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23.1: Shilliq qavatlar va immunitetga chidamlilik - Biologiya

23.1: Shilliq qavatlar va immunitetga chidamlilik - Biologiya


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Hozirgacha muhokama qilingan tug'ma va adaptiv immunitet reaktsiyalari shilliq qavat immun tizimidan ajralib turadigan tizimli immunitet tizimini (butun tanaga ta'sir qiladi) o'z ichiga oladi. Shilliq qavat bilan bog'langan limfoid to'qima (MALT), 1-rasmda tasvirlangan, butun tanadagi shilliq qavatni qoplaydigan epiteliya to'qimasi bilan birlashadigan limfa to'qimalarining to'plami. Keyin faollashtirilgan T hujayralari limfa tizimi orqali va qon aylanish tizimiga infektsiyaning shilliq qavatiga o'tadi.

Shakl 1. Kattaroq rasm uchun bosing. Ichak MALT ning topologiyasi va funktsiyasi ko'rsatilgan. Patogenlar ichak epiteliysidagi M hujayralari tomonidan qabul qilinadi va hujayraning ichki yuzasida hosil bo'lgan cho'ntagiga chiqariladi. Cho'ntakda dendritik hujayralar kabi antigen taqdim etuvchi hujayralar mavjud bo'lib, ular antijenlarni yutadi, so'ngra ularni hujayra yuzasida MHC II molekulalari bilan taqdim etadi. Dendritik hujayralar Peyer yamog'i deb ataladigan asosiy to'qimalarga o'tadi. Antigen taqdim qiluvchi hujayralar, T hujayralari va B hujayralari Peyer patchida to'planib, uyushgan limfoid follikulalarni hosil qiladi. U erda ba'zi T hujayralari va B hujayralari faollashadi. Boshqa antigen yuklangan dendritik hujayralar limfa tizimi bo'ylab ko'chib o'tadi, ular limfa tugunlaridagi B hujayralarini, T hujayralarini va plazma hujayralarini faollashtiradi. Keyin faollashtirilgan hujayralar MALT to'qimalarining effektor joylariga qaytadi. IgA va boshqa antikorlar ichak lümeninde chiqariladi.

MALT funktsional immun tizimining muhim tarkibiy qismidir, chunki shilliq qavatlar, masalan, burun yo'llari, nafas olish yoki yutilgan patogenlar to'plangan birinchi to'qimalardir. Shilliq qavat to'qimalariga og'iz bo'shlig'i, farenks va qizilo'ngach, oshqozon-ichak, nafas olish va urogenital yo'llar kiradi.

Immunitet tizimini zararsiz moddalarga isrofgarchilikka, keraksiz javoblarga yo'l qo'ymaslik va eng muhimi, "o'ziga" hujum qilmasligi uchun tartibga solish kerak. Kasallikka olib kelmasligi ma'lum bo'lgan aniqlangan begona moddaga keraksiz yoki zararli immunitet reaktsiyasini oldini olish uchun orttirilgan qobiliyat quyidagicha tavsiflanadi. immunitetga chidamlilik. Og'iz bo'shlig'i, farenks va oshqozon-ichak shilliq qavatining APClari duch keladigan juda ko'p miqdordagi begona moddalar (masalan, oziq-ovqat oqsillari) hisobga olinsa, immunitetga chidamlilik shilliq qavat gomeostazini saqlash uchun juda muhimdir. Immunitetga chidamlilik jigar, limfa tugunlari, ingichka ichak va o'pkada juda xilma-xil populyatsiyaga zararsiz antijenlarni taqdim etadigan maxsus APClar tomonidan yuzaga keladi. tartibga soluvchi T (Treg) hujayralar, mahalliy yallig'lanishni bostiradigan va ogohlantiruvchi immun omillarning sekretsiyasini inhibe qiluvchi maxsus limfotsitlar. T ning umumiy natijasireg hujayralar istalmagan to'qimalar bo'linmalarida immunologik faollashuv va yallig'lanishni oldini olish va immunitet tizimining o'rniga patogenlarga e'tibor qaratish imkonini beradi. Zararsiz antijenlarning immunitetga chidamliligini oshirishdan tashqari, T.ning boshqa kichik guruhlarireg hujayralar profilaktikasida ishtirok etadi otoimmün javob, bu xost hujayralariga yoki o'z-o'zidan antijenlarga mos bo'lmagan immun javobdir. Yana bir Treg klass yallig'lanish va hujayra lizisi natijasida kelib chiqqan xost hujayralarining shikastlanishini minimallashtirish uchun infektsiya tozalangandan so'ng zararli patogenlarga qarshi immunitetni bostiradi.


