Обзоры, проблемы - Сельскохозяйственная биология

ÑÅËÜÑÊÎÕÎÇßÉÑÒÂÅÍÍÀß ÁÈÎËÎÃÈß, 2013, ¹ 4, ñ. 3-25
Îáçîðû, ïðîáëåìû
ÓÄÊ 636.5:591.1:577.27
ÊÈØÅ×ÍÛÉ ÈÌÌÓÍÈÒÅÒ Ó ÏÒÈÖ: ÔÀÊÒÛ È
ÐÀÇÌÛØËÅÍÈß
(îáçîð)
Â.È. ÔÈÑÈÍÈÍ1, Ï. ÑÓÐÀÉ2, 3
Èììóííàÿ ñèñòåìà êèøå÷íèêà èãðàåò âàæíåéøóþ ðîëü â ïîääåðæàíèè èììóííîé çàùèòû îðãàíèçìà, ïîñêîëüêó ïðåäñòàâëÿåò ñîáîé ïåðåäîâóþ ëèíèþ ñòîëêíîâåíèÿ ñ ðàçëè÷íûìè ïàòîãåíàìè, ïîñòóïàþùèìè ñ êîðìîì è ñïîñîáíûìè êîëîíèçèðîâàòü êëåòêè è òêàíè õîçÿèíà. Ïðè
ýòîì ðîëü çàùèòíûõ ìåõàíèçìîâ êèøå÷íèêà òðóäíî ïåðåîöåíèòü. Ïðîöåññû îáó÷åíèÿ ðàñïîçíàâàíèþ «ñâîé—÷óæîé», ïðîèñõîäÿùèå â êèøå÷íèêå, îòíîñÿòñÿ ê îñíîâîïîëàãàþùèì äëÿ âûðàáîòêè
êàê ýôôåêòèâíîé èììóííîé çàùèòû, òàê è òîëåðàíòíîñòè ê ðàçëè÷íûì íóòðèåíòàì. Ïðè ýòîì
ìèêðîñòðóêòóðíûå èçìåíåíèÿ â êèøå÷íèêå, â ÷àñòíîñòè â ñëèçèñòîé, îòâå÷àþò çà ñíèæåíèå àññèìèëÿöèè íóòðèåíòîâ. Ñëåäîâàòåëüíî, åãî ñîñòîÿíèå îïðåäåëÿåò çäîðîâüå ïòèöû, ýôôåêòèâíîñòü èñïîëüçîâàíèÿ ïèòàòåëüíûõ è áèîëîãè÷åñêè àêòèâíûõ âåùåñòâ, ÷òî, â ñâîþ î÷åðåäü, ñâÿçàíî ñ ðîñòîì
è ðàçâèòèåì, êîíâåðñèåé êîðìà è äðóãèìè âàæíûìè ïðîìûøëåííûìè ïîêàçàòåëÿìè â ïòèöåâîäñòâå.
 îáçîðå îáîáùåíû ñîâðåìåííûå ïðåäñòàâëåíèÿ î ðàçâèòèè è ìîðôîôóíêöèîíàëüíûõ îñîáåííîñòÿõ
çàùèòíûõ èììóíîëîãè÷åñêèõ ìåõàíèçìîâ êèøå÷íèêà ó ïòèö. Îñîáîå âíèìàíèå óäåëåíî âîçìîæíîñòè
èììóíîìîäóëÿöèè â êèøå÷íèêå ïîñðåäñòâîì èñïîëüçîâàíèÿ ýôôåêòèâíîé êîìáèíàöèè ðàçëè÷íûõ
áèîëîãè÷åñêè àêòèâíûõ âåùåñòâ.
Êëþ÷åâûå ñëîâà: ïòèöà, ñòðåññ, èììóíèòåò, êèøå÷íèê, âèòàãåíû.
Èçâåñòíî, ÷òî ìàññà ñâåæåâûëóïèâøåãîñÿ öûïëåíêà çà 1-þ íåä æèçíè óâåëè÷èâàåòñÿ â 4,4 ðàçà, çà 5 íåä — íà 5000 % è äîñòèãàåò 2 êã. Ñòîëü
âûñîêèå ïîêàçàòåëè âîçìîæíû áëàãîäàðÿ èíòåíñèâíîé ñåëåêöèè íà ñêîðîñòü ðîñòà, ìåðîïðèÿòèÿì ïî ïîääåðæàíèþ çäîðîâüÿ è îïòèìàëüíûõ óñëîâèé ñîäåðæàíèÿ ïîãîëîâüÿ, ïðîãðåññó â êîðìëåíèè, ñïîñîáñòâóþùåìó
óäîâëåòâîðåíèþ ïîòðåáíîñòè âî âñåõ îñíîâíûõ ïèòàòåëüíûõ è áèîëîãè÷åñêè àêòèâíûõ âåùåñòâàõ. Ïîñêîëüêó ïåðèîä âûðàùèâàíèÿ ïîñòîÿííî ñîêðàùàåòñÿ, à êîíâåðñèÿ êîðìà óëó÷øàåòñÿ, ïîääåðæàíèå çäîðîâüÿ ïòèöû è
îïòèìèçàöèÿ êîðìëåíèÿ îòíîñÿòñÿ ê ïðèîðèòåòíûì çàäà÷àì. Âñå ÷àùå äåòàëèçàöèÿ òåõíîëîãèé âûðàùèâàíèÿ îñóùåñòâëÿåòñÿ íà òîíêîì óðîâíå, ñ
ó÷åòîì ôàêòîðîâ, êîòîðûì ðàíåå ó÷åíûå è ïðàêòèêè íå óäåëÿëè âíèìàíèÿ.
Íàïðèìåð, ìèêðîñòðóêòóðíûå èçìåíåíèÿ â êèøå÷íèêå, â ÷àñòíîñòè â ñëèçèñòîé, îòâå÷àþò çà ñíèæåíèå àññèìèëÿöèè íóòðèåíòîâ. Ñëåäîâàòåëüíî, åãî
ñîñòîÿíèå îïðåäåëÿåò çäîðîâüå ïòèöû, ýôôåêòèâíîñòü èñïîëüçîâàíèÿ ïèòàòåëüíûõ è áèîëîãè÷åñêè àêòèâíûõ âåùåñòâ, ÷òî, â ñâîþ î÷åðåäü, ñâÿçàíî ñ
ðîñòîì è ðàçâèòèåì, êîíâåðñèåé êîðìà è äðóãèìè âàæíûìè ïðîìûøëåííûìè ïîêàçàòåëÿìè â ïòèöåâîäñòâå. Êèøå÷íèê ïðåäñòàâëÿåò ñîáîé íå òîëüêî ïåðâóþ ëèíèþ çàùèòû îò ýêçîãåííûõ ïàòîãåíîâ, ñïîñîáíûõ êîëîíèçîâàòü êëåòêè è òêàíè õîçÿèíà, íî è ñàìûé áîëüøîé îðãàí, ó÷àñòâóþùèé â
îáåñïå÷åíèè èììóíèòåòà.
 ýòîé ñâÿçè çàùèòíûå ìåõàíèçìû êèøå÷íèêà, âêëþ÷àÿ èììóííóþ
ñèñòåìó, òðåáóþò îñîáîãî âíèìàíèÿ. Îòìåòèì, ÷òî çàòðàòû íà îáåñïå÷åíèå
ôóíêöèè èììóííîé ñèñòåìû äëÿ ðàñòóùåãî îðãàíèçìà âåñüìà çíà÷èòåëüíû. Íàïðèìåð, â óñëîâèÿõ îñòðîé ôàçû èììóííîãî îòâåòà ó öûïëÿò ñíèæàåòñÿ ïîòðåáëåíèå êîðìà, ïàäàåò ïðîäóêòèâíîñòü è ðàñõîäóåòñÿ äîïîëíèòåëüíî äî 10 % ïèòàòåëüíûõ âåùåñòâ, êîòîðûå ìîãëè áû ïîéòè íà ðîñò è
ðàçâèòèå (1). Ó áûñòðî ðàñòóùåãî áðîéëåðà ïðèìåðíî 12 % âíîâü ñèíòåçèðóåìûõ áåëêîâ íàïðàâëÿåòñÿ íà ïîääåðæàíèå ãîìåîñòàçà â ïèùåâàðèòåëüíîì òðàêòå. Óñèëåíèå ïðîëèôåðàöèè ïðèâîäèò ê ñíèæåíèþ âîçðàñòà è çðåëîñòè ãîáëåò-êëåòîê (goblet cells, áîêàëîâèäíûå êëåòêè), ÷òî ñïîñîáíî ïîâëèÿòü íà êà÷åñòâî ñåêðåòèðóåìîãî èìè ìóöèíà è, êàê ñëåäñòâèå, ñíèçèòü
3
âñàñûâàíèå íóòðèåíòîâ (2). Ê òîìó æå áûñòðîå îáíîâëåíèå ýòèõ êëåòîê
ïîâûøàåò ïîòðåáíîñòü â ýíåðãèè äëÿ ïîääåðæàíèÿ ïëàñòè÷åñêèõ è ôåðìåíòàòèâíûõ ïðîöåññîâ â êèøå÷íèêå. Èçìåíåíèÿ â ìîðôîëîãèè êèøå÷íèêà
ìîãóò ïðèâåñòè ê ïîäàâëåíèþ âñàñûâàíèÿ, ïîâûøåíèþ ñåêðåöèè, äèàðåå,
ñíèæåíèþ óñòîé÷èâîñòè ê áîëåçíÿì è ïðîäóêòèâíîñòè â öåëîì (3).
Öåëüþ íàñòîÿùåãî îáçîðà ñòàëî îáîáùåíèå ïîñëåäíèõ äîñòèæåíèé
â èçó÷åíèè çàùèòíûõ ìåõàíèçìîâ êèøå÷íèêà ó ïòèö.
Ôèçè÷åñêèå áàðüåðû
Èììóííûå ìåõàíèçìû
Ìèêðîôëîðà
Ìóöèí
ðÍ
Ñåêðåòû ïîäæåëóäî÷íîé
æåëåçû
Ïåðèñòàëüòèêà
Àýðîáèîç
M-êëåòêè
NK-êëåòêè
B-êëåòêè
Ò-êëåòêè
Ëèçîöèì
Ôàãîöèòû
Àíòèìèêðîáíûå ïåïòèäû
(äåôåíñèíû, êàòåëèöèäèíû)
Êîíêóðåíöèÿ çà íóòðèåíòû
è ìåñòà ïðèêðåïëåíèÿ
Áàêòåðèîöèíû
Áàêòåðèîôàãè
Êîðîòêîöåïî÷å÷íûå
æèðíûå êèñëîòû
Çàùèòíûå ìåõàíèçìû æåëóäî÷íî-êèøå÷íîãî òðàêòà ïòèö (îïèñàíèå ñì. â òåêñòå).
Îáùàÿ õàðàêòåðèñòèêà çàùèòíûõ ìåõàíèçìîâ æåë ó ä î ÷ í î - ê è ø å ÷ í î ã î ò ð à ê ò à (ðèñ.). Ïåðâàÿ ãðóïïà ôàêòîðîâ âêëþ÷àåò ôèçè÷åñêèå áàðüåðû è ñïåöèàëüíûå óñëîâèÿ ñðåäû. Ýòî íàëè÷èå ñëèçèñòîãî ñëîÿ, êëåòêè êîòîðîãî îáëàäàþò âûñîêîé ñêîðîñòüþ îáíîâëåíèÿ,
÷òî ïðåïÿòñòâóåò êîëîíèçàöèè ïàòîãåííûìè ìèêðîîðãàíèçìàìè; çàùèòíûå ñâîéñòâà ìóöèíà, ïðåäóïðåæäàþùåãî ïðîíèêíîâåíèå ìèêðîîðãàíèçìîâ è èõ ïðèêðåïëåíèå ê âîðñèíêàì êèøå÷íèêà; ïîääåðæàíèå â æåëåçèñòîì æåëóäêå è òîíêîì êèøå÷íèêå íèçêèõ çíà÷åíèé ðÍ, íåáëàãîïðèÿòíûõ
äëÿ ðàçâèòèÿ ïàòîãåííûõ ìèêðîáîâ; ïðèñóòñòâèå êèñëîðîäà, ïðåäîòâðàùàþùåãî ðàçìíîæåíèå àíàýðîáîâ; ïðîòåêòèâíûå ñâîéñòâà ñåêðåòîâ ïîäæåëóäî÷íîé æåëåçû è æåë÷è (íåïåðåâàðåííûé êîðì ñëóæèò ñóáñòðàòîì äëÿ
ðàçâèòèÿ ìíîãèõ, â òîì ÷èñëå ïàòîãåííûõ, ìèêðîîðãàíèçìîâ); ïåðèñòàëüòèêà êèøå÷íèêà è ïîñòîÿííîå äâèæåíèå õèìóñà, ñíèæàþùåå âåðîÿòíîñòü
ïðèêðåïëåíèÿ ïàòîãåíîâ ê âîðñèíêàì êèøå÷íèêà. Êî âòîðîé îòíîñÿò êîìïîíåíòû ñîáñòâåííî èììóííîé ñèñòåìû, â ÷àñòíîñòè àíòèìèêðîáíûå ïåïòèäû (äåôåíñèíû); ëèçîöèì; ìóöèí, ñèíòåç êîòîðîãî ðåãóëèðóåòñÿ öèòîêèíàìè, áàêòåðèàëüíûìè ïðîäóêòàìè è ôàêòîðàìè ðîñòà; èììóíîãëîáóëèíû êèøå÷íèêà, ñïîñîáñòâóþùèå óñïåøíîé àíòèìèêðîáíîé çàùèòå; ëèìôîèäíàÿ òêàíü, â êîòîðîé ïðîèñõîäèò ðàñïîçíàâàíèå ÷óæåðîäíûõ àíòèãåíîâ è îñóùåñòâëÿåòñÿ îòâåò ñ ó÷àñòèåì ôàêòîðîâ âðîæäåííîãî (ôàãîöèòàðíûå êëåòêè, natural killer cells, èëè NK-êëåòêè, è äð.) è ïðèîáðåòåííîãî
(B- è Ò-ëèìôîöèòû è ïðîäóêòû èõ æèçíåäåÿòåëüíîñòè) èììóíèòåòà. Òðåòüÿ ãðóïïà ôàêòîðîâ — ýòî ñèíåðãè÷åñêèå ìèêðîîðãàíèçìû (ìèêðîáèîòà)
êèøå÷íèêà, èõ áàêòåðèîôàãè è ïðîäóêòû æèçíåäåÿòåëüíîñòè (áàêòåðèîöèíû, êîðîòêîöåïî÷å÷íûå æèðíûå êèñëîòû).
Ó ñåëüñêîõîçÿéñòâåííûõ æèâîòíûõ è ïòèöû ñëèçèñòàÿ îáîëî÷êà
êèøå÷íèêà ôîðìèðóåò íàèáîëüøóþ ïîâåðõíîñòü êîíòàêòà ñ âíåøíåé ñðåäîé è ïðåäñòàâëÿåò ñîáîé îñíîâíûå âîðîòà äëÿ ïðîíèêíîâåíèÿ ÷óæåðîäíûõ, â òîì ÷èñëå âðåäíûõ, àíòèãåíîâ (ïàòîãåíîâ). Ïîýòîìó çäåñü ñóùåñòâóåò ñïåöèàëüíûé ìåõàíèçì, îáåñïå÷èâàþùèé ýôôåêòèâíóþ çàùèòó îò èíâàçèè. Ãëàâíûå ãèñòîëîãè÷åñêèå îñîáåííîñòè áàðüåðîâ â ðàçíûõ ñëèçèñòûõ
èäåíòè÷íû, îäíàêî èìåþòñÿ è ëîêàëüíûå ðàçëè÷èÿ âñëåäñòâèå îñîáåííîñòåé àíàòîìè÷åñêîãî ñòðîåíèÿ è ðàñïîëîæåíèÿ òêàíè, à òàêæå åå ôèçèîëîãè÷åñêèõ ôóíêöèé. Íà ýòîì îñíîâàíèè èììóíîëîãè÷åñêèå áàðüåðû ñëèçèñòîé (MALT — mucosal-associated lymphoid tissue) ðàçäåëåíû íà ðÿä ïîäãðóïï: GALT (gastrointestinal-associated lymphoid tissue), BALT (bronchus-as4
sociated lymphoid tissue), NALT (nasal-associated lymphoid tissue), ïðåäñòàâëÿþùèõ ëèìôîèäíóþ òêàíü, àññîöèèðîâàííóþ ñîîòâåòñòâåííî ñ êèøå÷íèêîì, áðîíõàìè, íîñîãëîòêîé, à òàêæå èìåþùóþñÿ â ñëþííûõ æåëåçàõ è
ìî÷åïîëîâîé ñèñòåìå.
GALT — ãëàâíûé êîìïîíåíò MALT, îí ïðåäñòàâëåí ñëîæíîé èíôðàñòðóêòóðîé îðãàíîâ è èììóííûõ êëåòîê, íàõîäÿùèõñÿ â ýïèòåëèàëüíîì ñëîå è ïðèëåãàþùèõ ê ñîáñòâåííîé ïëàñòèíêå (lamina propria). GALT
ñîñòîèò èç íåñêîëüêèõ òèïîâ êëåòîê, âêëþ÷àÿ ñïåöèàëèçèðîâàííûå èíäóêòîðû, èììóíîðåãóëÿòîðû è ýôôåêòîðû, îòëè÷àþùèåñÿ îò òåõ, êîòîðûå ó÷àñòâóþò â îáåñïå÷åíèè ôóíêöèé ñèñòåìíîãî èììóíèòåòà (4). Ó öûïëÿò, äëÿ
êîòîðûõ õàðàêòåðíî îòñóòñòâèå ëèìôàòè÷åñêèõ óçëîâ, ñâîéñòâåííûõ ìëåêîïèòàþùèì, èíäóêöèÿ è ãåíåðàöèÿ èììóííîãî îòâåòà ïðîèñõîäèò â îñíîâíîì â GALT è ñåëåçåíêå. Ïîýòîìó ïîíèìàíèå ìåõàíèçìîâ ðàçâèòèÿ è
ôóíêöèîíàëüíîãî ñîçðåâàíèÿ GALT îòíîñèòñÿ ê ôóíäàìåíòàëüíûì çàäà÷àì â ïîçíàíèè èììóíîëîãè÷åñêîãî ôåíîìåíà ó ïòèö, âêëþ÷àÿ ôîðìèðîâàíèå èììóííîãî îòâåòà èëè òîëåðàíòíîñòè ïî îòíîøåíèþ ê ðàçëè÷íûì
àíòèãåíàì (4, 5). Âàæíåéøàÿ çàäà÷à èììóííîé ñèñòåìû êèøå÷íèêà — ðàñïîçíàâàíèå «ñâîé—÷óæîé» è âûðàáîòêà òîëåðàíòíîñòè ê «ñâîèì» àíòèãåíàì (íàïðèìåð, íóòðèåíòàì èëè ñèíåðãè÷åñêîé ìèêðîáíîé ïîïóëÿöèè)
ïðè àêòèâíîì èììóííîì îòêëèêå íà «÷óæèõ», âêëþ÷àÿ ðàçëè÷íûå ïàòîãåíû. Ëþáûå íàðóøåíèÿ â ýòîé ñèñòåìå ìîãóò ïðèâåñòè êàê ê àëëåðãè÷åñêèì ðåàêöèÿì íà íóòðèåíòû, òàê è ê ïðîÿâëåíèþ òîëåðàíòíîñòè ê ïàòîãåíàì, íå ãîâîðÿ óæå î ïåðåðàñõîäå ïèòàòåëüíûõ è áèîëîãè÷åñêè àêòèâíûõ
âåùåñòâ êîðìà. Òàêèì îáðàçîì, òîíêèå ìåõàíèçìû ðåãóëÿöèè óêàçàííîé
ñèñòåìû îòíîñÿòñÿ ê îñíîâîïîëàãàþùèì, èõ îñîáåííîñòè è îòëè÷èÿ îò
îáùèõ ìåõàíèçìîâ, îïèñàííûõ äëÿ äðóãèõ âèäîâ æèâîòíûõ, â ÷àñòíîñòè
ìëåêîïèòàþùèõ, áóäóò ðàññìîòðåíû íèæå.
Ôàêòîðû íåñïåöèôè÷åñêîé è ñïåöèôè÷åñêîé çàù è ò û. Ôèçè÷åñêèå áàðüåðû êèøå÷íèêà. Ñëèçèñòûé ñëîé êèøå÷íèêà ïîêðûò ïðîñòûì ìèêðîâîðñèí÷àòûì öèëèíäðè÷åñêèì ýïèòåëèåì (ýíòåðîöèòû), êîòîðûé ôóíêöèîíèðóåò êàê ôèçè÷åñêèé áàðüåð ìåæäó âíåøíåé è
âíóòðåííåé ñðåäîé îðãàíèçìà è ñëóæèò äëÿ ïåðåâàðèâàíèÿ è âñàñûâàíèÿ
íóòðèåíòîâ. Ýíòåðîöèòû îáëàäàþò ñïåöèôè÷åñêèìè ðåöåïòîðàìè àïèêàëüíîé ìåìáðàíû, ðàñïîçíàþùèìè áàêòåðèàëüíûå àíòèãåíû, àêòèâàöèÿ êîòîðûõ ïðèâîäèò ê ëîêàëüíûì èììóííûì ðåàêöèÿì (6). Íàðÿäó ñ ýíòåðîöèòàìè â èììóííîé çàùèòå ó÷àñòâóþò ãîáëåò-êëåòêè (áîêàëîâèäíûå êëåòêè), Ì-êëåòêè è êëåòêè Ïàíåòà.  êèøå÷íèêå ó ïòèö õîðîøî èçó÷åíû ëèøü
ãîáëåò-êëåòêè öèëèíäðè÷åñêîãî ýïèòåëèÿ: èõ ãëàâíàÿ ôóíêöèÿ çàêëþ÷àåòñÿ
â ñåêðåöèè ìóöèíà è îíè äèôôåðåíöèðóþòñÿ èç òîãî æå ïðåäøåñòâåííèêà
(ïðîãåíèòîðà), ÷òî è ýíòåðîöèòû (7, 8).
