitivna još uvijek nije obrađena i zaslužuje detaljnu pažnju. Otkriven je primarni defekt u ranoj toleranciji B stanica,
jer većina naivnih B limfocita izražava polireaktivna autoantitijela, uključujući RF i ACPA. Te B ćelije otporne su na
demencija i odnos
prema bolestima i
apoptozu izazvanu Fasom i stoga ih Treg ne suzbija ( 101)). Međutim, B-ćelije su uključene u RA pomoću drugih
samehanizama,
godinama u dvosmjernoj podršci pomoćnih T-limfocita, kao ćelija koje predstavljaju samo-antigen, uz oslobađanje
upalnih medijatora i s promocijom limfoidne neogeneze (koja je istaknuta u sinovitisu RA ). RF + B ćelije su u stanju
Zaključne napomene
da preuzmu imunološke komplekse koji sadrže IgG i predstave antigen T ćelijama, aktivirajući tako recipročno
Prilozi autora
pojačan odgovor ( 102 ).
Izjava o sukobu
interesa
Finansiranje
Fenotip B limfocita u RA detaljno je proučavan u perifernoj krvi i u sinovijalnom tkivu, s nekim neskladnim podacima
Reference
zbog ispitivanja različitih stadijuma bolesti. Opšti konsenzus je povećana prisutnost memorijskih (CD27 + ) B ćelija s
aktiviranim (CD95 + , CD21 nizak ) fenotip i u perifernoj krvi i u sinovijalnom odjeljku ( 103 ). Te ćelije su se još više
povećale nakon terapije iscrpljivanja B ćelija (BCDT) rituximabom. Postoji i slaganje sa činjenicom da se odgovor na
BCDT oslanja na eliminaciju memorijskih B ćelija, a njihova repopulacija, zajedno s tranzicijskim B limfocitima, može
predvidjeti recidiv ( 103). Uloga homeostatske limfoproliferacije obje memorijske B stanice i opseg BCDT-a u koštanoj
srži i sinovijalnom tkivu predstavljaju kritične točke koje još uvijek moraju biti rasvijetljene. Budući da je primijećeno
da se aktivacija CD4 + T ćelija smanjuje nakon BCDT ( 104 ), promjene ne samo B podskupova ćelija, nego i T ćelijskih
podskupova mogu biti u osnovi reakcije RA pacijenata na terapiju. Na Treg odjeljak manje utječu tretmani RA ( 105 ),
no čini se da prisutnost Bregovih limfocita (smanjena u netretiranom RA) igra ulogu u uravnoteženju imunoloških
abnormalnosti i predviđa ishod liječenja ( 106 ). Proizvodnja citokina pomoću podskupova B ćelija također je
relevantna za patogenezu RA i aktivnost bolesti [pregledano u Ref. ( 107))], sa inflamatornim citokinima koji
prevladavaju u neliječenom teškom RA, kao aktivirane memorije B ćelije preferencijalno izdvajaju TNF-α, dok BCDT
inducira prelazak na subpopulacije koje proizvode IL-10. Nedavna identifikacija podskupine B ćelija koja mogu
proizvesti velike količine RANKL ( 108) omogućava mehaničku vezu između aktiviranih memorijskih B ćelija i
resorpcije kostiju indukcijom osteoklastogeneze. Važno je napomenuti da su ACPA povezani s većim oštećenjima
zglobova i kostiju i da terapija ne eliminira autoreaktivne B stanice koje stvaraju ACPA u sinovijalnom tkivu.
Centralna uloga B limfocita u patogenezi RA i u oštećenju tkiva čini ove ćelije i njihove proizvode privlačnim metama
za liječenje; međutim, još uvijek postoji neizvjesnost o korisnim ili čak zaštitnim učincima podskupina B ćelija.
Osteoartritis (OA), starenje i gojaznost