Immunitetga chidamlilik

Immunitetga chidamlilik, yoki immunologik bardoshlik, yoki immunitetga chidamlilik, ma'lum bir organizmda immunitet reaktsiyasini qo'zg'atish qobiliyatiga ega bo'lgan moddalar yoki to'qimalarga immunitet tizimining javob bermasligi holati. U o'ziga xos antigenga oldindan ta'sir qilish natijasida paydo bo'ladi [1] [2] va begona antijenlarning an'anaviy immun vositachiligida yo'q qilinishidan farq qiladi (qarang "Immunitetga javob"). Tolerantlik holatning paydo bo'lgan joyiga qarab markaziy tolerantlik yoki periferik bardoshlik deb tasniflanadi - timus va suyak iligida (markaziy) yoki boshqa to'qimalarda va limfa tugunlarida (periferik). Ushbu bag'rikenglik shakllarini o'rnatish mexanizmlari har xil, ammo natijada ta'sir o'xshash.

Immunitetga chidamlilik normal fiziologiya uchun muhimdir. Markaziy bag'rikenglik - bu immunitet tizimining o'zini o'zi bo'lmagandan ajratishni o'rganishining asosiy usuli. Periferik bardoshlik immunitet tizimining turli xil atrof-muhit omillariga (allergenlar, ichak mikroblari va boshqalar) haddan tashqari reaktivligini oldini olish uchun kalit hisoblanadi. Markaziy yoki periferik bardoshlik etishmovchiligi, shuningdek, tizimli qizil yuguruk, [3] revmatoid artrit, 1-toifa diabet, [4] 1-toifa otoimmun poliendokrin sindromi (APS-1), [5] va immunodisregulyatsiya poliendokrinopatiyasi kabi sindromlarga olib keladigan otoimmün kasalliklarni keltirib chiqaradi. enteropati X-bog'langan sindromi (IPEX), [6] va potentsial astma, allergiya, [7] va yallig'lanishli ichak kasalliklariga hissa qo'shadi. [4] Homiladorlik davridagi immun tolerantlik ona hayvonga homiladorlikning oldini olish uchun alloimmun reaksiyaga ega boʻlgan genetik jihatdan farq qiluvchi nasl tugʻishiga imkon beradi.

Biroq, bag'rikenglik o'zining salbiy tomonlariga ham ega. Bu ba'zi patogen mikroblarga xostni muvaffaqiyatli yuqtirish va ularni yo'q qilishdan qochish imkonini beradi. [8] Bundan tashqari, mahalliy mikro muhitda periferik tolerantlikni qo'zg'atish bir qator o'smalar uchun umumiy omon qolish strategiyasi bo'lib, ularni xost immun tizimi tomonidan yo'q qilinishiga to'sqinlik qiladi. [9]


Kirish

Umurtqali hayvonlarning alohida turlari atrof-muhitdan doimiy ravishda kislorod olish uchun noyob evolyutsion bosimlarga duch keldi, bu esa turli xil gaz almashinuvi tuzilmalarining (ya'ni nafas olish organlarining) rivojlanishiga olib keldi 1 . Aksariyat umurtqali hayvonlarda nafas olish ixtisoslashgan gaz almashinadigan sirtlar (ya'ni, gill, o'pka) orqali sodir bo'ladi, ammo gaz almashinuvining kichik foizi teri orqali ham sodir bo'lishi mumkin (ya'ni teri nafasi) 2 . Ixtisoslashgan nafas olish organlarining dizayni bir qancha omillarga, eng muhimi, organizm yashaydigan muhitga, shuningdek, organizmning hajmi va filogenetik holatiga javoban rivojlandi. Umuman olganda, suvli muhitda yashovchi umurtqali hayvonlarda evaginatsiyalangan gaz almashinuvi tuzilmalari (ya'ni gillalar), havodan kislorod oladiganlar esa qurib qolishning oldini olish uchun invaginatsiyalangan tuzilmalarni (ya'ni o'pkalarni) ishlab chiqdilar. Samarali gaz almashinuvi organi tashqi muhitdan (suv / havo) kislorodning qon bilan aloqa qilish samaradorligini oshirishi kerak. Teleost baliqlarida bu yuzlab gill filamentlaridan tashkil topgan to'rt juft tomirlangan gill yoylari orqali amalga oshiriladi, ular ikkilamchi lamelga buklanish orqali ularning aloqa yuzasini oshiradi. Nafas olishdan tashqari, gillalar osmoregulyatsiya, pH muvozanati, ammiakning chiqarilishi, gormonlarni tartibga solish, detoksifikatsiya va immunitetni himoya qilish kabi boshqa funktsiyalarni ham bajaradi. Gills suv bilan to'g'ridan-to'g'ri aloqa qiladi va shuning uchun doimiy ravishda atrof-muhitning toksinlari va patogenlariga ta'sir qiladi. Shunday qilib, baliqning bunday katta va nozik sirtni patogen hujumdan himoya qilish zarurati aniq. Gill immuniteti qanday ishlashi haqida kam ma'lumotga ega bo'lsa-da, gill to'qimasida sezilarli miqdordagi tug'ma va adaptiv immunitet hujayralari borligi va bir nechta tug'ma va adaptiv immun molekulalari va yo'llari gillda ishlaydi 3,4,5,6.