Ðîëü ìóöèíîâ â çàùèòå êèøå÷íèêà. Ìóêóñ îáðàçóåòñÿ è ñåêðåòèðóåòñÿ áîêàëîâèäíûìè êëåòêàìè â ñëèçèñòîé îáîëî÷êå êèøå÷íèêà (ìóêîçå),
ãäå îí äåéñòâóåò êàê çàùèòíûé áàðüåð, ñâîåîáðàçíàÿ ñìàçêà è ñèñòåìà
òðàíñïîðòà ìåæäó ñîäåðæèìûì êèøå÷íèêà è ýïèòåëèàëüíûìè êëåòêàìè.
Ìóöèíû ïðåäñòàâëåíû ãðóïïîé ãëèêîëèçèðîâàííûõ áåëêîâ ñ ìîëåêóëÿðíîé ìàññîé äî 20 000 Äà, èãðàþùèõ öåíòðàëüíóþ ðîëü â ïðåäîòâðàùåíèè
ïðîíèêíîâåíèÿ ðàçëè÷íûõ ïàòîãåíîâ ÷åðåç ñëèçèñòóþ (9-11). Ìîëåêóëà
ìóöèíà — ñëîæíûé áèîïîëèìåð ãëèêîïðîòåèíîâîé ïðèðîäû, â êîòîðîì
îëèãîñàõàðèäû, ñîñòàâëÿþùèå äî 50-80 % ìîëåêóëÿðíîé ìàññû ìóöèíà,
÷åðåç Î-ãëèêîçèäíóþ ñâÿçü ïðèêðåïëåíû ê ãèäðîêñèãðóïïàì ñåðèíà èëè
òðåîíèíà áåëêîâûõ ñóáúåäèíèö. Ìóöèíû òàêæå ñîäåðæàò ìíîãî ñóëüôàòíûõ (ñóëüôîìóöèíû) è êàðáîêñèëàòíûõ (ñèàëîìóöèíû) ãðóïï, ÷òî ñîçäàåò
îòðèöàòåëüíûé çàðÿä ìóêîçíîãî ñëîÿ.
Ñåêðåòèðóåìûé ìóöèí ïîêðûâàåò ïîâåðõíîñòü ýíòåðîöèòîâ äâóìÿ
ñëîÿìè — âíóòðåííèì ïëîòíûì è âíåøíèì áîëåå ðàçæèæåííûì (10). Òà5
êèå ñëîè ñóùåñòâåííî çàòðóäíÿþò äîñòóï áàêòåðèé ê ñëèçèñòîé è âîçìîæíîñòü ïðèêðåïèòüñÿ ê êëåòêàì ýïèòåëèÿ. Êðîìå òîãî, ìóöèíû ñâÿçûâàþòñÿ
ñ áàêòåðèàëüíûìè ðåöåïòîðàìè, òåì ñàìûì áëîêèðóÿ èõ ñïîñîáíîñòü àäñîðáèðîâàòüñÿ íà ïîâåðõíîñòè êëåòêè ïåðåä ïðîíèêíîâåíèåì â íåå (7).
Àêòèâíîñòü ãåíîâ, îòâåòñòâåííûõ çà ñèíòåç ìóöèíîâ, íà óðîâíå òðàíñêðèïöèè ðåãóëèðóþò öèòîêèíû, áàêòåðèàëüíûå ïðîäóêòû è ôàêòîðû ðîñòà. Áèîñèíòåç ìóöèíà òàêæå îïðåäåëÿåòñÿ óñëîâèÿìè è/èëè àãåíòàìè, êîòîðûå âëèÿþò íà äèôôåðåíöèàöèþ ïðåäøåñòâåííèêîâ â çðåëûå áîêàëîâèäíûå êëåòêè. Íà íåãî òàêæå îêàçûâàþò ýôôåêò ðåàêöèè ãëèêîçèëèðîâàíèÿ è ñèíòåçà áåëêà, ðÿä äðóãèõ ïðîöåññîâ (12). Ìóöèíû, êîòîðûå îáðàçóþò ñëîé íàä âîðñèíêàìè, ñîñòîÿò èç íåéòðàëüíûõ è êèñëûõ ìîëåêóë. Ñ
ïðèñóòñòâèåì çàðÿæåííûõ ãðóïï â ìîëåêóëå ìóöèíîâ ÷àñòî ñâÿçûâàþò
ñïîñîáíîñòü çàùèùàòü ýïèòåëèé îò ðàçëè÷íûõ ïàòîãåíîâ è ó÷àñòèå âî
âñàñûâàíèè íóòðèåíòîâ. Ñëåäóåò òàêæå èìåòü â âèäó, ÷òî ìóöèíîâûé ñëîé
íà ïîâåðõíîñòè ñëèçèñòîé ñëóæèò èñòî÷íèêîì íóòðèåíòîâ äëÿ ìíîãèõ êèøå÷íûõ îðãàíèçìîâ è íåêîòîðûå âèäû áàêòåðèé, æèâóùèå â êèøå÷íèêå,
ìîãóò óòèëèçèðîâàòü ïîëèñàõàðèäû ìóöèíà.
Òàêèì îáðàçîì, â êèøå÷íèêå ñóùåñòâóåò òîíêàÿ ñâÿçü ìåæäó ìèêðîôëîðîé è êîëè÷åñòâîì ìóöèíà. Ïðè ýòîì äâà òèïà ìóöèíà, ïîêðûâàþùèå
ïîâåðõíîñòü êëåòîê, êîîïåðèðóþò äðóã ñ äðóãîì è îáðàçóþò íåñìåøèâàþùèéñÿ âîäíûé ñëîé â íåïîñðåäñòâåííîé áëèçîñòè îò ìóêîçíîãî, áëàãîäàðÿ
÷åìó ñîçäàåòñÿ è ïîääåðæèâàåòñÿ íà ïîñòîÿííîì óðîâíå ñïåöèôè÷åñêîå
çíà÷åíèå ðÍ. Ìîëåêóëÿðíûå ìåõàíèçìû îïèñàííîãî ÿâëåíèÿ ðàñøèôðîâàíû ïîêà íå ïîëíîñòüþ, íî åñòü ïðåäïîëîæåíèÿ, ÷òî îíî ñîïðîâîæäàåòñÿ
ñâÿçûâàíèåì èîíîâ âîäîðîäà áèêàðáîíàòîì, ñåêðåòèðóåìûì ìóêîçíûì
ñëîåì. Ïðèíÿòî ñ÷èòàòü, ÷òî ñðåäà çäåñü ñëåãêà êèñëàÿ èëè íåéòðàëüíàÿ
(ðÍ ≈ 7). Âîäîðîäíûé ïîêàçàòåëü (êèñëîòíîñòü) âëèÿåò íà ðîñò ìèêðîîðãàíèçìîâ è, ñëåäîâàòåëüíî, èãðàåò âàæíóþ ðîëü â ðåãóëÿöèè ÷èñëåííîñòè è
ñîñòàâà êèøå÷íîé ìèêðîôëîðû. Êðîìå òîãî, íåñìåøèâàþùèéñÿ âîäíûé
ñëîé äåéñòâóåò êàê ìîëåêóëÿðíûé ôèëüòð ìåæäó ïîëîñòüþ êèøå÷íèêà è
ïîâåðõíîñòüþ ìèêðîâîðñèíîê. Ãëàâíàÿ ñòðàòåãèÿ ïèùåâàðåíèÿ â òîíêîì êèøå÷íèêå çàêëþ÷àåòñÿ â òîì, ÷òîáû ôåðìåíòû ïîäæåëóäî÷íîé æåëåçû ñìîãëè
óìåíüøèòü ÷àñòè÷êè êîðìà äî ðàçìåðîâ, ïîçâîëÿþùèõ ïðîéòè ÷åðåç òàêîé
ñëîé äëÿ çàâåðøåíèÿ ïèùåâàðåíèÿ. Ïðè ýòîì ïîâåðõíîñòíûå ôåðìåíòû çàùèùåíû îò ïðîòåîëèòè÷åñêîé äåñòðóêöèè, â òî âðåìÿ êàê ïðîäóêòû ïèùåâàðåíèÿ íå äîñòóïíû ìèêðîáàì, íàõîäÿùèìñÿ â ïðîñâåòå êèøå÷íèêà. Èíòåðåñåí òîò ôàêò, ÷òî ãîáëåò-êëåòêè ìîãóò èçìåíèòü ñîñòàâ ñåêðåòèðóåìîãî
ìóöèíà â îòâåò íà ïðèñóòñòâèå ìèêðîîðãàíèçìîâ (11). Íàïðèìåð, ïðè êîëîíèçàöèè Clostridium perfringens âìåñòî íåéòðàëüíûõ ìîëåêóë ñèíòåçèðóþòñÿ
êèñëûå, ÷òî ìîæåò ðàññìàòðèâàòüñÿ êàê ïîïûòêà ïîääåðæàòü îïòèìàëüíîå
çíà÷åíèå ðH â èçìåíèâøèõñÿ óñëîâèÿõ. Äî ïîïàäàíèÿ ìóöèíà â àíàýðîáíûå óñëîâèÿ òîëñòîãî êèøå÷íèêà ñêîðîñòü åãî äåãðàäàöèè íåâåëèêà.
Äèåòè÷åñêèå ôàêòîðû, íàïðèìåð ôèòàò è êëåò÷àòêà, ñïîñîáñòâóþò
ñåêðåöèè ìóöèíà. Óñèëåíèå åãî ïðîäóêöèè àíòèïèòàòåëüíûìè ôàêòîðàìè
ïðîèñõîäèò èç-çà àáðàçèâíîãî äåéñòâèÿ ïîñëåäíèõ íà ñëèçèñòóþ, ïðèâîäÿùåãî ê óäàëåíèþ ñëîÿ ìóöèíà, ïîòåðþ êîòîðîãî, â ñâîþ î÷åðåäü, êîìïåíñèðóþò ãîáëåò-êëåòêè çà ñ÷åò àêòèâèçàöèè ñèíòåçà. Áåëêè è ñïåöèôè÷åñêèå àìèíîêèñëîòû òàêæå âëèÿþò íà îáðàçîâàíèå/cåêðåöèþ ìóöèíà è
ìîãóò âçàèìîäåéñòâîâàòü íàïðÿìóþ ñ ãîáëåò-êëåòêàìè èëè æå ñ íåðâíûìè
îêîí÷àíèÿìè êèøå÷íèêà. Àìèíîêèñëîòû òðåîíèí, ñåðèí è öèñòåèí ñóùåñòâåííî âëèÿþò íà ïðîäóêöèþ ìóöèíà, ïîñêîëüêó âõîäÿò â åãî ñîñòàâ. Â
÷àñòíîñòè, òðåîíèí ñîñòàâëÿåò ïðèìåðíî 11 % àìèíîêèñëîòíîé ïîñëåäîâàòåëüíîñòè ìóöèíà. Ïîäàâëåíèå ñèíòåçà ìóöèíà ó ïòèö ìîæåò ïðèâåñòè ê
íàðóøåíèÿì â ñëèçèñòîé êèøå÷íèêà è ñíèçèòü ïðîèñõîäÿùóþ çäåñü óòèëèçàöèþ íóòðèåíòîâ (13).
6
Àíòèìèêðîáíûå ïåïòèäû. Èçâåñòíî, ÷òî ó ïòèö â ãåòåðîôèëàõ îòñóòñòâóåò ôåðìåíò ìèåëîïåðîêñèäàçà, êîòîðàÿ òðåáóåòñÿ äëÿ îáðàçîâàíèÿ
òîêñè÷íûõ ìåòàáîëèòîâ àçîòà, âûçûâàþùèõ ãèáåëü ïàòîãåíîâ. Ïîýòîìó áàêòåðèöèäíûå ôóíêöèè ãåòåðîôèëîâ îñíîâàíû ãëàâíûì îáðàçîì íà íåîêèñëèòåëüíûõ ìåõàíèçìàõ è ðåàëèçóþòñÿ áëàãîäàðÿ äåéñòâèþ ôåðìåíòîâ è
àíòèáàêòåðèàëüíûõ âåùåñòâ, ñîäåðæàùèåñÿ â ãåòåðîôèëüíûõ ãðàíóëàõ (14,
15). Àíòèìèêðîáíûå ïåïòèäû (AMP) — âàæíåéøèå êîìïîíåíòû âðîæäåííîãî èììóíèòåòà â æèâîòíîì ìèðå (îò ìóõ äî ìëåêîïèòàþùèõ). Ýòè ñîåäèíåíèÿ ñïîñîáíû íàðóøàòü öåëîñòíîñòü ìåìáðàí ìèêðîîðãàíèçìîâ (16).
Ó ïîçâîíî÷íûõ èçâåñòíû äâà ñåìåéñòâà AMP: äåôåíñèíû è êàòåëèöèäèíû.
Ó ìëåêîïèòàþùèõ ðàçëè÷àþò α- è β-äåôåícèíû (17). Ïðè ýòîì α-äåôåícèíû óíèêàëüíû äëÿ ìëåêîïèòàþùèõ, â òî âðåìÿ êàê β-äåôåíñèíû ðàñïðîñòðàíåíû áîëåå øèðîêî, è óæå íà ðàííèõ ýòàïàõ èññëåäîâàíèé ó öûïëÿò èäåíòèôèöèðîâàëè ÷åòûðå âèäà β-äåôåíñèíîâ, èçâåñòíûõ êàê ãàëëèíàöèíû (18-20). Ãîìîëîãè÷íûå ïåïòèäû îïèñàíû è ó èíäååê (18, 20). Ãàëëèíàöèíû Gal-1, Gal-1α è Gal-2 áûëè âûäåëåíû èç ãåòåðîôèëîâ öûïëÿò, â
òî âðåìÿ êàê Gal-3 îáíàðóæèâàëñÿ â ðàçëè÷íûõ ýïèòåëèàëüíûõ òêàíÿõ, à
ïðè èíôåêöèè ïðîèñõîäèëà åãî èíäóêöèÿ, íàïðèìåð, â òðàõåå (20). Ãàëëèíàöèíû õàðàêòåðèçîâàëèñü ðàçëè÷íîé ñïåöèôè÷íîñòüþ äåéñòâèÿ â îòíîøåíèè çíà÷èòåëüíîãî ÷èñëà ãðàìïîëîæèòåëüíûõ è ãðàìîòðèöàòåëüíûõ âèäîâ
áàêòåðèé. Êðîìå òîãî, Gal-1 è Gal-1α òàêæå ïðîÿâëÿëè àêòèâíîñòü ïðîòèâ
äðîææåé Candida albicans (14, 21, 22). Àíòèáàêòåðèàëüíûå β-äåôåíñèíû
Gal-1 è Gal-2, îáíàðóæåííûå â ãåòåðîôèëàõ ïòèö, ðàññìàòðèâàþòñÿ â êà÷åñòâå ãëàâíîãî ôàêòîðà çàùèòû îò ïàòîãåííûõ áàêòåðèé è ãðèáîâ (23).
Çàòåì ó öûïëÿò îïèñàëè åùå ñåìü ãàëëèíàöèíîâ (îò Gal-4 äî Gal10) (24). Àâòîðû ïîêàçàëè óìåðåííóþ ýêñïðåññèþ Gal-1 è Gal-2 â ôàáðèöèåâîé ñóìêå (bursa Fabricii) è â êèøå÷íèêå. Ýêñïðåññèÿ äðóãèõ (íîâûõ)
ãàëëèíàöèíîâ âàðüèðîâàëà â ðàçíûõ òêàíÿõ, â òîì ÷èñëå â òîíêîì è òîëñòîì êèøå÷íèêå. Òàêæå îáíàðóæåíî, ÷òî ãàëëèíàöèíû ó÷àñòâîâàëè â àäàïòèâíîé ýâîëþöèè è áûëè îäíèì èç ìåõàíèçìîâ ïðèñïîñîáëåíèÿ æèâîòíûõ è ïòèö ê íîâûì óñëîâèÿì îáèòàíèÿ è ðàñòóùåìó ðàçíîîáðàçèþ ïàòîãåíîâ. Ïðè èçó÷åíèè ïðîäóêöèè β-äåôåíñèíà Gal-6 ó öûïëÿò è åãî äåéñòâèÿ íà ðàçëè÷íûå ïàòîãåíû óñòàíîâëåíà âûñîêàÿ ýêñïðåññèÿ óêàçàííîãî
äåôåíñèíà â ïèùåâîäå è çîáå, óìåðåííàÿ — â æåëåçèñòîì æåëóäêå è íèçêàÿ — â äðóãèõ îòäåëàõ êèøå÷íèêà (25). Gal-6 îáëàäàë ñèëüíîé àíòèáàêòåðèàëüíîé àêòèâíîñòüþ â îòíîøåíèè Campylobacter sp., Salmonella sp., Clostridia sp. è Escherichia coli è ïîäàâëÿë èõ ðàçâèòèå, âûçûâàÿ äîçîçàâèñèìûå
èçìåíåíèÿ â ìîðôîëîãèè (âíóòðèêëåòî÷íàÿ ãðàíóëÿöèÿ, âòÿãèâàíèå öèòîïëàçìû, íåðåãóëÿðíîå ôîðìèðîâàíèå ïåðåãîðîäîê â äåëÿùèõñÿ êëåòêàõ)
è ëèçèñ. Ïî ýôôåêòó íà ñàëüìîíåëë ãàëëèíàöèíû Gal-9, Gal-4 è Gal-7
ðàñïîëàãàëèñü â ïîñëåäîâàòåëüíîñòè Gal-9 ≥ Gal-4 > Gal-7 (26), êðîìå
òîãî, ïîêàçàí ñèíåðãèçì äåéñòâèÿ Gal-7 è Gal-9 ïðîòèâ S. enteriditis. Òîëüêî Gal-11 õàðàêòåðèçîâàëñÿ âûñîêîé ýêñïðåññèåé â òîíêîì êèøå÷íèêå, ïå÷åíè, æåë÷íîì ìåøêå è ñåëåçåíêå öûïëÿò, Gal-13 îáíàðóæèâàëñÿ â òîëñòîì êèøå÷íèêå; âûÿâèòü äðóãèå β-äåôåíñèíû â êèøå÷íèêå àâòîðàì ïðàêòè÷åñêè íå óäàëîñü (24, 27, 28). Ïðè èññëåäîâàíèè ñâîéñòâ ñèíòåòè÷åñêîãî
Gal-11 ïðîäåìîíñòðèðîâàíà åãî ýôôåêòèâíîñòü ïðîòèâ êèøå÷íûõ ïàòîãåíîâ, âêëþ÷àÿ S. typhimurium è Listeria monocytogenes (27). Äëÿ âîñüìè èç
14 íåäàâíî èçó÷åííûõ β-äåôåíñèíîâ öûïëÿò ïîêàçàíà òêàíåâàÿ ñïåöèôè÷íîñòü: AvBD1, AvBD7 è AvBD9 îáíàðóæèâàþòñÿ â çîáå, AvBD8, AvBD10 è
AvBD13 — â êèøå÷íèêå, AvBD1 è AvBD7 — â ñåëåçåíêå (29).
Êàòåëèöèäèíû — åùå îäíî ñåìåéñòâî àíòèìèêðîáíûõ áåëêîâ, îáíàðóæåííûõ ãëàâíûì îáðàçîì â íå ñîäåðæàùèõ ïåðîêñèäàçó ãðàíóëàõ íåéòðîôèëîâ. Êàòåëèöèäèíû çàêîäèðîâàíû â ãåíîìå â âèäå ïðîïåïòèäîâ, èç
êîòîðûõ ïîä äåéñòâèåì ïðîòåàç îáðàçóþòñÿ áèîëîãè÷åñêè àêòèâíûå ïåï7
òèäû äëèíîé 12-97 àìèíîêèñëîò (30). Áîëüøèíñòâî êàòåëèöèäèíîâ ïîðàçíîìó ïðåçåíòèðîâàíû â òêàíÿõ, îáëàäàþò íåîäèíàêîâîé àíòèìèêðîáíîé
àêòèâíîñòüþ ïðîòèâ ðÿäà ãðàìïîëîæèòåëüíûõ è ãðàìîòðèöàòåëüíûõ áàêòåðèé, ãðèáîâ, ïðîñòåéøèõ è âèðóñîâ (31). Îíè òàêæå ñâÿçûâàþò è íåéòðàëèçóþò ýíäîòîêñèíû (32) è èíäóöèðóþò õåìîòàêñèñ íåéòðîôèëîâ, Têëåòîê è ìîíîöèòîâ (33). Êàòåëèöèäèíû øèðîêî ïðåäñòàâëåíû ó ìëåêîïèòàþùèõ (34) è îáíàðóæåíû ó öûïëÿò (24). Îñíîâíûìè ïðîäóöåíòàìè êàòåëèöèäèíîâ ñëóæàò íåéòðîôèëû.
Íåäàâíî ó öûïëÿò îïèñàí íîâûé êàòåëèöèäèí — ìèåëîèäíûé àíòèìèêðîáíûé ïåïòèä 27 (CMAP27). Åãî íàèáîëüøóþ ýêñïðåññèþ çàðåãèñòðèðîâàëè â ìèåëîèäíûõ/ëèìôîèäíûõ òêàíÿõ è ñåìåííèêàõ. Àêòèâíûé
ñèíòåç ìÐÍÊ CMAP27 âûÿâëåí â ôàáðèöèåâîé ñóìêå è êîñòíîì ìîçãå.
