Cytokine-specific autoantibodies in AIRE deficiency
| dc.contributor.advisor | Peterson, Pärt, juhendaja | |
| dc.contributor.advisor | Kisand, Kai, juhendaja | |
| dc.contributor.author | Kärner, Jaanika | |
| dc.contributor.other | Tartu Ülikool. Meditsiiniteaduste valdkond. | et |
| dc.date.accessioned | 2016-11-14T13:34:52Z | |
| dc.date.available | 2016-11-14T13:34:52Z | |
| dc.date.issued | 2016-11-14 | |
| dc.description | Väitekirja elektrooniline versioon ei sisalda publikatsioone. | et |
| dc.description.abstract | Autoimmuunhaiguste tekkepõhjuste uurimine on keerukas protsess, kuna need kujunevad enamasti mitmete geenide ja keskkonna koosmõjul. APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) sündroomi põhjuseks on aga mutatsioonid ainult ühes geenis – Autoimmuunsuse Regulaatoris (AIRE). AIRE osaleb omandatud immuunsüsteemi rakkude – T-rakkude - väljakoolitamises, kuna reguleerib immuunsüsteemi ühes keskses organis, tüümuses, koespetsiifiliste geenide avaldumist. See protsess on oluline, et eemaldada oma keha valke äratundvad T-rakud. APECED patsientidel on see süsteem aga puudulik ning viib mitmete organite kahjustusteni. APECED patsientidele on väga iseloomulikud ka (immuun)rakkude vaheliste suhtlusmolekulide – tsütokiinide – vastaste autoantikehade esinemine. Tüüp I interferoonide (IFN) vastased autoantikehad on abiks haiguse diagnoosimisel ning interleukiin (IL)-17A/F ja IL-22 spetsiifilised autoantikehad on otseselt seotud kroonilise seeninfektsiooni väljakujunemisega. Käesolevas doktoritöös määrati tsütokiini-spetsiifiliste autoantikehade peamine klass ja alaklassid. Need annavad olulist informatsiooni keskkonna ja immuunrakkude kohta, mis osalevad autoantikehade tekkimisel. Lisaks näidati, et patsientide autoantikehad tunnevad tsütokiinide juures eelistatult ära konformatsiooni ning et kõrges tiitris tüüp I IFNe neutraliseerivad autoantikehad kaitsevad esimest tüüpi diabeedi kujunemise eest. Samuti kirjeldati APECED patsientides uusi IL-6 spetsiifilisi autoantikehi. Esmakordselt näidati ka Aire-puudulikes hiirtes IL-17A/F ja IL-22 autoantikehade esinemist. Viimaseks kirjeldati AIRE ning koespetsiifiliste geenide ekspressiooni tümoomi koes, kuna tümoomiga patsientidel on teatud sarnasusi APECED sündroomiga. Kuna APECED on hea mudel autoimmuunhaiguste uurimiseks, siis aitavad saadud tulemused paremini mõista autoimmunsuse tekkemehhanisme. | et |
| dc.description.abstract | The pathogenesis of autoimmune diseases is complex, as they are usually caused by the interaction of several genes and environmental cues. APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) is the result of mutations only in one gene – Autoimmune Regulator (AIRE). AIRE participates in the shaping of the repertoire of immune cells by regulating tissue- specific genes in the thymus – the central organ of immune system. This process is important to eliminate T cells that recognize self-proteins. This system is defective in APECED patients and leads to destruction of several organs. The hallmarks of APECED patients are the autoantibodies against cytokines – proteins that mediate communication between immune and other cells. Those against type I interferons (IFN) are important For APECED diagnostics and those specific to (IL)-17A/F and IL-22 are directly responsible for the development of chronic fungal infections. In this thesis the main class and subclasses of cytokine-specific autoantibodies were determined; these results give important information about the immune cells and environment needed for the generation of autoantibodies. In addition, it was shown, that patients’ autoantibodies recognize mainly the conformational epitopes of the cytokines and the high titer neutralizing autoantibodies against type I IFNs can be protective against type I diabetes. In addition, novel IL-6 specific autoantibodies were discovered in APECED patients. For the first time, IL-17A/F and IL-22 specific autoantibodies were found in Aire deficient mice. Finally, the expression of AIRE and tissue specific genes was characterized in thymoma tissue as thymoma patients share some features with APECED. As APECED is a good model to study autoimmune diseases our results are very useful for further understanding the mechanisms of autoimmunity. | en |
| dc.identifier.isbn | 978-9949-77-273-5 | |
| dc.identifier.isbn | 978-9949-77-274-2 (pdf) | |
| dc.identifier.issn | 1024-395X | |
| dc.identifier.uri | http://hdl.handle.net/10062/54477 | |
| dc.language.iso | en | et |
| dc.relation.ispartofseries | Dissertationes medicinae Universitatis Tartuensis;247 | |
| dc.subject | autoimmuunhaigused | et |
| dc.subject | regulaatorgeenid | et |
| dc.subject | mutatsioonid | et |
| dc.subject | tsütokiinid | et |
| dc.subject | autoimmuunsus | et |
| dc.subject | interleukiinid | et |
| dc.subject | antikehad | et |
| dc.subject | autoimmune diseases | en |
| dc.subject | regulator genes | en |
| dc.subject | mutations | en |
| dc.subject | cytokines | en |
| dc.subject | autoimmunity | en |
| dc.subject | interleukins | en |
| dc.subject | antibodies | en |
| dc.subject.other | dissertatsioonid | et |
| dc.subject.other | ETD | en |
| dc.subject.other | dissertations | en |
| dc.subject.other | väitekirjad | et |
| dc.title | Cytokine-specific autoantibodies in AIRE deficiency | en |
| dc.title.alternative | Tsütokiinide spetsiifilised autoantikehad AIRE puudulikkuse korral | et |
| dc.type | Thesis | en |
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