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001-es BibID:	BIBFORM044274
Első szerző:	Martucciello, Stefania
Cím:	RhoB is associated with the anti-angiogenic effects of celiac patient transglutaminase 2-targeted autoantibodies / Martucciello Stefania, Lavric Miha, Toth Boglarka, Korponay-Szabo Ilma, Nadalutti Cristina, Myrsky Essi, Rauhavirta Tiina, Esposito Carla, Sulic Ana-Marija, Sblattero Daniele, Marzari Roberto, Mäki Markku, Kaukinen Katri, Lindfors Katri, Caja Sergio
Dátum:	2012
ISSN:	0946-2716
Megjegyzések:	Celiac patient-derived anti-transglutaminase 2 (TG2) antibodies disturb several steps in angiogenesis, but the detailed molecular basis is not known. Therefore, we here analyzed by microarray technology the expression of a set of genes related to angiogenesis and endothelial cell biology in order to identify factors that could explain our previous data related to vascular biology in the context of celiac disease. To this end, in vitro models using human umbilical vein endothelial cells (HUVECs) or in vivo models of angiogenesis were used. A total of 116 genes were analyzed after treatment with celiac patient autoantibodies against TG2. Compared to treatment with control IgA celiac patient, total IgA induced a consistent expression change of 10 genes, the up-regulation of four and down-regulation of six. Of these genes the up-regulated RhoB was selected for further studies. RhoB expression was found to be up-regulated at both messenger RNA and protein level in response to celiac patient total IgA as well as anti-TG2-specific antibody derived from a celiac patient. Interestingly, down-regulation of RhoB by specific small interfering RNA treatment in endothelial cells could rescue the deranged endothelial length and tubule formation caused by celiac disease autoantibodies. RhoB function is controlled by its post-translational modification by farnesylation. This modification of RhoB required for its correct function can be prevented by the cholesterol lowering drug simvastatin, which was also able to abolish the anti-angiogenic effects of celiac anti-TG2 autoantibodies. Taken together, our results would suggest that RhoB plays a key role in the response of endothelial cells to celiac disease-specific anti-TG2 autoantibodies
Tárgyszavak:	Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Journal Of Molecular Medicine-Jmm. - 90 : 7 (2012), p. 817-826. -
További szerzők:	Lavric, Miha Tóth Boglárka Korponay-Szabó Ilma (1959-) (gyermekgyógyász) Nadalutti, Cristina Myrsky, Essi Rauhavirta, Tiina Esposito, Carla Sulic, Ana-Marija Sblattero, Daniele Marzari, Roberto Mäki, Markku Kaukinen, Katri Lindfors, Katri Caja, Sergio
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001-es BibID:	BIBFORM025441
Első szerző:	Simon-Vecsei Zsófia (biológus)
Cím:	A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects / Zsófia Simon-Vecsei, Róbert Király, Péter Bagossi, Boglárka Tóth, Ingrid Dahlbom, Sergio Caja, Éva Csősz, Katri Lindfors, Daniele Sblattero, Éva Nemes, Markku Mäki, László Fésüs, Ilma R. Korponay-Szabó
Dátum:	2012
Megjegyzések:	The multifunctional, protein cross-linking transglutaminase 2 (TG2) is the main autoantigen in celiac disease, an autoimmune disorder with defined etiology. Glutamine-rich gliadin peptides from ingested cereals, after their deamidation by TG2, induce T-lymphocyte activation accompanied by autoantibody production against TG2 in 1-2% of the population. The pathogenic role and exact binding properties of these antibodies to TG2 are still unclear. Here we show that antibodies from different celiac patients target the same conformational TG2 epitope formed by spatially close amino acids of adjacent domains. Glu153 and 154 on the first alpha-helix of the core domain and Arg19 on first alpha-helix of the N-terminal domain determine the celiac epitope which is accessible both in the closed and open conformation of TG2 and dependent on the relative position of these helices. Met659 on the C-terminal domain also can cooperate in antibody binding. This composite epitope is disease-specific, recognized by antibodies derived from celiac tissues and associated with biological effects when passively transferred from celiac mothers into their newborns. These findings suggest that celiac antibodies are produced in a surface-specific way for which certain homology of the central glutamic acid residues of the TG2 epitope with deamidated gliadin peptides could be a structural basis. Monoclonal mouse antibodies with partially overlapping epitope specificity released celiac antibodies from patient tissues and antagonized their harmful effects in cell culture experiments. Such antibodies or similar specific competitors will be useful in further functional studies and in exploring whether interference with celiac antibody actions leads to therapeutic benefits.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban antibody epitope transglutaminase Molekuláris medicina
Megjelenés:	Proceedings of the National Academy of Sciences of the United States of America. - 109 : 2 (2012), p. 431-436. -
További szerzők:	Király Róbert (1975-) (biológus) Bagossi Péter (1966-2011) (biokémikus, vegyész) Tóth Boglárka Dahlbom, Ingrid Caja, Sergio Csősz Éva (1977-) (biokémikus, molekuláris biológus) Lindfors, Katri Sblattero, Daniele Nemes Éva (1957-) (csecsemő- és gyermekgyógyász, gasztroenterológus) Mäki, Markku Fésüs László (1947-) (orvos biokémikus) Korponay-Szabó Ilma (1959-) (gyermekgyógyász)
Pályázati támogatás:	TÁMOP-4.2.1/B-09/1/KONV-2010-0007 TÁMOP Molekuláris mechanizmusok és sejtszintű eltérések coeliakiában
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