Èíòåíñèâíóþ ïðîäóêöèþ ýòîãî ïîëèïåïòèäà îòìå÷àëè â ìèíäàëèíàõ ñëåïûõ îòðîñòêîâ êèøå÷íèêà, à òàêæå â ëèìôîèäíîé òêàíè, ëîêàëèçîâàííîé
âîçëå ñîåäèíåíèÿ ïîäâçäîøíîé êèøêè ñ îáîäî÷íîé, íèçêóþ — â äðóãèõ
îòäåëàõ, âêëþ÷àÿ æåëåçèñòûé æåëóäîê (35). Êàòåëèöèäèí-2 ÷àñòî îáíàðóæèâàåòñÿ â ãåòåðîôèëàõ, ëîêàëèçîâàí â ïàëî÷êîâèäíûõ ãðàíóëàõ, íî îòñóòñòâóåò â èíûõ ïåðèôåðè÷åñêèõ êëåòêàõ êðîâè è êèøå÷íîì ýïèòåëèè öûïëÿò. Áûëî óñòàíîâëåíî, ÷òî ëèïîïîëèñàõàðèäû ñàëüìîíåëëû ñòèìóëèðóþò
âûäåëåíèå êàòåëèöèäèíà-2 ãåòåðîôèëàìè, îêàçûâàÿ âðåìÿ-çàâèñèìûé ýôôåêò (36). Òàêèì îáðàçîì, êàòåëèöèäèí-2 ïîêàçàë àíòèáàêòåðèàëüíóþ è
ôóíãèöèäíóþ àêòèâíîñòü â îòíîøåíèè ðÿäà ìèêðîîðãàíèçìîâ, âêëþ÷àÿ
ñàëüìîíåëëó. Êàòåëèöèäèíû òàêæå îêàçûâàþò èììóíîðåãóëÿòîðíîå äåéñòâèåì, âëèÿÿ íà îáðàçîâàíèå öèòîêèíîâ è îáíîâëåíèå ïóëà èììóíîêîìïåòåíòíûõ êëåòîê, êðîìå òîãî, îíè ñâÿçûâàþò ýíäîòîêñèíû è ñíèæàþò ýíäîòîêñèíîïîñðåäîâàííûé âîñïàëèòåëüíûé îòâåò (37).
Ëèçîöèìíàÿ àêòèâíîñòü. Ëèçîöèì (Å.Ñ. 3.2.17) — ôåðìåíò ñ îòíîñèòåëüíî íåáîëüøîé ìîëåêóëÿðíîé ìàññîé, êàòàëèçèðóþùèé ðàñùåïëåíèå
ñïåöèôè÷åñêèõ ïîëèñàõàðèäîâ (ïåïòèäîãëèêàíû è õèòîäåêñòðèí) â êëåòî÷íîé ñòåíêå áàêòåðèé. Ïî àìèíîêèñëîòíîé ïîñëåäîâàòåëüíîñòè ëèçîöèìû æèâîòíîãî ïðîèñõîæäåíèÿ äåëÿòñÿ íà òðè òèïà — c (êóðèíûé), g (ãóñèíûé) è i (òèï áåñïîçâîíî÷íûõ) (38).  ÿè÷íîì áåëêå ó áîëüøèíñòâà âèäîâ ïòèö, âêëþ÷àÿ êóð-íåñóøåê, èìååòñÿ ëèçîöèì ñ-òèïà, òîãäà êàê ó ãóñåé è ñòðàóñîâ — ëèçîöèì g-òèïà. Ëèçîöèì ÿè÷íîãî áåëêà ïðåäñòàâëÿåò
ñîáîé ïîëèïåïòèä ñ ìîëåêóëÿðíîé ìàññîé 14 300 Äà, ñîäåðæàùèé 129 àìèíîêèñëîòíûõ îñòàòêîâ. Ìîëåêóëà ëèçîöèìà ñîñòîèò èç äâóõ äîìåíîâ, ìåæäó
êîòîðûìè ðàñïîëîæåí àêòèâíûé öåíòð (39). Íà ëèçîöèì ïðèõîäèòñÿ 3,5 %
îò îáùåãî êîëè÷åñòâà ïðîòåèíîâ ÿè÷íîãî áåëêà. Íàèáîëüøåå ñîäåðæàíèå
ýòîãî ôåðìåíòà íàáëþäàåòñÿ â ÿè÷íîì áåëêå, à òàêæå â ýìáðèîíå, ïîêà
àäàïòèâíûé èììóíèòåò ðàçâèò åùå íå ïîëíîñòüþ è çàùèòíûå ôóíêöèè
îáåñïå÷èâàþòñÿ çà ñ÷åò íåñïåöèôè÷åñêèõ ìåõàíèçìîâ, òî åñòü ïîêà ó ýìáðèîíà è öûïëåíêà íå íà÷íóò ñèíòåçèðîâàòüñÿ èììóíîãëîáóëèíû, áèîëîãè÷åñêàÿ ðîëü ÿè÷íîãî ëèçîöèìà ñâÿçàíà ñ åãî ïðîòåêòèâíûìè ñâîéñòâàìè. Ó
âñåõ æèâîòíûõ ëèçîöèìû âûïîëíÿþò ðîëü êëþ÷åâûõ ýôôåêòîðîâ âðîæäåííîãî èììóíèòåòà. Îíè ãèäðîëèçóþò β-ãëèêîçèäíóþ ñâÿçü ìåæäó N-àöåòèëìóðàìèíîâîé êèñëîòîé è N-àöåòèëãëþêîçàìèíîì, ñîñòàâëÿþùèìè îñíîâó
ïåïòèäîãëèêàíà — ãëàâíîãî êîìïîíåíòà êëåòî÷íîé ñòåíêè áàêòåðèé (40).
Ëèçîöèì ñîäåðæèòñÿ â ôàãîöèòàðíûõ è ñåêðåòîðíûõ ãðàíóëàõ íåéòðîôèëîâ, ñèíòåçèðóåòñÿ ìîíîöèòàìè, ìàêðîôàãàìè è ýïèòåëèàëüíûìè
êëåòêàìè. Îí â ñóùåñòâåííûõ êîëè÷åñòâàõ îáíàðóæèâàåòñÿ â ñëþíå, ñëèçèñòîé äûõàòåëüíûõ ïóòåé, ìîëîêå è äðóãèõ ñåêðåòàõ îðãàíèçìà è ðàññìàòðèâàåòñÿ â êà÷åñòâå ôàêòîðà ïåðâîé ëèíèè çàùèòû ïðîòèâ áàêòåðèàëüíîé
èíôåêöèè. Ìíîãèå ãðàìïîëîæèòåëüíûå áàêòåðèè áûñòðî ïîãèáàþò ïðè
äåéñòâèè ëèçîöèìà in vitro, îäíàêî ãðàìîòðèöàòåëüíûå áàêòåðèè ê íåìó
óñòîé÷èâû áëàãîäàðÿ âíåøíåé ìåìáðàíå, ïðåäîòâðàùàþùåé ïðÿìîé äîñ8
òóï ôåðìåíòà ê ïåïòèäîãëèêàíàì. Òåì íå ìåíåå, in vivo ãðàìîòðèöàòåëüíûå áàêòåðèè ñåíñèòèðóþòñÿ (ñòàíîâÿòñÿ óçíàâàåìûìè è ÷óâñòâèòåëüíûìè
ê ëèçîöèìó) êîìïîíåíòàìè âðîæäåííîãî èììóíèòåòà — ñïåöèôè÷åñêèìè
àíòèìèêðîáíûìè ïåïòèäàìè äåôåíñèíàìè è ñèñòåìîé êîìïëåìåíòà, êîòîðûå íàðóøàþò ñòðóêòóðó âíåøíåé ìåìáðàíû. Ïîñêîëüêó ëèçîöèì øèðîêî ðàñïðîñòðàíåí â æèâîòíîì öàðñòâå, áàêòåðèè âûðàáîòàëè ñâîè ìåõàíèçìû çàùèòû: â ÷àñòíîñòè, ãðàìîòðèöàòåëüíûå ôîðìû ñïîñîáíû âûäåëÿòü ñïåöèôè÷íûå èíãèáèòîðû êàæäîãî èç òðåõ òèïîâ ëèçîöèìà (41).
Ïîçâîíî÷íûå èìåþò ãåíû, êîäèðóþùèå êàê c-, òàê è g-òèï ôåðìåíòà, íî èõ ýêñïðåññèÿ âèäîñïåöèôè÷íà. Íàïðèìåð, ãåíîì öûïëåíêà ñîäåðæèò ãåíû îäíîãî ñ-òèïà è äâóõ g-òèïîâ ëèçîöèìà. Äëÿ ñ-òèïà õàðàêòåðíà âûñîêàÿ ýêñïðåññèÿ â ÿéöåâîäå è êîíòðîëü ñî ñòîðîíû ñòåðîèäíûõ
ãîðìîíîâ. Ñèíòåç òîãî æå òèïà ëèçîöèìà îòìå÷åí â ìàêðîôàãàõ, ïðè÷åì
îí óñèëèâàåòñÿ âîä âîçäåéñòâèåì áàêòåðèàëüíûõ ëèïîïîëèñàõàðèäîâ.  êèøå÷íèêå ìîëîäûõ öûïëÿò ýêñïðåññèÿ ëèçîöèìà ñ-òèïà íàáëþäàåòñÿ äî 8ñóòî÷íîãî, g-òèïîâ — äî 38-ñóòî÷íîãî âîçðàñòà. Ó öûïëÿò g-ëèçîöèì îáíàðóæåí òàêæå â ïå÷åíè, ïî÷êàõ, êîñòíîì ìîçãå, ëåãêèõ (38). Âàæíîñòü ïðîòåêòèâíîé ôóíêöèè ëèçîöèìà â êèøå÷íèêå óæå íå âûçûâàåò ñîìíåíèé, íî
ýêñïåðèìåíòàëüíûõ ïîäòâåðæäåíèé ýòîãî ïîêà íåäîñòàòî÷íî.
Èììóíîãëîáóëèíû. Êàê óæå îòìå÷àëîñü, çàùèòà êèøå÷íèêà äîñòèãàåòñÿ áëàãîäàðÿ âðîæäåííîìó è ïðèîáðåòåííîìó èììóíèòåòó. Î÷åâèäíî,
÷òî íàèëó÷øàÿ ñòðàòåãèÿ ïðåäîòâðàùåíèÿ èíôåêöèè — íå äîïóñòèòü êîíòàêòà è àáñîðáöèè ïàòîãåíà ýíòåðîöèòîì (42), ÷òî äîñòèãàåòñÿ çà ñ÷åò ñåêðåöèè íåñïåöèôè÷åñêèõ àíòèáàêòåðèàëüíûõ âåùåñòâ êëåòêàìè ýïèòåëèàëüíîé âûñòèëêè èëè, áîëåå ñïåöèôè÷åñêè, ïðè âûäåëåíèè íåéòðàëèçèðóþùèõ
àíòèòåë â ïðîñâåò êèøå÷íèêà (42). Ïðåèìóùåñòâî àíòèòåë çàêëþ÷àåòñÿ â
«àäðåñíîì» ïîäàâëåíèè êîíêðåòíîãî ïàòîãåíà, â òî âðåìÿ êàê îáùèé «àíòèáàêòåðèàëüíûé àðñåíàë» ìîæåò óáèâàòü è ñèìáèîòè÷åñêóþ ìèêðîôëîðó.
 òî æå âðåìÿ ìíîãèå íåïàòîãåííûå áàêòåðèè èìåþò îáùèå àíòèãåííûå
äåòåðìèíàíòû ñ ïàòîãåííûìè è, êàê ñëåäñòâèå, íåéòðàëèçóþùèå àíòèòåëà
ìîãóò ïðîÿâëÿòü êðîññ-ðåàêòèâíîñòü.
Ôóíêöèþ íåéòðàëèçàöèè (ïðåäîòâðàùåíèÿ ñâÿçûâàíèÿ áàêòåðèé ñ
ýïèòåëèàëüíûìè êëåòêàìè), ðàññìàòðèâàåìóþ â êà÷åñòâå ãëàâíîãî çàùèòíîãî ìåõàíèçìà â êèøå÷íèêå, âûïîëíÿþò àíòèòåëà — IgG, à òàêæå ìîíîìåðíûå èëè äèìåðíûå IgA (5, 43). IgG è ìîíîìåðíûé IgA ñåêðåòèðóþòñÿ ñ
æåë÷üþ â âåðõíþþ ÷àñòü êèøå÷íèêà èëè ÷åðåç áóðñàëüíûé êàíàë â çàäíèé
êèøå÷íèê (44). Ïëàçìàòè÷åñêèå êëåòêè, ñèíòåçèðóþùèå IgG èëè äèìåðíûé IgA, íàõîäÿòñÿ â ñòåíêå êèøå÷íèêà (êðîìå òîãî, èõ âûÿâèëè â êîñòíîì ìîçãå è ñåëåçåíêå) (45, 46). Äèìåðíûå IgA, ëîêàëüíî ïðîäóöèðóåìûå
ïëàçìàòè÷åñêèìè êëåòêàìè, ñåêðåòèðóþòñÿ ÷åðåç ýíòåðîöèòû (43): ñâÿçûâàÿñü ïîëèìåðíûìè Ig-ðåöåïòîðàìè (ïîêà íå îïèñàííûìè ó ïòèö) â áàçàëüíîé ìåìáðàíå ýíòåðîöèòîâ, îíè äàëåå òðàíñïîðòèðóþòñÿ ê àïèêàëüíîé ìåìáðàíå è âûäåëÿþòñÿ â ïðîñâåò êèøå÷íèêà (6). Ýòà ôîðìà IgA çàùèùåíà îò ïðîòåîëèçà ïåïòèäîì — òàê íàçûâàåìûì ñåêðåòîðíûì êîìïîíåíòîì (SC), êîòîðûé ïðåäñòàâëÿåò ñîáîé ôðàãìåíò ïîëèìåðíîãî ðåöåïòîðà èììóíîãëîáóëèíà, îòâåòñòâåííîãî çà òðàíñöèòîëèç äèìåðíîãî IgA èç
ñîáñòâåííîé ïëàñòèíêè â ïðîñâåò êèøå÷íèêà (6). Ïîäîáíî ìóöèíó, äèìåðíûé IgA áëîêèðóåò ïðèêðåïëåíèå áàêòåðèè ê ïîâåðõíîñòè êëåòîê. Áóäó÷è ôàêòîðàìè âðîæäåííîãî èììóíèòåòà, IgA, ïî ñóòè, îáëàäàþò ñïåöèôè÷íîñòüþ, èñòîðè÷åñêè îáóñëîâëåííîé ïðåäûäóùèìè âîçäåéñòâèÿìè àíòèãåíîâ íà ñîáñòâåííóþ ïëàñòèíêó êèøå÷íèêà (43, 47).
Ëèìôîèäíàÿ òêàíü êèøå÷íèêà (GALT ). GALT â îòëè÷èå îò äðóãèõ
ýëåìåíòîâ èììóííîé ñèñòåìû, ñâÿçàííûõ ñ ïîëîñòÿìè â îðãàíèçìå, êîíòàêòèðóåò ñ äâóìÿ òèïàìè àíòèãåííûõ ìîëåêóë — áåçîïàñíûìè (÷àñòî ýòî
íóòðèåíòû, êîòîðûå íå äîëæíû âûçûâàòü èììóííûé îòâåò) è âûäåëÿåìû9
ìè ýíäîãåííûìè èëè ýêçîãåííûìè ïàòîãåíàìè. Òàêèì îáðàçîì, áàëàíñ
ìåæäó èììóííûì îòâåòîì è òîëåðàíòíîñòüþ ðåãóëèðóåòñÿ î÷åíü òîíêî è çàâèñèò îò âçàèìîäåéñòâèÿ ìåæäó èììóííûìè êëåòêàìè è êëåòêàìè ïàðåíõèìû êèøå÷íèêà. Èíûìè ñëîâàìè, ëþáàÿ àíòèãåííàÿ ìîëåêóëà, âñàñûâàåìàÿ
÷åðåç ýíòåðîöèòû (âíóòðèêëåòî÷íûé òðàíñöèòîç), òîëåðîãåííà, â òî âðåìÿ
êàê âñå àíòèãåíû, êîòîðûå ïðîíèêàþò ÷åðåç êèøå÷íûé ñëîé òðàíñêëåòî÷íî èëè ÷åðåç ôàãîöèòàðíûå êëåòêè (Ì-êëåòêè), èììóíîãåííû (42, 48).
GALT ó öûïëÿò ñîñòîèò èç îòäåëüíûõ èììóííûõ êëåòîê, ðàñïðåäåëåííûõ â ýïèòåëèàëüíîì ñëîå êèøå÷íèêà, à òàêæå â ïîäëåæàùèõ ñëîÿõ
(49, 50). Äîïîëíèòåëüíûå ëèìôîèäíûå àãðåãàòû è ñòðóêòóðû ñîñðåäîòî÷åíû â íåñêîëüêèõ ó÷àñòêàõ âäîëü ïèùåâàðèòåëüíîãî òðàêòà. Âûñøèé ñåãìåíò êèøå÷íèêà, âåäóùèé ê ìûøå÷íîìó æåëóäêó, ñîäåðæèò ìàëî ëèìôîèäíûõ ñòðóêòóð; èñêëþ÷åíèå ñîñòàâëÿþò ìèíäàëèíû ïèùåâîäà, íàõîäÿùèåñÿ íà ñî÷ëåíåíèè ïèùåâîäà è æåëåçèñòîãî æåëóäêà (51), è àãðåãàòû íà
ñîáñòâåííîé ïëàñòèíêå æåëåçèñòîãî æåëóäêà (52).  ìûøå÷íîì æåëóäêå â
ìåñòå èëåîöåêàëüíîãî ñîåäèíåíèÿ îáíàðóæåíû ðàññåÿííûå áëÿøêè Ïåéåðà (53, 54), à â äèâåðòèêóëå Ìåêêåëÿ — ñêîïëåíèå ëèìôîèäíîé òêàíè (55).
 íà÷àëå 12-ïåðñòíîé êèøêè ãèñòîëîãè÷åñêèå èññëåäîâàíèÿ ïîêàçàëè íàëè÷èå çíà÷èòåëüíîãî êîëè÷åñòâà ëèìôîèäíîé òêàíè (56), ôîðìèðóþùåé
ïîëíîå êîëüöî íà ó÷àñòêå, ãäå êðèïòû Ëèáåðêþíà òðàíñôîðìèðóþòñÿ â
ìèíäàëåâèäíûå êðèïòû ñ ëèìôîýïèòåëèàëüíîé âûñòèëêîé. Ýòè òàê íàçûâàåìûå ïèëîðè÷åñêèå ìèíäàëèíû — íîâûé ëèìôîýïèòåëèàëüíûé îðãàí
æåëóäî÷íî-êèøå÷íîãî òðàêòà ó ïòèö. Òàêèì îáðàçîì, ïîëó÷åííûå äàííûå
ñâèäåòåëüñòâóþò î òîì, ÷òî ó íèõ â îòëè÷èå îò ìëåêîïèòàþùèõ èìååòñÿ
íàäåæíàÿ èììóíîëîãè÷åñêàÿ çàùèòà òîíêîãî êèøå÷íèêà.
Ïðîöåññû îáðàçîâàíèÿ è ôóíêöèîíèðîâàíèÿ B- è Ò-ëèìôîöèòîâ äåòàëüíî îïèñàíû íàìè ðàíåå (57). Çäåñü óïîìÿíåì òîëüêî î ôîðìèðîâàíèè
àíòèãåí-ðàñïîçíàþùåãî Ò-êëåòî÷íîãî ðåöåïòîðà êàê ðåøàþùåì ñîáûòèè â
ðàçâèòèè Ò-ëèìôîöèòîâ. Î÷åâèäíî, ÷òî äëÿ îáåñïå÷åíèÿ âîçìîæíîñòè îòëè÷àòü ëþáîé àíòèãåí îò äðóãèõ íóæíû ìèëëèîíû ðàçíûõ ïî ñïåöèôè÷íîñòè àíòèãåí-ðàñïîçíàþùèõ ðåöåïòîðîâ. Ôîðìèðîâàíèå îãðîìíîãî ðàçíîîáðàçèÿ òàêèõ ðåöåïòîðîâ âîçìîæíî áëàãîäàðÿ ïåðåñòðîéêå ãåíîâ â ïðîöåññå
ïðîëèôåðàöèè è äèôôåðåíöèðîâêè êëåòîê-ïðåäøåñòâåííèö. Ïî ìåðå ñîçðåâàíèÿ Ò-ëèìôîöèòîâ íà èõ ïîâåðõíîñòè ïîÿâëÿþòñÿ àíòèãåí-ðàñïîçíàþùèå ðåöåïòîðû è äðóãèå ìîëåêóëû, îïîñðåäóþùèå âçàèìîäåéñòâèå ñ àíòèãåí-ïðåäñòàâëÿþùèìè êëåòêàìè. Ñî÷åòàíèå ïîâåðõíîñòíûõ ìîëåêóë Ò-ëèìôîöèòîâ, êîòîðûå ïðèíÿòî îáîçíà÷àòü ïîðÿäêîâûìè íîìåðàìè êëàñòåðîâ
äèôôåðåíöèðîâêè (clusters of differentiation — CD), íàçûâàþò ïîâåðõíîñòíûì ôåíîòèïîì êëåòêè, à ñàìè ìîëåêóëû — ìàðêåðàìè, òàê êàê îíè ñëóæàò
ìåòêàìè êîíêðåòíûõ ñóáïîïóëÿöèé è ñòàäèé äèôôåðåíöèðîâêè. Â ðàñïîçíàâàíèè ñîáñòâåííûõ ìîëåêóë ãëàâíîãî êîìïëåêñà ãèñòîñîâìåñòèìîñòè
(MHC) íàðÿäó ñ Ò-êëåòî÷íûì ðåöåïòîðîì ó÷àñòâóþò ìîëåêóëû CD4 èëè
CD8. Íà ïîçäíèõ ýòàïàõ äèôôåðåíöèðîâêè ó Ò-ëèìôîöèòîâ ñîõðàíÿåòñÿ
îäèí èç ýòèõ ìàðêåðîâ, ïîýòîìó ñðåäè çðåëûõ Ò-ëèìôîöèòîâ ðàçëè÷àþò
ôîðìû CD4+ (Ò-õåëïåðû) è CD8+ (öèòîòîêñè÷åñêèå Ò-ëèìôîöèòû).