Teleost baliqlarida uchta immunoglobulin sinfi IgM, IgD va IgT/Z 7 mavjud. IgM eng keng tarqalgan sinfni ifodalasa-da, infektsiya yoki emlashga kuchli IgM immun javoblari asosan plazmada aniqlanadi, ichak, teri yoki gillalar kabi shilliq qavat to'qimalarida IgM titrlari past bo'lib qoladi 7 . Bundan tashqari, IgM alabalık terisi, ichak va burun mikrobiotalarining muhim qismini qoplagani ko'rsatilgan 8,9,10. Yashirin IgD baliq va alabalık plazmasida aniqlangan 11,12 , garchi uning teleostlarda funktsiyasi hali ham aniqlanmagan. alabalık sekretor IgD dan farqli o'laroq, baliq IgD ning ajratilgan shakli V hududiga ega emas va bu immunoglobulin tug'ma naqshni aniqlash molekulasi 11 vazifasini bajarishi mumkinligi taxmin qilingan. IgM va IgD ga qo'shimcha ravishda teleostlarda birinchi marta 2005 yilda genom darajasida aniqlangan IgT (shuningdek, IgZ deb ham ataladi) uchinchi immunoglobulin sinfi mavjud (13, 14-raqamlar). Mushuk va medakadan tashqari, o'rganilgan barcha boshqa teleost turlari bu immunoglobulin 15 ni ifodalaydi. Biz ilgari teleost IgT ichak va teri shilliq qavatining immuniteti uchun ixtisoslashgan immunoglobulin ekanligini xabar qilgan edik 8,9. Aniqroq qilib aytganda, biz IgT patogen ta'sirda ichak va teri shilliq qavatida induktsiya qilingan asosiy immunoglobulin ekanligini ko'rsatdik, shuningdek, IgT ushbu sirtlarda topilgan mikrobiotalarni qoplashda keng tarqalgan rol o'ynashini ko'rsatdik. Bundan tashqari, biz alabalık ichaklari, terisi va burunlari bilan bog'langan limfoid to'qimalarda (GALT, SALT va NALT) 8,9,10 ning asosiy B-hujayralari to'plamini ifodalovchi IgT sirtini noyob tarzda ifodalovchi yangi B-hujayra avlodini topdik. Umuman olganda, baliq IgT umurtqali hayvonlar turida topilgan eng qadimgi shilliq qavat immunoglobulinini ifodalaydi. Darhaqiqat, IgT ning shilliq qavat immunitetida yangi atalgan roli, immunoglobulin izotiplarining shilliq qavat va tizimli javoblarga ixtisoslashuvi tetrapod evolyutsiyasi 8 davrida paydo bo'lgan oldingi paradigmaga qarshi chiqdi.

11-sonli baliqda uchta B-hujayra to'plami aniqlangan: IgM + IgD -, IgM + IgD +, IgM - IgD +, odatda ikkita B-hujayra to'plamini IgT/IgZ o'z ichiga olgan barcha boshqa turlarda, shu jumladan IgMda aniqlash mumkin. + IgD + IgT - va IgM - IgD - IgT + (ref. 12). Bundan tashqari, yaqinda bir tadqiqotda IgD + B xujayralari yuzasida IgM ifodasidan mahrum bo'lgan alabalık IgD + B hujayralarining yangi populyatsiyasi tasvirlangan, bu gill 16 ning asosiy B-hujayralari to'plamini ifodalashi ko'rsatilgan. Yuqorida aytib o'tilgan tadqiqotda ishlatilgan bir xil antikorlar oldingi tadqiqotda 12 bu IgD + IgM - B hujayralarini aniqlay olmaganligi sababli, bu B-hujayra to'plami faqat Evropa alabalık liniyasida mavjud bo'lishi mumkinligi taklif qilindi 16 .

