Transcriptional mechanisms in thymic central tolerance
Date
2017-07-04
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Abstract
Immuunsüsteemi üheks alustalaks on T-rakkude võime eristada haigustekitajatest pärinevaid („võõraid“) valke kehaomastest („omadest“) valkudest. Selle eristusvõime tagab immuuntolerantsuse mehhanism, mis jaguneb tolerantsust tekitava keskkonna põhjal kaheks: tsentraalseks ja perifeerseks tolerantsuseks. Tsentraalse T-rakulise tolerantsuse tekkepaigaks on südame ees asuv organ, tüümus ehk harknääre, kus arenevaid T-rakke „õpetatakse“ vältima immuunvastust „omale“. Selles protsessis on keskne roll tüümuse epiteelirakkudel ja neis rakkudes avalduvatel valgufaktoritel, nn transkriptsioonifaktoritel, mis reguleerivad teisi geene ja mille osalusel tehakse kahjutuks „oma“ valkudega reageerivad T-rakud. Üheks oluliseks transkriptsioonifaktoriks on Autoimmuunsuse Regulaator (Aire), mille mutatsiooni puhul T-rakud reageerivad „omale“ ning patsientidel tekivad mitmeid organeid mõjutavad autoimmuunsed haigused. Seega aitab tüümuses avalduvate transkriptsioonifaktorite uurimine paremini mõista immuunsüsteemi haigusi, kus „oma“ ja „võõra“ eristamine on häiritud, nagu autoimmuunhaigused ning iseeneslikud raseduse katkemised.
Käesolev töö keskendus tüümuse epiteelis tsentraalse tolerantsuse ja seega immuunsüsteemi terviklikku toimimist mõjutavate geenide regulatsiooni uurimisele. Tuvastasime imetajate genoomis geenidevahelise piirkonna, ilma milleta ei ole Aire avaldumine tüümuses võimalik. Leidsime ka, et tiinuse ajal muutub tüümuses olevate epiteelirakkude arv ja geenide avaldumine sedavõrd, et väheneb võime meelitada tüümusesse T-rakkude eellasrakke ning suunata nende arengut. Käesoleva töö viimases osas leidsime, et lisaks Aire-le on tüümuse epiteelis teine transkriptsioonifaktor, Irf4, mis otseselt mõjutab tüümuses T-rakulist tolerantsust.
A functional immune system is capable of reacting to antigens from invading pathogens (non-self) and maintaining immune tolerance towards autologous (self) and beneficial or benign foreign antigens. Immune tolerance is divided into central or peripheral tolerance depending on the time and site of induction. One of the two sites for central tolerance induction is an organ called thymus, where maturating T cells are taught to avoid reaction to self-antigens. The maturation of all T cells depends on thymic stromal cells, especially thymic epithelial cells that express a protein called Autoimmune Regulator (Aire). Aire regulates the expression of genes that help to eliminate T cells that consider self to be non-self. Mutations in the gene responsible for Aire protein are sufficient to cause a complex autoimmune syndrome affecting multiple organs in the body. Characterizing the mechanisms by which thymic transcription factors induce tolerance helps us to understand conditions such as autoimmune diseases and spontaneous abortions where the immune system is incapable of differentiating between self and non-self The current thesis concentrates on transcriptional processes in thymic stromal cells that enforce central tolerance and therefore immune system as a whole. We identified an intergenic region critical for the expression of Aire in thymic epithelial cells. We also found pregnancy to affect the numbers and gene expression profiles of thymic stromal cells in a way which renders these cells suboptimal in attracting T cell progenitors into the thymus and directing their maturation. In the last part of the thesis we identified a transcription factor Irf4 to be one of first factors besides Aire that regulates T cell tolerance in the thymic epithelium
A functional immune system is capable of reacting to antigens from invading pathogens (non-self) and maintaining immune tolerance towards autologous (self) and beneficial or benign foreign antigens. Immune tolerance is divided into central or peripheral tolerance depending on the time and site of induction. One of the two sites for central tolerance induction is an organ called thymus, where maturating T cells are taught to avoid reaction to self-antigens. The maturation of all T cells depends on thymic stromal cells, especially thymic epithelial cells that express a protein called Autoimmune Regulator (Aire). Aire regulates the expression of genes that help to eliminate T cells that consider self to be non-self. Mutations in the gene responsible for Aire protein are sufficient to cause a complex autoimmune syndrome affecting multiple organs in the body. Characterizing the mechanisms by which thymic transcription factors induce tolerance helps us to understand conditions such as autoimmune diseases and spontaneous abortions where the immune system is incapable of differentiating between self and non-self The current thesis concentrates on transcriptional processes in thymic stromal cells that enforce central tolerance and therefore immune system as a whole. We identified an intergenic region critical for the expression of Aire in thymic epithelial cells. We also found pregnancy to affect the numbers and gene expression profiles of thymic stromal cells in a way which renders these cells suboptimal in attracting T cell progenitors into the thymus and directing their maturation. In the last part of the thesis we identified a transcription factor Irf4 to be one of first factors besides Aire that regulates T cell tolerance in the thymic epithelium
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Keywords
harkelund, epiteelrakud, T-lümfotsüüdid, transkriptsioon (biol.), autoimmuunsus, immuunregulatsioon, homöostaas, thymus, epithelial cells, T lymphocytes, transcription (biol.), autoimmunity, immune regulation, homeostasis