Ëèìôîèäíûå ôîëëèêóëû ñîñòîÿò èç B-êëåòîê, ïîãðóæåííûõ â ñåòü
ôîëëèêóëÿðíûõ äåíäðèòíûõ êëåòîê ñ íåçíà÷èòåëüíûì êîëè÷åñòâîì CD4+
Ò-êëåòîê è ìàêðîôàãîâ. Èíòåðôîëëèêóëÿðíûå îáëàñòè ïðåäñòàâëåíû ãëàâíûì îáðàçîì ÑD4+ è CD8+ Ò-êëåòêàìè (58-60). Ïîïóëÿöèÿ Ò-ëèìôîöèòîâ ñîñòîèò èç αβ- è γδ-T-êëåòîê, èìåþùèõ ñîîòâåòñòâåííî ãåòåðîäèìåðíûå αβ- è γδ-ðåöåïòîðû. Ïðè ýòîì αβ-Ò-êëåòêè óçíàþò àíòèãåííûå
ïåïòèäû â ñîñòàâå MHC I èëè II êëàññà ñ ïîìîùüþ ìîëåêóë CD8 èëè
ÑD4. Óñòàíîâëåíà êðèñòàëëè÷åñòêàÿ ñòðóêòóðà òðèìåðíîãî êîìïëåêñà, ñîñòîÿùåãî èç αβ-ðåöåïòîðîâ Ò-êëåòîê (TCR-αβ), ïåïòèäà è MHC, è ðàñøèôðîâàí òî÷íûé ìåõàíèçì óçíàâàíèÿ íà ìîëåêóëÿðíîì óðîâíå (61-64). Â
10
ñâîþ î÷åðåäü, γδ-T-êëåòêè ðàñïîçíàþò íåïåïòèäíûå àíòèãåíû, òàêèå êàê
ïèðîôîñôîìîíîýôèðû è àëêèëèðîâàííûå àìèíû, îáðàçóåìûå ìèêðîáèàëüíûìè ïàòîãåíàìè, áåç ó÷àñòèÿ MHC (65-68). Çàùèòíûå ìåõàíèçìû
ïðîòèâ áàêòåðèé èëè äðóãèõ èíôåêöèîííûõ àãåíòîâ, ñïîñîáíûõ íàðóøàòü
ýïèòåëèàëüíóþ âûñòèëêó, îñíîâàíû íà àêòèâíîñòè èíòåðýïèòåëèàëüíûõ
ëèìôîöèòîâ, âêëþ÷àÿ NK-êëåòêè (êëåòêè-óáèéöû), αβ- è γδ-T-ëèìôîöèòû (62). Èíòåðåñíî, ÷òî óíèêàëüíàÿ ïîïóëÿöèè èíòðåëåéêèí-17-ïðîäóöèðóþùèõ CD4+ Ò-êëåòîê (Th17-êëåòîê), îòëè÷àþùèõñÿ îò îáû÷íûõ Th1èëè Th2-êëåòîê, â îñíîâíîì ëîêàëèçîâàíà â ñîáñòâåííîé ïëàñòèíêå êèøå÷íèêà ó çäîðîâûõ æèâîòíûõ (69, 70). Äî ñèõ ïîð íå ÿñíî, ÿâëÿþòñÿ ýòè
êëåòêè ïàòîãåííûìè èëè çàùèòíûìè, à ìåõàíèçìû èõ äèôôåðåíöèðîâêè
è ðàçâèòèÿ íóæäàþòñÿ â äàëüíåéøåì óòî÷íåíèè (71).
 áîëåå îðãàíèçîâàííûõ ëèìôîèäíûõ ñòðóêòóðàõ (ìèíäàëèíû ñëåïûõ îòðîñòêîâ è áëÿøêè Ïåéåðà) ïðèñóòñòâóþò CD4+ αβ-T-êëåòêè è Bêëåòêè (58, 60), â òî âðåìÿ êàê íà ó÷àñòêàõ ñ áîëåå äèñïåðñíûì ðàñïðåäåëåíèåì ëèìôîèäíîé òêàíè (ýïèòåëèé è ñîáñòâåííàÿ ïëàñòèíêà) ïðåâàëèðóþò γδ-T-êëåòêè (49).  ôàáðèöèåâîé ñóìêå çíà÷èòåëüíî ìåíüøå CD4+ è
CD8+ Ò-êëåòîê, ïîñêîëüêó îíà âûïîëíÿåò ôóíêöèþ ïåðâè÷íîãî èñòî÷íèêà IgM-îáðàçóþùèõ Ì-êëåòîê (60).
Ëåéêîöèòû, ïðåäñòàâëÿþùèå êëåòî÷íîå çâåíî âðîæäåííîãî èììóíèòåòà, γδ-T-ëèìôîöèòû è NK-êëåòêè ïðåèìóùåñòâåííî ëîêàëèçîâàíû â
ýïèòåëèè (72) è èìåþò áîëüøîå ñõîäñòâî ïî ðàçâèòèþ è ôóíêöèÿì ñ òàêîâûìè ó ìëåêîïèòàþùèõ (49, 73). Ó öûïëÿò γδ-T-ëèìôîöèòû äèôôåðåíöèðóþòñÿ â òèìóñå (74, 75), íî âîçìîæíîñòü èõ êèøå÷íîãî ïðîèñõîæäåíèÿ,
êàê ýòî ïîêàçàíî ó ìûøåé (76), ïîêà îñòàåòñÿ íå èññëåäîâàííîé â ïîëíîé
ìåðå. Ôóíêöèîíàëüíî γδ-T- è NK-êëåòêè ñïîñîáíû îòâå÷àòü íà ñòèìóë
íåìåäëåííî ïîñëå àêòèâàöèè, ÷òî êîíòðîëèðóåòñÿ ýêçîãåííûìè öèòîêèíàìè è àíòèãåíîì (77, 78). Öèòîêèíû ìîãóò ïðîäóöèðîâàòüñÿ àêòèâèðîâàííûìè ÑD4- èëè CD8-ëèìôîöèòàìè ïðè èììóííîì îòâåòå (77) è, âîçìîæíî, ñòðåññèðîâàííûìè ýíòåðîöèòàìè â íà÷àëüíóþ ôàçó âîñïàëåíèÿ
(79, 80). Òàêèì îáðàçîì, àêòèâèðîâàííûå êëåòêè, ó÷àñòâóþùèå â ðåàêöèÿõ
âðîæäåííîãî èììóíèòåòà â âûñòèëêå êèøå÷íèêà, âíîñÿò âêëàä â çàùèòó è
îäíîâðåìåííî ó÷àñòâóþò â àêòèâàöèè êëåòîê, íàõîäÿùèõñÿ íà ñîáñòâåííîé ïëàñòèíêå. Îñîáåííîñòü ðåàêöèé ïðèîáðåòåííîãî èììóíèòåòà îáóñëîâëåíà íàëè÷èåì ëèìôîèäíûõ ôîëëèêóëîâ, îáðàçîâàííûõ Â- è Ò-ëèìôîöèòàìè, êîòîðûå ïîäâåðãàþòñÿ äèôôåðåíöèàöèè è äåëÿòñÿ â ïðîöåññå
îáðàçîâàíèÿ ýôôåêòîðíûõ ëèìôîöèòîâ. Äåëÿùèåñÿ ëèìôîöèòû îòáèðàþòñÿ ïî ñïåöèôè÷åñêîìó ñâÿçûâàíèþ àíòèãåíà, ïðåçåíòèðóåìîãî ôîëëèêóëÿðíûìè äåíäðèòíûìè êëåòêàìè. Îòñåëåêòèðîâàííûå êëåòêè çàòåì äèôôåðåíöèðóþòñÿ â ýôôåêòîðíûå êëåòêè èëè êëåòêè ïàìÿòè, êîòîðûå ìîãóò
ìèãðèðîâàòü â òêàíè. Ïåðâè÷íûå ôîëëèêóëû ýòîé ïðèðîäû îáíàðóæèâàþòñÿ â ìèçåðíîì êîëè÷åñòâå â òîíêîì êèøå÷íèêå öûïëÿò (54). Ýòî íå
îçíà÷àåò, ÷òî èììóííûé îòâåò íå ìîæåò áûòü ãåíåðèðîâàí â âåðõíåì îòäåëå êèøå÷íèêà, íî âñå æå â îñíîâíîì ïåðâè÷íûå îòâåòû, âåðîÿòíî, ôîðìèðóþòñÿ â çàäíåì êèøå÷íèêå (hindgut), áóðñàëüíîì êàíàëå, ôàáðèöèåâîé
ñóìêå è ñåëåçåíêå. Òàê, ïðîäåìîíñòðèðîâàíî çíà÷åíèå êëîàêàëüíîé (ôàáðèöèåâîé) ñóìêè â ïåðâè÷íîì èììóííîì îòâåòå (81).
Ñëåäîâàòåëüíî, ïî áîëüøåé ÷àñòè èììóíîëîãè÷åñêàÿ àêòèâíîñòü,
íàáëþäàåìàÿ â âåðõíåé ÷àñòè êèøå÷íèêà (â ïåðåäíåé êèøêå), èìååò âòîðè÷íûé õàðàêòåð è îáóñëîâëåíà ôóíêöèîíèðîâàíèåì ñîáñòâåííîé ïëàñòèíêè ëèáî ïîñòóïëåíèåì èììóííûõ ìîëåêóë â ïðîñâåò êèøå÷íèêà èç
æåë÷è èëè ïðè òðàíñöèòîëèçå ñ ó÷àñòèåì ýíòåðîöèòîâ, òîãäà êàê ïåðâè÷íûå ðåàêöèè íà àíòèãåí ãåíåðèðóþòñÿ ãëàâíûì îáðàçîì â çàäíåì êèøå÷íèêå. Ýòè ïåðâè÷íûå îòâåòû ñòàíîâÿòñÿ ñèñòåìíûìè, ïîñêîëüêó àíòèòåëà,
ñèíòåçèðóåìûå ëîêàëüíî, ïîïàäàþò â ïëàçìó è ýôôåêòîðíûå êëåòêè è
11
ìèãðèðóþò äàëåå — â äðóãèå ó÷àñòêè êèøå÷íèêà èëè îðãàíû, âêëþ÷àÿ ñåëåçåíêó, êîñòíûé ìîçã è ò.ä. Êëþ÷åâûì ôàêòîðîì ïðè ãåíåðèðîâàíèè
ïåðâè÷íîãî èììóííîãî îòâåòà â çàäíåì êèøå÷íèêå ñëóæèò åãî ñïîñîáíîñòü «îòáèðàòü» àíòèãåííûé ìàòåðèàë èç ñðåäû. Äîêàçàòåëüñòâà ýòîãî ïîêà íåïðÿìûå è áàçèðóþòñÿ íà îáíàðóæåíèè ðåòðîãðàäíûõ (îáðàòíûõ) ñîêðàùåíèé êèøå÷íîãî ïðîòîêà ó ïòèö. Òàêóþ ðåòðîãðàäíóþ ïåðèñòàëüòèêó
îáîäî÷íîé êèøêè àâòîðû ñâÿçûâàëè ñ ïîòðåáíîñòüþ óëó÷øèòü ðåàáñîðáöèþ èç ìî÷è è ñîäåðæèìîãî ñëåïûõ îòðîñòêîâ êèøå÷íèêà äëÿ áîëåå ïîëíîãî ïîãëîùåíèÿ ïðîäóêòîâ ðàñùåïëåíèÿ öåëëþëîçû è àçîòèñòûõ âåùåñòâ
(82-84). Ýêñïåðèìåíòû ñî ñâåæåâûëóïèâøèìèñÿ öûïëÿòàìè è âçðîñëûìè
êóðàìè ïîêàçàëè íàëè÷èå îáðàòíîé ïåðèñòàëüòèêè ïèùåâàðèòåëüíîãî êàíàëà ìåæäó ñðåäèíîé òîùåé êèøêè è 12-ïåðñòíîé êèøêîé è äàæå ìûøå÷íûì æåëóäêîì (85). Ýòè äàííûå ñâèäåòåëüñòâóþò î âîçìîæíîñòè ïîïàäàíèÿ âíåøíåãî ìàòåðèàëà â èììóíîàêòèâíûå ñëåïûå îòðîñòêè êèøå÷íèêà è, ÷òî áîëåå âàæíî, óêàçûâàþò íà âåðîÿòíîå ïåðåìåùåíèå àíòèòåë, îáðàçîâàííûõ â áóðñå, ââåðõ â òîíêèé êèøå÷íèê. Ïðåäïîëîæåíèå î òîì, ÷òî
â èììóííîì îòâåòå â GALT àêòèâíî ó÷àñòâóåò áóðñà, íå íîâî, õîòÿ áîëüøèíñòâî èññëåäîâàòåëåé ãëàâíîå âíèìàíèå óäåëÿëè äèôôåðåíöèðîâêå â íåé
íåçðåëûõ Â-ëèìôîöèòîâ (86, 87). Îäíàêî íàêàïëèâàåòñÿ âñå áîëüøå äîêàçàòåëüñòâ òîãî, ÷òî áóðñà è áóðñàëüíûé êàíàë èãðàþò âàæíóþ ðîëü â èììóííîì îòâåòå.  ÷àñòíîñòè, ïîêàçàíî, ÷òî àíòèãåíû àêòèâíî ïåðåíîñÿòñÿ
÷åðåç áóðñàëüíûé êàíàë â ïðîñâåò áóðñû (88).
Ì î ð ô î ë î ã è ÷ å ñ ê è å î ñ î á å í í î ñ ò è G A L T. Âíóòðåííÿÿ âûñòèëêà êèøå÷íèêà ôîðìèðóåò âîðñèíêè è êðèïòû. Âîðñèíêè ïîêðûòû ïðîñòûì âñàñûâàþùèì ñòîëá÷àòûì ýïèòåëèåì ñî ùåòî÷íîé êàåìêîé, â êîòîðîì èìåþòñÿ ñåêðåòîðíûå ãîáëåò-êëåòêè, à òàêæå ìíîæåñòâî âíóòðèýïèòåëèàëüíûõ ëåéêîöèòîâ.  êðèïòàõ ïðîèñõîäèò äèôôåðåíöèðîâêà è ñîçðåâàíèå ýíòåðîöèòîâ, ãîáëåò- è ýíòåðîýíäîêðèííûõ êëåòîê, êëåòîê Ïàíåòà (ïîñëåäíèå ïîêà ñëàáî îõàðàêòåðèçîâàíû ó ïòèö) (89, 90).
Ó öûïëÿò âíóòðèýïèòåëèàëüíûå ëèìôîöèòû ïðåäñòàâëåíû ðàçíîîáðàçíîé ïîïóëÿöèåé êëåòîê, âêëþ÷àþùåé NK-êëåòêè (91), αβ- è γδ-T-êëåòêè (49) è ãåòåðîôèëû (ïîñëåäíèå îòìå÷åíû â ñëåïûõ îòðîñòêàõ êèøå÷íèêà). Ó ìëåêîïèòàþùèõ çîíà êðèïò ñîäåðæèò êëåòêè Ïàíåòà, ñïîñîáíûå
ñåêðåòèðîâàòü ëèçîöèì, äåôåíñèíû è äðóãèå àíòèáàêòåðèàëüíûå âåùåñòâà
(92, 93). Õîòÿ ó ïòèö (â òîì ÷èñëå ó öûïëÿò) ýïèòåëèàëüíûå äåôåíñèíû
îïèñàíû, êëåòêè, îòâåòñòâåííûå çà èõ ñåêðåöèþ, äî ñèõ ïîð ÷åòêî íå îïðåäåëåíû (94). Ïîñêîëüêó êëåòêè Ïàíåòà âñòðå÷àþòñÿ ó ïòèö î÷åíü ðåäêî,
áîëåå âåðîÿòíî, ÷òî ãëàâíûì èñòî÷íèêîì àíòèáàêòåðèàëüíûõ ñóáñòàíöèé
ìîãóò áûòü íå òèïè÷íûå êëåòêè, ïîäîáíûå êëåòêàì Ïàíåòà ìëåêîïèòàþùèõ, à ìàêðîôàãè èëè ãåòåðîôèëû (23, 95).
Ñîáñòâåííàÿ ïëàñòèíêà êèøå÷íèêà ó ïòèö, êàê è ó ìëåêîïèòàþùèõ, ñîäåðæèò íàáîð èììóííûõ êëåòîê âñåõ òèïîâ, âêëþ÷àÿ ïëàçìàòè÷åñêèå êëåòêè, ýôôåêòîðíûå Ò-ëèìôîöèòû è ëèìôîöèòû ïàìÿòè, ìàêðîôàãè è ãðàíóëîöèòû (14, 73, 96). Åùå îäíà îòëè÷èòåëüíàÿ îñîáåííîñòü ìîðôîëîãèè èììóííîé ñèñòåìû êèøå÷íèêà ó ïòèö — íåäîðàçâèòîñòü áëÿøåê
Ïåéåðà. Òàê, íà ñòîðîíå òîíêîé êèøêè öûïëÿò, ïðîòèâîïîëîæíîé áðûæåå÷íîìó êðàþ, îáíàðóæèâàëîñü äî øåñòè áëÿøåê Ïåéåðà (54) (èõ åùå íàçûâàþò êèøå÷íûìè ãëàíäàìè è îíè ïîõîæè íà òàêîâûå ó ìëåêîïèòàþùèõ). Îäíà èç áëÿøåê íàõîäèòñÿ â ïîäâçäîøíîé êèøêå (54). Èõ ëèìôîèäíàÿ òêàíü íå òîëüêî ëîêàëèçîâàíà â cîáñòâåííîé ïëàñòèíêå, íî òàêæå
ïðîíèêàåò ÷åðåç ïîäñëèçèñòóþ îáîëî÷êó. Îíà ñîñòîèò èç ïåðâè÷íûõ è
âòîðè÷íûõ ëèìôîèäíûõ ôîëëèêóëîâ, êîòîðûå ñîäåðæàò ãëàâíûì îáðàçîì
Â-ëèìôîöèòû è ðàçäåëåíû èíòåðôîëëèêóëÿðíûìè îáëàñòÿìè, áîãàòûìè
Ò-ëèìôîöèòàìè (51, 54, 97). Ýïèòåëèé, êîòîðûé ïîêðûâàåò áëÿøêè Ïåéåðà, îáðàçóåòñÿ èç íåäèôôåðåíöèðîâàííûõ ýíòåðîöèòîâ è âûðàæåííî èí12
ôèëüòðîâàí ëèìôîèäíûìè êëåòêàìè. Ýòîò ëèìôîýïèòåëèé îòâå÷àåò çà
êîíòàêò ìåæäó õèìóñîì è êèøå÷íîé èììóííîé ñèñòåìîé. Áëÿøêè Ïåéåðà
ðàçâèâàþòñÿ î÷åíü áûñòðî. Ó ñâåæåâûëóïèâøèõñÿ öûïëÿò òàêèå áëÿøêè
íå ïðîñìàòðèâàþòñÿ ïðè ìèêðîñêîïèðîâàíèè ãèñòîëîãè÷åñêèõ ïðåïàðàòîâ, íî èíôèëüòðàöèÿ ëèìôîèäíûõ êëåòîê âûÿâëÿåòñÿ ëåãêî, ïîñêîëüêó
ñ 10-õ ñóò îíè âèäíû íåâîîðóæåííûì ãëàçîì. Èõ îáúåì óâåëè÷èâàåòñÿ äî
3-ìåñÿ÷íîãî âîçðàñòà. Èç-çà àòðîôèè ïîñëå 12-ìåñÿ÷íîãî âîçðàñòà ëèøü
îäíà áëÿøêà Ïåéåðà îñòàåòñÿ â ìåñòå ïåðåõîäà ïîäâçäîøíîé êèøêè â ñëåïûå îòðîñòêè (54, 98).