Gills shilliq qavat deb hisoblanadi va konvergent evolyutsiya orqali ular sutemizuvchilarning nafas olish shilliq qavatiga o'xshash tuzilmalar va tarkibiy qismlarga ega bo'lgan 1 . Shu munosabat bilan, gill birlamchi va ikkilamchi lamellar epiteliyasi sutemizuvchilarning yuqori nafas yo'llarida topilganiga o'xshash bir-to'rt qavatli kubsimon yoki skuamoz hujayrali epiteliya 17 bilan qoplangan. Bu sirtlar orasidagi yana bir o'xshashlik - bu shilliq qavatning I tipidagi epiteliyasiga xos bo'lgan 18 ga xos bo'lgan mahalliy shilliq ajraladigan hujayralar (ya'ni goblet hujayralari) mavjudligi va himoya va hujayra himoyasining birinchi chizig'ini ifodalaydi. I turdagi sutemizuvchilar shilliq qavatini ifodalovchi o'pkada sekretor IgA (sIgA) mahalliy darajada ishlab chiqariladi va shilliq qavatning nafas olish immunologik reaktsiyalarida ishtirok etadigan asosiy immunoglobulindir 19,20,21. Bir qator hisobotlarda patogen chaqiruv yoki emlash 22,23,24,25 gill patogeniga xos IgM titrlarining induksiyasi tasvirlangan, boshqa teleost immunoglobulinlar vositachiligida antigenga xos javoblar hozircha noma'lum. Baliqdagi IgT ichak va teri shilliq qavatining immunitetida asosiy rol o'ynaganligi sababli, IgT gill immunitetida hal qiluvchi rol o'ynashi mumkin. Biroq, so'nggi paytlarda alabalık IgD gill immun javoblarida muhim rol o'ynashi mumkinligi taxmin qilingan 12,16,24. Shunday qilib, turli xil teleost immunoglobulinlarining gilldagi roli aniq belgilanishi kerak.

Hozirgacha ixtisoslashgan nafas olish yuzalarida mahalliy shilliq qavat immunoglobulin reaktsiyalari faqat tetrapodlarda tasvirlangan. Shuning uchun bu tadqiqot tetrapodlardan oldingi turlarda gaz almashinuvi tuzilmalari va ixtisoslashgan shilliq qavat immunoglobulin reaktsiyalari o'rtasida birlamchi bog'liqlik mavjudligini tekshirish uchun olib borildi. Shu maqsadda, bu erda biz evolyutsion va qiyosiy immunologiya sohasida namunali tur bo'lgan kamalak alabalığının gillalarida ajratilgan shilliq qavat B-hujayrasi va immunoglobulin javoblari mavjudligini tekshirdik 26,27. Bu yerdagi topilmalar IgT patogenga xos immun javoblarda ishtirok etuvchi asosiy gill immunoglobulini degan gipotezamizni qo'llab-quvvatlaydi, shu bilan birga biz gill IgD + IgM - B-hujayra to'plami yoki patogenga xos IgD javoblari haqida hech qanday dalil topmadik. Birinchi marta umurtqali hayvonlar turida biz nafas olish organi bilan bog'liq bo'lgan mikrobiota shilliq qavatning immunoglobulin tomonidan tan olinishini ko'rsatamiz, bu bu erda gill mikrobiotalarining IgT bilan keng tarqalgan qoplamasi bilan tasdiqlanadi. Bundan tashqari, biz IgT ning mahalliy avlodini va IgT + B hujayralarining patogenlarga qarshi ko'payishini ko'rsatamiz, bu esa sut emizuvchi bo'lmagan turning shilliq qavatida ajratilgan shilliq immunoglobulinlarning mahalliy ravishda induktsiya qilinishini birinchi namoyishini taqdim etamiz.


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Xulosa

Ichaklarimizdagi ko'plab bakteriyalar bilan hech qanday salbiy ta'sir ko'rsatmasdan yashayotganimiz, ayniqsa mikroblarning kirib kelishiga yallig'lanish yoki tug'ma immunitet reaktsiyalarini qo'zg'atish uchun mavjud bo'lgan sezgi va effektor tizimlarining boyligini hisobga olgan holda, tananing immun tizimining ajoyib muvaffaqiyatidir. Shunday qilib, kommensal ichak florasi mavjudligida saqlanadigan gomeostatik muvozanat va ichak shilliq qavatini bosib olgan bakterial patogenlarga majburiy ravishda halokatli javob o'rtasida nozik chiziq mavjud. Ushbu sharhda javob bermaslik va ichakdagi faol immunitet himoyasini boshlash o'rtasidagi "muloqot" ni o'rnatish va nazorat qilish mexanizmlari muhokama qilinadi. Si vis pacem, para bellum. (Agar siz tinchlikni xohlasangiz, urushga tayyorlaning.)


Muhokama

Bizning tadqiqotimiz, bizning ma'lumotlarimiz bo'yicha, birinchi bo'lib, sichqon sut bezlarida shilliq qavatning asosiy immun profilini tavsiflaydi va begona agsga qarshi immunitetning reproduktiv holatga bog'liqligini isbotlaydi. Xususan, biz nullipar sut bezida shilliq qavat bilan bog'liq bo'lgan etuk bo'lmagan dendritik hujayralar va ROR γT + CD4 + T hujayralari ustunlik qiladi. Laktatsiya davrida biz antimikrobiyal IgA va musin mRNKlari, tolerogen xususiyatlarga ega dendritik hujayralar, ROR γT + CD4 + T hujayralari va Ag-ga bog'liq immun bardoshlik uchun funktsional dalillarni topamiz. Involyutsiya jarayonida bu shilliq qavatning xususiyatlari antimikrobiyal gen ekspressiyasining kuchayishi uchun kengaytiriladi va Th17'Treg CD4 + T hujayralari xotirasining Ag-mustaqil to'planishi va Gata3 +, Foxp3 + va PD-1 + CD4 + T hujayralarining yuqori darajalarini o'z ichiga oladi. . Involyutsiyaning kuchaygan shilliq atributlari sutdan ajratishdan keyin 6 hafta o'tkinchi bo'lib, immunitet muhiti nullipar holatga o'xshaydi (8-rasm). Ushbu tadqiqotlar sut bezini shilliq qavat sifatida qo'llab-quvvatlaydi va bu shilliq qavatning atributlari ustidan reproduktiv nazoratni yanada aniqlaydi.

