WikiDer > Epstein-Barr virusi bilan bog'liq bo'lgan limfoproliferativ kasalliklar - Vikipediya

Epstein-Barr virusi bilan bog'liq lenfoproliferativ kasalliklar (shuningdek, nomlangan EBV bilan bog'liq bo'lgan limfoproliferativ kasalliklar yoki EBV + LPD) - bu bir yoki bir nechta turlari bo'lgan kasalliklar guruhidir limfoid hujayralar (turi oq qon hujayrasi), ya'ni B hujayralari, T hujayralari, NK hujayralariva histiyositik-dendritik hujayralar, bilan yuqtirilgan Epstein-Barr virusi (EBV). Bu yuqtirilgan hujayralarni haddan tashqari bo'linishiga olib keladi va turli xil saraton bo'lmagan kasalliklarning rivojlanishi bilan bog'liq saratondan oldinva saraton limfoproliferativ kasalliklar (LPD). Ushbu LPDlarga EBV bilan dastlabki infektsiya paytida yuzaga kelgan taniqli buzilish kiradi, yuqumli mononuklyozva keyinchalik yuzaga kelishi mumkin bo'lgan keyingi tartibsizliklarning ko'pligi. Virus odatda ushbu LPD rivojlanishida va / yoki rivojlanishida ishtirok etadi, ammo ba'zi hollarda bu "aybsiz" bo'lishi mumkin kuzatuvchi, ya'ni kasallikda mavjud, ammo unga hissa qo'shmaydi.^[1]

EBV bilan bog'liq LPD'lar pastki toifadir EBV bilan bog'liq kasalliklar. EBV infektsiyasi bilan bog'liq holatlarning sezilarli foiziga ega bo'lgan LPD bo'lmagan (qarang Epstein-Barr virusi infektsiyasi) o'z ichiga oladi immunitet buzilishi ning skleroz va tizimli eritematoz;^[2] kabi xavfli kasalliklar oshqozon saratoni,^[3] yumshoq to'qima sarkomalar, leiomyosarkomava farqlanmagan nazofarengeal saraton;^[4] bolalik kasalliklari Alice Wonderland sindromida;^[5] va o'tkir serebellar ataksiya.^[6]

Dunyo aholisining taxminan 95% EBV bilan kasallangan. Dastlabki infektsiya paytida virus yuqumli mononuklyozni keltirib chiqarishi mumkin, faqat kichik o'ziga xos bo'lmagan alomatlar, yoki hech qanday alomat yo'q. Shunga qaramay, virus a ga kiradi kechikish uning mezbonidagi faza va yuqtirgan odam butun umrga aylanadi asemptomatik tashuvchi EBV. Haftalar, oylar, yillar yoki o'nlab yillar o'tgach, ushbu tashuvchilarning ozgina qismi, ayniqsa an immunitet tanqisligi, EBV + LPD ishlab chiqing. Dunyo bo'ylab EBV infektsiyasi 1% bilan bog'liq^[7] 1,5% gacha^[8] barcha saraton kasalliklari.^[1] Ushbu EBV bilan bog'liq saraton kasalliklarining aksariyati LPD. EBV + LPD ning zararli bo'lmagan, premalign va malign shakllari dunyo sog'lig'iga katta ta'sir ko'rsatadi.^[1]

Bu erda keltirilgan LPD tasnifi va nomenklaturasi Jahon Sog'liqni saqlash tashkiloti 2016 yilda. Ushbu tasnif EBV + LPD ni beshta toifaga ajratadi: EBV bilan bog'liq bo'lgan reaktiv lenfoid proliferatsiyalari, EBV bilan bog'liq B hujayra lenfoproliferativ kasalliklari, EBV bilan bog'liq NK / T hujayralari lenfoproliferativ kasalliklari, EBV bilan bog'liq immunitet tanqisligi bilan bog'liq lenfoproliferativ kasalliklar va EBV bilan bog'liq histiyositik-dendritik kasalliklar.^[9]

Patofiziologiya

EBV + LPDda qatnashadigan limfoid hujayralar

B hujayralarining normal pishishi uchun "germinal markaz modeli" da, sodda B hujayralari kiriting germinal markazlar ning limfa tugunlari va boshqa limfoid to'qimalar va ishlab chiqarish uchun vakolatli bo'lish jarayonida antikorlar, ichiga etuk limfoblastlar, sentroblastlar, tsentrotsitlar, xotira B hujayralariva oxir-oqibat plazma hujayralari. Ushbu pishib etish jarayonida B hujayralari ularni qayta joylashtiradi immunoglobulin bir nechta joylarda genlar.^[8] EBV tomonidan ishg'ol qilingan birinchi limfoid hujayralar turi - bu sodda B hujayrasi. Ushbu ishg'oldan so'ng, virus ushbu hujayralar rivojlanishini boshqaradigan genlarni ekspluatatsiya qilish bosqichlarini bosib o'tadi; u yuqadigan sodda B hujayrasini majburlashi mumkin: ushbu bosqichlarning har qandayida kamolotni to'xtatish; xost tomonidan yuqtirilgan hujayra sifatida aniqlanmaydi immunitet tizimi; haddan tashqari ko'payish; va B hujayralari asosida LPDga aylanadi. Virus dastlab yuqtirgan B hujayradan ham chiqishi mumkin; T- yoki NK hujayralarini bosib olish; va bu hujayralarni immunitet tizimi tomonidan aniqlanmasligi, ko'payishi va T- yoki NK hujayralarga asoslangan LPD ga o'tishiga olib keladi.^[10] EBV bilan yuqishi mumkin bo'lgan T hujayralari tabiiy qotil T hujayralari (NK hujayralari), Gamma delta T hujayralari (γδ T hujayralari), sitotoksik T hujayralari (CTL), yordamchi T hujayralari (T_h hujayralar), va follikulyar B yordamchi T hujayralari (T_FH hujayralar).^[11] EBV dendritik-histiyositik hujayrani yaratadigan vosita (ya'ni. follikulyar dendritik hujayra) infektsiya aniq emas. Follikulyar dendritik hujayralar lenfoid hujayralarga qaraganda biriktiruvchi to'qima. Biroq, ular sirt membranasi retseptorlariga ega, CD21 (shuningdek, komplement retseptorlari 2 turi sifatida ham tanilgan), bulardan EBV B hujayralariga kirish uchun foydalanadi. EBV ushbu CD21 kirish yo'li orqali follikulyar dendritik hujayralarni bosib olish uchun yuqtirilgan B hujayradan qochib qutulishi mumkin. Shu bilan birga, EBV yuqtirilgan lenfoid hujayrasini aniq follikulyar dendritik hujayraga etishish uchun yo'naltirishi mumkin degan fikr ham mavjud.^[12]

Epstein-Barr virusi infektsiyasi

Epstein-Barr virusi (shuningdek, odamning herpesvirusi 4 deb nomlanadi) Herpes oilasi I guruh DNK viruslari. U yuqtirilgan odamning og'iz / burun sekretsiyasidan boshqasiga o'tish yo'li bilan tarqaladi og'iz bo'shlig'i yuqtirilmagan shaxsning. Og'iz bo'shlig'iga kirib, virus kirib boradi, ko'payadi, va uning litik fazasini o'rnatadi lizislar (ya'ni portlashlar ochiladi) epiteliy og'zaki satrda joylashgan hujayralar shilliq qavat yangi yuqtirilgan shaxs. Keyin ozod qilingan virus ishg'ol qiladi sodda B hujayralari joylashgan submukozal limfoid to'qima masalan. bodomsimon bezlar yoki adenoidlar. Bu erda u boshqa limfoid hujayralarni yuqtirishga imkon beradigan yoki litik tsiklni bostiradigan va to'rtta kechikish fazalaridan birini o'rnatadigan genlarni ekspluatatsiya qiladigan litik fazani o'rnatadi. Dastlab, virus o'rnatiladi kechikish III ifodalash orqali yadroviy uning tomonidan kodlangan oqsillar EBNA-1, -2, -3A, -3B, -3C, LP, LMP-1, -2A, va -2B va BART genlar; hujayra sirt membranasi uning tomonidan kodlangan oqsillar LMP-1, -2A, va 3A genlar; va mikroRNKlar tomonidan kodlangan EBER-1 va EBER-2 genlar. Ushbu genlarning mahsulotlari abadiylashadi, o'sishi va omon qolishiga yordam beradi va infektsiyalangan B hujayrasining pishib etishini tartibga soladi. Shu bilan birga, ba'zi bir kechikish III genlarining mahsulotlari (xususan, virusli hujayra yuzasi oqsillari) yuqtirgan hujayralarni xujayraning immun tizimi hujumiga moyil qiladi. Virus bunga yo'l qo'ymaydi, uning kechikish genlarini ifodalashni cheklaydi EBNA-1, LMP-1, -2A, -2B, ba'zi BART va ikkita EBER. Bu Kechikish II gen ekspressioni virusga chalingan hujayralarning abadiylashishi va ko'payishini davom ettiradi, hujayralarga qochishga yordam beradi immunitet nazorativa ularni majbur qiladi farqlash (ya'ni etuk) ichiga xotira B hujayralari. EBV tashkil qilishi va saqlab turishi mumkin Kechikish I uning ifloslangan xotirasidagi B hujayralarini faqat ifoda etish orqali bildiring EBNA1 va ikkita EBER geni. Oxirgi genlarning mahsulotlari virusni asosan harakatsiz holatda saqlaydi. Va nihoyat, EBV a-ni o'rnatishi va saqlab turishi mumkin Kechikish 0 faqat EBER genlarini ifodalash orqali faza. 0 kechikishida EBV xotira B hujayralarida to'liq harakatsiz, reproduktiv bo'lmagan viruslar mavjud, ammo boshqa barcha kechikish bosqichlarida bo'lgani kabi, u ham litik fazasiga qaytishi mumkin.^[8] Quyidagi jadvalda EBV kechikish genlarining harakatlari to'g'risida ko'proq ma'lumot berilgan.

EBV bilan bog'liq reaktiv lenfoid proliferatsiyalari

EBV bilan bog'liq bo'lgan reaktiv lenfoid proliferatsiyalar - bu B hujayralari yoki NK / T hujayralari EBV infektsiyasiga aniq reaktsiya sifatida ko'payadigan buzilishlar majmui. Ular odatda o'z-o'zini cheklaydigan, zararli bo'lmagan kasalliklarga ega, ammo xavfli limfoproliferativ kasallikka o'tish ehtimoli o'zgaruvchan.^[1]

Epstein-Barr virus-musbat reaktiv lenfoid giperplaziyasi

EBV-musbat reaktiv lenfoid giperplaziyasi (yoki EBV-musbat reaktiv lenfoid proliferatsiyasi) - bu benign shakl limfadenopatiya, ya'ni shishgan, ko'pincha og'riqli limfa tugunlari. Buzilish asoslanadi histologik da uchraydigan topilmalar limfoid to'qima ko'p yillar oldin EBV yuqtirgan asosan keksa odamlarning. Immunitet tanqisligi har qanday yoshdagi shaxslar ham bu kasallikka duch kelishlari mumkin. Immunologik normal odamlarda gistologik topilmalar ichida joylashgan kichik B hujayralarining mavjudligini o'z ichiga oladi ekstrafollikulyar yoki kamdan-kam hollarda follikulyar maydon normal yoki minimal giperplastik limfa tugunlari. Ushbu hujayralar odatda EBV + bo'lib, EBER virusli genlarini ifoda etadi va virusni I yoki II fazada kechikishida olib yuradi. Ushbu hujayralar ichida ham bo'lishi mumkin ilik. Kasallik sababli immunitet tanqisligi bo'lgan shaxslar, immunosupressiv dorilaryoki qarilik immunosenesensiya ta'sirlangan tugunlarning giperplaziyasi, EBV + hujayralarining ko'pligi va polimorfik limfoproliferativ buzilish deb ataladigan ko'proq tarqalgan buzilishlarni namoyon qilishi mumkin.^[1] Ushbu buzilishlar deyarli har doim o'z-o'zidan o'tib ketadi, ammo kamdan-kam hollarda bir necha oy yoki yillar davomida EBV + ga o'tib ketadi Xodkin limfomasi yoki Keksalarning EBV + diffuzli yirik B-hujayrali limfomasi.^[15]

Epshteyn-Barr virus-musbat yuqumli mononuklyoz

Yuqumli mononukleoz (IM) ~ 90% hollarda EBV tufayli kelib chiqadi; qolgan holatlar sabab bo'ladi inson sitomegalovirusi, adenovirus, yoki toksoplazma.^[16] OIV, qizilcha, va A, B va C gepatit viruslari IMga o'xshash kasallikni keltirib chiqarishi mumkin. O'tkir EBV infektsiyasi odatda <5 yoshdagi bolalarda asemptomatik yoki engil kechadi, o'spirinlar va kattalarning 25-75% infektsiyadan keyin aniq IM rivojlanadi.^[10] IMning belgilari va alomatlari EBV infektsiyasidan bir necha hafta o'tgach sodir bo'ladi. Aksariyat hollarda o'z-o'zini cheklaydigan grippga o'xshash kasallik yoki isitma, og'iz tomog'i, bosh va bo'yin qismidagi og'riqli limfa tugunlari va / yoki kattalashgan engil va o'rtacha darajadagi kasalliklar mavjud. taloq. Ushbu namoyishlar odatda 6 hafta ichida pasayadi. Keyinchalik og'ir holatlar 6 xaftadan keyin davom etaveradi va ular kabi kam uchraydigan, ammo jiddiy asoratlar bilan birga bo'lishi mumkin gepatit, anemiya, trombotsitopeniya, gemofagotsitoz, meningoensefalit, miyokardit, perikardit, pnevmonit, parotit, pankreatit^[16] va kamdan-kam hollarda, ammo o'ta og'ir holatlarda, hayot uchun xavfli bo'lgan asoratlar yorilish yoki taloq yoki gemofagotsitik lenfogiziyositoz (HLH), surunkali faol EBV (CAEBV) yoki limfoma kabi boshqa LPDga o'tish.^[17]