Òàêèì îáðàçîì, áîëüøèíñòâî ëèìôîèäíûõ ôîëëèêóëîâ îáíàðóæèâàåòñÿ â ñëåïûõ îòðîñòêàõ, â êðîäåóìå è ïðîêòîäåóìå (54) è â áóðñàëüíîì
êàíàëå. Íåñìîòðÿ íà òî, ÷òî îíè ìåíüøå ïî ðàçìåðó, èõ ñòðóêòóðà íàïîìèíàåò áëÿøêè Ïåéåðà ó ìëåêîïèòàþùèõ: cïåöèàëèçèðîâàííûé ëèìôîýïèòåëèé ñîäåðæèò Ì-êëåòêè (97, 99, 100), à òàêæå ôîëëèêóëÿðíûå ñòðóêòóðû,
áîãàòûå Ò- è Â-ëèìôîöèòàìè, â êîòîðûõ îíè äåëÿòñÿ è äèôôåðåíöèðóþòñÿ. Ïîãðàíè÷íûå çîíû ôîëëèêóëîâ ñîäåðæàò ìàêðîôàãè è ýôôåêòîðíûå
ëèìôîöèòû âñåõ òèïîâ (73). Ñëåäîâàòåëüíî, ó ïòèö (ïî àíàëîãèè ñ ìëåêîïèòàþùèìè) â êèøå÷íîì ëèìôîýïèòåëèè Ì-êëåòêàì ñ ìåëêèìè, îêðóãëûìè àïèêàëüíûìè âîðñèíêàìè ïðèíàäëåæèò îñíîâíàÿ ôóíêöèÿ çàõâàòà,
ïåðåðàáîòêè è òðàíñïîðòà àíòèãåíîâ èç ïîëîñòè êèøå÷íèêà ÷åðåç ýïèòåëèàëüíûé áàðüåð â ïîäëåæàùèå èììóííûå êëåòêè, ãäå ïðîèñõîäèò ïðåäñòàâëåíèå àíòèãåíîâ è èíèöèàöèÿ èììóííîãî îòâåòà (97). Íà òî, ÷òî Ìêëåòêè íå âîâëå÷åíû âî âñàñûâàíèå è ïåðåâàðèâàíèå, óêàçûâàåò ñëàáîðàçâèòàÿ ùåòî÷íàÿ êàåìêà è îòñóòñòâèå ôåðìåíòàòèâíîé àêòèâíîñòè íà àïèêàëüíîé ÷àñòè. Ëèìôîèäíûå ôîëëèêóëû øèðîêî ðàñïðîñòðàíåíû â ñëåïûõ
îòðîñòêàõ. Êðîìå ãëàâíûõ ëèìôîèäíûõ ôîëëèêóëîâ, êîòîðûå èçâåñòíû
êàê ìèíäàëèíû ñëåïîé êèøêè è ëîêàëèçîâàíû â åå ïðîêñèìàëüíîé ÷àñòè,
îáíàðóæåíî çíà÷èòåëüíîå êîëè÷åñòâî ëèìôàòè÷åñêèõ óçëîâ ïî âñåìó ñëåïîìó îòðîñòêó è èõ ñêîïëåíèå â åãî àïèêàëüíîé ÷àñòè (101, 102). Âûÿâëåíû òàêæå ëèìôîèäíûå óçåëêè íà âåðøèíå ñëåïîé êèøêè (103).  òîëñòîé
êèøêå ëèìôîèäíûå ôîëëèêóëû îòñóòñòâóþò, îäíàêî èõ ìíîãî â êàíàëå,
âåäóùåì ê êëîàêàëüíîé áóðñå — ëèìôîèäíîìó îðãàíó, ðàñïîëîæåííîìó â
ïðîêòîäåàëüíîé îáëàñòè êëîàêè è ó÷àñòâóþùåìó â ïåðâè÷íîì è âòîðè÷íîì
èììóííîì îòâåòå. Ñëèçèñòàÿ è ïîäñëèçèñòàÿ áóðñàëüíîãî êàíàëà óñåÿíû
ëèìôîèäíûìè ôîëëèêóëàìè (85). Îòäåëüíûå ëèìôîèäíûå óçëû òàêæå
îáíàðóæèâàþòñÿ â ïðîêäåóìå (çàäíåé êèøêå) è óðîäåóìå (÷àñòü êëîàêè, êóäà îòêðûâàþòñÿ ìî÷åòî÷íèêè) (54). Áóðñàëüíûé êàíàë èìååò ñòðóêòóðó ïèùåâàðèòåëüíîãî: ñòîëá÷àòûé ýïèòåëèé ñ ñîáñòâåííîé ïëàñòèíêîé ïîä íèì,
ïîäñëèçèñòûé ñëîé, ñîäåðæàùèé ýêçîêðèííûå æåëåçû è, ÷òî íàèáîëåå âàæíî, ìûøå÷íûé ñëîé, ôóíêöèÿ êîòîðîãî çàêëþ÷àåòñÿ â ïðîòàëêèâàíèè áóðñàëüíûõ ñåêðåòîâ ê êëîàêå. Ñëèçèñòûé è ïîäñëèçèñòûé ñëîè ãóñòî óñåÿíû
ëèìôîèäíûìè ôîëëèêóëàìè. Èíòðàýïèòåëèàëüíûå ëèìôîöèòû è ëèìôîèäíûå êëåòêè ñîáñòâåííîé ïëàñòèíêè, à òàêæå ëåéêîöèòû â êèøå÷íèêå âåñüìà ìíîãî÷èñëåííû (49, 50). Òî åñòü â áóðñå ïðîèñõîäèò äèôôåðåíöèàöèÿ
B-ëèìôîöèòîâ è îäíîâðåìåííî ýòîò îðãàí âûïîëíÿåò ôóíêöèþ ïåðèôåðè÷åñêîãî ëèìôàòè÷åñêîãî óçëà.
Îñîáåííîñòè ðàçâèòèÿ GALT ó öûïëÿò ïîñëå âûâ î ä à. Ïèùåâàðèòåëüíàÿ ñèñòåìà öûïëåíêà ïîäâåðãàåòñÿ ñèñòåìíûì èçìåíåíèÿì ñðàçó ïîñëå âûâîäà. Ýòè èçìåíåíèÿ âêëþ÷àþò çíà÷èòåëüíîå óâåëè÷åíèå ìàññû, ÷èñëà è äëèíû âîðñèíîê, ÷èñëà ýíòåðîöèòîâ, ãëóáèíû
êðèïò è ÷èñëà äåëÿùèõñÿ êëåòîê.  êèøå÷íèêå áûñòðîå ðàçâèòèå ëèìôîèäíîé òêàíè ïðîèñõîäèò îäíîâðåìåííî ñ ðàçâèòèåì ïèùåâàðèòåëüíûõ ñòðóêòóð è ôóíêöèé. Ýòà ëèìôîèäíàÿ ñèñòåìà äåéñòâóåò â òåñíîì êîíòàêòå ñ
ïàðåíõèìîé êèøå÷íèêà.
Ê âûâîäó öûïëåíêà â êèøå÷íèêå ñîäåðæèòñÿ ìàëî ëåéêîöèòîâ è
13
ëèìôîöèòîâ, îáåñïå÷èâàþùèõ àäàïòèâíûé (ñïåöèôè÷åñêèé) èììóíèòåò. Èõ
÷èñëî — ðåçóëüòàò ðàííèõ âîëí ìèãðàöèè êëåòîê â ýìáðèîãåíåçå èç òèìóñà
è ôàáðèöèåâîé ñóìêè; ñëåäóþùèå âîëíû íàáëþäàþòñÿ ïîñëå 4-ñóòî÷íîãî
âîçðàñòà â òå÷åíèå âñåãî îíòîãåíåçà. Îäíîâðåìåííî ñ èçìåíåíèåì ÷èñëà
ëèìôîöèòîâ ðàçâèâàåòñÿ àäàïòèâíûé èììóíèòåò, è åãî ïîëíàÿ ôóíêöèîíàëüíîñòü äîñòèãàåòñÿ ê 10-14-ì ñóò æèçíè (104). Îò âûâîäà äî ñîçðåâàíèÿ
àäàïòèâíîé èììóííîé ñèñòåìû çàùèòà â êèøå÷íèêå îñóùåñòâëÿåòñÿ èñêëþ÷èòåëüíî çà ñ÷åò âðîæäåííîãî èììóíèòåòà è ìàòåðèíñêèõ èììóíîãëîáóëèíîâ, ïîëó÷åííûõ ÷åðåç ÿéöî (ñëåäóåò îòìåòèòü, ÷òî ìîëåêóëÿðíûå ìåõàíèçìû ðåãóëÿöèè ýòèõ ïðîöåññîâ íóæäàþòñÿ â äàëüíåéøåé ðàñøèôðîâêå). Ïîñëå ñîçðåâàíèÿ èììóííîé ñèñòåìû åå ýëåìåíòû â îñíîâíîì ñîñðåäîòî÷åíû â äèñòàëüíîé ÷àñòè êèøå÷íèêà, âêëþ÷àÿ áëÿøêè (ìèíäàëèíû)
ñëåïîé êèøêè è ôàáðèöèåâó ñóìêó, ñ ïîñëåäóþùèì ðàññåëåíèåì ñîîòâåòñòâóþùèõ êëåòîê â äðóãèå îòäåëû òîíêîãî êèøå÷íèêà.
Ðàçâèòèå GALT ó öûïëÿò ïåðåä è ñðàçó ïîñëå âûâîäà íå ïîëó÷èëî
äîñòàòî÷íîãî îòðàæåíèÿ â ñïåöèàëüíîé ëèòåðàòóðå (çà èñêëþ÷åíèåì äàííûõ îá èçó÷åíèè Â-ëèìôîöèòîâ â ôàáðèöèåâîé ñóìêå) (105, 106). Íà ãèñòîëîãè÷åñêèõ ñðåçàõ êèøå÷íèêà ó ñâåæåâûëóïèâøèõñÿ öûïëÿò âûÿâëÿåòñÿ
ìàëî ëèìôîèäíûõ îáðàçîâàíèé, îáåñïå÷èâàþùèõ êàê âðîæäåííûé, òàê è
ïðèîáðåòåííûé èììóíèòåò. Îäíàêî èñïîëüçîâàíèå áîëåå ÷óâñòâèòåëüíûõ
ìîëåêóëÿðíûõ ìåòîäîâ, íàïðèìåð, îöåíêà ýêñïðåññèè ãåíîâ ðåöåïòîðîâ Bè Ò-êëåòîê, ñâèäåòåëüñòâóåò î òîì, ÷òî â ïåðèîä âûâîäà êèøå÷íèê öûïëÿò
óæå ñîäåðæèò ëèìôîöèòû (107). Îòìå÷àëîñü, ÷òî èçìåíåíèå èõ ÷èñëåííîñòè ñîâïàäàåò ñ âîëíàìè ìèãðàöèè Ò-ëèìôîöèòîâ èç òèìóñà (74) è ïîÿâëåíèåì ïåðèôåðè÷åñêèõ Â-ëèìôîöèòîâ (86, 108). Ôóíêöèîíàëüíî ýòè ëèìôîöèòû íàõîäÿòñÿ â íåàêòèâíîé ôîðìå âñëåäñòâèå ñëàáîé ýêñïðåññèè öèòîêèíîâ (IL-2 è IFN-γ) â ýòîò ïåðèîä (107).
Ãëàâíàÿ (âòîðàÿ) âîëíà ðàññåëåíèÿ èììóííûõ êëåòîê (ïîñëå 4-õ ñóò
æèçíè) ñîâïàäàåò ñ ðàçâèòèåì êèøå÷íîé ïàðåíõèìû ó öûïëÿò è èìååò
îäèíàêîâóþ äèíàìèêó äëÿ T- è Â-ëèìôîöèòîâ (107).  êèøå÷íèêå è â
ìèíäàëèíàõ ñëåïîé êèøêè ïëîòíîñòü ïîïóëÿöèè ëèìôîöèòîâ ïðèìåðíî
îäèíàêîâà, íî â êèøå÷íèêå îíà ôîðìèðóåòñÿ íåñêîëüêî ðàíåå. Äðàìàòè÷åñêîå ïîâûøåíèå ýêñïðåññèè öèòîêèíîâ (IL-2 è IFNγ, ñîîòâåòñòâåííî ôàêòîðû àêòèâàöèè è ýôôåêòîðíîé ôóíêöèè), ñâèäåòåëüñòâóåò î íàëè÷èè â
ýòîò ïåðèîä ïîëíîñòüþ çðåëûõ ëèìôîöèòîâ, êîòîðûå ñòèìóëèðóþòñÿ â îòâåò íà àêòèâàöèþ (107). Óñèëåíèå ëèìôîèäíîé ôóíêöèè â êèøå÷íèêå çàâèñèò îò ïðèñóòñòâèÿ áàêòåðèé è ñîâïàäàåò ïî âðåìåíè ñ ðàçâèòèåì ýíòåðîöèòîâ è âîðñèíîê (109). Ïðè ýòîì ôóíêöèîíàëüíîå ñîçðåâàíèå òîëñòîãî
êèøå÷íèêà (ñëåïûå îòðîñòêè è îáîäî÷íàÿ êèøêà) ïðîèñõîäèò ðàíüøå, ÷åì
òîíêîãî (107, 109). Èìåþùèåñÿ äàííûå ïîäòâåðæäàþò âçàèìîñâÿçü ìåæäó
ôóíêöèîíàëüíîé çðåëîñòüþ êèøå÷íèêà è çàâåðøåíèåì ôîðìèðîâàíèÿ ìåñòíîé èììóííîé ñèñòåìû.
Âàæíàÿ ðîëü ìàòåðèíñêèõ àíòèòåë â ïðåäîòâðàùåíèè áîëåçíåé â ïåðèîä âûâîäà öûïëÿò èçâåñòíà äàâíî (110), îäíàêî â äåòàëÿõ îíà èçó÷åíà íåäîñòàòî÷íî. Òàê, ïîêàçàíî, ÷òî ìàòåðèíñêèå àíòèòåëà ñïîñîáíû çàùèùàòü
êèøå÷íèê öûïëÿò îò êîëîíèçàöèè Campylobacter jejuni (111), íî ìåíåå ýôôåêòèâíû ïðîòèâ òàêèõ áàêòåðèé, êàê Sallmonella spp., ñòðàòåãèÿ ðàñïðîñòðàíåíèÿ êîòîðûõ ñâÿçàíà ñ âíóòðèêëåòî÷íûì ïàðàçèòèçìîì (112). Òàêæå
òðåáóåò äàëüíåéøåãî àíàëèçà ñâÿçü ìåæäó àêòèâíîñòüþ çàùèòíûõ ìåõàíèçìîâ âðîæäåííîãî èììóíèòåòà â 1-þ íåä æèçíè è ýôôåêòèâíîñòüþ çàùèòû
îò ïàòîãåííûõ ýíòåðîáàêòåðèé.  òî æå âðåìÿ, íàïðèìåð, ïðîäåìîíñòðèðîâàíî, ÷òî ïðè îðàëüíîì èíôèöèðîâàíèè 1-ñóòî÷íûõ öûïëÿò ñàëüìîíåëëîé
ïðîèñõîäèò ëîêàëüíûé õåìîòàêñèñ ôàãîöèòîâ è äàëüíåéøèé ôàãîöèòîç (113).
Ïðè íàáëþäåíèè çà ðàçâèòèåì êèøå÷íîé èììóííîé ñèñòåìû ó çäîðîâûõ öûïëÿò â 1-þ íåä æèçíè (114) áûëà èçó÷åíà ýêñïðåññèÿ òðåõ ãåíîâ,
14
êîäèðóþùèõ ïðîâîñïàëèòåëüíûå öèòîêèíû è õåìîêèíû IL1β, IL8 è K203A.
IL1β — ãëàâíûé ìåäèàòîð âîñïàëåíèÿ ó ìëåêîïèòàþùèõ è ïòèö, îí ñèíòåçèðóåòñÿ ãëàâíûì îáðàçîì òêàíåâûìè ìîíîöèòàìè è ìàêðîôàãàìè (115,
116), íî òàêæå äðóãèìè êëåòêàìè, âêëþ÷àÿ ýíòåðîöèòû (117-120). Ó öûïëÿò IL1β âîâëå÷åí â âîñïàëèòåëüíûé îòâåò, âûçâàííûé áàêòåðèàëüíîé èíôåêöèåé èëè ñòèìóëÿöèåé ëèïîïîëèñàõàðèäîì, è èíäóöèðóåò ëèõîðàäêó
(æàð), à òàêæå ïðîäóêöèþ õåìîêèíîâ (115, 116).  òî âðåìÿ êàê â îáîäî÷íîé êèøêå è ñëåïûõ îòðîñòêàõ àêòèâíîñòü ñèíòåçà ìÐÍÊ IL1β ïî÷òè íå
èçìåíÿëàñü ïî ñðàâíåíèþ ñ ðåãèñòðèðóåìîé íà äàòó âûâîäà, â 12-ïåðñòíîé
êèøêå íà 2-å ñóò ïîñëå âûâîäà àíàëèçèðóåìûé ïîêàçàòåëü ïî÷òè óäâîèëñÿ
(ïðåäïîëîæèëè, ÷òî ýòî ìîæåò áûòü ïîñëåäñòâèåì ïåðâîãî êîðìëåíèÿ è
êîëîíèçàöèè êèøå÷íèêà áàêòåðèÿìè) (121, 122).
IL8 è K203 — ãëàâíûå õåìîêèíû, ïðèíàäëåæàùèå ñîîòâåòñòâåííî ê
ïîäñåìåéñòâó CXC (õàðàêòåðèçóþòñÿ íàëè÷èåì îäíîé àìèíîêèñëîòû ìåæäó N-êîíöåâûìè öèñòåèíàìè) è CC (β-õåìîêèíû, ó êîòîðûõ äâà N-êîíöåâûõ öèñòåèíà íå ðàçäåëåíû äðóãèìè àìèíîêèñëîòàìè) (123, 124). Õåìîêèíû ïîäñåìåéñòâà ÑÕÑ ó÷àñòâóþò â àêòèâàöèè íåéòðîôèëîâ, óñèëèâàÿ
õåìîòàêñèñ, ýêñïðåññèþ àäãåçèâíûõ ìîëåêóë è ñïîñîáñòâóÿ ïðèëèïàíèþ ê
ýíäîòåëèàëüíûì êëåòêàì. Êðîìå òîãî, îíè ïîâûøàþò ýêçîöèòîç ëèçîñîìàëüíûõ ôåðìåíòîâ àíãèîãåíåçà è ýêñïðåññèþ ðåöåïòîðîâ ê êîìïëåìåíòó.
Õåìîêèíû ïîäñåìåéñòâà CC èíäóöèðóþò ìèãðàöèþ ìîíîöèòîâ, à òàêæå
äðóãèõ êëåòîê (â ÷àñòíîñòè, NK è äåíäðèòíûõ). Ëîêàëüíàÿ ïðîäóêöèÿ ñèãíàëîâ õåìîòàêñèñà (õåìîêèíû è èõ ðåöåïòîðû) ðåãóëèðóåò èíôèëüòðàöèþ
ëåéêîöèòîâ â òêàíè. Ïîêàçàíî, ÷òî ó öûïëÿò IL8 è K203 âîâëå÷åíû â ðåêðóòèíã ìîíîíóêëåàðíûõ êëåòîê è ðàçâèòèå ìèåëîèäíûõ ïðåäøåñòâåííèêîâ
(125, 126).  ðàçíûõ ó÷àñòêàõ êèøå÷íèêà ýêñïðåññèÿ K203 è IL8 âàðüèðóåò: åñëè îáðàçîâàíèå ìÐÍÊ K203 óñèëèâàëîñü êàê â 12-ïåðñòíîé, òàê è â
îáîäî÷íîé êèøêå, òî â îòíîøåíèè ìÐÍÊ IL8 àêòèâèçàöèþ ýêñïðåññèè
îòìå÷àëè â îñíîâíîì â ñëåïûõ îòðîñòêàõ êèøå÷íèêà ñ íåçíà÷èòåëüíûì
ïîâûøåíèåì â îáîäî÷íîé êèøêå. Ðàçëè÷íàÿ ýêñïðåññèÿ õåìîêèíîâ â èçó÷åííûõ ó÷àñòêàõ ìîæåò îáúÿñíÿòüñÿ íåîäèíàêîâûì ðàñïðåäåëåíèè êëåòîê,
îáóñëîâëèâàþùèõ âðîæäåííûé èììóíèòåò. Íàïðèìåð, áîëüøåå ÷èñëî ãåòåðîôèëîâ â îáîäî÷íîé êèøêå êîððåëèðóåò ñ óñèëåíèåì ýêñïðåññèè IL8
(127, 128). Îòâåòñòâåííû ëè ýòè êëåòêè çà îáðàçîâàíèå IL8 (128) èëè ýòîò
õåìîêèí, ñèíòåçèðîâàííûé â äðóãèõ êëåòêàõ, ïðîñòî ïðèâëåê ãåòåðîôèëû
(128), ïîêà íå ñîâñåì ÿñíî. Íåäàâíî ïîêàçàíî, ÷òî öûïëÿòà îòâå÷àþò íà
åñòåñòâåííóþ êîëîíèçàöèþ ñëåïûõ îòðîñòêîâ ïîâûøåííîé ýêñïðåññèåé
öèòîêèíîâ (IL8 è IL17) â 1-þ íåä æèçíè (129). Ýòî ïîçâîëÿåò ìîäèôèöèðîâàòü èììóííûé îòâåò è ïîâûøàòü óñòîé÷èâîñòü ê ñàëüìîíåëëåçíîé èíôåêöèè. Äîïóñòèìî ïðåäïîëîæèòü, ÷òî âàðèàöèÿ â ýêñïðåññèè ãåíîâ õåìîêèíîâ ìîæåò áûòü ðåçóëüòàòîì îòâåòà ìåõàíèçìîâ âðîæäåííîãî èììóíèòåòà
íà èíäèâèäóàëüíûå ðàçëè÷èÿ â ìèêðîáíîé ïîïóëÿöèè. Ïðè ýòîì íå âûçûâàåò ñîìíåíèé òîò ôàêò, ÷òî íîðìàëüíàÿ ìèêðîôëîðà ó öûïëÿò (121) è
ìëåêîïèòàþùèõ íåîäèíàêîâà è ñïîñîáíà ïî-ðàçíîìó ìîäóëèðîâàòü ýêñïðåññèþ ãåíîâ â òêàíÿõ êèøå÷íèêà (130-132).