U starijih osoba artritis je često povezan s drugim bolestima s višestrukim starenjem ili degenerativnim značajkama (
109 ). OA i RA imaju zajedničke karakteristike u starijih bolesnika i značajno doprinose invalidnosti ( 110 ). OA se
obično razlikuje od RA po dobi u dijagnozi, trajanju jutarnje ukočenosti, obrascu zahvatanja zglobova i radiografskim
nalazima. Razlikovanje bolesti može biti izazovno, ali u dobnoj skupini starijoj od 60 godina OA je daleko češća.
Unatoč činjenici da OA izravno korelira s godinama, stvarni uzrok ove povezanosti nije jasan, a razvoj OA može se
razdvojiti na procese ovisne o starenju i starenje ( 111 - 114). I povećana proizvodnja matriksnih metaloproteinaza i
citokina, smanjena razina sinteze kolagena tipa II i povećana proizvodnja ROS-a induciraju promene hondrocita
povezanih sa starenjem ( 114 ). Ove promjene mijenjaju funkciju hrskavice, a sarkopenija dalje dovodi do smanjenja
stabilnosti
SADRŽAJ zgloba ( 115 ). Stanično starenje, oslabljena regeneracija i oporavak prepoznati su faktori koji doprinose
oštećenju hrskavice sa starenjem ( 115 , 116 ).
Sažetak
In patients younger than 60 years of age with symptomatic OA, joint pain and disabilities are less recognized as
Uvod
inevitable consequences of growing old, compared to OA patients older than 70 years (117). Several factors contribute
Veze pretilosti sa
to the development of OA: acute injury (including fracture), excessive mechanical overloading (113, 118), diabetes, and
inzulinskom
chronic tobacco
rezistencijom (IR) i smoking, all playing a role in the amplification of senescence-inducing stresses (118–121). These
T2D
factors develop before symptoms appearance and may cause early onset of OA; multimorbidity including OA and
obesityi can be seen at an adult age (122). The prevalence of arthritis is increasing, with 29.3% ever reported doctor-
Pretilost
reumatoidni
diagnosedartritis
arthritis in individuals aged 45–64 years versus 49.6% in individuals aged 65 or older in the United States
(RA): dokazi i
(123). However, obesity prevalence did not change significantly over time among middle-aged and younger adults
mehaničke veze
with doctor-diagnosed arthritis (124) despite increasing significantly over time among older adults with RA and
Osteoartritis (OA),
remaining
starenje also higher when compared with adults without RA. Obesity impacts progression of OA and has a negative
i gojaznost
influence on outcomes (125). Exercise and loss of at least 10% of body weight can effectively lead to improvement in
symptoms,
demencija pain relief, and physical function. Physical activity may reactivate a regenerative process by mobilizing
i odnos
prema
stembolestima
cells andi increase proteoglycan production, restoring the cartilage structure (113, 115, 126).
sa godinama
Cognitive Impairment, Dementia, and Relationship to Age-Associated