Ayol sichqon sut bezlarida shilliq qavatning immun xususiyatlarini dinamik tartibga solish modeli. Dendritik hujayralar to'plami, T hujayralari infiltrati, musinlar va IgA Iglar reproduktiv holatga ko'ra sezilarli darajada o'zgaradi. Nullipar xostlardagi asosiy ROR γT + CD4 + T hujayralari infiltrati laktatsiya davrida va erta involyutsiya (InvD2) davrida sezilarli darajada kengayadi, shu bilan birga musin va IgA ifodasi kuchayadi, bu esa to'siq funktsiyasining yaxshilanishini ko'rsatadi. InvD6 - noyob immunologik holat bo'lib, u immun infiltratlar cho'qqisiga chiqishi va regulyator immun hujayralari paydo bo'lishi bilan tavsiflanadi, ular Treglarning to'qimalarni qayta qurishdagi ma'lum roliga mos keladigan kuzatuvlardir. Regressiyaga uchragan mezbon nullipar xost bilan o'xshashliklarga ega, bu esa shilliq qavatning asosiy immunitet holatiga qaytishni ko'rsatadi.

Bizning ma'lumotlarimiz sut bezlari to'sig'i funktsiyasi va immunitetga chidamlilik ayollarning laktatsiya davrida sog'lig'ini saqlash uchun zarur bo'lganiga mos keladi, bu boshqalar tomonidan ilgari surilgan dalillar (12, 44). Kengaytirilgan to'siq funktsiyasi va immunitetga chidamlilik zarur bo'lishi mumkin bo'lgan sabablardan biri sutning begona Ag xavfini anglatishidir. Xususan, sut sut bezining tabiiy endogen mahsuloti bo'lsa-da, sut oqsillari kamdan-kam uchraydigan Aglarni ifodalashi va markaziy va periferik o'z-o'zini bardoshlik mexanizmlariga qarshi turishi mumkin (15, 45 �). Bundan tashqari, laktatsiya davrida sutda turli xil yashovchan bakteriyalar mavjudligi sababli (20, 48), sut bezini ichakka o'xshatganligi sababli, laktatsiya davrida begona Ag ta'sir qilish xavfi ortadi. Ushbu bakteriyalar sut shakarlari tomonidan qo'llab-quvvatlanadi va chaqaloq ichak sog'lig'ida muhim rol o'ynaydi (49). Shunday qilib, laktatsiya davrida sutga qarshi immunitet reaktsiyasini oldini olish, shuningdek, sut bilan bog'liq bakteriyalarga reaktivlikni kamaytirish muhimligini ta'kidlash mumkin. Bu argument IgA va musin mRNKlari, tolerogen dendritik hujayralar va laktatsiya davrida biz tasvirlaydigan ROR' + CD4 + T hujayralarining ko'payishi bilan mos keladi, chunki bular shilliq a'zolarda immunitetga chidamlilik va sog'lom epitelial to'siqlarni saqlashning asosiy omillari (1'). x020134).

Bizning ma'lumotimizga ko'ra, ushbu tadqiqot shilliq qavat to'siqlari va immunitetga chidamlilik dasturlarini aniqlash uchun birinchi bo'lib, o'tgan laktatsiya davrini va sutdan ajratish natijasida paydo bo'lgan involyutsiyani kengaytiradi. Ko'krakdan ajratish bilan bog'liq bo'lgan shilliq qavat dasturlari, ehtimol, laktatsiya davriga mos keladigan sut bezining sekretsiyasiz, homiladorlikdan oldingi holatga o'tishini qo'llab-quvvatlaydi. Involyutsiya paytida biz tolerantlik mexanizmlari uchun stimul sutdan ajratilgandan keyin sodir bo'ladigan massiv alveolyar hujayralar o'limi ekanligini taklif qilamiz (50). Buning sababi shundaki, o'layotgan hujayralarni iste'mol qilish dendritik hujayralarning tolerogen funktsiyalarini qo'zg'atadi va o'z-o'zidan reaktiv immunitet paydo bo'lishining oldini olishning asosiy mexanizmi hisoblanadi (51�). Xususan, apoptotik hujayralarning dendritik hujayra fagotsitozi CD86 kamayishi bilan o'lchanadigan dendritik hujayralarning kamolotini inhibe qilishi ma'lum, bu esa umuman sodda T hujayralarini faollashtirish qobiliyatining pasayishiga olib keladi (51�).