×òî êàñàåòñÿ ñèíòåçà ìÐÍÊ β-äåôåíñèíà, òî îí áûë ïîâûøåí óæå
ïðè âûâîäå, ïðè÷åì âî âñåõ ó÷àñòêàõ êèøå÷íèêà, è ñíèæàëñÿ â òå÷åíèå
1-é íåä æèçíè, ÷åìó âîçìîæíû äâà îáúÿñíåíèÿ. Âî-ïåðâûõ, ñåêðåòèðîâàòü
β-äåôåíñèíû, âåðîÿòíî, ñïîñîáíû íå òîëüêî è íå ñòîëüêî ãåòåðîôèëû,
ñêîëüêî äðóãèå òêàíè, âêëþ÷àÿ êèøå÷íûé ýïèòåëèé, è çíà÷èòåëüíîå êîëè÷åñòâî ýòèõ àíòèáàêòåðèàëüíûõ ïåïòèäîâ ó ñâåæåâûëóïèâøåãîñÿ öûïëåíêà
ìîæåò îòðàæàòü ïîäãîòîâêó âûñòèëêè ýíòåðîöèòîâ ê ïðåäñòîÿùèì áàêòåðèàëüíûì èíâàçèÿì (îòìåòèì, îäíàêî, ÷òî ïîêàçàòü ýêñïðåññèþ ãàëëèíàöèíîâ â ýïèòåëèè êèøå÷íèêà íå óäàëîñü). Âî-âòîðûõ, åñëè â êèøå÷íèêå ãàëëèíàöèíû ñâÿçàíû èñêëþ÷èòåëüíî ñ ãåòåðîôèëàìè èëè ãðàíóëàìè ãðàíóëî15
öèòîâ, èìåþùèåñÿ äàííûå ïîäòâåðæäàþò, ÷òî áåëêîâûå ãðàíóëû ñîçðåâàþò
ïðè ïîäãîòîâêå êèøå÷íèêà ê ïåðèîäó ïîñòíàòàëüíîãî ðàçâèòèÿ (íåçàâèñèìî
îò êîëîíèçàöèè áàêòåðèÿìè). Òî åñòü îáà îáúÿñíåíèÿ ñâÿçûâàþò ïðîäóêöèþ
äåôåíñèíîâ ñ ïîäãîòîâêîé êèøå÷íèêà ê áàêòåðèàëüíîé èíâàçèè. Ïîâûøåííàÿ ýêñïðåññèÿ äåôåíñèíîâ ó ñâåæåâûëóïèâøèõñÿ öûïëÿò ìîæåò ñâèäåòåëüñòâîâàòü î ñîçðåâàíèè ãåòåðîôèëîâ ê ýòîìó ñðîêó, ÷òî áûëî ïîäòâåðæäåíî ãèñòîëîãè÷åñêè. Òàêæå âûÿâëåíî óñèëåíèå ýêñïðåññèè äåôåíñèíîâ â êèøå÷íèêå öûïëÿò ïîñëå 7-ñóòî÷íîãî âîçðàñòà, ÷òî, âåðîÿòíî, ñâÿçàíî ñ çàâåðøåíèåì ðàçâèòèÿ íåçðåëûõ ãåòåðîôèëîâ (êàê ïîñòóïèâøèõ â
êèøå÷íèê, òàê è îáðàçîâàâøèõñÿ çäåñü ïîñëå äèôôåðåíöèðîâêè).
 êèøå÷íèêå öûïëÿò òàêæå èçó÷èëè ýêñïðåññèþ ãåíà PS1, âëèÿþùåãî íà ðàííèå ýòàïû ãðàíóëîïîýçà (133, 134). Ó ìëåêîïèòàþùèõ îíà ñâÿçàíà ñ àçóðîôèëüíûìè ãðàíóëàìè ïîëèìîðôíî-ÿäåðíûõ ëåéêîöèòîâ (133). Ó
öûïëÿò â âåðõíåé ÷àñòè êèøå÷íèêà (12-ïåðñòíàÿ è ïîäâçäîøíàÿ êèøêà)
äî è ñðàçó ïîñëå âûâîäà çàðåãèñòðèðîâàëè àêòèâíûé ñèíòåç ïðîäóêòà PS1
(÷òî ïðåäïîëàãàåò óñèëåíèå ãðàíóëîïîýçà), ïðè÷åì â äàëüíåéøåì îí ñíèæàëñÿ. Ïðè ýòîì â òîëñòîì êèøå÷íèêå ýêñïðåññèÿ PS1 ïîñòåïåííî íàðàñòàëà îò âûâîäà ê 7-ñóòî÷íîìó âîçðàñòó, ÷òî ìîæåò áûòü ðåçóëüòàòîì ïðèâëå÷åíèÿ äîïîëíèòåëüíûõ ãðàíóëîöèòîâ ïðè áàêòåðèàëüíîé ñòèìóëÿöèè.
Ñëåäîâàòåëüíî, ïîëó÷åííûå äàííûå (114) óêàçûâàþò íà çðåëîñòü
ñèñòåìû âðîæäåííîãî èììóíèòåòà â ðàçâèâàþùåìñÿ êèøå÷íèêå, ïðåäñòàâëåííîé äâóìÿ ãðóïïàìè çàùèòíûõ ìåõàíèçìîâ. Îòíîñÿùèåñÿ ê ïåðâîé íå
çàâèñÿò îò âîçäåéñòâèÿ êîðìà è áàêòåðèé è ðåàëèçóþòñÿ ÷åðåç ëîêàëüíûå
ïðîöåññû ýêñòðàìåäóëëÿðíîãî ãðàíóëîïîýçà. Ýòî ïîäòâåðæäàþò êàê ãèñòîëîãè÷åñêèå íàáëþäåíèÿ, òàê è äàííûå îá ýêñïðåññèè ðÿäà ãåíîâ (PS1, ãåíû β-äåôåíñèíîâ). Ýêñòðàìåäóëëÿðíûå èçìåíåíèÿ ïðîèñõîäÿò ïåðåä âûâîäîì öûïëÿò â òîíêîì êèøå÷íèêå è íå íàáëþäàþòñÿ â òîëñòîì êèøå÷íèêå. Ìåõàíèçìû âòîðîé ãðóïïû ñâÿçàíû ñ âîçäåéñòâèåì êîðìà, ìèêðîôëîðû, è èõ ïðîÿâëåíèå ñîïðîâîæäàåòñÿ ýêñïðåññèåé ãåíîâ ïðîâîñïàëèòåëüíûõ öèòîêèíîâ è õåìîêèíîâ. Ýòîò îòâåò ðàçâèâàåòñÿ ñðàçó ïîñëå âûâîäà è íàèáîëåå âûðàæåí â òîëñòîì êèøå÷íèêå êàê îñíîâíîé çîíå áàêòåðèàëüíîé êîëîíèçàöèè. Áûñòðîå óñèëåíèå ýêñïðåññèè óêàçàííûõ ãåíîâ ñâèäåòåëüñòâóåò î ñïîñîáíîñòè èììóííîé ñèñòåìû êèøå÷íèêà îïåðàòèâíî ðåàãèðîâàòü íà âíåøíèå ñòèìóëû. Óñòàíîâëåíî òàêæå óâåëè÷åíèå ÷èñëà ïîëèìîðôíî-ÿäåðíûõ êëåòîê âî âñåõ îòäåëàõ êèøå÷íèêà (îñîáåííî â ñëåïîé
êèøêå) â ïåðâûå 2 íåä ïîñëå âûâîäà (114).
Òàêèì îáðàçîì, ó ñâåæåâûëóïèâøåãîñÿ öûïëåíêà ïðîèñõîäèò ñòèìóëÿöèÿ âðîæäåííîãî èììóíèòåòà â êèøå÷íîì òðàêòå ñ ó÷àñòèåì ïðîâîñïàëèòåëüíûõ ìåäèàòîðîâ, ðåçèäåíòíûõ ëåéêîöèòîâ è ðåêðóòìåíòà ëåéêîöèòîâ êðîâè, à ïîçäíåå è ëèìôîöèòîâ. Ïîñêîëüêó öûïëåíîê ñðàçó ïîñëå âûâîäà íà÷èíàåò åñòü, èììóííàÿ ñèñòåìà êèøå÷íèêà ñíà÷àëà ñîðèåíòèðîâàíà
íà âûðàáîòêó òîëåðàíòíîñòè, íî ïðè êîëîíèçàöèè êèøå÷íèêà ìèêðîôëîðîé ïîñëåäíÿÿ âñòðå÷àåòñÿ ñ èììóíîëîãè÷åñêè çðåëîé GALT, çàïðîãðàììèðîâàííîé íà èììóííûé îòâåò. Âàæíî îòìåòèòü, ÷òî ïîääåðæàíèå àíòèãåí-ñïåöèôè÷íîé òîëåðàíòíîñòè, èíäóöèðîâàííîé â ïåðâûå 4 ñóò æèçíè,
çàâèñèò îò ïîâòîðíîãî âîçäåéñòâèÿ àíòèãåíà, ê êîòîðîìó îíà âûðàáàòûâàåòñÿ: ïðè îòñóòñòâèè êîíòàêòà â òå÷åíèå 4-6-íåä òîëåðàíòíîñòü çàìåíÿåòñÿ
èììóííûì îòâåòîì íà îðàëüíîå ïîñòóïëåíèå àíòèãåíà. Â íàñòîÿùåå âðåìÿ
íå èçâåñòíî, ãäå èíäóöèðóåòñÿ òîëåðàíòíîñòü — â êèøå÷íèêå, ïåðèôåðè÷åñêèõ èëè öåíòðàëüíûõ îðãàíàõ èììóííîé ñèñòåìû.
 òî âðåìÿ êàê ñîçðåâàíèå ýíòåðîöèòîâ çàâèñèò îò êîðìëåíèÿ,
ôîðìèðîâàíèå ôóíêöèîíàëüíî àêòèâíîé GALT áîëåå ïîäâåðæåíî âëèÿíèþ ìèêðîôëîðû. Êàê ñëåäñòâèå, ñîçðåâàíèå GALT â çàäíåì êèøå÷íèêå
ïðåäøåñòâóåò òàêîâîìó â òîíêîì, ãäå ïîïóëÿöèÿ áàêòåðèé çíà÷èòåëüíî
ìåíüøå, ÷åì â òîëñòîì êèøå÷íèêå. Ýòî îçíà÷àåò, ÷òî êîðì ïòèöå íåîáõî16
äèìî äàâàòü êàê ìîæíî áûñòðåå ïîñëå âûâîäà, ÷òî ïîçâîëèò ïîâûñèòü òîëåðàíòíîñòü ê íóòðèåíòàì, ïîëó÷èòü áîëåå ðàííèé îòâåò èììóííîé ñèñòåìû, ëó÷øå îáåñïå÷èòü èììóííóþ çàùèòó è ðàçâèòèå êèøå÷íèêà öûïëÿò.
Äîïîëíèòåëüíî òðåáóåòñÿ ñòèìóëèðîâàòü ôîðìèðîâàíèå ìûøå÷íîé òêàíè,
÷òî íàìè óæå îáñóæäàëîñü (135). Êîíå÷íî, âîçäåéñòâèå âíåøíèõ àãåíòîâ
íà ôîíå íåçðåëîé ëèìôîèäíîé ñèñòåìû ïîòåíöèàëüíî ìîæåò èìåòü îòðèöàòåëüíûå ïîñëåäñòâèÿ, íî îíè ÷àñòè÷íî ïðåîäîëåâàþòñÿ áëàãîäàðÿ ïðèñóòñòâèþ ìàòåðèíñêèõ àíòèòåë, ÷òî ïîä÷åðêèâàåò âàæíîñòü âàêöèíàöèè êóð
ðîäèòåëüñêîãî ïîãîëîâüÿ. È, íàêîíåö, ðàííèé êîíòàêò öûïëÿò ñ ïîìåòîì
ñòèìóëèðóåò ðàçâèòèå èììóíèòåòà, ïîñêîëüêó óñêîðÿåò äîñòóï âíåøíåé
ìèêðîôëîðû ê çàäíåìó êèøå÷íèêó.
Ì î ä ó ë ÿ ö è ÿ ê è ø å ÷ í î ã î è ì ì ó í è ò å ò à. Èììóííàÿ ñèñòåìà
êèøå÷íèêà òàêæå ïîäâåðæåíà ñòðåññàì, êàê è èììóííàÿ ñèñòåìà îðãàíèçìà â öåëîì (57, 136, 137). Ñëåäîâàòåëüíî, çäåñü âàæíû òå æå ïðèíöèïû
èììóíîìîäóëÿöèè, ÷òî è ïðåäñòàâëåííûå íàìè ðàíåå.  ÷àñòíîñòè, ãëàâåíñòâóþùóþ ðîëü èãðàåò àíòèîêñèäàíò-ïðîîêñèäàíòíûé áàëàíñ â êèøå÷íèêå (138-140), êîòîðûé âî ìíîãîì îïðåäåëÿåò íàäåæíîñòü èììóííûõ ìåõàíèçìîâ. Êðîìå âèòàìèíà Å è ñèñòåìû åãî ðåöèêëèçàöèè, äëÿ ïîääåðæàíèÿ ýòîãî áàëàíñà íåîáõîäèìû Zn è Mn êàê ýëåìåíòû, âõîäÿùèå â àêòèâíûé öåíòð îñíîâíîãî àíòèîêñèäàíòíîãî ôåðìåíòà — ñóïåðîêñèääèñìóòàçû.
Ýòè êîìïîíåíòû, à òàêæå àñêîðáèíîâàÿ êèñëîòà è Se âõîäÿò â ñîñòàâ àíòèñòðåññîâîãî ïðåïàðàòà íîâîãî ïîêîëåíèÿ Feed-Food Magic Antistress
Mix™, ÷òî ïîçâîëÿåò îáåñïå÷èòü ýôôåêòèâíîñòü êèøå÷íîãî èììóíèòåòà.
Äëÿ ñîõðàíåíèÿ öåëîñòíîñòè ñëèçèñòûõ îáîëî÷åê, ïðåïÿòñòâóþùèõ
ïðîíèêíîâåíèþ ïàòîãåíîâ, â êèøå÷íèêå íåîáõîäèìî îáåñïå÷èòü îïòèìàëüíûé îñìîòè÷åñêèé áàëàíñ. Ïîýòîìó â ñîñòàâ Feed-Food Magic Antistress
Mix™ âõîäèò îñìîëèò áåòàèí â ñî÷åòàíèè ñ ñìåñüþ ýëåêòðîëèòîâ. Áåòàèí
êðàéíå âàæåí äëÿ ïîääåðæàíèÿ ñòðóêòóðû òîíêîãî êèøå÷íèêà ó öûïëÿò,
îñîáåííî ñòðåññèðîâàííûõ (141, 142). Îí èãðàåò ðîëü îñìîïðîòåêòîðà äëÿ
ìàêðîôàãîâ, óñèëèâàÿ ó íèõ õåìîòàêñèñ è îáðàçîâàíèå îêèñè àçîòà â îòâåò
íà ñòðåññ, âûçâàííûé êîêöèäèÿìè (143). Çàùèòíûé ýôôåêò áåòàèíà âî
ìíîãîì ñâÿçàí ñ ïîäàâëåíèåì ôàêòîðà âîñïàëåíèÿ, ïåðåêèñíîãî îêèñëåíèÿ ëèïèäîâ (ÏÎË), ïðåäîòâðàùåíèåì îêèñëèòåëüíîãî ñòðåññà â ýíäîïëàçìàòè÷åñêîì ðåòèêóëóìå è àïîïòîçà (144-147). Áåòàèí òàêæå ñïîñîáåí
èíãèáèðîâàòü ñèíòåç òîëë-ïîäîáíîãî ðåöåïòîðà 4 (TLR4, èëè CD284, —
ìåìáðàííûé áåëîê, ó÷àñòâóþùèé â ðåàêöèÿõ âðîæäåííîãî èììóíèòåòà),
÷òî îêàçûâàåò çàùèòíûé ýôôåêò ïðè ñòðåññå (148).
Ïðîöåññû, ïðîèñõîäÿùèå ñ ó÷àñòèåì ñëèçèñòîé îáîëî÷êè êèøå÷íèêà, îòíîñÿòñÿ ê ÷èñëó íàèáîëåå äèíàìè÷íûõ â îðãàíèçìå. Îíà ñëóæèò
ôèçè÷åñêèì è õèìè÷åñêèì áàðüåðîì äëÿ ÷óæåðîäíûõ àãåíòîâ, ïîïàäàþùèõ â æåëóäî÷íî-êèøå÷íûé òðàêò, è èìåííî çäåñü êëåòêè ýïèòåëèÿ îïîñðåäóþò âçàèìîäåéñòâèå ìåæäó èììóííîé ñèñòåìîé îðãàíèçìà è ðàçëè÷íûìè áåëêàìè, êîòîðûå íàõîäÿòñÿ â ïðîñâåòå êèøå÷íèêà è ïðåäñòàâëÿþò
îïðåäåëåííóþ îïàñíîñòü.  êà÷åñòâå êëþ÷åâîãî ôàêòîðà â ðåãóëÿöèè ýòèõ
âçàèìîäåéñòâèé (íàðÿäó ñ îêèñëèòåëüíûì ñòðåññîì, ñòåïåíüþ àêòèâàöèè
èììóííûõ êëåòîê è öåëîñòíîñòüþ ýïèòåëèàëüíîãî áàðüåðà) ðàññìàòðèâàåòñÿ åùå îäèí êîìïîíåíò àíòèñòðåññîâãî ïðåïàðàòà — êàðíèòèí (149). Îí
óëó÷øàåò êîíòðîëü çà îáðàçîâàíèÿ ñóïåðîêñèä-ðàäèêàëîâ â íåéòðîôèëàõ
(150) è ìàêðîôàãàõ (151), ïîëó÷åííûõ îò ñòàðûõ êðûñ, à òàêæå óñèëèâàåò
èõ õåìîòàêñèñ. Êàðíèòèí îêàçûâàåò âûðàæåííîå çàùèòíîå äåéñòâèå ïðè
æåëóäî÷íûõ íàðóøåíèÿõ ó êðûñ (152). Ó ìûøåé, äåôèöèòíûõ ïî ñïåöèôè÷åñêèì òðàíñïîðòåðàì êàðíèòèíà, ðàçâèâàåòñÿ ñïîíòàííàÿ àòðîôèÿ ýïèòåëèàëüíûõ êëåòîê òîíêîãî êèøå÷íèêà è âîñïàëåíèå â òîëñòîì êèøå÷íèêå
(153). Ó ñòàðûõ êðûñ ââåäåíèå êàðíèòèíà â ðàöèîí â òå÷åíèå 21 ñóò äîñòîâåðíî ñíèçèëî îáðàçîâàíèå ïðîäóêòîâ ÏÎË è îïòèìèçèðîâàëî àêòèâíîñòü
17
àíòèîêñèäàíòíûõ ôåðìåíòîâ, âêëþ÷àÿ ñóïåðîêñèääèñìóòàçó, êàòàëàçó, ãëóòàòèîíïåðîêñèäàçó è ãëóòàòèîíðåäóêòàçó. Ïðè ýòîì óñèëèâàëàñü ïðîëèôåðàöèÿ Ò-ëèìôîöèòîâ â îòâåò íà ðàçëè÷íûå âîçäåéñòâèÿ, óìåíüøàëàñü ÷àñòîòà ïîâðåæäåíèÿ ÄÍÊ è àïîïîòîçà ëèìôîöèòîâ (154). Ó ñòàðûõ æèâîòíûõ ïðèñóòñòâèå êàðíèòèíà íîðìàëèçîâàëî ôóíêöèþ íåéòðîôèëîâ, èììóíîðåàêòèâíîñòü è ïîâûøàëî êîëè÷åñòâî IgA è IgG (òî åñòü ñòàðåíèå áûëî
ñâÿçàíî ñî ñíèæåíèåì èììóíîêîìïåòåíòíîñòè, à êàðíèòèí âîññòàíàâëèâàë
ýòó ôóíêöèþ) (155). Âêëþ÷åíèå êàðíèòèíà â ðàöèîí ðàñòóùèõ öûïëÿò ïîâûøàëî ãóìîðàëüíûé èììóíèòåò (156) è óñèëèâàëî ñèíòåç ïðîòåèíîâ îñòðîé ôàçû âîñïàëåíèÿ (157). Ïðè òåïëîâîì ñòðåññå ïîëîæèòåëüíûé ýôôåêò
êàðíèòèíà ïðîÿâëÿëñÿ îñîáåííî ÷åòêî (158): åãî âûïàèâàíèå â òå÷åíèå
ïåðâûõ 3 íåä æèçíè äîñòîâåðíî óâåëè÷èëî ïîòðåáëåíèå êîðìà è óëó÷øèëî
ðîñò öûïëÿò (159). Èíòåðåñíî, ÷òî ââåäåíèå êàðíèòèíà â ðàöèîí êóð èç
ðîäèòåëüñêîãî ñòàäà ïîëîæèòåëüíî ñêàçûâàëîñü íà ðàçâèòèè èììóíèòåòà â
èõ ïîòîìñòâå (160).
Ñëåäóþùèé âàæíåéøèé ýëåìåíò àíòèñòðåññîâîãî ïðåïàðàòà — âèòàìèí À, êîòîðûé, ïðåâðàùàÿñü â ðåòèíîåâóþ êèñëîòó, ó÷àñòâóåò â ðåãóëÿöèè àêòèâíîñòè Ò-ëèìôîöèòîâ â êèøå÷íèêå (161, 162). Êàê èçâåñòíî, ýíäîòåëèàëüíûå êëåòêè è äåíäðèòíûå êëåòêè êèøå÷íèêà îáëàäàþò ðåòèíàëüäåãèääåãèäðîãåíàçíîé àêòèâíîñòüþ, êîòîðàÿ íåîáõîäèìà äëÿ ïðåâðàùåíèÿ âèòàìèíà À â ðåòèíîåâóþ êèñëîòó. Ïðè ýòîì ðåòèíîåâàÿ êèñëîòà
èãðàåò êëþ÷åâóþ ðîëü â óñòàíîâëåíèè èììóíîòîëåðàíòíîñòè â êèøå÷íèêå
(163), òî åñòü ýôôåêòèâíîãî ðàñïîçíàâàíèÿ «ñâîé—÷óæîé», è ïðåäîòâðàùåíèè àëëåðãè÷åñêèõ ðåàêöèé. Ê òîìó æå ðåòèíîåâàÿ êèñëîòà íåîáõîäèìà
äëÿ îáðàçîâàíèÿ êèøå÷íûõ äåíäðèòíûõ êëåòîê (164).
Ôîëèåâàÿ êèñëîòà — åùå îäèí âèòàìèí, âàæíûé äëÿ ïîääåðæàíèÿ
ôóíêöèè ðåãóëÿòîðíûõ Ò-ëèìôîöèòîâ. Ó íèõ ñèëüíî âûðàæåí ôîëàò-ðåöåïòîð 4 (165), à ôîëèåâàÿ êèñëîòà îòíîñèòñÿ ê ëèìèòèðóþùèì ôàêòîðàì
âûæèâàíèÿ Ò-ëèìôîöèòîâ-ðåãóëÿòîðîâ (166). Òàê, óñòàíîâëåíî, ÷òî Ò-ðåãóëÿòîðíûå êëåòêè äèôôåðåíöèðóþòñÿ èç íàèâíûõ Ò-êëåòîê, íî ñðàçó ïîãèáàþò ïðè íåäîñòàòêå ôîëèåâîé êèñëîòû. Îñîáî ïîä÷åðêèâàåòñÿ, ÷òî äåôèöèò ôîëèåâîé êèñëîòû ïðèâîäèò ê ñíèæåíèþ ÷èñëà Ò-ðåãóëÿòîðíûõ
ëèìôîöèòîâ â êèøå÷íèêå.