Infektsiyaning o'tkir davrida, odatda, odamlarda og'iz / burun sekretsiyasida yuqumli EBV miqdori yuqori bo'ladi va qonda EBV, atipik limfotsitlar, CD8 T hujayralariva xotira B hujayralari (oxirgi hujayralarning 50% gacha EBV +). The bodomsimon bezlar va bachadon bo'yni limfa tugunlari bu holatlarda giperplazik bo'lib, normal ko'rinishda bo'lgan limfotsitlar aralashmalarini o'z ichiga oladi, faol limfotsitlar, plazma hujayralariva Reed - Sternbergga o'xshash hujayralar.^[14] Ushbu normal ko'rinadigan va faollashtirilgan B hujayralarining aksariyati va to'qimalarning T va NK hujayralarining ozgina qismi EBV + bo'lib, virus asosan yashirin fazalarda emas, balki uning litik tsiklida bo'ladi.^[1] Yengil IM holatlarining diagnostikasi ko'pincha e'tibordan chetda qoladi yoki klinik va odatiy laboratoriya natijalariga asoslanib amalga oshiriladi. Ushbu holatlar, shuningdek asemptomatik va og'irroq EBV infektsiyalari EBV bilan aniq tashxis qo'yilgan bo'lib, dastlabki infektsiya davrida Epshteyn-Barr virusini topib, IgM antikor EBV virusli-kapsidli antijeni (VCA-IgM), IgG VCA (IgG-VCA) ga qarshi antikor va IgG antikorga EBV virusli-kapsid antigeni (EBNA1-IgG) qonda^[10] va / yoki og'iz / burun sekretsiyasida EBV topilishi.^[14] Murakkab bo'lmagan EBV + IMni davolash bo'yicha nazorat qilinadigan tadqiqotlar mavjud emas. Ning qisqa muddatli kurslari kortikosteroid dorilar ko'pincha nafas yo'llarining obstruktsiyasi, otoimmun reaktsiyalari bilan og'rigan bemorlarga buyuriladi (masalan. otoimmun anemiya yoki trombotsitopeniya), yoki kasallikning boshqa asoratlari.^[17] Ushbu va eng og'ir IM holatlarini davolashda odatda har bir asorat turining o'ziga xos xususiyatlariga yo'naltirilgan rejimlar qo'llaniladi.^[10]

Epshteyn-Barr virusi bilan bog'liq gemofagotsitik lenfohistiyotsitoz

Gemofagotsitik limfohistiyotsitoz (HLH) - bu a bilan xarakterlanadigan kam uchraydigan kasallik tizimli yallig'lanish yoki o'ta og'ir holatlarda juda ko'p sitokin bo'roni holat. Bu benign patologik ko'payish va faollashishga bog'liq histiositlar, makrofaglar, va limfotsitlar ortiqcha bo'shatish bilan birga proinflamatuar sitokinlar bu hujayralar tomonidan.^[1] HLH ikkita alohida turga ega. Birlamchi HLH (shuningdek, genetik yoki oilaviy HLH deb ataladi) sabab bo'ladi funktsiyalarni yo'qotish (ya'ni inaktivatsiya qiluvchi) mutatsiyalar sitotoksik T va / yoki NK hujayralari EBV bilan kasallanganlar kabi maqsadli hujayralarni yo'q qilish uchun foydalanadigan genlarda. Bularga mutatsiyalar kiradi UNC13D, STX11, RAB27A, STXBP2va LYST maqsadli hujayralarga toksik oqsillarni tushirish uchun ushbu hujayralar uchun zarur bo'lgan elementlarni kodlovchi genlar; mutatsiyalar PFP ushbu toksik oqsillardan birini kodlovchi gen, perforin 1; va mutatsiyalar SH2D1A, BIRC4, ITK1, CD27va MAGT1 sitotoksik T va / yoki NK hujayralarining rivojlanishi, omon qolishi va / yoki boshqa hujayralarni o'ldirish funktsiyalari uchun zarur bo'lgan oqsillarni kodlovchi genlar.^[18]

Ikkinchi darajali HLH birlamchi HLH kabi, shuningdek, zararli va xavfli bo'lmagan kasalliklar bilan bog'liq va ularni kuchaytiradi deb o'ylashadi. immunitet tizimiEBV bilan kasallangan hujayralarga hujum qilish qobiliyati. Ikkinchi darajali HLH bilan bog'liq bo'lgan xavfli kasalliklarga quyidagilar kiradi T-hujayrali limfoma, B-hujayrali limfoma, o'tkir limfotsitik leykemiya, o'tkir miyeloid leykemiya, va miyelodisplastik sindrom. Ikkinchi darajali HLH bilan bog'liq bo'lgan xavfli bo'lmagan kasalliklarga quyidagilar kiradi: kabi otoimmun kasalliklar voyaga etmagan idyopatik artrit, voyaga etmagan Kavasaki kasalligi, tizimli eritematoz, voyaga etmaganlarning boshlanishi va Still kasalligining kattalar uchun boshlanadigan shakllariva romatoid artrit;^[18] immunitet tanqisligi kasalliklari kabi og'ir birlashgan immunitet tanqisligi, DiJeorge sindromi, Wiskott-Aldrich sindromi, ataksiya telangiektaziva diskeratoz konjenita);^[19] va EBV sabab bo'lgan infektsiyalar, sitomegalovirus, OIV / OITS, bakteriyalar, protozoava qo'ziqorinlar. Ikkilamchi HLH ham kelib chiqishi mumkin yatrogen suyak iligi yoki boshqa organ transplantatsiyasi kabi sabablar; kimyoviy terapiya; yoki immunitetni bostiruvchi vositalar bilan davolash;^[20] Mutatsiyalar natijasida kelib chiqqan HLH holatlarining taxminan 33%, Osiyo HLH holatlarining ~ 75% va HLH holatlarining deyarli 100%. SH2D1A (qarang X-bog'langan lenfoproliferatgiv kasalligi 1-turi) EBV infektsiyasi bilan bog'liq va ularni keltirib chiqaradigan yoki ilgari suradigan fikr. Ushbu holatlar Epstein-Barr virus-musbat gemofagotsitik lymfohististotsitoz (EBV + HLH) deb nomlanadi.^[21] EBV + HLH da virus B hujayralarida bo'lishi mumkin, lekin asosan NK va T hujayralarini, shu jumladan sitotoksik T hujayralarini zararlaydi. Virus sitotoksik T hujayralarining boshqa EBV bilan kasallangan hujayralarni o'ldirish qobiliyatidagi nuqsonlarni keltirib chiqaradi va ularning ortiqcha yallig'lanishli sitokinlarni ishlab chiqarishiga olib keladi. Ushbu sitokinlar histiyosit va makrofaglarning rivojlanishini, faollashishini, ko'payishini va sitokin ishlab chiqarilishini rag'batlantiradi.^[1] Ushbu sitokinlarning haddan tashqari chiqarilishi (masalan, o'sma nekrozi omil-a, interferon-γ, Interleykin 1 beta-versiyasi, interleykin 18va CXCL9) tizimli va ko'pincha og'ir yallig'lanish holatini keltirib chiqaradi.^[21]

Birlamchi HLH ko'pincha osiyoliklarda kuzatiladi <4 yoshda, ikkinchi darajali HLH esa ko'pincha turli yoshdagi bolalar va kattalarda kuzatiladi.^[1] Odatda buzilish isitma bilan kechadi, qon aylanishi kamayadi oq qon hujayralari va / yoki trombotsitlar, kengaygan jigar va / yoki taloq, klinik dalillar gepatitva / yoki markaziy asab tizimi buzilishlar^[21] asabiylashish, ong darajasining pasayishi, tutilish, meningit (ya'ni bo'yinning qattiqligi, fotofobiva bosh og'rig'i), buzilgan kranial asab funktsiyasi, hemipleji, ataksiya (ya'ni mushaklarning murakkab harakatlarini yomon koordinatsiyasi) va mushaklarning ohangini pasayishi.^[18] Laboratoriya tadqiqotlari g'ayritabiiylikni ko'rsatadi jigar funktsiyasi testlari, qon fibrinogenining pasaygan darajasi, qon ivishining buzilishiva qonning yuqori darajasi ferritin, triglitseridlar, eriydi interleykin-2 retseptorlari, va, EBV + HLH holatlarida, aylanma EBV. Keyingi holatlarda gistologik tekshiruv limfatik, suyak iligi, jigar, neyron va boshqa ishtirok etgan to'qimalarda kichik EBV + T hujayralari, atrofda joylashgan kichik EBV + B hujayralari, reaktiv gistiositlar, reaktiv makrofaglar va ~ 70% hollarda infiltratsiya kuzatiladi. gemofagotsitoz, ya'ni eritrotsitlar, leykotsitlar, trombotsitlar va / yoki ularning kashshof hujayralarini histiyositlar va makrofaglar tomonidan yutish. (Gemofagotsitozning dalillari HLH tashxisi uchun juda muhim emas.) Yuqtirilgan limfotsitlarda EBV har qanday yashirin fazadan ko'ra uning litik tsiklida.^[1] Histiocytic Society (2004) tomonidan ishlab chiqilgan HLH tashxisiga mos mezonlarga quyidagi 8 ta alomat yoki alomatning 5 tasini topish kiradi: isitma -38,5 ° C; splenomegali; qonning quyi darajalari, gemoglobin (<10 mg / L), trombotsitlar (<100000 / mkL) yoki <1000 / ml neytrofillar; quyida keltirilganlardan biri yoki ikkalasi ham qonda ochlik triglitseridlari darajasi> 265 mg / dL yoki fibrinogen darajasi <150 mg / dL; limfoid to'qimalarda gemofagotsitoz; qon hujayralari izolatlarida in vitro sinovdan o'tkazilgandek NK hujayralarining past yoki yo'qligi; ferritinning qon darajasining ko'tarilishi; qon darajasining ko'tarilishi yoki eruvchan IL-2 retseptorlari.^[21] EBV-assotsiatsiya kasalligini aniqlash uchun qonning T hujayralarida yoki ishtirok etgan to'qimalarda EBV topilishi talab qilinadi.^[1]

1994 yilgacha, HLH uchun qo'llaniladigan muolajalar, odatda, terapevtik aralashuvlarga o'rtacha javob stavkalari ~ 10% va median omon qolish vaqtlari ~ 12 oy. 1994 yilda Histiocytic Society tomonidan giyohvandlik rejimi o'rnatildi deksametazon + etopozid bu javob tezligini 70% ga oshirdi. Hozirgi vaqtda ushbu rejim tavsiya etiladi, ayniqsa yosh bolalardagi boshlang'ich HLH uchun induktsiya terapiyasi EBV + HLH uchun puls bo'lgan makrofag aktivatsiyasi sindromi bo'lgan bemorlar bundan mustasno metilprednizolon afzal qilingan davolash usuli hisoblanadi. Javob darajasi kattalarnikiga qaraganda yosh bolalarda va ikkilamchi kasalliklarga qaraganda birmuncha yuqori. Induktiv terapiyadan so'ng, allogenik gemopoetik ildiz hujayrasini transplantatsiyasi oldin pasaytirilgan intensivlik konditsionerlik rejimi tanlangan holda, ayniqsa, boshlang'ich HLH bo'lgan holatlarda ishlatilgan va dastlabki natijalar ma'lum bir muvaffaqiyat haqida xabar bergan.^[22] EBV + HLH ni boshqarish ikkinchi darajali HLH ning boshqa sabablari bilan taqqoslaganda unchalik muvaffaqiyatli bo'lmagan.^[10] HLHga yangi yondashuvlar, ayniqsa refrakter yoki takrorlanadigan kasallik holatlarida ulardan foydalanish kiradi antitimotsit globulini, DEP rejimi (ya'ni lipozomal) doksorubitsin, etopozid, metilprednizolon), qarshiinterferon gamma monoklonal antikor,^[22] va, ayniqsa, EBV + -HLH bilan og'rigan bemorlarda, rituximab.^[10]

Surunkali faol Epstein-Barr virusi infektsiyasi

Surunkali faol Epstein-Barr virusli infektsiyasi (CAEBV) (shuningdek T va NK hujayralarining surunkali faol EBV infektsiyasi deb ataladi, tizimli shakl) - bu kam uchraydigan LPD^[1] bolalar va kamdan-kam hollarda kattalar.^[23] CAEBV yuqumli mononukleoz (IM) yoki simptomatik (ya'ni IM) yoki asemptomatik EBV infektsiyasidan keyingi bir necha oydan keyin davom etadigan og'ir LPD buzilishi shaklida namoyon bo'ladi. Buzilishning diagnostik mezonlari bo'lgan xarakterli topilmalar: 1) yuqumli mononuklyozga o'xshash alomatlar, ammo> 3 oy davom etadi; 2) qonda EBV DNKning yuqori darajasi (ya'ni DNKning bir mg uchun> 25 ta virus nusxasi); 3) histologik organ kasalligi dalillari; 4) azoblangan organ yoki to'qimalarda EBV RNK (masalan, EBER) mavjudligi; va 5) ushbu topilmalar ma'lum immunitet tanqisligi, malignite yoki autoimmun buzilishi bo'lmagan odamlarda paydo bo'lishi. CAEBV ning boshqa alomatlariga doimiy yoki davriy isitma, limfa tugunlari, taloq va / yoki jigar kattalashishi, chivin chaqishi uchun kuchli allergiya, toshmalar, gerpes virusiga o'xshash terida pufakchalar, diareya va boshqalar kiradi. üveit. Ushbu buzuqlik bir necha yil davomida davom etmasdan uzoq davom etishi yoki hayot uchun xavfli asoratlar bilan to'la kechishi mumkin. Gemofagotsitoz (ya'ni bloklangan hujayralarni yutish histiositlar), miyokardit, jigar etishmovchiligi, interstitsial pnevmoniya, yoki ichaklarning yorilishi.^[14] CAEBV agressiv NK hujayra leykemiyasi, NK / T hujayra leykemiyasi yoki periferik T hujayra lenfomasi kabi xavfli EBV + T-hujayrali LPD turiga o'tishi mumkin.^[24]