Dendritik hujayralar eng kuchli bo'lgan APClarning sodda T hujayralari faollashuvini bostirishning asosiy mexanizmi - bu kostimulyator signallar bo'lmaganda Ag taqdimoti. Ushbu dendritik hujayra / T hujayralarining o'zaro ta'siri T hujayralarining apoptoz, T hujayralari anergiyasi (yoki falajlanishi) yoki tartibga soluvchi fenotipga (Treg) polarizatsiyasi orqali T hujayralarining yo'q qilinishidir (35). Biz laktatsiya va involyutsiya davrida Ag-ga bog'liq sodda T hujayralarining to'planishi bostirilishini va tartibga soluvchi fenotiplarga T hujayralarining qutblanishini ko'rsatgan bo'lsak-da, dendritik hujayraning ushbu T-hujayra javoblarini amalga oshirishdagi o'ziga xos roli noma'lum, chunki boshqa immun hujayralar ham bunga qodir. funktsiyalari. Shu bilan birga, laktatsiya va involyutsiya davrida MHCII va CD86 ning dendritik hujayralar ekspressiyasining kamayishi T hujayralariga Ag taqdimotining kamayishi va kostimulyatsiyaning kamayishi bilan mos keladi. Bundan tashqari, emizuvchi sichqon bezining sitokin muhiti yaxshi o'rganilmagan bo'lsa-da, involyutsiya sut bezlari ichidagi sitokin muhitida TGF-β, COX2, IL-10, IL-4 va IL-13 ning yuqori darajasi mavjud (23, 24, 54�). Ushbu sitokin muhiti tolerogen dendritik hujayra funktsiyalarini rag'batlantirish va / yoki T hujayralarini bevosita bostirish bilan mos keladi.

Ajablanarlisi shundaki, laktatsiya va involyutsiya davrida qarindosh Ag ta'siridan keyin T hujayralarining bostirilishi kuzatilganiga qaramay, biz, ayniqsa involyutsiya paytida sut bezida Ag-mustaqil xotira T hujayralarining to'planishini ham kuzatdik. Ushbu xotira T hujayralarining vazifasi atrof-muhitni immunitetni bostirish (Treg) tomon burish va bezlar qulashi paytida epitelial to'siqning yaxlitligini (Th17) saqlab turish bo'lishi mumkin. Shu bilan birga, Treg–Th17-qiyshiq CD4 + T hujayralari ichak shilliq qavatida yallig'lanishga qarshi rolga ega ekanligi haqida xabar berilgan (57). Shunday qilib, involyutsiya bilan bog'liq bo'lgan CD4 + T hujayralari populyatsiyalari bezning sutsiz holatga qaytishi bilan to'qimalarni qayta qurish va proinflamatuar immun dasturlari bilan muvozanatlashtirilgan tartibga solish dasturlarini ta'minlashi mumkin. Garchi ushbu dasturlar sutdan ajratilgandan keyin yuzaga keladigan epiteliya hujayralarining katta yo'qolishi va bezlarni qayta qurish paytida yuzaga kelishi mumkin bo'lgan Th1 ni shikastlovchi yallig'lanishni cheklashi kutilsa ham, bezlar involyutsiyasi paytida CD4 + T hujayra populyatsiyalarining o'ziga xos rollarini baholash uchun kelajakdagi tadqiqotlar talab etiladi.

Involyutsiya paytida CD4 + T-hujayralarining xotirani qanday jalb qilish mexanizmi noma'lum, ammo faollashtirilgan tomirlarni taxmin qilish mumkin (58). Darhaqiqat, sut bezlari qon tomirlari reproduktiv sikl davomida juda dinamik (59, 60) va immun hujayralarini differentsial jalb qilish va drenajlashda rol o'ynashi mumkin. Bundan tashqari, CD4 + T hujayralarining ushbu xotira manbai noma'lum. Boshqa shilliq qavatlardan jalb qilish mumkin, chunki shilliq qavat to'qimalari bo'ylab integratsiya o'pka va ichak uchun qayd etiladi va ichak mikrobiomasi tomonidan tizimli immun reaktsiyalarning o'zgarishi bilan tasdiqlanadi (61, 62). Shilliq qavat atributlari uchun biz baholamagan qiziqarli rivojlanish oynalaridan biri homiladorlik davridagi sut bezlari. Biroq, ma'lumki, tizimli immunitet modulyatsiyasi / bostirilishi homilaning o'z-o'zidan bo'lmagan Aglarga tolerantlikni ta'minlash uchun sodir bo'ladi (63). Homiladorlik davrida tizimli immunitetni susaytirish sut bezlari immunitetiga qanday ta'sir qilishini aniqlash kerak.