Äîïîëíèòåëüíîå âêëþ÷åíèå â àíòèñòðåññîâûé ïðåïàðàò îðãàíè÷åñêèõ êèñëîò ïîëîæèòåëüíî ñêàçûâàåòñÿ íà ãèñòîëîãè÷åñêîé ñòðóêòóðå òîíêîãî êèøå÷íèêà (167), ÷òî, â ñâîþ î÷åðåäü, ïîâûøàåò ôóíêöèîíàëüíóþ ðåàêòèâíîñòü åãî èììóííîé ñèñòåìû.
 ñâÿçè ñ àêòèâíûì ðàçâèòèåì èììóííîé ñèñòåìû êèøå÷íèêà â
íåñêîëüêî ïåðâûõ ñóòîê ïîñëå âûâîäà àíòèñòðåññîâûé ïðåïàðàò, ïîëó÷àåìûé öûïëÿòàìè â ýòîò ïåðèîä, ñïîñîáñòâóåò ëó÷øåìó ðàçâèòèþ êèøå÷íèêà è åãî èììóííîé ñèñòåìû (135, 168). Êðîìå òîãî, â êîðìå ÷àñòî ïðèñóòñòâóþò ìèêîòîêñèíû — âàæíåéøèå ñòðåññîðû, ïîäàâëÿþùèå êàê îáùèé
èììóíèòåò, òàê è çàùèòíûå ñèñòåìû êèøå÷íèêà (169). Âûïàèâàíèå àíòèñòðåññîâîãî ïðåïàðàòà ïîçâîëÿåò ñíèçèòü îòðèöàòåëüíîå äåéñòâèå ìèêîòîêñèíà ÄÎÍ (170, 171), îõðàòîêñèíà (172, 173) è Ò-2 òîêñèíà (174, 175).
Îòìåòèì òàêæå, ÷òî êîíöåïöèÿ âëèÿíèÿ íóòðèåíòîâ íà àêòèâíîñòü âèòàãåíîâ è ïîâûøåíèå àäàïòèâíûõ âîçìîæíîñòåé îðãàíèçìà â óñëîâèÿõ ñòðåññà
ïðèìåíèìà è ê èììóíèòåòó êèøå÷íèêà (176).
Èòàê, àíàëèç ñïåöèàëüíîé ëèòåðàòóðû óáåäèòåëüíî ïîêàçûâàåò, ÷òî
èììóííàÿ ñèñòåìà êèøå÷íèêà èãðàåò âàæíåéøóþ ðîëü â ïîääåðæàíèè çäîðîâüÿ, ïðîäóêòèâíûõ è âîñïðîèçâîäèòåëüíûõ êà÷åñòâ ñåëüñêîõîçÿéñòâåííûõ æèâîòíûõ è ïòèöû. Ìåõàíèçìû òîëåðàíòíîñòè ê íóòðèåíòàì è ïîëåçíûì ìèêðîîðãàíèçìàì (ðàñïîçíàâàíèå «ñâîé—÷óæîé») è èììóííîãî îòâåòà, ïðîÿâëÿåìîãî íà ýòîì óðîâíå, êîíå÷íî, íóæäàþòñÿ â äàëüíåéøåì èçó÷åíèè.  òî æå âðåìÿ îïûò âûïàèâàíèÿ ñ âîäîé ðàçðàáîòàííîãî êîìïëåêñ18
íîãî àíòèñòðåññîâîãî ïðåïàðòà äëÿ èììóíîìîäóëÿöèè îêàçàëñÿ âåñüìà óñïåøíûì, ÷òî äàåò îñíîâàíèå ðàçâèâàòü ïðåäëîæåííóþ íàìè êîíöåïöèþ.
1ÃÍÓ
Âñåðîññèéñêèé íàó÷íî-èññëåäîâàòåëüñêèé
è òåõíîëîãè÷åñêèé èíñòèòóò ïòèöåâîäñòâà
Ðîññåëüõîçàêàäåìèè,
Ïîñòóïèëà â ðåäàêöèþ
12 ìàðòà 2013 ãîäà
141311 Ðîññèÿ, Ìîñêîâñêàÿ îáë., ã. Ñåðãèåâ Ïîñàä, óë. Ïòèöåãðàäñêàÿ, 10,
e-mail: [email protected];
2Feed-Food. Ltd,
53 Dongola Road, Ayr, KA7 3BN, UK, Scotland,
e-mail: [email protected];
3Scottish Agricultural College (SAC, Øîòëàíäñêèé
ñåëüñêîõîçÿéñòâåííûé êîëëåäæ),
King's Buildings, West Mains Road, Edinburgh, EH9 3JG, UK, Scotland
GUT IMMUNITY IN BIRDS: FACTS AND REFLECTIONS
(review)
V.I. Fisinin1, P. Surai 2, 3
1All-Russian
Research and Technological Institute of Poultry, Russian Academy of Agricultural Sciences, 10, ul. Ptitsegradskaya, Sergiev Posad, Moscow Province, 141311 Russia, e-mail [email protected];
Ltd, 53 Dongola Road, Ayr, KA7 3BN, UK, Scotland, e-mail [email protected];
3Scottish Agricultural College, King's Buildings, West Mains Road, Edinburgh, EH9 3JG, UK, Scotland
Received March 12, 2013
2Feed-Food.
Abstract
Gut immunity plays a crucial role in maintenance of the whole body immunity being the
first and most important line of defence from various pathogenic organisms and substances consumed with feed and able to colonize host cells and tissues. The role of protective mechanisms in the
gut is difficult to overestimate. For example, the process of learning distinguishing between «self and
non-self» taking place in the gut are fundamental for the immunity development as well as for the
development of nutrient tolerance. It is necessary to underline that structural changes in the gut, in
particular at the mucosa level are responsible for decreasing efficacy of nutrient assimilation from the
feed. Therefore, gut status determines the chicken health, utilization of nutrients and biologically active substances (FCR) and other important commercially relevant parameters of the poultry production. This review summarises recent knowledge about the development and functioning of protective
immunological mechanisms in the gut. A particular attention is paid to the possibilities on the
modulation of gut immunity by a mixture of biological active substances.
Keywords: ñhicken, stress, immunity, gut, vita-genes.
REFERENCES
1.
2.
Klasing K.C. Nutrition and the immune system. Br. Poult. Sci., 2007, 48: 525-537.
Hampson D.J. Alterations in piglet small intestinal structure at weaning. Res. Vet. Scie., 1986,
40: 313-317.
3. Nabuurs M.J., Hoogendoorn A., Van der Molen E.J., Van Osta A.L. Villus height and crypt
depth in weaned and unweaned pigs, reared under various circumstances in the Netherlands.
Res. Vet. Scie., 1993, 55: 78-84.
4. Friedman A., Al-Sabbagh A., Santos L.M., Fishman-Lobell J., Polanski M., Das M.P., Khoury
S.J., Weiner H.L. Oral tolerance: a biologically relevant pathway to generate peripheral tolerance against external and self antigens. Chem. Immunol., 1994, 58: 259-290.
5. Klipper E., Sklan D., Friedman A. Response, tolerance and ignorance following oral exposure
to a single protein antigen in gallus domesticus. Vaccine, 2001, 19: 2890-2897.
6. Brandtzaeg P. The mucosal immune system and its integration with the mammary glands. J.
Pediatr., 2010, 156: S8-15.
7. Deplancke B., Gaskins H.R. Microbial modulation of innate defense: goblet cells and the intestinal mucus layer. Am. J. Clin. Nutr., 2001, 73: 1131S-1141S.
8. Specian R.D., Oliver M.G. Functional biology of intestinal goblet cells. Am. J. Physiol., 1991,
260: C183-193.
9. Chadee K., Petri W.A. Jr., Innes D.J., Ravdin J.I. Rat and human colonic mucins bind to and
inhibit adherence lectin of Entamoeba histolytica. J. Clin. Invest., 1987, 80: 1245-1254.
10. Kim Y.S., Ho S.B. Intestinal goblet cells and mucins in health and disease: recent insights and
progress. Curr. Gastroenterol. Rep., 2010, 12: 319-330.
19
11. Forder R.E., Howarth G.S., Tivey D.R., Hughes R.J. Bacterial modulation of small intestinal
goblet cells and mucin composition during early posthatch development of poultry. Poult. Sci.,
2007, 86: 2396-2403.
12. Smirnov A., Sklan D., Uni Z. Mucin dynamics in the chick small intestine are altered by starvation. J. Nutr., 2004, 134: 736-742.
13. Horn N.L., Donkin S.S., Applegate T.J., Adeola O. Intestinal mucin dynamics: response of
broiler chicks and White Pekin ducklings to dietary threonine. Poult. Sci., 2009, 88: 1906-1914.
14. Harmon B.G. Avian heterophils in inflammation and disease resistance. Poult. Sci., 1998, 77:
972-977.
15. Lillehoj H.S., Min W., Dalloul R.A. Recent progress on the cytokine regulation of intestinal
immune responses to Eimeria. Poult. Sci., 2004, 83: 611-623.
16. Satchell D.P., Sheynis T., Shirafuji Y., Kolusheva S., Ouellette A.J., Jelinek R. Interactions of
mouse Paneth cell α-defensins and α-defensin precursors with membranes. Prosegment inhibition of peptide association with biomimetic membranes. J. Biol. Chem., 2003, 278: 1383813846.
17. Liu L., Zhao C., Heng H.H., Ganz T. The human β-defensin-1 and α-defensins are encoded
by adjacent genes: two peptide families with differing disulfide topology share a common ancestry. Genomics, 1997, 43: 316-320.
18. Evans E.W., Beach G.G., Wunderlich J., Harmon B.G. Isolation of antimicrobial peptides from
avian heterophils. J. Leukoc. Biol., 1994, 56: 661-665.
19. Harwig S.S., Swiderek K.M., Kokryakov V.N., Tan L., Lee T.D., Panyutich E.A., Aleshina G.M., Shamova O.V., Lehrer R.I. Gallinacins: cysteine-rich antimicrobial peptides of
chicken leukocytes. FEBS Lett., 1994, 342: 281-285.
20. Zhao C., Nguyen T., Liu L., Sacco R.E., Brogden K.A., Lehrer R.I. Gallinacin-3, an inducible
epithelial β-defensin in the chicken. Infect. Immun., 2001, 69: 2684-2691.
21. Evans E.W., Harmon B.G. A review of antimicrobial peptides: defensins and related cationic
peptides. Vet. Clin. Pathol., 1995, 24: 109-116.
22. Evans E.W., Beach F.G., Moore K.M., Jackwood M.W., Glisson J.R., Harmon B.G. Antimicrobial activity of chicken and turkey heterophil peptides CHP1, CHP2, THP1, and THP3.
Vet. Microbiol., 1995, 47: 295-303.
23. Sugiarto H., Yu P.-L. Avian antimicrobial peptides: the defence role of beta defensins. Biochem.
Biophys. Res. Commun., 2004, 323: 721-727.
24. Lynn D.J., Higgs R., Gaines S., Tierney J., James T., Lloyd A.T., Fares M.A., Mulcahy G.,
O’Farrelly C. Bioinformatic discovery and initial characterisation of nine novel antimicrobial
peptide genes in the chicken. Immunogenetics, 2004, 56: 170-177.
25. Van Dijk A., Veldhuizen E.J., Kalkhove S.I., Tjeerdsma-van Bokhoven J.L., Romijn R.A.,
Haagsman H.P. The beta-defensin gallinacin-6 is expressed in the chicken digestive tract and
has antimicrobial activity against food-borne pathogens. Antimicrob Agents Chemother., 2007, 51:
912-922.
26. Milona P., Townes C.L., Bevan R.M., Hall J. The chicken host peptides, allinacins 4, 7, and
9 have antimicrobial activity against Salmonella serovars. Biochem. Biophys. Res. Commun.,
2007, 356: 169-174.
27. Higgs R., Lynn D.J., Gaines S., McMahon J., Tierney J.T., James T., Lloyd A.T., Mulcahy G.,
O’Farrelly C. The synthetic form of a novel chicken beta-defensin identified in silico is predominantly active against intestinal pathogens. Immunogenetics, 2005, 57: 90-98.
28. Xiao Y., Hughes A.L., Ando J., Matsuda Y., Cheng J.-F., Skinner-Noble D., Zhang G. A genome-wide screen identifies a single β-defensin gene cluster in the chicken: implications for the
origin and evolution of mammalian defensins. BMC Genomics, 2004, 5: 56.
29. Hong Y.H., Song W., Lee S.H., Lillehoj H.S. Differential gene expression profiles of βdefensins in the crop, intestine, and spleen using a necrotic enteritis model in 2 commercial
broiler chicken lines. Poult. Sci., 2012, 91: 1081-1088.
30. Ramanathan B., Davis E.G., Ross C.R., Blecha F. Cathelicidins: microbicidal activity, mechanisms of action, and roles in innate immunity. Microbes Infect., 2002, 4: 361-372.
31. Zaiou M., Gallo R.L. Cathelicidins, essential gene-encoded mammalian antibiotics. J. Mol.
Med., 2002, 80: 549-561.
32. Giacometti A., Cirioni O., Ghiselli R., Mocchegiani F., D’Amato G., Circo R., Orlando F.,
Skerlavaj B., Silvestri C., Saba V., Zanetti M., Scalise G. Cathelicidin peptide sheep myeloid
antimicrobial peptide 29 prevents endotoxin-induced mortality in rat models of septic shock.
Am. J. Respir. Crit. Care Med., 2004, 169: 187-194.
33. Yang D., Chen Q., Schmidt A.P., Anderson G.M., Wang J.M., Wooters J., Oppenheim J.J.,
Chertov O. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood
neutrophils, monocytes, and T cells. J. Exp. Med., 2000, 192: 1069-1074.
34. Skerlavaj B., Scocchi M., Gennaro R., Risso A., Zanetti M. Structural and functional analysis
of horse cathelicidin peptides. Antimicrob. Agents Chemother., 2001, 45: 715-722.
35. Van Dijk A., Veldhuizen E.J., Van Asten A.J., Haagsman H.P. CMAP27, a novel chicken cathelicidin-like antimicrobial protein. Vet. Immunol. Immunopathol., 2005, 106: 321-327.
36. Van Dijk A., Tersteeg-Zijderveld M.H., Tjeerdsma-van Bokhoven J.L., Jansman A.J., Veld-
20
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
huizen E.J., Haagsman H.P. Chicken heterophils are recruited to the site of Salmonella infection and release antibacterial mature Cathelicidin-2 upon stimulation with LPS. Mol. Immunol.,
2009, 46: 1517-1526.
Van Dijk A., Molhoek E.M., Bikker F.J., Yu P.L., Veldhuizen E.J., Haagsman H.P. Avian
cathelicidins: paradigms for the development of anti-infectives. Vet. Microbiol., 2011, 153:
27-36.
Sahoo N.R., Kumar P., Bhusan B., Bhattacharya T.K., Dayal S., Sahoo M. Lysozyme in livestock: a guide to selection for disease resistance: a review. J. Anim. Sci. Adv., 2012, 2: 347-360.
Myers F.A., Lefevre P., Mantouvalou E., Bruce K., Lacroix C. Developmental activation of the
lysozyme gene in chicken macrophage cells is linked to core histone acetylation at its enhancer
elements. Nucleic Acids Res., 2006, 34: 4025-4035.
Callewaert L., Michiels C.W. Lysozymes in the animal kingdom. J. Biosci., 2010, 35: 127-160.
Leśnierowski G., Cegielska-Radziejewska R. Potential possibilities of production, modifi cation
and practical application of lysozyme. Acta Sci. Pol., Technol. Aliment., 2012, 11: 223-230.
Sanderson I.R., Walker W.A. Mucosal barrier: an overview. London, 1999: 5-18.
Mestecky J., Moro I., Underdown B.J. Mucosal immunoglobulins. In: Mucosal Immunology.
P.L. Ogra, J. Mestecky, M.E. Lamm, W. Strober, J. Bienenstock, J.R. McGhee (eds.). London,
Academic Press, 1999: 133-152.
Klipper E., Sklan D., Friedman A. Immune response of chickens to dietary protein antigens.
Vet. Immunol. Immunopathol., 2000, 74: 209-223.
Fagerland J.A., Arp L.H. Distribution and quantitation of plasma cells, T lymphocyte subsets,
and B lymphocytes in bronchus-associated lymphoid tissue of chickens: age-related differences.
Reg. Immunoly, 1993, 5: 28-36.
Sharma J.M. Overview of the avian immune system. Vet. Immunol. Immunopathol., 1991, 30:
13-17.
Muir W.I., Bryden W.L., Husband A.J. Investigation of the site of precursors for IgA-producing
cells in the chicken intestine. Immunol. Cell Biol., 2000, 78: 294-296.
McGhee J.R., Mestecky J., Dertzbaugh M.T., Eldridge J.H., Hirasawa M., Kiyono H. The mucosal immune system: from fundamental concepts to vaccine development. Vaccine, 1992, 10:
75-88.
Lillehoj H.S., Chung K.S. Postnatal development of T-lymphocyte subpopulations in the intestinal intraepithelium and lamina propria in chickens. Vet. Immunol. Immunopathol., 1992, 31:
347-360.
Vervelde L., Jeurissen S.H. Postnatal development of intra-epithelial leukocytes in the chicken
digestive tract: phenotypical characterization in situ. Cell Tiss. Res., 1993, 274: 295-301.
Olah I., Nagy N., Magyar A., Palya V. Esophageal tonsil: a novel gut-associated lymphoid organ. Poult. Sci., 2003, 82: 767-770.
Matsumoto R., Hashimoto Y. Distribution and developmental change of lymphoid tissues in the
chicken proventriculus. J. Vet. Med. Sci., 2000, 62: 161-167.
Kajiwara E., Shigeta A., Horiuchi H., Matsuda H., Furusawa S. Development of Peyer's patch
and cecal tonsil in gut-associated lymphoid tissues in the chicken embryo. J. Vet. Med. Sci.,
2003, 65: 607-614.
Befus A.D., Johnston N., Leslie G.A., Bienenstock J. Gut associated lymphoid tissue in the
chicken. I. Morphology, ontogeny, and some functional characteristics of Peyer's patches. J.
Immunol., 1980, 125: 2626-2632.
Olah I., Glick B., Taylor R.L. Jr. Meckel's diverticulum. II. A novel lymphoepithelial organ in
the chicken. Anat. Rec., 1984, 208: 253-263.
Nagy N., Olah I. Pyloric tonsil as a novel gut-associated lymphoepithelial organ of the chicken.
J. Anat., 2007, 211: 407-411.
Fisinin V.I., Surai P.F. Zhivotnovodstvo segodnya, 2011, 9: 40-47.
Lillehoj H.S., Trout J.M. Avian gut-associated lymphoid tissues and intestinal immune responses to Eimeria parasites. Clinic. Microbiol. Rev., 1996, 9: 349-360.
Yasuda M., Tanaka S., Arakawa H., Taura Y., Yokomizo Y., Ekino S. A comparative study of
gut-associated lymphoid tissue in calf and chicken. Anatom. Rec., 2002, 266: 207-217.
Liebler-Tenorio E.M., Pabst R. MALT structure and function in farm animals. Vet. Res., 2006,
37: 257-280.
Garboczi D.N., Ghosh P., Utz U., Fan Q.R., Biddison W.E., Wiley D.C. Structure of the
complex between human T-cell receptor, viral peptide and HLA-A2. Nature, 1996, 384:
134-141.
Garboczi D.N., Biddison W.E. Shapes of MHC restriction. Immunity, 1999, 10: 1-7.
Parham P. Pictures of MHC restriction. Nature, 1996, 384: 109-110.
Garcia K.C., Teyton L., Wilson I.A. Structural basis of T cell recognition. Annu. Rev. Immunol.,
1999, 17: 369-397.
Morita C.T., Beckman E.M., Bukowski J.F., Tanaka Y., Band H., Bloom B.R., Golan D.E.,
Brenner M.B. Direct presentation of nonpeptide prenyl pyrophosphate antigens to human gd T
cells. Immunity, 1995, 3: 495-507.
Morita C.T., Tanaka Y., Bloom B.R., Brenner M.B. Direct presentation of non-peptide prenyl
pyrophosphate antigens to human gd T cells. Res. Immunol., 1996, 147: 347-353.
Morita C.T., Lee H.K., Leslie D.S., Tanaka Y., Bukowski J.F., Marker- Hermann E. Recogni-
21
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
22
tion of nonpeptide prenyl pyrophosphate antigens by human gd T cells. Microbes Infect., 1999,
1: 175-186.
Morita C.T., Mariuzza R.A., Brenner M.B. Antigen recognition by human gd T cells: pattern recognition by the adaptive immune system. Springer Semin. Immunopathol., 2000, 22:
191-217.
Harrington L.E., Hatton R.D., Mangan P.R., Turner H., Murphy T.L., Murphy K.M., Weaver
C.T. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T
helper type 1 and 2 lineages. Nat. Immunol., 2005, 6: 1123-1132.
Ivanov I.I., McKenzie B.S., Zhou L., Tadokoro C.E., Lepelley A., Lafaille J.J., Cua D.J.,
Littman D.R. The orphan nuclear receptor RORgammat directs the differentiation program of
proinflammatory IL-17+ T helper cells. Cell, 2006, 126: 1121-1133.
Weaver C.T., Hatton R.D., Mangan P.R., Harrington L.E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol., 2007, 25: 821-852.