Buzilish EBV + T, NK yoki kamdan-kam hollarda B hujayralarini o'z ichiga olishi mumkin. EBV + T va NK hujayralari bilan bog'liq kasalliklarda CAEBV ta'sirlangan to'qimalarda odatda gistologiya namoyon bo'lib, u malignanlikni ko'rsatmaydi: limfa tugunlarida giperplaziya, fokusli nekrozva kichik granulomalar; taloq namoyishlari atrofiya ning oq pulpa tiqilib qolgan qizil pulpa; jigarda portal tomirlar va sinuslar atrofida mayda limfotsitlar infiltratsiyasi mavjud; va o'pka va yurakda topilmalar mavjud interstitsial pnevmonit va virusli miyokarditnavbati bilan. Eritrofagotsitoz (ya'ni yutish qizil qon hujayralari suyak iligi, taloq va / yoki jigarda tez-tez uchraydi. Ushbu to'qimalardagi asosiy EBV + hujayralari ~ 59% gacha bo'lgan T hujayralari, ~ 40% da T- va NK hujayralari,^[14] va ~ 2% hollarda B hujayralari. EBV + B hujayralaridagi ishtirok etgan limfoid to'qimalarda ko'payish mavjud Immunoblastlar (ya'ni faollashtirilgan B hujayralari), plazma hujayralariva Reed-Sternberg-lide hujayralari.^[1] CAEB tarkibidagi EBV + hujayralari asosan LMP1, LMP2 va EBNA1 virusli oqsillarni va EBER mikroRNKlarni ifoda etadi,^[14] virusning kechikish II bosqichida ekanligini taxmin qilish.^[1] CAEBV rivojlanishining mexanizmi aniq emas. Shu bilan birga, CAEBV bilan og'rigan bemorlarda qon darajasi bir xil bo'lgan hiperflamatuar holat mavjud sitokinlar (ya'ni IL-1β, Il-10va IFNγ) gemofagotsitik limfististotsitozda kuzatiladi. Bundan tashqari, kasallik Sharqiy Osiyoliklar uchun kuchli irqiy imtiyozlarga ega. Ushbu assotsiatsiyalar kasallikning rivojlanishida kuchli genetik moyillik mavjudligini va bu rivojlanish sitokinlarning T- va / yoki NK hujayralari ishlab chiqarilishi bilan bog'liqligini ta'kidlamoqda.^[14]

Dastlab, CAEBV alevlenmeler va tiklanishlar bilan nisbatan sustkashlik kursiga o'tishi mumkin. Shu bilan birga, kasallik deyarli har doim bitta yoki bir nechta organlarning ishlamay qolishi kabi o'limga olib keladigan asoratlarni rivojlantiradi. Yaponiyada olib borilgan tadqiqotlarga asoslangan hozirgi tavsiyalar CAEBV tashxisi qo'yilgan bemorlarni kasallikning boshida intensiv 3 bosqichli ketma-ket rejim bilan davolashni taklif qiladi: 1) immunoterapiya (prednizolon, siklosporin Ava etopozid; 2) sitoreduktsiya (vinkristin, siklofosfamid, pirarubitsin, va prednizolon yoki, muqobil ravishda, prednizolon va siklosporin A); va 3) qayta qurish: allogeneik gematopoetik ildiz hujayrasi transplantatsiyasi oldin kamaytirilgan intensivligi dori-darmonlarni davolash (ya'ni etopozid va sitozin arabinozidi dan so'ng fludarabin, melfalan, timotsitlarga qarshi globulin, metilprednizolon, va etopozid). Ushbu rejimni qabul qilgan bemorlar g'ayrioddiy yuqori 3 yillik hodisalarsiz va umuman omon qolish darajasi> 87% ni olishdi. Ushbu hodisasiz va umumiy omon qolish darajasi qancha davom etishini aniqlash uchun qo'shimcha tadqiqotlar talab qilinadi.^[25]

Chivin chaqishi uchun kuchli allergiya

Kuchli chivin chaqishi allergiyasi (SMBA) kamdan-kam uchraydigan kasallik bo'lib, asosan Sharqiy Osiyolik yoshlarda (o'rtacha 6,7 ​​yosh) uchraydi. Ko'pgina hollarda, bu EBV + NK hujayra turining CAEBV infektsiyasining namoyon bo'lishidir: ~ CAEBV bilan kasallangan odamlarning 33% bu allergiyani rivojlantiradi. SMBA, shuningdek, EBV musbat Xojkin kasalligining kamdan-kam holatlarida uchraydi,^[26] hydroa vacciniforme, agressiv NK-hujayrali leykemiya (shuningdek, agressiv NK-hujayrali leykemiya / limfoma deb ataladi) va ekstranodal NK / T-hujayrali limfoma, burun turi,^[27] kabi EBV salbiy LPD-da surunkali limfotsitik leykemiya va mantiya hujayrasi lenfomasi.^[26] EBV + SMBA - bu yuqori sezuvchanlik reaktsiya. CAEV-da, eng yaxshi o'rganilgan yoki buzilishga moyil bo'lgan SMBA terining qizarishi, shishishi, oshqozon yarasi, nekroz va / yoki chivin chaqishi joyida chandiq paydo bo'lishi. Bu ko'pincha isitma va bilan birga keladi bezovtalik;^[14] kengaygan limfa tugunlari, jigar va / yoki taloq; jigar funktsiyasining buzilishi; gematuriya; va proteinuriya.^[26] Jabrlangan odamlarda qon darajasi oshdi immunoglobulin E (bu rivojlanishda muhim rol o'ynaydi I turdagi yuqori sezuvchanlik teri va boshqa to'qimalarning reaktsiyalari) va EBV + NK hujayralari.^[1] Og'ir holatlarda buzilish murakkablashadi gemofagotsitoz, NK / T-hujayrali limfoma, yoki agressiv NK hujayra leykemiyasi.^[14] Diagnostik ravishda teri lezyonlari epidermisda NK hujayralarining infiltratsiyasini va teri osti to'qimasi bu hujayralarning kichik qismi EBV + virusi bilan kechikish II fazasida. Ushbu lezyonlarda EBV + NK hujayralarining juda yuqori zichligi buzilish NK / T hujayra lenfoma yoki NK hujayra leykemiyasiga aylanganligini ko'rsatadi.^[1] Buzilishning etiologiyasi noma'lum bo'lsa-da, chivin tupurik bezining allergik oqsillari yashirin yuqtirilgan NK hujayralarida EBV reaktivatsiyasini keltirib chiqaradi deb o'ylashadi. Reaktivatsiyadan so'ng, LMP1 kabi EBV genlari, abadiylashuv, ko'payish va ba'zi holatlarda EBV ning qayta faollashtirilgan NK hujayralarining malignitesini keltirib chiqaradigan mahsulotlarni ekspluatatsiya qiladi.^[26] SMBA uchun eng yaxshi davolash usuli aniq emas. Yengil va aniq asoratlanmagan holatlar konservativ tarzda davolanishi mumkin, bunda terida tirnash xususiyati, isitma va bezovtalik kabi alomatlar paydo bo'ladi.^[28] Biroq, CAEFV ning muhim asoratlari bo'lgan gemofagotsitoz, NK / T hujayra lenfomasi yoki agressiv NK hujayra lenfomasi rivojlanishi kabi holatlar ushbu asoratlarga yo'naltirilgan kimyoviy terapevtik rejimlardan foydalanishni qo'llab-quvvatlaydi. Bir vaqtning o'zida agressiv CAEBV ning aniq dalillari bilan bog'liq bo'lgan EBV + SMBA holatlari CAEBVni davolash uchun ishlatiladigan 3 bosqichli rejim tomonidan nisbiy muvaffaqiyatga erishildi.^[25] Kamdan kam hollarda SMBA kasalliklari aniq predispozitsiya qiluvchi kasalliklarga ega bo'lmagan, ammo keyinchalik CAEBV rivojlangan odamlarda uchraydi.^[27][28] Bunday holatlar moyillikni keltirib chiqaradigan kasallikning rivojlanishini diqqat bilan baholashni va kuzatishni talab qiladi.^[28]

Gidroa vaktsiniformasiga o'xshash limfoproliferativ kasallik

Hydroa vaktsiniformasi kam uchraydi fotodermatit quyosh nurlari terining qichishini keltirib chiqaradigan reaktsiya papules va pufakchalar rivojlanmoqda qobiqlar va oxir-oqibat chandiqli to'qima bo'lib qoladi. Shikastlanishlar, birinchi navbatda, yuzning quyosh nurlari ostida va qo'lning orqa qismida paydo bo'ladi. Bu EBV + kasalligi bo'lib, aksariyat holatlar bolalarda rivojlanib, mum va susayish kursini kuzatib boradi va katta yoshga to'lganida hal qilinadi. Biroq, buzilish kattalarda paydo bo'lishi mumkin. Bundan tashqari, bolalar yoki kattalardagi kasallik, quyosh nurlari, yuz shishishi va isitma, vazn yo'qotish, limfa tugunlari, jigar va / yoki taloqning kattalashishi kabi tizimli namoyishlar bilan bog'liq bo'lmagan og'ir, keng va o'zgaruvchan teri lezyonlarini keltirib chiqarishi mumkin. . Bunday holatlar, masalan, EBV + LPD ga o'tishi mumkin T hujayralari limfomasi, T hujayralari leykemiyasi, B hujayrali limfoma, yoki B hujayralari leykemiyasi.^[23] Hidroaktsiniformaning engilroq va tajovuzkor shakllari dastlab navbati bilan klassik gidroaktsiniforma va gidroaktsiniformaga o'xshash lenfoma deb nomlangan, ammo ikkala kasallik turi o'rtasidagi keng qamrovli to'qnashuv 2016 yilga olib keladi Jahon Sog'liqni saqlash tashkiloti ularni Hydroa vacciniforme-ga o'xshash lenfoproliferativ kasallik deb nomlangan bitta kasallikka qayta tasniflash va CAEBV subkategori bo'lish. Terining shikastlanishlarini gistologik tekshirganda infiltratsion limfotsitlar aniqlanadi, ularning aksariyati T hujayralari, ozchilik qismi NK- yoki B- hujayralari.^[23] Terining shikastlanishlarida EBV asosan T hujayralarida uchraydi^[1] va kamroq darajada NK hujayralari.^[14] Marker tadqiqotlari shuni ko'rsatadiki, bu hujayralardagi EBV II kechikish bosqichida.^[1]

Gidroaktsinformaga o'xshash lenfoproliferativ kasallikning agressiv bo'lmagan holatlarini davolash xavfli bo'lmagan kasalliklar uchun standart dermatologik amaliyotlarga amal qiladi. Kasallikning xavfli holatlari uchun, Immunoterapevtik giyohvand moddalar prednizon, interferon-a, xlorokinva talidomid) vaqtinchalik remissiyalar va yaxshilanishlar bergan; standart kimyoviy terapiya va radioterapiya lenfoma va leykemiyani davolash uchun ishlatiladigan rejimlar faqat vaqtinchalik foyda keltirar ekan, ko'pincha qabul qilinishi mumkin bo'lmagan toksikalarni keltirib chiqaradi.^[23] Bir vaqtning o'zida CAEBV ning aniq dalillari bilan bog'liq bo'lgan EBV + gidroksinli vaktsiniformaga o'xshash lenfoproliferativ kasallik holatlari CAEBVni davolash uchun ishlatiladigan 3 bosqichli rejim tomonidan nisbiy muvaffaqiyatga erishildi.^[25]

Epstein-Barr virusi musbat mukokutanoz yarasi

EBV + mukokutanöz yara - bu kam uchraydigan limfoproliferativ buzilish bo'lib, unda infiltratsiya qilinadigan B hujayralari yakka, yaxshi o'ralgan oshqozon yarasini keltirib chiqaradi. shilliq pardalar va teri.^[1] Ushbu kasallik tufayli immuniteti past bo'lgan shaxslar azoblanadi qarilik, immunosupressant kasalliklar (masalan, OIV / OITS), immunosupressiv dori terapiyasi, yoki allogenik gemopoetik ildiz hujayrasini transplantatsiyasi. Ushbu oshqozon yarasi rivojlanishi bilan bog'liq immunosupressiv dorilarga quyidagilar kiradi metotreksat (kasallik keltirib chiqaradigan eng ko'p keltirilgan dori), siklosporin A, azatiyoprin, mikofenolat, TNF inhibitörleri, takrolimusva mahalliy steroidlar. Samaradorligini pasaytiradi deb o'ylashadi immunitet nazorati ushbu predispozitsiya sharoitlari yoki davolash usullari bilan bog'liq holda EBVni harakatsiz holatda ushlab turadi, ammo EBV + B hujayralari tarqalgan joyda emas, ya'ni zararlangan shilliq pardalar va terida. Binobarin, ushbu joylardagi EBV + hujayralari ko'payib, yara yaralarini hosil qilish uchun to'qimalarni yo'q qiladi.^[23]

