Author/Editor		Goropevšek, Aleš; Homšak, Evgenija; Gorenjak, Maksimiljan; Malešič, Ivan; Krajnc, Ivan; Cencič, Avrelija
Title		Novejši biooznačevalci in spremljenje znotrajceličnih signalnih poti pri avtoimunskih boleznih
Translated title		New biomarkers and monitoring intracellular signaling pathways in autoimmune diseases
Type		članek
Source		Zdrav Vestn
Vol. and No.		Letnik 77, št. 9
Publication year		2008
Volume		str. 615-22
Language		slo
Abstract		Background. Almost all current therapeutic concepts in many autoimmune and chronic inflammatory diseases are based on the systemic suppression of immune functions and are not curative. Identification of cytokines TNF and IFN-alpha as major factors in the pathogenesis of diseases such as rheumatoid arthritis and systemic lupus erythematosus (SLE) represent a substantial improvement in understanding of autoimmune diseases. Intracellular signalling pathways that are activated in response to those clinically relevant cytokines, mediate signals through kinase phosphorylation of proteins and are at the core of immune cell function. However, little is known about their changes in autoimmune disease states. Recent trials emphasized the importance of directl yassessing the human immune responses, and that not all of what we learn for example in the mouse can be directly translated to humans. Thus, there is a need for the development of tools and assays to directly assess the human immune system, and to predict its responses to novel therapeutic entities. Newly discovered biomarkers represent promising tools. Even more promising are approaches, that are based on monitoring immune signaling on the single cell level. Conclusions. A series of assay systems for flow cytometric-based biochemical analysis at the single-cell level for kinase and phosphoprotein profiling have been developed. This will give us opportunity to study signal pathways also in autoimmune and chronic inflammatory diseases, as the analysing systems are adapted to immunocytes for example in peripheral blood. First results show characteristic phospho-signature of cytokines (interferons) in immune cells from SLE patients. Monitoring signaling pathways on the single cell level can lead to developments in new diagnostic tools, especially in monitoring of disease activity. Results can also identify new targets of more specific and less toxic therapy with kinase inhibitors.
Summary		Izhodišča. Avtoimunske in kronične vnetne bolezni se še vedno pogosto zdravijo le z nespecifično imunosupresijo, ki ne prinaša ozdravitve. Spoznanje, da so citokini TNF in IFN-alfa bistveni v patogenezi bolezni, kot sta revmatoidni artritis in sistemski lupus eritematozus, pomeni napredek v razumevanju avtoimunskih bolezni. Znotrajcelične signalne poti, ki se aktivirajo kot odgovor na te klinično pomembne citokine, prenašajo signale s kinazno fosforilacijo proteinov in so bistvene za delovanje celic imunskega sistema. Malo je znanega o spremembah teh signalnih poti pri avtoimunskih boleznih. Nedavne klinične raziskave so pokazale, da se spoznanja iz živalskih modelov ne morejo neposredno prenesti na človeka. Za spremljanje aktivnosti bolezni in napoved odziva na novejše zdravljenje je potrebno razviti nova orodja za spremljanje humanega imunskega odziva. Obetajoče orodje v prihodnosti so novo odkriti biomarkerji. Še več si obetamo od pristopov, ki temeljijo na spremljanju signalnih poti na celični ravni. Zaključki. Razviti so bili biokemični analizni sistemi, ki temeljijo na pretočni citometriji in omogočajo profiliranje kinaz in fosfoproteinov na ravni posameznih celic. To bo omogočilo študije signalnih poti pri avtoimunskih in kroničnih vnetnih boleznih, saj so analizni sistemi prilagojeni prav celicam imunskega sistema, npr. v periferni krvi. Prvi rezultati kažejo značilne fosfo-signature citokinov (interferonov) v imunskih celicah bolnikov s SLE. Možnost spremljanja signalnih poti na celični ravni lahko prinese razvoj novih diagnostičnih možnosti, predvsem za spremljanje aktivnosti bolezni in vodenja zdravljenja. Rezultati študij pa lahko nakažejo tudi nove tarče, bolj specifičnega in manj toksičnega, zdravljenja z inhibitorji kinaz.
Descriptors		LUPUS ERYTHEMATOSUS, SYSTEMIC FLOW CYTOMETRY CYTOKINES INTERFERON-ALPHA AUTOIMMUNE DISEASES