Sut bezlari immuniteti bo'yicha tadqiqotlarimiz laktatsiya va involyutsiya davrida yuzaga keladigan patologik sharoitlarni tushunishga keng qamrovli ta'sir ko'rsatishi mumkin. Masalan, bu ikkita reproduktiv oyna o'z-o'zidan va begona Ag ta'sirining ko'payishi bilan tavsiflanadi va agar immunitet tolerantligi to'g'ri bajarilmasa, otoimmunitet paydo bo'lishi mumkin. Laktatsiya etishmovchiligida otoimmunitetning roli o'rganilmagan bo'lsa-da, to'qimalarni yo'q qilish otoimmün kasallikning keng tarqalgan natijasidir va bezlar to'qimalarining etarli emasligi ayollarda laktatsiya etishmovchiligi bilan bog'liq (64, 65). Potentsial oqibatlar qo'shimcha tekshirishni talab qiladi, chunki laktatsiya etishmovchiligi barcha parous ayollarning 5% ni tashkil qiladi va bu chaqaloqning jiddiy to'yib ovqatlanmasligiga olib keladi (64). Bundan tashqari, sut oqsillariga xos bo'lgan Th1 immuniteti otoimmunga o'xshash laktatsiya etishmovchiligini keltirib chiqarishi ko'rsatilgan, bu esa muvaffaqiyatli laktatsiya uchun immunitetga chidamlilik uchun potentsial ehtiyojni qo'llab-quvvatlaydi (66). Bizning tadqiqotimiz, shuningdek, ko'krak bezi saratoni xavfini o'rganish va targ'ib qilish uchun yangi yo'llarni taqdim etishi mumkin, chunki immun bardoshlik immunitetni kuzatishga qarshidir. Potentsial ahamiyatga ega bo'lgan narsa shundaki, tug'ruqdan keyingi davrda ko'krak bezi saratoni rivojlanish xavfi ortadi va tug'ruqdan keyingi davrda rivojlanadigan saratonlar, hatto o'simta bosqichi va biologik pastki turiga mos kelganidan keyin ham, yoshga to'g'ri keladigan tug'ilgan ayollarda ko'krak saratoniga qaraganda yomonroq prognozga ega (9). Bundan tashqari, kemiruvchilar modellarida tug'ruqdan keyingi o'smalarning rivojlanishiga qo'zg'atuvchi bezning immun muhiti ta'sir ko'rsatadi (24, 54, 67). Bizning tadqiqotimiz shuni ko'rsatdiki, tolerogen dendritik hujayralar tomonidan amalga oshirilishi mumkin bo'lgan immunitet tolerantligi sutdan ajratish natijasida paydo bo'lgan involyutsiya paytida kuchayadi va bu immunitetga chidamlilikni sut o'smalari rivojlanishining potentsial mexanizmi sifatida anglatadi.

Umuman olganda, ushbu tadqiqot, bizning ma'lumotlarimizga ko'ra, birinchi marta sichqonchaning normal sut bezining immun muhiti barcha reproduktiv bosqichlarda tabiatda shilliq qavat bo'lishini tavsiflaydi, bu boshlang'ich etuk bo'lmagan dendritik hujayra fenotiplari va ROR's + CD4 + T bilan ko'rsatilgan. hujayralar. Ushbu mukozal immunitet dasturlari laktatsiya va involyutsiya davrida immunosupressiv va immunitetga chidamli dasturlarni o'z ichiga olgan holda kuchaytiriladi va kengaytiriladi. Ushbu tadqiqot sut bezini shilliq qavat organi sifatida qo'shish uchun mantiqiy asosni taqdim etadi, bu sut bezlari ichida va, ehtimol, shilliq qavatning kattaroq tizimida yangi tadqiqot tushunchalariga olib kelishi mumkin.


Qo'llash doirasi

Immunologiya sohasidagi tadqiqotlar uy egasining begona antijenlarga javob berish jarayonlarini tushunishda juda samarali bo'ldi. Aksincha, mezbonning o'ziga immunologik tolerantlikni ta'minlaydigan mexanizmlarini o'rnatishda kamroq muvaffaqiyatga erishildi. Immun tizimi ko'plab nazorat mexanizmlari va nazorat punktlariga bo'ysunishi tobora ravshan bo'lib bormoqda, ularning barchasi o'z-o'zidan bardoshli bo'lishga yordam beradi. Shuningdek, tolerantlik mexanizmlari rivojlanayotgan homila, mikroblar va saraton kasalliklari tomonidan ham qo'llanilishi va immunitet reaktsiyalari paytida to'qimalarga minimal zarar etkazishi aniq bo'ldi.