Ushbu oshqozon yarasini rivojlantiradigan odamlar odatda qariyalardir. Ularning yaralari odatda ajratiladi, og'iz orqali paydo bo'ladi shilliq qavat va kamroq tez-tez terida yoki oshqozon-ichak trakti shilliq qavat. EBV + mukokutanöz yarasi bo'lgan odamlarda oshqozon yarasi og'rig'i va mahalliy to'qimalarning yo'q bo'lib ketishi (bu og'ir bo'lishi mumkin). limfadenopatiya (ya'ni kengaygan va og'riqli limfa tugunlari), boshqa to'qimalarda qatnashish yoki B belgilari. Ammo oshqozon-ichak traktidagi oshqozon yarasi turli xil qorin alomatlari bilan kechishi mumkin, shu jumladan o'tkir favqulodda teshiklar. EBV + LPD ning boshqa ko'plab shakllaridan farqli o'laroq, EBV bilan bog'liq bo'lgan mukokutant yaralar, odatda, EBV ning aniqlanadigan qon darajasi bilan bog'liq emas.^[23] Mikroskopik usulda oshqozon yarasi limfotsitlardan, shu jumladan EBV + B hujayralaridan, ba'zida esa boshqa EBV + limfoid hujayralarining tarqalishidan va histiositlar, plazma hujayralari, eozinofillarva katta tarqalgan immunoblastlar yaqindan o'xshash bo'lishi mumkin, ammo unday emas Reed-Sternberg hujayralari Xodkin limfomasida kuzatilgan.^[14] Rid-Sternbergga o'xshash hujayralar - bu ifodalaydigan EBV + B hujayralaridir o'simta belgisi hujayra yuzasi membranasi oqsili, CD30, B hujayra sirt membranasi belgisi, CD20,^[23] va EBV replikatsiya tsiklining kechikish II yoki III fazalariga xos bo'lgan oqsillar.^[1]

Immunosupressiyani keltirib chiqaradigan boshqa sabablari bo'lmagan keksa odamlarda EBV + mukokutanoz kasalligi ularning yaralari yomonlashib, keyin o'z-o'zidan regresslashi bilan qaytalanuvchi va qaytalanuvchi yo'lni ko'rsatishi mumkin.^[23] Doimiy va / yoki jiddiy simptomatik holatlar juda yaxshi javob bergan rituximab, tijorat monoklonal antikor B hujayralarida mavjud bo'lgan CD20 oqsiliga qarshi qaratilgan.^[14] Boshqa kasalliklarga qarshi immunosupressiv terapiya natijasida ushbu oshqozon yarasini rivojlantirayotgan odamlar, odatda, ularning immunosupressiv davolash rejimida ishlatiladigan dorilarning dozalari kamaytirilgandan so'ng remissiyaga ega. Ushbu bemorlarning aksariyati relapsni boshdan kechirmaydilar.^[23]

EBV + B hujayralari limfoproliferativ kasalliklari

Dastlab B hujayralariga kirgandan so'ng, Epstein-Barr virusi boshqa B hujayralarini yuqtiradi va shu bilan yuqumli mononuklyoz, ya'ni simptomatik kasallikka olib kelishi mumkin yoki bo'lmasligi mumkin. Har qanday holatda ham, virus tez orada uxlab yotgan holatga o'tadi, virusli kechikish 0 ichida faza xotira B hujayralari va yuqtirgan shaxs asemptomatik, umr bo'yi EBV tashuvchisi bo'ladi. Ammo bundan keyin istalgan vaqtda virus qayta faollashishi mumkin, yoki uning litik tsikliga, kechikish bosqichi II yoki kechikish fazasiga kirishi mumkin; boshqa limfoid hujayralarga tarqaladi va uning yuqtirilgan hujayralarini haddan tashqari ko'payishiga, g'ayritabiiy omon qolishiga va EBV + LPD hosil bo'lishiga olib keladi.^[1]

Epstein-Barr virusli musbat Burkitt limfomasi

Burkitt limfomasi uch shaklda uchraydi. Epidemik Burkitt limfomasi (eBL) Afrika, Yaqin Sharq, Braziliya, Papua-Yangi Gvineya va boshqa mintaqalarda keng tarqalgan. bezgak endemik hisoblanadi. Odatda 4-7 yoshli bolalarda namoyon bo'ladi va deyarli barcha holatlarda EBV infektsiyasi bilan bog'liq.^[29] Sporadik Burkitt limfomasi (sBL) kam uchraydi. Bu bolalarda va kamdan-kam hollarda katta (> 60 yosh) kattalarda uchraydi.^[14] It is found primarily in Northern and Eastern Europe, East Asia, and North America.^[30] There are ~1,200 cases/year in the USA.^[29] Only 10–15% of sBL cases are associated with EBV infection.^[31] The immunodeficiency-related form of Burkitt lymphoma (iBL) strikes 30–40% of individuals with OIV- tushuntirilgan OITS^[14] and rare cases of patients who received a ilik yoki boshqa organ transplantatsiyasi; in the latter cases, individuals have almost always received intensive kimyoviy terapiya and therefore are immunodeficient.^[30] About 30% of iBL cases are infected with EBV.^[32]

eBL commonly presents with a jaw mass; periorbital swelling due to an orbital tumor; or an abdominal mass caused by a tumor in the retroperitoneum, kidney, or ovary. Less commonly, it present as a sudden onset of paraplegiya yoki siydikni tutmaslik due to tumor infiltration into neural tissue. sBL commonly presents with abdominal pain, nausea, vomiting, and/or oshqozon-ichakdan qon ketish caused by the growth of an abdominal tumor; a head or neck tumor in lymph nodes, tonsils, nose, sinuses, and/or orofarenks); or extensive bone marrow infiltrations by malignant tumor cells.^[30] iBL commonly presents with fever, other constitutional symptoms, and tumors in the gastrointestinal tract, bone marrow, liver, lung, and central nervous system.^[33] Gistologik examination of BL-involved tissues shows infiltrations by a uniform population of rapidly proliferating (i.e. mitotik indeks approaching 100%) and rapidly turning over (i.e. cells not only rapidly proliferate but also rapidly die due to apoptoz) lymphocytes punctuated by intermittent clear spaces where macrophagess containing ingested dead cells give the tissues the impression of a "starry sky" pattern. The lymphocytes are primarily B cells (e.g., express CD20 va CD10 markers) with rare T cells evident only in the background.^[30] The B cells are derived mostly from germinal center B cells, contain EBV in latency I phase, and express high levels of EBNA1 and EBER viral products. Some cases also express other EBNA and the LMP2A products.^[1] EBNA1 and EBER proteins may contribute to the development and/or progression of BL by inhibiting the death by apoptosis of the cells they infect while the product of LMP2A may activate the infected cell's PI3K hujayra signalizatsiyasi pathway thereby stimulating this cell's proliferation.^{[iqtibos kerak]}

The malignant B cells in all three forms of BL commonly have acquired xromosoma translokatsiyalari involving their MYC gen. MYC a proto-onkogen (i.e. a cancer-causing gene if appropriately mutated or overexpressed) located on the long ("q") arm of human chromosome 8 at position 24 (i.e. at 8q24). In ~90% of BL cases, MYC bu ko'chirilgan uchun IGH (ya'ni Immunoglobulin og'ir zanjiri) gene locus at position 14q32, the IGK (ya'ni immunoglobulin kappa light chain) gene at position 2p12 ("p" stands for short chromosome arm), or the IGL (ya'ni immunoglobulin lambda light chain) gene at position 22q11. These translocations bring MYC ostida transkripsiyaviy control of these antibody-forming loci and thereby cause the MYC mahsulot, Myc to be overexpressed and continuously driving the infected cell to proliferate. Mutations in other genes of the infected cell may promote its malignancy, e.g. ~30% of BL cases harbor B cell P53 gene mutations which may promote cell survival.^[14] These alternate, potentially EBV-independent routes to malignancy and the fact that some BL cases do not involve EBV allow that many cases of EBV+ BL are not caused and/or promoted by EBV: the ubiquitous virus is the likely cause of almost all cases of eBL but be an innocent yo'lovchi virusi in many cases of sBL and iBL.^[1]

Patients with any of the three forms of BL (with or without an association with EBV) are treated with multiple drug kimyoviy terapiya rejimlar. While past studies found much better results in children than adults using this approach, recent studies report that more aggressive chemotherapy regimens that include the intratekal administratsiya of drugs give better results. The COCOX-M-IVAC regimen (systemic siklofosfamid, vinkristin, doksorubitsin, and high-dose metotreksat alternating with ifosfamid, etoposideva sitarabin plus intrathecal methotrexate and cytarabine) give event-free 2 year response rates of >90% in both children and adults. Qo'shilishi rituximab, a monoklonal antikor against the CD20 antigen expressed on B cells, may be added to this or other multiple drug regimens. Avtomatik stem cell bone marrow transplantation has not improved the results of these regiments. Treatment of HIV-associated iBL is similar to, and has success rates comparable, to non-HIV BL, particularly when coupled with treatment directed at HIV although adults >40 years old have had poorer responses to these regiments. Cases refractory to these regimens have a poor prognosis with average overall 3 year survival rates of ~7%.^[29]

Epstein–Barr virus-positive lymphomatoid granulomatosis

EBV+ lymphomatoid granulomatosis (EBV+ LG, also termed limfomatoid granulomatoz [LG]) is a rare disease that involves malignant B cells and reactive, non-malignant T cells; it is almost always EBV+.^[1] This LPD occurs primarily in middle aged males (male:female ratio 2:1). EBV+ LG usually (~90% of cases) presents as a lung disorder with coughing, hemoptizi, shortness of breath, and chest X-rays showing multiple nodular lesions at the base of both lungs. It may also evidence signs and symptoms caused by nodular or infiltrative lesions in the skin, central nervous system,^[34] kidney, liver,^[1] va / yoki periferik asab tizimi,^[35] At presentation the disease usually does not involve lymph nodes.^[1] In rare cases it may not even involve the lung.^[36] The lesions in EBV+ LG consist of occasional large, atypical B cells^[34] located in a background of numerous reactive CD4+ Helper T cells, plazma hujayralari, makrofaglar, and variable numbers of large atypical lymphoid cells which resemble immunoblastlar, plasmablasts, yoki Reed-Sternberg hujayralari. The lesions often center around and evidence destruction of small blood vessels but, paradoxically, do not contain well‑formed granulomalar.^[36] Only the lymphoid B cells in the lesions are EBV+; these cells express LMP1 and EBNA2 viral proteins and therefore carry EBV in its latency III phase.^[1]

Individuals with the disease may be immune deficient due to subtle reductions in their immune function^[1] or, based on individual ish bo'yicha hisobotlar, immunodeficiency diseases such as OIV / OITS, umumiy o'zgaruvchan immunitet tanqisligi, X bilan bog'langan agammaglobulinemiya, gipogammaglobulinemiya, sarkoidoz,^[37] metotreksat- davolangan romatoid artrityoki Wiskott-Aldrich sindromi.^[36] They may also have, again based on case reports, a history of inflammatory/autoimmune diseases such as surunkali gepatit, ülseratif kolit, retroperitoneal fibroz, yoki primary biliary cholangitis.^[37] EBV+ LG may progress to or become complicated by the non-malignant skin disease, limfomatoid papulyoz, or a second lymphoid malignancy such as Hodgkin lymphoma, mikoz qo'ziqorinlari, CD30+ anaplastic large cell lymphoma, follikulyar lenfoma, surunkali limfotsitik leykemiya, or diffuse large B cell lymphoma.^[38] EBV+ LG appears in part due to the virus causing its infected B cell to release kimyoviy moddalar which attract, and thereby stimulate T cells to injure tissues, particularly blood vessels. Impaired host immune function and failure of infected cells to express viral proteins recognized by sitotoksik T hujayralari allows EBV+ B cells to evade the immune system and proliferate.^[36]

LG presents as one of three grades based on the gistologiya of biopsied tissues: grade I (<5 EBV+ cells per high power microscopic field (hpf), no atypical cells/hpf, and minimal nekroz); grade II (5–20 EBV+ cells/hpf, occasional atypical cells/hpf, and moderate necrosis); and grade III (>20 EBV+ cells/hpf, predominance of atypical cells/hpf, and extensive necrosis). Grade I disease may not need therapy and, in rare cases, remits spontaneously.^[36] Grade II and severe grade I disease is treated with immune regimens that include various interferonlar^[36] va / yoki rituximab, a monoklonal antikor against the B cell protein, CD20.^[34] Grade III and severe grade II disease are treated with either high dose glyukokortikoidlar; kimyoviy terapiya sxemalari kabi CHOP, ICE, yoki Hyper-CVAD; or combinations of these treatments. However, the efficacy of interferon-α and rituximab in EBV+G is disputed.^[34]) While EBV+ LG often responds to these treatments, there are no controlled clinical trials proving their long-term therapeutic value.^[36] Medium survival times for all cases of the disease are ~4 years with many cases progressing to other lymphoid malignancies that shorten survival times.^[36]

Epshteyn-Barr virusli musbat Xojkin limfomasi

Xodkin limfomasi (HL) falls into two histologik forms, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and classical Hodgkin lymphoma (cHL) with cHL being divided into nodular sclerosis (NSHD), mixed cellularity (MCHD), lymphocyte rich (LRHD), and lymphocyte depleted (LDHD) subtypes. EBV is found in 30% to 50% of HL cases, but occurs in ~90% of NSHD and MCHD but ≤10% of LRHD, LPHD, or NLPHD cases. HL involves the infiltration of T cells, B cells, makrofaglar, eozinofillar, fibroblastlarva Reed-Sternberg hujayralari (HRS cells, also termed Hodgkin Reed-Sternberg cells) into limfoid va boshqa to'qimalar. HRS cells are large mono- or poly-nuclear cells which: 1) derive from lymph node and/or spleen germinal markaz B cells; 2) may contain EBV and viral products indicative of stage II latency; va 3) are the only malignant cells in, and the mediators of, HD.^[39] EBV in HRS cells are thought to play a role in the patogenez (i.e. development) of EBV+ HL. These cells express uniquely high levels of the virus's LMP1 gene. This gene product protein, LMP1, mimics activated human TNF receptors (masalan, CD40, CD40va RANK) in continuously stimulating the NF-DB, PI3K va JAK-STAT signalizatsiya yo'llari which promote cell proliferation, survival, and production of sitokinlar that may suppress the EBV's lytic cycle to maintain the HRS cells viability.^[39] HRS cells also express the virus's LMP2A gene protein product which mimics the human BCR geni product) in promoting the survival of its parent cells.^[1] And, EBV, by undefined mechanisms, causes nogironlik mutations in the HRS cell's rearranged immunoglobulin G genes to prevent them from expressing immunoglobulins and inducing them to secrete cytokines which recruit the other cited cell types into the EBV+HL's pathological infiltrates. This helps create a local environment conducive for HRS cells to evade the immune system and proliferate.^[39]