Zaključne napomene
Diseases and Obesity

Prilozi autora
Izjava o sukobu
interesa
Finansiranje
Our summary of conditions where inflammation, obesity, and aging converge in defining particular features and
Reference
outcomes of disease must also briefly mention the dementias, whose prevalence has been reported to be declining
among older US adults between 2000 and 2012 (127). However, dementia rates are growing at an alarming
proportion in most regions of the world and are related to population aging (128). Prevalence varies in countries with
different mean population ages. However, differences persist after adjusting for age (129). The decline in the United
States occurred in those older than 65 years and was related to increased number of years in education despite the
age- and sex-adjusted increase in the prevalence of hypertension, diabetes, and obesity in the same years. There is a
long unresolved debate on the prodromal phase of the neurodegenerative disorders with inflammatory features, such
as Alzheimer’s dementia, but it is undisputed that prevalence of dementias of all types increase with old age, from
about 2–3% among those aged 70–75 years to 20–25% among those aged 85 years or more (130). The known risk
factors include obesity, depression, diabetes, decreased physical activity, hypertension, smoking,
hypercholesterolemia, coronary heart disease, and alcohol use; and assessment of these provide an estimate of the
risk of developing dementia (131) despite the fact that in the oldest-old (80–97 years old), these factors did not
increase the risk for dementia, so that age plays a major role.
Taken together for the two most frequent types of dementia (Alzheimer’s and Vascular) (129), vascular risk factors
such as dietary fat intake, high cholesterol, obesity, T2D, and hypertension have emerged as the most important
determinants (132). Vascular risk is seldom isolated and is accompanied by alterations in hormonal metabolism.
Overweight/obesity, due to excess AT, increase the CV risk and also for late-onset dementia. This is exemplified in the
prodromal phases of dementia, as vascular and metabolic parameters decline in direct relation to cognitive
impairment and in a way which seems to differ from that occurring in “normal” aging. With regard to obesity, its
presence at midlife is associated with an increased risk of dementia and Alzheimer’s later in life (133), and in
particular central obesity in midlife increases the risk of dementia independent of diabetes and CV comorbidities
(134). The risk is reversed when late-life BMI is considered: underweight persons had an increased risk of dementia,
whereas being overweight was not associated and being obese reduced the risk of dementia compared with normal
BMI. This has been dubbed as an “obesity paradox” also in this case (135). A recent systematic review and meta-
analysis suggests a positive association between obesity in mid-life and later dementia but the opposite in late life
(136). A successive study confirmed the association of mid-life obesity and dementia, but that of being underweight
and dementia remained controversial (137). It is difficult to draw a clear distinction between visceral adiposity and
total body fat in most studies, and this is reflected on the paucity of mechanistic hypotheses supported by
experimental data. The attention has been focused on the role of several adipokines and mainly the two major
hormones
SADRŽAJ produced by the AT, leptin and adiponectin, that interact directly with the brain (138). They have the
capability to cross the blood–brain barrier and influence dementia processes within the brain (139), but evidence for a
Sažetak
direct role is missing. Another postulated link is through altered gut microbial flora, which may participate in the
Uvod
development of obesity, T2D, and subsequent initiation of AD (140). Also lacking is the evidence that weight reduction
Veze pretilosti may
in mid-life sa produce beneficial effects on dementia development. However, in older adults, regular exercise
inzulinskom
provides numerous health benefits that include improvements in blood pressure, coronary artery disease, diabetes,
lipid profile, OA, osteoporosis, mood, neurocognitive function, and overall morbidity so that studies in this area
T2D
shouldi be encouraged.
Pretilost
(RA): dokazi i
Concluding Remarks
mehaničke veze
Osteoartritis (OA),
Immunity
starenje and metabolism are highly integrated factors in aging and age-related diseases. This is an expanding field
i gojaznost
of investigation. Obesity and related complications are a major global epidemic. Scientific research must be a crucial
part of the
demencija solution to understand all implications of obesity, but this research is still in its initial phase. The
i odnos
prema bolestima of
investigation i the mechanisms whereby inflammation and immune activation disrupt a functional immune response
adds novel insights to the understanding of the relationship between inflammation and long-term metabolic disease
sa godinama
outcome and opens new ways for effective therapeutic interventions.
Zaključne napomene
Prilozi autora
Author Contributions
Izjava o sukobu
interesa
Na ovojAll
webauthors
stranici were involved
koristimo inzawriting
kolačiće the article
poboljšanje and had final
vašeg korisničkog approval
iskustva. of the
Nauči više submitted version.
(//www.frontiersin.org/legal/list-of-cookies) ZATVORI
Finansiranje
Reference
Con ict of Interest Statement

The research was conducted in the absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Funding
This study was supported by NIH AG-32576 (BBB), AI096446, AG042826, and AG032576 (BBB and DF).
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oštećenja,
demencija i odnos
prema bolestima i
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Keywords: aging, obesity, in ammation, type-2 diabetes, rheumatoid arthritis

SADRŽAJ
Citation: Frasca D, Blomberg BB and Paganelli R (2017) Aging, Obesity, and In ammatory Age-Related Diseases. Front. Immunol. 8:1745. doi:
Sažetak
10.3389/ mmu.2017.01745
Received: 24 October 2017; Accepted: 23 November 2017;

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Granice Starenje, Pretilost I Upalne Bolesti Povezane S Godinama - Imunologija

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20. 10. 2019.

Granice | Starenje, pretilost i upalne bolesti povezane s godinama | Imunologija

MINI PREGLED ARTICLE

Starenje, pretilost i upalne bolesti povezane sa

Proizvodnja proupalnih posrednika u prekomorskoj AT

Hipoksija i oslobađanje "samo" antigena u pretiloj AT

Osteoartritis (OA), starenje i gojaznost

Cognitive Impairment, Dementia, and Relationship to Age-Associated

Diseases and Obesity

Con ict of Interest Statement

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