Tolerantlik mexanizmlarini tushunish otoimmunitet, allergiya va transplantatsiyani rad etishni yaxshiroq nazorat qilish va mikrob patogenlari va saraton kasalliklariga optimal immunitet reaktsiyasini ta'minlash uchun bag'rikenglikni bekor qilish uchun yangi avlod terapevtiklarini yaratadi.

Immunologik bag'rikenglik va tartibga solish bag'rikenglik mexanizmlari, ulardan foydalanish va ulardan qochishga qaratilgan bo'lib, immunologiyaning tez rivojlanayotgan sohasiga ish jalb qilishga qaratilgan. Mutaxassislik bo'limi &ldquoimmunologiya&rdquo bilan shug'ullanadigan ko'plab turkumlardan biridir va faqat ilmiy mazmunga asoslanmagan hozirgi &ldqueditorial siyosatlardan&rdquo qochishga qaratilgan.

Ushbu mavzuga tegishli:

- turli tartibga soluvchi hujayralarning roli va mexanizmlari

- Tolerantlik uchun ruxsat beruvchi mikro muhit

- onaning immunitet tizimi tomonidan homilani rad etishning oldini olish

- tolerantlik mexanizmlarini chetlab o'tish yo'llari va buning oqibatlari


OpenSIUC

Oshqozon-ichak, nafas olish va reproduktiv yo'llarning shilliq qavatlari patogenlarning ko'pchiligi uchun kirish darvozasi bo'lib xizmat qiladi. Tizimli (parenteral) vaktsinalar poliovirus va gripp virusi kabi ba'zi shilliq qavat patogenlaridan himoyani ta'minlashi mumkin, ammo ular shilliq qavat patogenlaridan himoyalanish uchun muhim bo'lgan shilliq qavatning immun reaktsiyalarini keltirib chiqarmaydi. Shilliq qavatdagi vaktsinalarning rivojlanishi shilliq qavat yuzalarida antigenlarning yomon so'rilishi, vaktsina formulalarining immunogenligi yo'qligi va shilliq qavatning immun reaktsiyalarini yaxshiroq tushunish zarurati kabi bir qator omillar tufayli cheklangan muvaffaqiyatga erishdi. Immunitet reaktsiyasini qo'zg'atish uchun shilliq qavat antijenlari epiteliydan o'tib, subepitelial immun bo'limlariga etib borishi kerak. Shilliq qavatda antijenlarning qanday qilib ichkariga singishi va antigen tabiati va antigenni qabul qilish yo'li ularning immunogenligiga qanday ta'sir qilishini tushunish shilliq qavat vaktsinalarini muvaffaqiyatli ishlab chiqishda katta yordam beradi. Bundan tashqari, hatto hozirda litsenziyalangan shilliq qavat orqali yuboriladigan vaktsinalar ham immunitetning zaif xotirasini qo'zg'atadi va birinchi darajali immunizatsiya sxemalari shilliq qavat va tizimli gumoral immun xotiraga qanday ta'sir qilishini tushunish vaktsinani yaratish uchun juda muhim bo'lgan etarli darajada o'rganilmagan tadqiqot sohasi bo'lib qolmoqda. Ushbu ishda biz shilliq qavat antijenini ichkilashtirish yo'llarini va shilliq qavat antijenlariga immun reaktsiyalarini turli shilliq qavat va tizimli immunizatsiya strategiyalaridan keyin ko'rib chiqdik. Biz ingichka ichakni (SI) va ayol jinsiy yo'llarini (FRT) qoplaydigan epitelial hujayralar (EK) NPlarni o'z ichiga olishi mumkinligini ko'rsatdik.

Ulashish

Kirish

Ushbu dissertatsiya faqat SIUC hamjamiyatiga yuklab olish mumkin. Hozirgi SIUC filiallari, shuningdek, ProQuest-dan Janubiy Illinoys universiteti Karbondeylidagi dissertatsiyalar va tezislarni qidirish orqali ushbu maqolaga kampusdan tashqarida kirishlari mumkin. Boshqalar esa mahalliy kutubxonangizning kutubxonalararo abonent bo‘limiga yoki ProQuestning Dissertation Express xizmatiga murojaat qilishlari kerak.


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XULOSA

The mucosal immune system promotes intestinal tolerance by controlling localization and composition of the commensal microbiota. Equally, the commensal microbiota is a fundamental stimulus for priming and activation of both mucosal and peripheral immune responses. However, dysregulated immune responses to the commensal microbiota have profound effects on human health. The dynamic interactions between microbiota and the immune system represent the key to targeted future therapies in chronic intestinal inflammation. To use natural tolerogenic mechanisms occurring under homeostatic microbial-mammalian dialogue, we require not only greater understanding of how the immune system regulates the microbiota, but equally how the distinct microbial communities influence host immunity.


Videoni tomosha qiling: IMMUNITETNI VA KAMQONLIKNI TEZDA KOTARISH (Iyul 2022).


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