EBV+ HL is more prevalent in young children and young adults but can occur in those over 80 years old, perhaps because of old age-related deterioration in immune system function, infectious diseases, or malnutrition.^[1] The incidence of EBV+ HD's in individuals with OIV / OITS is also high, ~10-fold greater than the general population, but the causes for this is unclear.^[39] The presentation of EBV+ HL is similar to that of EBV-HL, e.g. fever, night sweats, weight loss in the setting of swollen lymph nodes, and/or evidence of tumor invasion of other tissues. Treatment of the EBV+ HD is also similar to EBV- HD and offers cure rates approaching 90%,^[14] ba'zi bo'lsa ham population based studies have found a higher incidence of relatively adverse outcomes in older individuals with EBV+ HL.^[1]

Epstein–Barr virus-positive diffuse large B cell lymphoma, not otherwise specified

Diffuse large B-cell lymphoma (DLBCL) is the second most common type of lymphoma. It occurs primarily in elderly adults, far less frequency in younger adults, and rarely in children. Elderly adults present with B belgilari (i.e. fever, night sweats, and weight loss), swollen lymph nodes, and symptoms due to malignant cell infiltrations into the upper gastrointestinal tract, lungs, upper airways, and/or other organs. Younger individuals present with swollen lymph nodes but frequently do not have class B symptoms or involvement of extra-nodal tissues. It is a more aggressive disease in the elderly.^[14] Gistologik features of DLBCL can be divided into three patterns based on the cell types in tissue infiltrates; the anplastic variant (~3% of cases) exhibits prominent Reed–Sternberg-like cells^[40] embedded in a background of histiocytes and lymphocytes;^[14] the immunoblastic variant (8–10% of cases) has 90% immunoblastlar; and the centroblastic variant (80% of cases) is dominated by sentroblastlar.^[40] These histological features are typically accompanied by the invasion and destruction (i.e. nekroz) of small blood vessels. An alternative classification is based on the disease's cell of origin: germinal center B cell DLBCL (GCB-DLBCL) and activated B cell DLBCL (ABC-DLBCL).^[14] Uncommonly, DLBCL occurs by what is known as a Richter transformation ning surunkali limfotsitik leykemiya (CLL) to an extremely aggressive form of DLBCL. Many of these transformations develop in EBV-associated CLL cases (~10–15% of all CLL cases are EBV-associated).^[41]

About 10–15% percent of DLBCL cases are EBV+. These cases, termed Epstein–Barr virus-positive (EBV+) diffuse large B cell lymphoma, not otherwise specified (EBV+ DLBCL), occur predominantly in East Asia and Mexico and less commonly in Europe and the USA. EBV+ DLBCL is distinguished from DLBCL (often termed diffuse large B-cell lymphoma, not otherwise specified, i.e. DLBCL, NOS) in that virtually all the large B cells in the tissue infiltrates of the EBV+ disease type express EBV genes characteristic of the virus's latency III (common in the elderly) or II (common in younger patients) phase.^[31] These large B cells in EBV+ DLBCL are centroblastic (i.e. activated) B-cells^[8] that express EBERs,^[14] LMP1, EBNA1, EBNA2, and other viral proteins;^[1] in >50% of cases, they also express classic B cell antigenic proteins such as CD20, BCL6va CD15. The viral proteins may be responsible for activating their infected cells' NF-DB, STAT/JAK, NODga o'xshash retseptorva Pullikga o'xshash retseptor hujayra signalizatsiyasi pathways which may act to promote the proliferation and survival of the infected cells.^[1]

EBV+ DLBCL commonly occurs in immune-deficient individuals. It is thought to arise in the elderly because of their immunosenesensiya as manifested by an age-related decline in the specific types of CD4 + va CD8 + lymphocytes that function to suppress the growth of EBV+ cells.^[1] EBV+ DLBCL also occurs in individuals who are overtly immunosuppressed due to OIV / OITS (~33% of HIV/AIDS cases are EBV+) or anti-rejection drug therapy following solid organ transplantation (30% to 70% or these cases are EBV+).^[39] Xuddi shunday, Richter transformation of EBV+ CLL to EBV+ DLBCL occurs primarily in CLL cases treated with immunosuppressant drugs and therefore appears due in part to immunosuppression-related reactivation of the latent EBV infecting these CLL cells.^[41] Currant treatments for EBV+ and EBV- DLBCL use either R-CHOP (rituximab, chimeric anti-CD20 monoclonal antibody, siklofosfamid, doksorubitsin, vinkristinva prednizon or R-EPOCH [rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH). Responses to these regimens are poor in EBV+ DLBCL (median survival 2 years),^[42] particularly in CLL-transformed EBV+ DLBCL (median survival 4 months).^[43]

Epstein–Barr virus-associated diffuse large B cell lymphoma associated with chronic inflammation

Diffuse large cell lymphoma associated with chronic inflammation (DLBCL-CI) is an extremely rare EBV-positive DLBCL^[1] that arises as a mass in areas of longstanding inflammation, usually tana bo'shliqlari or narrow spaces.^[44] Almost all of the reported cases of DLBCL involve pyothorax-associated lymphoma (PAL). PAL occurs years after a pnevmotoraks is medically induced in order to collapse a lobe or entire lung around a cavity^[44] yoki davolash uchun plevrit (inflammation of the pleural cavity)^[45] caused by an otherwise uncontrollable condition, almost always pulmonary sil kasalligi. Reports on it are primarily in Japanese elderly males. Far less commonly, DLBCL-CI occurs in association with other chronic inflammation conditions such as osteomyelitis, medical insertion of a foreign body (intrauterine contraceptive devices, metallic implants, surgical mesh), teri yaralariva venoz yaralar. Signs and symptoms of DLBCL-CI reflect the destructive effects of the malignancy in the afflicted areas. The infiltrative lesions consist of diffuse large EBV+ B cells in latency III amidst a variety of benign, EBV-negative chronic inflammatory oq qon hujayralari. The EBV+ large B cells in these lesions often have reduced expression of the CD20 antigen and contain genetic abnormalities such as mutations in P53, overexpression of Myc, and deletion of TNFAIP3. These abnormalities differ form those in the EBV+ large B cells of ordinary DLBCL. Studies suggest that the disease arises as the result of the EBV-driven proliferation of large B cells in a confined anatomical space that segregates them from immunitet nazorati.^[14] and/or of EBV-driven release of cytokines with anti-inflammatory activity (e.g. Interleykin 6 va Interleykin 10) that may also help the infected cells escape this surveillance.^[1]

While DLBCL-CI is an aggressive malignancy, its treatment, particularly in localized disease, should include efforts to remove its underlying inflammatory causes.^[46] For example, PAL is a particularly aggressive form of DLBCL-CI.^[44] Nonetheless, surgical removal of the pleural tumor effectively treats the few cases in which it is localized and of low-grade.^[14] More severe cases of PAL have been treated with chemotherapy regimens such as CHOP but overall 5 year survival rates with these regiments have been poor (~21%).^[47] There are too few reports on the treatment of non-PAF forms of DLBCL-CI to make recommendations.

Fibrin-associated diffuse large B cell lymphoma

Fibrin-associated diffuse large B cell lymphoma (FA-DLBCL) is included as a provisional entry as a type of DLBCL-CI by the World Health Organization, 2016. It is an extremely rare disease that occurs in immunologically competent individuals.^[1] It is due to the infiltration of large B cells into long-standing, avascular fibrin-based masses that develop in, on, or around long-standing hamartomalar, pseudocysts, yurak myxommas, protez yurak klapanlari,^[1] tromb-laden in endovascular grafts, gematomalar,^[14] gidrocellarva protez implantlari kestirib^[48] The infiltrations consist of sheets, ribbons, or clusters of proliferating large B cells within avascular tissue that are coated with or contain abundant fibrin plus a paucity or absence of other types of inflammatory cells.^[48] The large B cells are infected with EBV in latency III and express this virus's EBER, EBNA2, and LMP-1 genes.^[14] The infiltrations typically do not spread beyond these initial sites and there is no evidence of lymph node, spleen, or other tissue involvement: FA-DLBCL appears to be a non-malignant proliferation of EBV+ large B cells. Similar to DLBCL-CI, the development of FA-DLDCL may be due to localized immune suppression at its sites of origin. Unlike DLBCL-CI, however, the large B cells in FA-DLBCL appear unable to proliferate and survive long-term outside of the sequestered sites; consequently, the EBV+ cells tend to spread beyond these sequestered sits and FA-DKBCL does not appear to be a truly malignant disease.^[14] The two disorders also have other differences: the histology of the involved tissues in FA-DLBCL and DLBCL-CI are dissimilar and the large EBV+ B cells in FA-DLBCL, unlike those in DLBCL-CI, do not overexpress the Myc gene and have relatively few karyotip chromosomal abnormalities.^[48]

Patients with FA-DLBCL present with signs and symptoms reflecting the location of the infiltrative lesion. When these lesions occupy the heart (e.g. on myxommas or prosthetic valves) or vasculature (e.g. on thrombus-laden vascular grafts) the disease may present as a life-threatening cardiovascular symptoms, particularly zarbalar.. Outside of these cardiovascular complications, the disease typically takes an indolent course without spreading beyond its site of origin. Removal of the tissues along with any associated foreign implant is usually curative. Refractory or recurrent disease has been treated with the CHOP (± rituximab) with only limited success.^[48]

Epstein–Barr virus-positive human herpes virus 8-associated B cell lymphoproliferative disorders

Human herpes virus 8 (HHV8) is associated with four rare lymphoproliferative disorders: 1) a subset of diffuse large B cell lymphoma (DLBCL), b) large B-cell lymphoma arising in HHV8-associated multicentric Castleman's disease, v) birlamchi efuzion limfomava 4) germinotropic lymphoproliferative disorder. The latter two forms of HHV8+ lymphoproliferatvive disorders have been associated in rare ish bo'yicha hisobotlar with EBV infection.^[49]

Birlamchi efuzion limfoma

Primary effusion lymphoma (PEL) is a HHV8+ B cell lymphoma presenting as an effusion (i.e. excess fluid) in the plevra bo'shlig'i (qarang plevra effuziyasi), qorin bo'shlig'i (qarang peritoneal effusion), yoki perikard (qarang perikardial oqma). These effusions are due to the infiltration of HHV8-infected B cells into the membrane tissues that line these spaces. Tumor masses are infrequent and generally occur late in the disease. PEL is an aggressive, rapidly proliferating lymphoma that commonly spreads to multiple organs adjacent to the involved membrane tissues. Diagnosis of the diseases requires evidence of HHV8 virus involvement by detecting the HHV8 viral protein, LANA-1, in the malignant B cells.^[49] PEL occurs primarily in individuals who are immunodeficient due to OIV / OITS infection or solid organ transplantation. EBV is found in the malignant HHV8+ B cells of ~70% of PEL patients. However, a role for EBV in the development of PEL is not supported since HHV8 appears to drive the development and progression of the disease.^[1] Treatment of PEL with surgery, radiation, kimyoviy terapiya (masalan, CHOP yoki EPOCH drug regimens), antiviral agents, and/or experimental drugs (e.g. rituximab, bortezomib) have not given results that are sufficiently beneficial to make clear recommendations. PEL reportedly has a median overall survival time of 4.8 months and 1, 3, and 5 year overall survival rates of 30%, 18%, and 17%, respectively.^[50]

Epstein–Barr virus-positive, human herpes virus-positive germinotropic lymphoproliferative disorder

Human herpes virus-positive germinotropic lymphoproliferative disorder (HHV+ GLPD) is an extremely rare disorder characterized by the localized swelling of lymph nodes due to the infiltration by plasmablasts (i.e. immature plazma hujayralari). The disorder generally occurs in immune-competent individuals^[51] although it has been reported to occur in HIV-positive individuals. In most cases, the involved lymph nodes have a normal architecture with clusters of plasmablasts that are not only HHV8+ but also EBV+ with EBV likely being in its latency I phase. In the few cases reported, the disorder has shown good to excellent responses to chemotherapy. However, too few cases have been reported to make therapy recommendations or to define the role, if any, of EBV in the disorder.^[1]

Epstein–Barr virus-positive plasmablastic lymphoma

Plasmablastic lymphoma (PBL) is an uncommon lymphoma that occurs mostly in immune-deficient individuals, primarily those with OIV / OITS. Indeed, it is an OITSni aniqlaydigan klinik holat.^[14] The disease can also occur in those who have had an organ transplantation or chemotherapy treatment or are presumed to have age-related immune senescence.^[49] Surunkali otoimmun yoki yallig'lanish kasalliklari (masalan, romatoid artrit, Graves kasalligi, Gigant hujayralardagi arterit, sarkoidozyoki og'ir toshbaqa kasalligi) may also underlie development of PBL.^[52] The disease occurs in individuals (male:female ratio 4:1) of all ages. It presents as a tumor of the head, neck, oral cavity, sinuses or, less commonly, gastrointestinal tact, skin, or other tissues. Histologically, the tumors are classified as monomorphic PBL (consisting predominantly of immunoblastic cells) or plasmacytic PBL (consisting predominantly of cells with features of plasma cells at varying stages of development). While originating from B cells, these cells express plasma cell markers such as CD79a, IR4, BLIMP1, CD38va CD138.^[14] About 70% of PBL cases are EBV+, with most of the lymphoma cells expressing EBV genes indicating that this virus is in latency phase 0 or I.^[1] The disease appears to develop and progress as a result of the actions of both the EPV and inson immunitet tanqisligi virusi (i.e.HIV) and, particularly in EBV+ disease, to be associated with overexpression of the MYC gene in EBV+ cells. Overexpressed MYC protein is thought to drive the disease but the role of EPV in MYC gene overexpression as well as the development and/or progression of EBV+ PBL is not clear. The prognosis of patients with advanced stage PBL, which is a common presentation of the disease in patients with HIV/AIDS, is poor (media survival 6–7 months).^[49] However, PBL patients with early stages of the disease and/or EBV+ disease have a much better survival rate.^[14] Overall, patients with HIV+ PBL respond to CHOP yoki EPOCH chemotherapy regimens with early results for the EPOCH regimen achieving medium survival rates that extend beyond 1 year.^[53]