Bucy R.P., Chen C.L., Cihak J., Losch U., Cooper M.D. Avian T cells expressing gamma delta
receptors localize in the splenic sinusoids and the intestinal epithelium. J. Immunol., 1988, 141:
2200-2205.
Lillehoj H.S. Avian gut-associated immune system: implication in coccidial vaccine development. Poult. Sci., 1993, 72: 1306-1311.
Dunon D., Courtois D., Vainio O., Six A., Chen C.H., Cooper M.D., Dangy J.P., Imhof B.A.
Ontogeny of the immune system: gamma/delta and alpha/beta T cells migrate from thymus to
the periphery in alternating waves. J. Exp. Med., 1997, 186: 977-988.
Dunon D., Cooper M.D., Imhof B.A. Thymic origin of embryonic intestinal gamma/delta T
cells. J. Exp. Med., 1993, 177: 257-263.
Suzuki K., Oida T., Hamada H., Hitotsumatsu O., Watanabe M., Hibi T., Yamamoto H., Kubota E., Kaminogawa S., Ishikawa H. Gut cryptopatches: direct evidence of extrathymic anatomical sites for intestinal T lymphopoiesis. Immunity, 2000, 13: 691-702.
Arstila T.P., Toivanen P., Lassila O. Helper activity of CD4+ alpha beta T cells is required for
the avian gamma delta T cell response. Eur. J. Immunol., 1993, 23: 2034-2037.
Kasahara Y., Chen C.H., Cooper M.D. Growth requirements for avian gamma delta T cells include exogenous cytokines, receptor ligation and in vivo priming. Eur. J. Immunol., 1993, 23:
2230-2236.
Berin M.C., McKay D.M., Perdue M.H. Immune-epithelial interactions in host defense. Am. J.
Trop. Med. Hyg., 1999, 60: 16-25.
Berin M.C., Yang P.C., Ciok L., Waserman S., Perdue M.H. Role for IL-4 in macromolecular
transport across human intestinal epithelium. Am. J. Physiol., 1999, 276: C1046-1052.
Mehr R., Edelman H., Sehgal D.R.M. Analysis of mutational lineage trees from sites of primary
and secondary Ig gene diversification in rabbits and chickens. J. Immunol., 2004, 172: 47904796.
Clench M.H. The avian cecum: uptake and motility review. J. Exp. Zool., 1999, 283: 441-447.
Brummermann M., Braun E.J. Effect of salt and water balance on colonic motility of white
leghorn roosters. Am. J. Physiol., 1995, 268: R690-698.
Lai H.C., Duke G.E. Colonic motility in domestic turkeys. Am. J. Dig. Dis., 1978, 23:
673-681.
Friedman A., Bar Shira E., Sklan D. Ontogeny of gut associated immune competence in the
chick. World's Poultry Sci. J., 2003, 59: 209-219.
Yamamoto H., Watanabe H., Mikami T. Distribution of immunoglobulin and secretory component containing cells in chickens. Am. J. Vet. Res., 1977, 38: 1227-1230.
Mansikka A., Veromaa T., Vainio O., Toivanen P. B-cell differentiation in the chicken: expression of immunoglobulin genes in the bursal and peripheral lymphocytes. Scan. J. Immunol.,
1989, 29: 325-331.
Sorvari R., Sorvari T.E. Bursal fabricii as a peripheral lymphoid organ. Transport of various materials from the anal lips to the bursal lymphoid follicles with reference to its immunological
importance. Immunology, 1978, 32: 499-505.
Porter E.M., Bevins C.L., Ghosh D., Ganz T. The multifaceted Paneth cell. Cell. Mol. Life
Sci., 2002, 59: 156-170.
Nile C.J., Townes C.L., Michailidis G., Hirst B.H., Hall J. Identification of chicken lysozyme
g2 and its expression in the intestine. Cell. Mol. Life Sci., 2004, 61: 2760-2766.
Gobel T.W., Kaspers B., Stangassinger M. NK and T cells constitute two major, functionally distinct intestinal epithelial lymphocyte subsets in the chicken. Int. Immunol., 2001,
13: 757-762.
Lehrer R.I., Ganz T. Endogenous vertebrate antibiotics. Defensins, protegrins, and other cysteine-rich antimicrobial peptides. Ann. NY Acad. Sci., 1996, 797: 228-239.
Lehrer R.I., Ganz T. Defensins of vertebrate animals. Curr. Opin. Immunol., 2002, 14: 96-102.
Bezuidenhout A.J., Van Aswegen G. A light microscopic and immunocytochemical study of
the gastrointestinal tract of the ostrich (Struthio camelus L.). Onderstepoort J. Vet. Res., 1990,
57: 37-48.
Brockus C.W., Jackwood M.W., Harmon B.G. Characterization of beta-defensin prepropeptide
mRNA from chicken and turkey bone marrow. Animal Gen., 1998, 29: 283-289.
Lillehoj H.S., Min W., Dalloul R.A. Recent progress on the cytokine regulation of intestinal
immune responses to Eimeria. Poult. Sci., 2004, 83: 611-623.
97. Burns R.B., Maxwell M.H. Ultrastructure of Peyer's patches in the domestic fowl and turkey. J.
Anat., 1986, 147: 235-243.
98. Casteleyn C., Doom M., Lambrechts E., Van den Broeck W., Simoens P., Cornillie P. Locations of gut-associated lymphoid tissue in the 3-month-old chicken: a review. Avian. Pathol.,
2010, 39: 143-150.
99. Gallego M., Del Cacho E., Zapata A., Bascuas J.A. Ultrastructural identification of the splenic
follicular dendritic cells in the chicken. Anat. Rec., 1995, 242: 220-224.
100. Jeurissen S.H., Wagenaar F., Janse E.M. Further characterization of M cells in gut-associated
lymphoid tissues of the chicken. Poult. Sci., 1999, 78: 965-729.
101. Kitagawa H., Imagawa T., Uehara M. The apical caecal diverticulum of the chicken identified
as a lymphoid organ. J. Anat., 1996, 189: 667-672.
102. Kitagawa H., Hiratsuka Y., Imagawa T., Uehara M. Distribution of lymphoid tissue in the caecal mucosa of chickens. J. Anat., 1998, 192(Pt 2): 293-298.
103. Del Cacho E., Gallego M., Sanz A., Zapata A. Characterization of distal lymphoid nodules in
the chicken caecum. Anat. Rec., 1993, 237: 512-517.
104. Friedman A., Elad O., Cohen I., Bar Shira E. The gut associated lymphoid system in the posthatch chick: dynamics of maternal IgA. Israel J. Vet. Med., 2012, 67: 75-81.
105. Masteller E.L., Thompson C.B. B cell development in the chicken. Poult. Sci., 1994, 73: 9981011.
106. Masteller E.L., Pharr G.T., Funk P.E., Thompson C.B. Avian B cell development. Int. Rev.
Immunol., 1997, 15: 185-206.
107. Bar-Shira E., Sklan D., Friedman A. Establishment of immune competence in the avian GALT
during the immediate post-hatch period. Develop. Comp. Immunol., 2003, 27: 147-57.
108. Lawrence E.C., Arnaud-Battandier F., Grayson J., Koski I.R., Dooley N.J., Muchmore A.V.,
Blaese R.M. Ontogeny of humoral immune function in normal chickens: a comparison of immunoglobulin-secreting cells in bone marrow, spleen, lungs and intestine. Clin. Exp. Immunol.,
1981, 43: 450-457.
109. Bar-Shira E., Sklan D., Friedman A. Impaired immune responses in broiler hatchling hindgut
following delayed access to feed. Vet. Immunol. Immunopathol., 2005, 105: 33-45.
110. Malkinson M. The transmission of passive immunity to Escherichia coli from mother to young
in the domestic fowl (Gallus domesticus). Immunology, 1965, 9: 311-317.
111. Sahin O., Zhang Q., Meitzler J.C., Harr B.S., Morishita T.Y., Mohan R. Prevalence, antigenic
specificity, and bactericidal activity of poultry anti-Campylobacter maternal antibodies. Appl. Environ. Microbiol., 2001, 67: 3951-3957.
112. Popiel I., Turnbull P.C. Passage of Salmonella enteritidis and Salmonella thompson through chick
ileocecal mucosa. Infect. Immun., 1985, 47: 786-792.
113. Henderson S.C., Bounous D.I., Lee M.D. Early events in the pathogenesis of avian salmonellosis. Infect. Immun., 1999, 67: 3580-3586.
114. Bar-Shira E., Friedman A. Development and adaptations of innate immunity in the gastrointestinal tract of the newly hatched chick. Dev. Comp. Immunol., 2006, 30: 930-941.
115. Staeheli P., Puehler F., Schneider K., Gobel T.W., Kaspers B. Cytokines of birds: conserved
functions — a largely different look. J. Interferon Cyt. Res., 2001, 21: 993-1010.
116. Kaiser P., Poh T.Y., Rothwell L., Avery S., Balu S., Pathania U.S., Hughes S., Goodchild M.,
Morrell S., Watson M., Bumstead N., Kaufman J., Young J.R. A genomic analysis of chicken
cytokines and chemokines. J. Interferon Cytokine Res., 2005, 25: 467-484.
117. Bird S., Zou J., Wang T., Munday B., Cunningham C., Secombes C.J. Evolution of interleukin-1[beta]. Cyt. Growth Factor Rev., 2002, 13: 483-502.
118. Ogle C.K., Mao J.X., Wu J.Z., Ogle J.D., Alexander J.W. The production of tumor necrosis
factor, interleukin-1, interleukin-6, and prostaglandin E2 by isolated enterocytes and gut
macrophages: effect of lipopolysaccharide and thermal injury. J. Burn Care Rehab., 1994, 15:
470-477.
119. Radema S.A., Van Deventer S.J., Cerami A. Interleukin 1 beta is expressed predominantly by
enterocytes in experimental colitis. Gastroenterol., 1991, 100: 1180-1186.
120. Wigley P., Kaiser P. Avian cytokines in health and disease. Brazilian J. Poult. Sci., 2003, 5: 114.
121. Coloe P.J., Bagust T.J., Ireland L. Development of the normal gastrointestinal microflora of
specific pathogen-free chickens. J. Hyg., 1984, 92: 79-87.
122. Barnes E.M., Impey C.S., Cooper D.M. Manipulation of the crop and intestinal flora of the
newly hatched chick. Am. J. Clin. Nutr., 1980, 33: 2426-2433.
123. Sick C., Schneider K., Staeheli P., Weining K.C. Novel chicken CXC and CC chemokines.
Cytokine, 2000, 12: 181-186.
124. Kaiser P., Hughes S., Bumstead N. The chicken 9E3/CEF4 CXC chemokine is the avian
orthologue of IL8 and maps to chicken chromosome 4 syntenic with genes flanking the mammalian chemokine cluster. Immunogenetics, 1999, 49: 673-684.
125. Martins-Green M. The chicken chemotactic and angiogenic factor (cCAF), a CXC chemokine.
Int. J. Biochem. Cell Biol., 2001, 33: 427-432.
126. Petrenko O., Ischenko I., Enrietto P.J. Isolation of a cDNA encoding a novel chicken
chemokine homologous to mammalian macrophage inflammatory protein-1[beta]. Gene, 1995,
23
160: 305-306.
127. Kogut M.H. Dynamics of a protective avian inflammatory response: the role of an IL-8-like cytokine in the recruitment of heterophils to the site of organ invasion by Salmonella enteridis.
Comp. Immunol. Microbiol. Infect. Dis., 2002, 25: 159-172.
128. Kogut M.H., Rothwell L., Kaiser P. Priming by recombinant chicken IL-2 induces selective
expression of IL-8 and IL-18 mRNA in chicken heterophils during receptor-mediated phagocytosis of opsonized and nonopsonized Salmonella enterica serovar enteridis. Mol. Immunol., 2003,
40: 603-610.
129. Crhanova M., Hradecka H., Faldynova M., Matulova M., Havlickova H., Sisak F., Rychlik I.
Immune response of chicken gut to natural colonization by gut microflora and to Salmonella
enterica serovar enteritidis infection. Infect. Immun., 2011, 79: 2755-2763.
130. Lan J.G., Cruickshank S.M., Singh J.C., Farrar M., Lodge J.P., Felsburg P.J., Carding S.R.
Different cytokine response of primary colonic epithelial cells to commensal bacteria. World J.
Gastroenterol., 2005, 11: 3375-3384.
131. Hooper L.V., Midtvedt T., Gordon J.I. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu. Rev. Nutr., 2002, 22: 283-307.
132. Hooper L.V., Wong M.H., Thelin A., Hansson L., Falk P.G., Gordon J.I. Molecular analysis
of commensal host—microbial relationships in the intestine. Science, 2001, 291: 881-884.
133. Mirinics Z.K., Calafat J., Udby L., Lovelock J., Kjeldsen L., Rothermund K., Sisodia S.S.,
Borregaard N., Corey S.J. Identification of the presenilins in hematopoietic cells with localization of presenilin 1 to neutrophil and platelet granules. Blood Cells Mol. Dis., 2002, 28: 28-38.
134. Fraering P.C., Ye W., Strub J.M., Dolios G., LaVoie M.J., Ostaszewski B.L., Van Dorsselaer
A., Wang R., Selkoe D.J., Wolfe M.S. Purification and characterization of the human gammasecretase complex. Biochemistry, 2004, 43: 9774-9789.
135. Fisinin V.I., Surai P.F. Ptitsevodstvo, 2012, 3: 9-12.
136. Fisinin V.I., Surai P.F. Ptitsevodstvo, 2013 (v pechati).
137. Surai P.F., Fotina T.I. Suchasna Veterinarna Meditsina, 2012, 6: 14-19.
138. Surai K.P., Surai P.F., Speake B.K., Sparks N.H.C. Antioxidant-prooxidant balance in the
intestine: Food for thought. 1. Prooxidants. Nutritional Genomics & Functional Foods, 2003,
1: 51-70.
139. Surai K.P., Surai P.F., Speake B.K., Sparks N.H.C. Antioxidant-prooxidant balance in the intestine: Food for thought. 1. Antioxidants. Current Topics in Nutraceutical Research, 2004, 2: 2746.
140. Surai P.F. Selenium in nutrition and health. Nottingham, UK, 2006.
141. Kettunen H., Peuranen S., Tiihonen K. Betaine aids in the osmoregulation of duodenal epithelium of broiler chicks and affects the movement of water across the small intestinal epithelium
in vitro. Comp. Biochem. Physiol. A: Mol. Integr. Physiol., 2001, 129: 595-603.
142. Kettunen H., Tiihonen K., Peuranen S., Saarinen M.T., Remus J.C. Dietary betaine accumulates in the liver and intestinal tissue and stabilizes the intestinal epithelial structure in healthy
and coccidia-infected broiler chicks. Comp. Biochem. Physiol. A: Mol. Integr. Physiol., 2001, 130:
759-769.
143. Klasing K.C., Adler K.L., Remus J.C., Calvert C.C. Dietary betaine increases intraepithelial
lymphocytes in the duodenum of coccidia-infected chicks and increases functional properties of
phagocytes. J. Nutrit., 2002, 132: 2274-2282.
144. Ji C., Shinohara M., Vance D., Than T.A., Ookhtens M., Chan C., Kaplowitz N. Effect of
transgenic extrahepatic expression of betaine-homocysteine methyltransferase on alcohol or homocysteine-induced fatty ver. Alcohol. Clin. Exp. Res., 2008, 32: 1049-1058.
145. Ji C., Kaplowitz N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress,
and liver injury in alcohol-fed mice. Gastroenterology, 2003, 124: 1488-1499.
146. Samara K., Liu C., Soldevila-Pico C., Nelson D.R., Abdelmalek M.F. Betaine resolves severe
alcohol-induced hepatitis and steatosis following liver transplantation. Dig. Dis. Sci., 2006, 51:
1226-1229.
147. Kharbanda K.K., Mailliard M.E., Baldwin C.R., Sorrell M.F., Tuma D.J. Accumulation of
proteins bearing atypical isoaspartyl residues in livers of alcohol-fed rats is prevented by betaine
administration: effects on protein-L-isoaspartyl methyltransferase activity. J. Hepatol., 2007, 46:
1119-1125.
148. Shi Q.-Z., Wang L.-W., Zhang W., Gong Z.-J. Betaine inhibits Toll-like receptor 4 expression
in rats with ethanol-induced liver injury. World J. Gastroenterol., 2010, 16: 897-903.
149. Fortin G. L-Carnitine and intestinal inflammation. Vitam. Horm., 2011, 86: 353-366.
150. Izgüt-Uysal V.N., Ağaç A., Karadoğan I., Derin N. Effects of L-carnitine on neutrophil functions in aged rats. Mech. Ageing. Dev., 2003, 124: 341-347.
151. Izgüt-Uysal V.N., Ağaç A., Karadoğan I., Derin N. Peritoneal macrophages function modulation by L-carnitine in aging rats. Aging Clin. Exp. Res., 2004, 16: 337-341.
152. Derin N., Ağaç A., Bayram Z., Asar M., Izgüt-Uysal V.N. Effects of L-carnitine on neutrophilmediated ischemia-reperfusion injury in rat stomach. Cell Biochem. Funct., 2006, 24: 437-442.
153. Shekhawat P.S., Srinivas S.R., Matern D., Bennett M.J., Boriack R., George V., Xu H.,
Prasad P.D., Roon P., Ganapathy V. Spontaneous development of intestinal and colonic atro-
24
phy and inflammation in the carnitine-deficient jvs (OCTN2(−/−)) mice. Mol. Genet. Metab.,
2007, 92: 315-324.
154. Thangasamy T., Jeyakumar P., Sittadjody S., Joyee A.G., Chinnakannu P. L-carnitine
mediates protection against DNA damage in lymphocytes of aged rats. Biogerontology,
2009, 10: 163-172.
155. Thangasamy T., Subathra M., Sittadjody S., Jeyakumar P., Joyee A.G., Mendoza E., Chinnakkanu P. Role of L-carnitine in the modulation of immune response in aged rats. Clin. Chim.
Acta, 2008, 389: 19-24.
156. Deng K., Wong C.W., Nolan J.V. Long-term effects of early-life dietary L-carnitine on lymphoid organs and immune responses in Leghorn-type chickens. J. Anim. Physiol. Anim. Nutr.
(Berl.), 2006, 90: 81-86.
157. Buyse J., Swennen Q., Niewold T.A., Klasing K.C., Janssens G.P., Baumgartner M., Goddeeris B.M. Dietary L-carnitine supplementation enhances the lipopolysaccharide-induced
acute phase protein response in broiler chickens. Vet. Immunol. Immunopathol., 2007, 118:
154-159.
158. Celik L., Oztürkcan O. Effects of dietary supplemental L-carnitine and ascorbic acid on performance, carcass composition and plasma L-carnitine concentration of broiler chicks reared
under different temperature. Arch. Tierernahr., 2003, 57: 27-38.
159. Celik L., Oztürkcan O., Inal T.C., Canacankatan N., Kayrin L. Effects of L-carnitine and niacin supplied by drinking water on fattening performance, carcass quality and plasma L-carnitine
concentration of broiler chicks. Arch. Tierernahr., 2003, 57: 127-136.
160. Kheirkhah A.R., Rahimi S., Torshizi M.A.K., Malekmohamadi H. Effect of different levels of
L-carnitine supplementation in broiler breeders and their progeny's diets on performance, blood
factors, carcass characteristics and immune system of broilers. J. Vet. Res., 2009, 64: 283-289.
161. Mucida D., Park Y., Cheroutre H. From the diet to the nucleus: vitamin A and TGF-b join efforts at the mucosal interface of the intestine. Semin. Immunol., 2009, 21: 14-21.
162. Iwata M., Hirakiyama A., Eshima Y., Kagechika H., Kato C., Song S.Y. Retinoic acid imprints
gut-homing specificity on T cells. Immunity, 2004, 21: 527-538.
163. Cassani B., Villablanca E.J., De Calisto J., Wang S., Mora J.R. Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Mol. Aspects Med., 2012, 33: 63-76.
164. Feng T., Cong Y., Qin H., Benveniste E.N., Elson C.O. Generation of mucosal dendritic cells
from bone marrow reveals a critical role of retinoic acid. J. Immunol., 2010, 185: 5915-5925.
165. Yamaguchi T., Hirota K., Nagahama K., Ohkawa K., Takahashi T., Nomura T., Sakaguchi S.
Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity, 2007, 27: 145-159.
166. Kunisawa J., Hashimoto E., Ishikawa I., Kiyono H. A pivotal role of vitamin B9 in the maintenance of regulatory T cells in vitro and in vivo. PLoS ONE, 2012, 7(2): E32094.
167. Lallès J.P., Bosi P., Janczyk P., Koopmans S.J., Torrallardona D. Impact of bioactive substances on the gastrointestinal tract and performance of weaned piglets: a review. Animal, 2009,
3: 1625-1643.
168. Fisinin V.I., Surai P.F. Ptitsevodstvo, 2012, 2: 11-15.
169. Surai P.F., Dvorska J.E. Effects of mycotoxins on antioxidant status and immunity. In: The
Mycotoxins Blue Book. D.Å. Diaz (ed.). Nottingham University Press, 2005: 93-137.
170. Fisinin V.I., Surai P.F. Zhivotnovodstvo Rossii,2012, 5: 11-14.
171. Fisinin V.I., Surai P.F. Zhivotnovodstvo Rossii,2012, 6: 3-5.
172. Fisinin V.I., Surai P.F. Kombikorma, 2012, 5: 59-60.
173. Fisinin V.I., Surai P.F. Kombikorma, 2012, 5: 59-60.
174. Fisinin V.I., Surai P.F. Ptitsa i ptitseprodukty, 2012, 3: 38-41.
175. Fisinin V.I., Surai P.F. Ptitsa i ptitseprodukty, 2012, 4: 36-39.
176. Surai P.F., Fisinin V.I. Sel’skokhozyaistvennaya Biologiya [Agricultural Biology], 2012, 4: 3-13.
25