Epstein–Barr virus-associated plasma cell myeloma

Plasma cell myeloma (PCM, also termed ko'p miyeloma), is a common cancer in which malignant plasma cells infiltrate the ilik or form soft tissue masses termed plasmacytomas. Rarely, EBV may be associated with this disease, particularly in individuals with an Immunitet tanqisligi (e.g. HIV/AIDS, history of organ transplantation) or chronic inflammation (e.g. rheumatoid arthritis).^[54] EBV positivity is more common in the plasmacytoma rather than bone marrow infiltration form of PCM.^[1] Tissues involved in EBV+ PCM typically show foci of EBV+ cells with the appearance of rapidly proliferating (e.g. high mitotik indeks) voyaga etmagan yoki poorly differentiated anplastic plazma hujayralari.^[1] The cells express products of EBV genes such as EBER^[55] which suggest that EBV is in a restricted latency II phase.^[1] Although derived from B cells, these cells express plasma cell rather than B cell markers. The role of EBV in the development and progression of EBV+ PCM is unknown.^[14] EBER-positive patients with the localized plasmacytoma form of PCM are more likely to progress to the infiltrative (i.e. systemic) form of PCM compared to individuals with EBV- disease.^[55] The disorder has been treated with surgical removal in cases with one or two isolated plasmacytoma masses, radiation to isolated plasmacytoma tumor masses, and systemic chemotherapy (e.g. a doksorubitsin, deksametazonva talidomid regimen). However, post-therapeutic recurrence of the disease is common.^[55]

EBV+ NK/T cell lymphoproliferative diseases

While EBV preferentially infects B cells, it may also infect other lymphocyte types viz., CD4 + T hujayralari (i..e T helper cells), CD8+ cells (i.e. cytotoxic T cells), NK hujayralari (i.e. natural killer cells). The mechanism by which EBV infects these other cell types is unknown but may be their direct movement from B cells that are infected with the virus.^[1]

Peripheral T-cell lymphomas

Peripheral T cell lymphomas (PTCL) are a group of NK-cell or T-cell malignancies that include ekstranodal NK / T hujayralari limfomasi, burun turi, peripheral T cell lymphoma, not otherwise specified (PTL, NOS), angioimmunoblastik T-hujayrali lenfoma (AITL), and anaplastic lymphoma kinase positive or negative anaplastic large-cell lymphoma (AKL+/− ALCL).^[56] AKL+/− ALCL is rarely if ever associated with EBV and therefore not considered here.^[57]

Extranodal NK/T cell lymphoma, nasal type

Extranodal NK/T cell lymphoma, nasal type (ENKTL), is a malignancy of NK yoki kamroq, T hujayralari that afflicts primarily Asians and the indigenous populations of Mexico, Central America, and South America. It is less common in Western countries of the northern hemisphere. The disease usually consists of malignant tumors in the nasal cavities, paranasal sinuslar, tomoq, bodomsimon bezlar, nazofarenks, gipofarenksva / yoki gırtlak or, in ~20% of cases, tumors in the skin, yumshoq to'qimalar, oshqozon-ichak trakti, moyaklar, and/or central nervous system. Afflicted individuals are usually middle aged and present with obvious tumors, hemoptizi, ulcerating skin nodules, obstructions in the upper airways, and/or obstructions/bleeding in the lower gastrointestinal tract, particularly the colon. Involvement of lymph nodes is uncommon and generally due to the tumors' spread from their primary sites.^[1] About 70% of ENLTL cases are diagnosed as having saraton bosqichi I or II disease (tumors localized to a single site or region of the body ) with the remainder having disseminated stage III or IV disease.^[58] All stages of ENKTL involve destructive, ulcerating, and necrotic lesions. Histologically, these tumors are composed of small, medium-sized, or large malignant lymphoid cells often accompanied by a mixture of benign yallig'lanish hujayralari. The malignant cells express markers characteristic of NK and/or T cells (e.g. CD2, CD56, CD38), granzyme B, perforin, TIA1, and, with respect to T cells which are commonly gamma delta T cells in type, T-cell receptor gamma and delta chains).^[14] In nearly all cases, the lymphoma cells are EBER+, show a latency II pattern of EBV infection,^[1] have several somatic gene mutations among a group of >35 mutations know to be recurrent in the disease, and overexpress other genes (e.g. P53va / yoki PD-L1).^[11] The genes most often mutated are GAK (25.9% of cases), beta-katenin (22.9%), TP53 (22.7%), and ECSIT (19.3%). These genes regulate cell growth and survival.^[14] Other genes (e.g. JAK3, STAT3va STAT5B ) that are mutated in far lower percentages of cases also regulate these potentially pro-malignant cell functions. However, the relationship of EBV infection to these gene changes and the relationship of these changes to the development of ENKTL are unclear.^[14]

The diagnosis of ENKTL depends upon finding EBV and granzyme B in the disease's lymphoid tumor cells.^[14] Treatment varies with grade. For cancer grade I and II localized diseases, the recommended treatment is radiation directed at the tumor lesions plus a chemotherapy regimen such as DeVIC (deksametazon, etoposide, ifosfamidva karboplatin). Reported overall long-term survival and progression-free survival rates in Japan for individuals treated with this regimen are 72% and 61%, respectively. For stage III and IV disease, a more aggressive treatment regimen is used, SMILE (dexamethasone, metotreksat, leykovorin, ifosamide, L-asparaginase, and etoposide followed, in patients with ≥2 xavf omillari, tomonidan allogeneic bone marrow stem cell transplantation); this regimen reportedly achieves complete response and 5 year survival rates of 87% and 73%, respectively. Reported complete response and 5 year survival rates for relapsed or refractory ENKTL treated with the SMILE regimen are 45% and 47%, respectively.^[58] PD-L1 (programmed death-ligand 1) functions to suppress the proliferation of antigen-specific T cells and promote the survival of inflammation-suppressing T cells; it is over-expressed in >80% of ENKTL cases. Preparations of the monoklonal antikor directed against PD-L1 have given encouraging results in small clinical trials on patients with relapsed/refractory ENKTL. Masalan, pembrolizumab achieved clinical response in 8 of 15 patients and nivolumab in 2 of 3 patients with recurrent/refractory ENKTL. Pembrolizumab is now included as a treatment option for recurrent/refractory ENKTL by the Milliy keng qamrovli saraton tarmog'i.^[59]

Epstein–Barr virus-associated peripheral T cell lymphoma, not otherwise specified

Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS), is an aggressive, heterogeneous group of T cell malignancies with features that do not fit the diagnostic criteria for other types of PTCL.^[9] About 30–40% of all PTCL cases are classified as PTCL, NOS. This lymphoma commonly occurs in men (median age ~60 years) who present with advanced stage III or IV disease (~70% of cases) characterized by T cell infiltrations that cause prevalent lymph node swelling often accompanied by evidence of bone marrow, liver, spleen, and/or skin involvement.^[60] These individuals usually have B belgilari (i.e. fever, tungi terlar, weight loss).^[61] Involved tissues exhibit mature-appearing T cells that express CD4.^[62] However, attempts to define diagnostic criteria for PTCL, NOS by gistologiya va immunofenotiplash have not translated into clinical practice.^[63] Genlarning ekspluatatsiyasi has proven more useful for diagnosing the disease: gene abnormalities commonly associated with PTLC, NOS include various fusion rearrangements ning VAV1 yoki TBX21 genes and fusion rearrangements of the ITK gen bilan SYK, FER, yoki ERBB4 genlar. Two distinct profiles of gene overexpression have emerged from these studies: the malignant cells may overexpress GATA3, MYC, mTORva b-katenin genes or, alternatively, the TBX21, interferon-γva NF-DB genlar. Individuals whose malignant cells express the GATA3 gene group have a poorer overall 5 year survival than those whose malignant cells express the TBX2 gene group.^[60] As defined by the expression of EBER, ~30% of PTCL, NOS cases exhibit malignant T cells that are infected with EBV; in these cases, the virus is in its latency II phase. However, few of these cases evidence strong EBER expression in the malignant T cells. More often, EBER expression in this disease is limited to the small and large benign B cells the populate the background of the disease's lesions. Thus, the relationship of EBV to the development and progression of PTCL, NOS is unclear.^[1]

There are no controlled studies on the treatment of this disease. Recommended treatments for advanced stage PTCL, NOS (regardless of EBV status) include intensive chemotherapy regimens, e.g. CHOP, kabi induktsiya terapiyasi possibly followed by autolog gematopoetik ildiz hujayrasini transplantatsiyasi. These regimens have shown only limited results with 5 year overall survival rates <50% for chemotherapy alone. These survival rates may be improved in patients able to withstand follow-up bone marrow transplantation. Newer drug approaches using Pralatreksat, Romidepsin, Brentuximab vedotin, Belinostat, Bendamustin, lenalidomidva alisertib have shown activity against CTCL, NOS and are being further studied in randomized trials for use in treating refractory and relapsed as well as initial disease.^[60]

Angioimmunoblastic T cell lymphoma

Angioimmunoblastic T cell lymphoma (ATIL) is a systemic malignancy of mature follicular B helper T cells (T_FH hujayralar).^[1] ATIL is often manifested soon after individuals ingest antibiotics or have an infection or allergic reaction. The disease presents with generalized swelling of lymph nodes, enlarged liver and spleen, skin lesions (rash, or, less commonly, nodules, plaques, purpurava ürtiker), bone marrow involvement, and B belgilari isitma, vazn yo'qotish va tungi terlar. Jismoniy shaxslar ham taqdim etishlari mumkin artralgiya, artrit, plevra effuziyalari, astsitlar, o'pkaning shikastlanishi va nevrologik va oshqozon-ichak kasalliklari. Laboratoriya testlari odatda mavjudligini aniqlaydi immunitetli gemolitik anemiya; yuqori qon darajasi eozinofillar, gamma globulinlariva sut dehidrogenaza; yuqori eritrotsitlar cho'kindi jinslari; va ijobiy qon testlari otoantikorlar kabi romatoid omil, yadroga qarshi antikorva silliq mushaklarga qarshi antikor. Ushbu klinik va laboratoriya xususiyatlaridan bir nechtasi shuni ko'rsatadiki, azoblangan odamlarda ularning pastki qismida anormallik mavjud immunitet tizimi. Qatnashgan to'qimalar qon tomirlarining ko'payishini namoyon qiladi, atrofga to'plangan kichik limfoid hujayralar venulalar T ni o'z ichiga olgan fonda_FH hujayralar, faol limfotsitlar, follikulyar dendritik hujayralar, epiteliyoid hujayralar, plazma hujayralariva eozinofillar. Faqat T_FH hujayralar xavfli. Oxirgi hujayralar kasallikning barcha hujayralarining 5-30 foizini tashkil etadi, ekspresiya T_FH hujayra markeri oqsillari (masalan, CD3, CD4, CD10, dasturlashtirilgan hujayra o'lim oqsili 1 (PD-1), shuningdek B limfotsitini ifodalaydi kimyoviy davolash vositasi, ximokin (C-X-C motifi) ligand 13 (ya'ni CXCL13).^[64] Deyarli barcha holatlarda EBV + B hujayralarining tarqalishi, ehtimol virusning cheklangan kechikish II bosqichida bo'lishi mumkin. Ushbu lezyonlarda boshqa hujayra turlari, shu jumladan zararli T_FH hujayralar EBV salbiy. EBV + B hujayralarida ko'plab zararli bo'lmagan mutatsiyalar mavjud bo'lib, ular ko'pincha haddan tashqari ko'payib boradi va ba'zi hollarda o'zgartirish EBV + B hujayralari limfomalariga.^[1] EBV ushbu EBV + B hujayralarining lenfomaga aylanishida va / yoki transformatsiyasida ishtirok etishi mumkin, ammo virusning ATIL bilan bir qatorda uning roli ham noaniq.

AITL diagnostikasi Tni namoyish etishga bog'liq_FH tegishli markerlarni ifodalovchi hujayralar, xususan CXCL13; EBV + hujayralarining mavjudligi tashxisni qo'llab-quvvatlaydi. Xavfli T_FH AITLdagi hujayralar mutatsiyalarga ega TET2, IDH2, va RHOA 30-83% hollarda genlar, PTCL, NOS-da zararli hujayralar ushbu mutatsiyalarni mos ravishda 17%, 0% va 0% holatlarida namoyish etadi. Mutatsiyalar TET2 AITLda eng ko'p tarqalgan (48% dan 83% gacha) va odatda rivojlangan bosqichda uchraydi. Keyingi tadqiqotlar ushbu mutatsiyalarning mavjudligini qo'shishi mumkin, xususan TET2, AITL diagnostika mezonlariga muvofiq.^[65] ATILning prognozi yomon edi. Tomonidan baholanganidek Xalqaro prognostik indeks (ortib borayotgan ball bilan yanada og'ir kasallik), AITL bemorlarining 14% IPI 0-1, 59% 2-3 ball va 28% 4-5 ball bilan murojaat qilishdi. 0-1 andr 4-5 ballari bo'lgan bemorlarning 5 yillik umumiy hayot darajasi tavsiya etilgan davolanish bilan mos ravishda 56% va 25% ni tashkil qiladi. CHOP yoki CHOP-ga o'xshash kimyoviy terapiya rejim.^[66] Ning qo'shilishi etopozid yoki proteazom inhibitori, bortezomib, CHOP rejimlariga umumiy va to'liq javob berish darajasi kamtarona oshdi.^[67] Avtomatik gematopoetik ildiz hujayrasini transplantatsiyasi xuddi shunday CHOP rejimlarining natijalarini yaxshilaydi. Kichik tadqiqotlar shuni ko'rsatdiki, refrakter yoki relapsli AITL bo'lgan bemorlarga ijobiy javoblar mavjud pralatreksat, romidepsin, belinostat, brentuximab vedotin, lenalidomid, alisertibva mogamulizumab. Ushbu dorilar refrakter va relapslarga, shuningdek dastlab davolanmagan AITLga foydaliligi uchun qo'shimcha ravishda o'rganilmoqda.^[66]

Follikulyar T hujayrali limfoma

Oldindan periferik T hujayralari lenfomalarining bir varianti hisoblangan follikulyar T hujayrali limfoma (FTCL), Jahon sog'liqni saqlash tashkiloti tomonidan (2016) angioimmunoblastik T hujayralari lenfomasi (AITL) va boshqa tugunli T toifasidagi lenfoma turi sifatida qayta tasniflangan._FH hujayra limfomalari. Ushbu noyob kasallik AITLga o'xshaydi, chunki u limfa tuguniga asoslangan malignite yoki T_FH hujayralar; u AITLdan farq qiladi, chunki u erta, cheklangan va nisbatan kam tajovuzkor bosqichda tashxis qo'yilishi mumkin va uning to'qima lezyonlarida AITLga xos xususiyatlar mavjud emas, masalan. qon tomirlarining ko'payishini ko'rsatmaydi.^[1] FTCL asosan keksa odamlarda rivojlanadi, ammo 27 yoshgacha bo'lganlarda qayd etilgan. Odatda (~ 73% hollarda) rivojlangan shaxslar mavjud III yoki IV bosqich kasallik bilan tavsiflanadi limfadenopatiya bo'yin, qo'ltiq osti va / yoki naycha sohalarini o'z ichiga olgan (~ 86%); kengaygan jigar (~ 25%) va / yoki taloq (25%); suyak iligida (~ 25%) yoki kamdan-kam hollarda bodomsimon bezlar, tuprik bezlari va / yoki qattiq tanglayda hujayralardagi malign infiltratsiyalar. B belgilari isitma, tunda terlash va vazn yo'qotish <33% hollarda uchraydi. Laboratoriya anormalliklari orasida otoimmun gemolitik anemiya bilan birga bo'lgan yoki bo'lmasdan (~ 50%) musbat Coombs testi va qon darajasining ko'tarilishi kiradi. sut kislotasi dehidrogenaza (45%) va gamma globulinlari (19%).^[68] Ikki histologik jalb qilingan limfoid to'qimalarda patologiya naqshlari tasvirlangan, 1) follikulyar limfomaga o'xshash naqsh, unda malign T_FH hujayralar tugunlarni hosil qiladi va 2) zararli T bo'lgan germinal markazlarga o'xshash naqshning izchil o'zgarishi_FH o'rab olingan tartibsiz shakldagi tugunlardan hujayralar immunoglobulin D mantiya musbat hujayralari (B hujayralarining bir turi). Katta B hujayrasi immunoblastlar va vaqti-vaqti bilan Reed-Sternberg hujayrasio'xshash B hujayralari ham bu zararlanishlarni egallashi mumkin. FTCL ning 50-60% da ushbu B hujayralarining bir yoki bir nechtasi, ammo zararli T emas_FH hujayralar, EBV bilan kasallangan, aftidan II kechikish bosqichida.^[1] FTCLL diagnostikasi klinik va laborator tekshiruvlarga, shikastlanishlar patologiyasiga va limfa tugunlarida, terida yoki Tning boshqa lezyonlarida identifikatsiyaga bog'liq._FH tegishli marker oqsillarini ifodalash bilan belgilanadigan hujayralar (masalan.) PD-1, ICOS, CXCL13, CXCR5va TOX).

Kasallikni davolash bo'yicha nazorat qilinadigan tadqiqotlar haqida xabar berilmagan. I va II bosqich mahalliy FTCL jarrohlik, rentgen terapiyasi, PUVA terapiyasi, mahalliy steroidlar, xloretinva / yoki karustin. Kasallikning III va IV bosqichlari yanada keng qamrovli davolangan kimyoviy terapiya giyohvand moddalar (masalan, metotreksat); bir nechta kimyoviy terapiya dori-darmonlari (masalan, CHOP, R-CVP (ya'ni rituximab, sitoksin, vinkristin, prednizon); bilan Rituximab, bortezomib, talidomid, interferon-alfa, interferon-gamma, bexarotin, gemtsitabin; va bilan gematopoetik ildiz hujayrasini transplantatsiyasi. Ushbu muolajalarga javoblar o'zgaruvchan va ko'pincha umidsizlikka uchragan.^[69] Ammo yaqinda, bendamustin rituximab yoki rituximab bilan siklofosfamid bilan birlashtirilgan, doksorubitsin, vinkristin va prednizon yuqori darajadagi kasallik bilan og'rigan bemorlarda ham qisman javob darajasi> 90% ga erishdi. To'liq remissiya darajasi 90% dan sezilarli darajada past bo'lsa va davolangan bemorlar muqarrar ravishda relapsga uchragan bo'lsa, ushbu rejimlar simptomatik rivojlangan follikulyar lenfoma uchun oldingi bosqichda davolashni tavsiya qiladi.^[70]

Bolalikning tizimli Epstein-Barr virusli musbat T hujayralari lenfomasi

Tizimli EBV-musbat T-hujayralar lenfomasi (TCLC) bu juda kam uchraydigan va agressiv T-hujayralar lenfomasi bo'lib, u deyarli faqat bolalar, o'spirinlar va yosh kattalarda uchraydi. Bu Osiyo va Lotin Amerikalarida tez-tez uchraydi. Kasallik Epstein-Barr virus-musbat yuqumli mononukleoz (EPV + IM) yoki surunkali faol Epstein-Barr virusi infektsiyasining (CAEBV) asorati yoki rivojlanishi sifatida rivojlanadi.^[1] ya'ni EBV + IMga o'xshash kasallik boshlanganidan bir necha hafta o'tgach yoki CAEBV paytida biron bir vaqt o'tgach, belgilar / belgilarning kuchayishi. Ushbu kasalliklarda jigar va taloqning progressiv kattalashishi, jigar disfunktsiyasining kuchayishi, terining yangi toshmalari, pankitopeniya (ya'ni leykotsitlar, qizil qon tanachalari va trombotsitlar qon darajasiga tushadi), gemofagotsitoz (ya'ni qon hujayralarini yutish histiositlar) suyak iligi va taloqda), a koagulopatiya (qon ivishi yomon), sepsis, va / yoki bitta yoki bir nechta organlarning ishlamay qolishi. IM topilmalaridan farqli o'laroq, TCLK bilan og'rigan bemorlarda qon aylanishi darajasi past yoki aniqlanmagan IgM antikor, ammo aniqlanadigan darajalari IgG EBV kapsul antigenlariga qarshi qaratilgan antikor. Qatnashgan to'qimalarda tezda ko'payadigan mayda yoki kamroq tarqalgan, biroz kattaroq lenfoid hujayralar mavjud. Ushbu hujayralar EBV + sitotoksik T hujayralari va ifoda eting CD8, CD3, CD2, TAI1va granzim lekin emas CD56. Kamdan kam hollarda va asosan CAEBV kasalligi sharoitida bu hujayralar mavjud CD4+ T xujayralari yoki CD4 + va CD8+ T hujayralari. Kasallik odatda tashxis qo'yilganidan bir necha hafta ichida o'limga olib keladi. Bir nechta holatlar HLH-2004 ga javob berdi kimyoviy terapiya protokol (etopozid, deksametazon, siklosporin A yoki tanlangan holatlarda, kortikosteroidlar va intratekal metotreksat, qaysi amal qilishi mumkin yoki ko'p emas gematopoetik ildiz hujayrasini transplantatsiyasi.^[14]

Epstein-Barr virusi bilan bog'liq bo'lgan agressiv NK hujayra leykemiyasi

Epstein-Barr virusi bilan bog'liq bo'lgan agressiv NK hujayra leykemiyasi (EBV + ANKL) - bu NK hujayralarining kamdan-kam uchraydigan zararli kasalligi bo'lib, u osiyoliklarda va yoshdan o'rta yoshgacha bo'lgan kattalarda uchraydi. Ba'zan u to'g'ridan-to'g'ri boshqa NK hujayralari proliferativ kasalliklaridan, masalan, yosh odamlarda, surunkali faol EBV infektsiyasidan (CAEBV) rivojlanadi.^[1] Xitoyda o'tkazilgan bir tadqiqot shuni ko'rsatdiki, barcha yoki deyarli barcha bemorlarda B belgilari (vazn yo'qotish, isitma, tunda terlash) va jigar va / yoki taloq kattalashgan, ammo limfa tugunlari emas. Laboratoriya tadqiqotlari aniqlandi pankitopeniya (ya'ni muomaladagi kamaytirilgan sonlar) oq qon hujayralari, trombotsitlarva qizil qon hujayralari) deyarli barcha hollarda; 50% hollarda NK hujayralarining xavfli ekanligini ko'rsatadigan yoki gumon qilinadigan aylanma yirik donador limfotsitlar darajasining ozgina oshishi; barcha holatlarda suyak iligidagi NK hujayralarining ko'payishi; ning qon darajasi juda oshdi sut kislotasi dehidrogenaza va β₂ barcha holatlarda mikroglobulin; qon darajasining oshishi bilan belgilanadigan jigar shikastlanishi fermentlar, umumiy bilirubinva bilvosita umumiy bilirubin ortiqcha qon pıhtılaşma vaqti ≥30% hollarda; va KT tekshiruvi o'ziga xos bo'lmagan ko'rsatib interstitsial pnevmoniya 90% hollarda. Barcha holatlarda suyak iligida EPV + limfotsitlari va to'qima infiltratlari bo'lgan; ba'zan EBV + limfotsitlari aylanib yurgan.^[71] Boshqa tadqiqotlarda EBV + NK hujayralari 85-100% hollarda qayd etilgan.^[1] Gistologik ishtirok etgan to'qimalarni tahlil qilish odatda kichik qon tomirlari atrofida joylashgan, benign yallig'lanish hujayralari bilan aralashgan yirik donador EBV + NK hujayralarining infiltratlarini aniqlaydi; bu topilmalar odatda to'qima bilan birga keladi nekroz. EBV + NK hujayralari ekspresiya qiladi CD56 antijen va maligndir^[72] kechikish II bosqichida EBV bilan. NK hujayralari LMP1 virusli oqsilining nisbatan yuqori darajasini ifodalaydi; bu protein faollashtirishi mumkin NF-DB hujayra signalizatsiyasi yo'l va shu bilan EBV bilan kasallangan hujayralarni ko'payishini rag'batlantiradi.^[1] Ushbu topilmalar ~ 84% odamlarda uchraydi, ular "klassik ANKL" deb nomlanadi. "O'tkir ANKL" bilan og'rigan odamlarning 16%. So'nggi odamlarda yuqumli mononukleozga o'xshash alomatlar va alomatlar mavjud bo'lib, ular 3-15 oygacha davom etadi va keyinchalik klassik ANKLga xos bo'lgan fulminant kursni oladi.^[73]

Klassik va o'tkir o'tkir ANKL hayot uchun xavfli bo'lgan tez rivojlanadi gemofagotsitoz, tarqalgan tomir ichi qon ivishi, jigar etishmovchiligi, buyrak etishmovchiligi, nafas etishmovchiligiva / yoki bir nechta organlarning ishlamay qolishi. Klassik va pastki o'tkir kasallikni ajratib ko'rsatmaydigan tadqiqotlarda o'rtacha yashash muddati ~ 60 kun. Xitoylik bemorlarni o'rganish shuni ko'rsatdiki, o'rtacha omon qolish muddati 49 kun, klassik uchun 215 kun va o'tkir o'tkir ANKL uchun. ANKLni davolashda intensiv kimyoviy terapiya sxemalari ham qo'llanilgan CHOP ortiqcha L-asparaginaza yoki muqobil ravishda SMILE (ya'ni deksametazon, metotreksat, leykovorin, ifosfamid, L-Asparaginaza va etopozid. Biroq, ushbu rejimlarning natijalari omon qolish vaqtining ozgina yaxshilanishi bilan yomon bo'lgan.^[71] Yaqinda, ning qo'shilishi autolog autolog gemotopoetik ildiz hujayrasini transplantatsiyasi ushbu kimyoviy terapiya sxemalarida klassik va o'tkir o'tkir kasalliklarda o'rtacha yashash darajasi o'rtacha darajada yaxshilandi. ANKL uchun yanada samarali davolash sxemalarini topish uchun qo'shimcha tadqiqotlar o'tkazish kerak. Bunday ko'rib chiqilayotgan bitta rejim uchun AspaMetDex (L-asparagenaz, metotreksat, deksametazon) induktsiya terapiyasi uchun SMILE konsolidatsiya terapiyasi so'ngra autolog gemotopoetik ildiz hujayrasini transplantatsiyasi.^[73]

Qon tomir ichidagi NK / T-hujayrali limfomalar

Qon tomir ichidagi lenfomalarning juda noyob ikki turi, tomir ichidagi NK-hujayrali limfoma va tomir ichidagi T- hujayrali limfoma, NK- va EBV infektsiyalari bilan bog'liq va ular tomonidan boshqariladi sitotoksik T hujayralarinavbati bilan. Taqdimotda, azob chekayotgan shaxslar (yoshi 23-81 yosh) terining shikastlanishlarini namoyish etadi; kamroq, alomatlari va alomatlari markaziy asab tizimi ishtirok etish; va ozgina hollarda suyak iligi, jigar, buyraklar, tuxumdonlar va / yoki belgilari va alomatlari bachadon bo'yni ishtirok etish.^[74] O'sha paytda yoki birozdan keyin ular isitma, vazn yo'qotish, tungi terlar, artralgiya, sariqlik, muomaladagi sonlarning kamayishi qizil qon hujayralari, oq qon hujayralariva / yoki trombotsitlarva ko'plab organlarning ishtiroki.^[75] Ikki tomir ichidagi limfoma, umuman olganda, davolanishga yomon ta'sir ko'rsatadigan va qisqa (ko'pincha 12 oydan kam) omon qolish vaqtiga ega bo'lgan bemorlar bilan agressiv va tez sur'atlarda rivojlanib boradigan kasalliklardir.^{[76][77][78][79]}

EBV bilan bog'liq immunitet tanqisligi bilan bog'liq limfoproliferativ kasalliklar

EBV infektsiyasi turli xil limfoproliferativ kasalliklar bilan bog'liq bo'lib, ular immunitet tanqisligining har xil turlaridan biriga ega bo'lgan odamlarda tez-tez uchraydi. EBV + LPD ning ushbu toifasi heterojen bo'lib, EBV bilan kasallangan B hujayralari, T hujayralari va / yoki histiyositik / dendritik hujayralarni o'z ichiga oladi. Ushbu LPD ham sodir bo'ladi immunokompetent shaxslar va yuqorida keltirilgan "EBV + B hujayralari lenfoproliferativ kasalliklari" bo'limida batafsil ma'lumot berilgan.

EBV bilan bog'liq va OIV bilan bog'liq LPD

Tashiydigan shaxslar inson immunitet tanqisligi virusi (OIV, uning sababi OITS) poliklonal limfotsitlarning ko'payishidan (ya'ni benign limfotsitlarning ikki yoki undan ortiq klonlarining g'ayritabiiy proliferatsiyasi) ochiq malign LPDgacha bo'lgan LPD rivojlanish tezligi oshdi. EBV bilan bog'liq va OIV bilan bog'liq malign LPD quyidagilardir: plazablastik xususiyatlarga ega diffuz katta B hujayralari lenfomalari (DLBL); DLBL-ning o'ziga xos pastki turi birlamchi markaziy asab tizimining limfomasi (PCNSL); Burkitt limfomasi (BL); Xodkin limfomasi (HL); plazmablastik lenfoma (PBL); va birlamchi efuzion limfoma (PEL) (shuningdek, plevral effuziya lenfoma deb ataladi). (PEL holatlari nafaqat OIV bilan, balki ko'p hollarda EBV bilan ham yuqtiriladi) Kaposi sarkomasi bilan bog'liq bo'lgan herpesvirus (HHV8) barcha holatlarda.) Ushbu LPD - bu B hujayralari kasalliklari Jahon Sog'liqni saqlash tashkiloti (2016) quyidagilarga bo'linadi: 1) immunitetga ega, OIV-salbiy shaxslar; 2) OIV + shaxslari; va 3) boshqa immunitet tanqisligi kasalliklari bo'lgan shaxslar.^[1] Immunitetga ega, OIV-salbiy odamlarda uchraydigan LPD yuqorida ko'rsatilgan EBV + B hujayra lenfoproliferativ kasalliklari bo'limida batafsil bayon etilgan. Asosan OIV bilan kasallangan odamlarda uchraydigan LPD quyidagi jadvalda batafsil tavsiflangan bo'lib, LPD ning EBV + bo'lgan foizlari, har bir LPDda virusning kechikish bosqichi va rivojlanishiga yordam beradigan zararli hujayralar xostlari tomonidan ifodalangan ba'zi omillar, har bir LPDdagi xavfli hujayralarning o'sishi va / yoki omon qolishi.

Keyinchalik EBV bilan bog'liq va OIV bilan bog'liq LPDni davolash va davolash "EBV + B hujayralari limfoproliferativ kasalliklari" bo'limida keltirilgan. PELning mumkin bo'lgan istisnolari bundan mustasno,^[50] ushbu muolajalar davomiylikni yoki hali OITS bilan davolanmagan shaxslarning muassasasini o'z ichiga olishi kerak OIVga qarshi kombinatsiyalangan giyohvandlik sxemalari.^[1] OIV infeksiyasidan tashqari boshqa sabablarga ko'ra immunitet tanqisligi bo'lgan shaxslarda uchraydigan EBV + LPD toifasiga immunitetga layoqatsizlikning boshqa sabablari kiradi:

1) Kabi immunitet tanqisligi kasalliklari umumiy o'zgaruvchan immunitet tanqisligi, X bilan bog'langan agammaglobulinemiya, gipogammaglobulinemiya,^[37] The Wiskott-Aldrich sindromi, ataksiya telangiektazi, ning radiosensitiv shakllari og'ir birlashtirilgan immunitet tanqisligi kasalligi (SCID), otoimmun lenfoproliferativ sindrom, va WHIM sindromi.^[10]

2) Immunosupressiv dori terapiya, ayniqsa metotreksat va metotreksatni o'z ichiga olgan rejimlar.^[37]

3) Uchun genlarni ifodalashdagi genetik nuqsonlar XIAP apoptoz oqsilining X bilan bog'langan inhibitorini kodlash, IAK interlökin-2 induktsiyalangan T hujayra kinazini kodlash, CD27 ichidagi retseptorni kodlash o'simta nekroz omil retseptorlari superfamily, STK4 serin / treonin-protein kinaz 4 ni kodlash, 1CTPS1 CTP sythetase-ni kodlash, CORO1A koronin 1A kodlash, APDS faollashtirilgan fosfatidilinozitid 3-kinazni kodlash, CD16 kodlash FcγRIII, GATA2 GATA-majburiy omil 2 ni kodlash (a transkripsiya omili) va MCM4 DNK replikatsiyasini litsenziyalash omilini kodlash, MCM4.^[10]

4) Kabi yallig'lanish / otoimmun kasalliklar surunkali gepatit, ülseratif kolit, retroperitoneal fibrozva birlamchi biliar xolangit.^[37]

5) Surunkali otoimmun va yallig'lanish kasalliklari kabi romatoid artrit, Graves kasalligi, Gigant hujayralardagi arterit, sarkoidozva og'ir toshbaqa kasalligi), ayniqsa ushbu kasalliklarga qarshi immunosupressiv dorilarni qabul qiladigan shaxslarda.^[52]

Ushbu kasalliklarni davolash odatda LPD uchun immunitetga ega bo'lgan odamlarda uchraydi, ammo immunosupressiv dorilar dozalarini to'xtatish yoki kamaytirish va immunitet tanqisligini keltirib chiqaradigan asosiy kasallik bilan bog'liq.^[49]

Transplantatsiyadan keyingi limfoproliferativ kasalliklar

Transplantatsiyadan keyingi lenfoproliferativ kasalliklar (PTLD) - bu LPD guruhi bo'lib, ular keyinchalik paydo bo'ladi qattiq organ yoki gematopoetik ildiz hujayrasini transplantatsiyasi. Ushbu transplantatsiyalarga hamroh bo'ladigan immunosupressiv dori sxemalari tufayli. EBV-pozitivligi ushbu holatlarning 60-80% da uchraydi va EBV-salbiy holatlaridan farqli o'laroq, EBV + holatlari transplantatsiyadan keyingi birinchi yil ichida tez-tez rivojlanadi. JSSTning 2026 tasnifi ushbu kasalliklarni quyidagilarga ajratadi:^[49]

1) Buzilib ketmaydigan PTLD: ushbu buzilish xarakterlidir giperplaziya ning plazma hujayralari, florid giperplaziyasi limfa tuguni follikulalar va yuqumli mononukleoz. Ularning uchalasi ham zararli bo'lmagan kasalliklar bo'lib, ular plazmaning buzilmas proliferatsiyasi bilan qo'shilib, odatda EBV-salbiy, EBV-salbiy B hujayralari va kam uchraydigan EBV-musbat T hujayralari hisoblanadi.

2) Monomorfik PTLD: bu buzilish B- yoki T hujayrali lenfoma. EBV-pozitiv mukokutanoz yarasini kiritishdan tashqari, LPD ning barcha sustkash shakllarini hisobga olmaganda, unga faqat agressiv lenfomalar kiradi. Ushbu PTLDda ishtirok etgan hujayralarning EBV + pozitivligi immunitetga ega bo'lgan odamlarda uchraydi. EBV-pozitiv mukokutanoz yarada shikastlanishlarga odatda EBV-musbat plazma hujayralari kiradi.

3) Klassik Xodkin limfomasi: bu HD malignite EBV + hujayralari va uning zararlanishi bilan tavsiflanadi. Ushbu jarohatlar, aks holda, immunitetga ega bo'lgan odamlarda paydo bo'lganlarga o'xshashdir.

Uchta PTLDdagi virus III kechikish bosqichida bo'lib, ularning barcha kechikish genlarini, xususan, LMP1 va LMP2A ni o'z ichiga oladi. So'nggi ikkita EBV kechikish oqsillari ushbu PTLD ni faollashtirish orqali rivojlanishini va rivojlanishini ta'minlaydi deb o'ylashadi NFkB yo'l va shu bilan yuqtirilgan xujayra hujayralarining ko'payishi va omon qolishini rag'batlantirish.^[49]

EBV bilan bog'liq bo'lgan histiyositik-dendritik kasalliklar

Yallig'lanadigan psevdotumorga o'xshash follikulyar / fibroblastik dendritik hujayra sarkomasi

Yallig'lanadigan psevdotumorga o'xshash follikulyar / fibroblastik dendritik hujayra sarkomasi follikulyar dendritik hujayra sarkomasining (FDCS) variantidir. FDCS - bu kam uchraydigan malignite follikulyar dendritik hujayralar (FD hujayralari). Bular myofibroblasto'xshash hujayralar stromadan olingan (ya'ni.) biriktiruvchi to'qima) ning limfa tugunlari va boshqalar limfa to'qimasi va shuning uchun limfotsitlar emas. FD hujayralari limfotsitlar bilan ifodalangan bir nechta markerlarni ifodalaydi; egallash germinal markazlar limfoid to'qimalar; va, ning farqlanishini va tarqalishini jalb qiladi, rag'batlantiradi hozirgi xorijiy antijenler B hujayralariga.^[12] FDCSdagi FD hujayralari quyidagilardan kelib chiqishi mumkin follikulyar lenfoma jarayoni orqali hujayralar transdifferentsiya.^[12] FDCS, asosan, har ikki jinsdagi yoshdan o'rta yoshgacha bo'lgan kattalarga ta'sir qiladi. Odatda og'rigan odamlarda og'riqsiz, servikal limfa tugunlarining asta-sekin o'sib borishi kuzatiladi. Taxminan 33% holatlarda terining o'smalari (bo'yin bachadon limfa tugunlari shishgan yoki bo'lmagan holda), mediastin, bodomsimon bezlar, oshqozon-ichak trakti va / yoki yumshoq to'qimalar. Barcha holatlarning 10-20% i presedent yoki zamonaviy bilan bog'liq Castleman kasalligi, benign limfoproliferativ buzilish.^[81] FDCS ning an'anaviy va yallig'lanishli ikkita histopatologik shakli mavjud. An'anaviy FDCS kichik lenfotsitlar fonida shpindel shaklidagi FD hujayralarini namoyish etadi; yallig'lanishli FDCS fonida nisbatan kam uchraydigan shpindel shaklidagi hujayralarni namoyish etadi plazma hujayralari, o'rta va katta o'lchamdagi limfotsitlar va Reed - Sternbergga o'xshash hujayralar. EBV faqat FDCS ning yallig'lanish shakli bilan bog'liq.^[82] Bunday hollarda FD hujayralari FD-hujayra markerlarini ifoda etadi (masalan. CD21, CD23, CD35, klasterin, podoplanin, gamma-sinuklein)^[81] va> 90% hollarda EBER virusi mahsulotlari^[82] va LMLP1 genlari.^[1] Ushbu hujayralar II yoki III kechikish davrida EBV bilan kasallangan, fon hujayralari esa EBV-salbiy va zararli emas. Bir tadqiqotda, EBV + FDCS bilan kasallangan 5 kishidan ikkitasida, faollashtiruvchi mutatsiya bo'lgan BRAF. FDCSdagi EBV uchun roli isbotlanmagan bo'lib qolsa-da, LMP1 kalamush fibroblastlarini in vitro zararli xatti-harakatga aylantirishi mumkin. FD hujayralari tomonidan LMP1 ning ifodalanishi ushbu hujayralarning FDCSdagi malignitesiga hissa qo'shishi mumkin.^[1]

Umuman olganda, FDKS bilan kasallangan bemorlarda mahalliy takrorlanish darajasi 40-50 va ~ 20% kasallik tufayli uzoq muddatli o'lim darajasi mavjud.^[81] Shu bilan birga, FDSC, ayniqsa limfa tugunlarining tutilishi bo'lgan hollarda, odatda past darajadagi (~ 10%) metastaz. Bunday holatlarda jarrohlik yo'li bilan olib tashlash tanlov usuli hisoblanadi; bu erda radiatsiya va kemoterapiyaning roli yaxshi aniqlanmagan. Ekstranodal tutilish holatlari, ayniqsa qorin shishi bilan og'rigan bemorlarda metastatik ko'rsatkich yuqori (~ 20%). Xemoterapiya sxemalari tarqalgan FDKSni davolashda asosiy vosita bo'lib qolmoqda. Biroq, ushbu rejimlar (masalan, CHOP, ICEva ABVD) o'zgaruvchan natijalarga erishdi. Juda kam odam allogen bilan davolangan gematopoetik ildiz hujayrasini transplantatsiyasi uning FDSCni davolashdagi rolini aniqlash.^[12] BRAF onkogen inhibitori kabi nurlanish, ximioterapiya, suyak iligi transplantatsiyasi va boshqa yangi ximiyaviy bo'lmagan dorilarning foydaliligi bo'yicha keyingi tadqiqotlar, vemurafenib, (BRAF onkogenli shaxslar uchun) kerak.^[81]

Adabiyotlar