Celiac disease IgA modulates vascular permeability in vitro through the activity of transglutaminase 2 and RhoA.
Celiac disease is characterized by the presence of specific autoantibodies targeted against transglutaminase 2 (TG2) in untreated patients' serum and at their production site in the small-bowel mucosa below the basement membrane and around the blood vessels. As these autoantibodies have biological activity in vitro, such as inhibition of angiogenesis, we studied if they might also modulate the endothelial barrier function. Our results show that celiac disease patient autoantibodies increase endothelial permeability for macromolecules, and enhance the binding of lymphocytes to the endothelium and their transendothelial migration when compared to control antibodies in an endothelial cell-based in vitro model. We also demonstrate that these effects are mediated by increased activities of TG2 and RhoA. Since the small bowel mucosal endothelium serves as a "gatekeeper" in inflammatory processes, the disease-specific autoantibodies targeted against TG2 could thus contribute to the pathogenic cascade of celiac disease by increasing blood vessel permeability.
Myrsky
Essi
E
Pediatric Research Center, Medical School, University of Tampere, Tampere, Finland.
Caja
Sergio
S
Simon-Vecsei
Zsofi
Z
Korponay-Szabo
Ilma R
IR
Nadalutti
Cristina
C
Collighan
Russell
R
Mongeot
Alexandre
A
Griffin
Martin
M
Mäki
Markku
M
Kaukinen
Katri
K
Lindfors
Katri
K
D001323:Autoantibodies / Q000502:physiology*; D001808:Blood Vessels / Q000378:metabolism / Q000503:physiopathology; D002446:Celiac Disease / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D002448:Cell Adhesion; D004727:Endothelium / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007070:Immunoglobulin A / Q000502:physiology*; D008214:Lymphocytes / Q000378:metabolism; D010539:Permeability; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D001323:Autoantibodies; D007070:Immunoglobulin A; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
Clin Sci (Lond). 2005 Sep;109(3):227-41
16104843
J Immunol. 2001 Mar 15;166(6):4170-6
11238668
Gastroenterology. 1999 Mar;116(3):566-72
10029615
Reprod Biol Endocrinol. 2009 Feb 19;7:16
19228395
Clin Exp Immunol. 1993 May;92(2):303-7
7683588
J Biol Chem. 2001 Jun 22;276(25):22614-20
11309397
J Cell Sci. 2001 Apr;114(Pt 7):1343-55
11257000
J Autoimmun. 2006 Jun;26(4):278-87
16678998
Ann N Y Acad Sci. 2007 Jun;1107:319-28
17804560
Hum Pathol. 2009 May;40(5):699-704
19157500
N Engl J Med. 2007 Oct 25;357(17):1731-43
17960014
Gastroenterology. 2007 Apr;132(4):1245-53
17408665
Mol Biol Cell. 2006 Apr;17(4):1606-19
16452636
Gut. 2003 Feb;52(2):199-204
12524400
Curr Med Chem. 2005;12(20):2357-72
16181137
PLoS Med. 2006 Sep;3(9):e358
16984219
J Cell Biochem. 2007 Dec 15;102(6):1358-67
17979153
Neurology. 2006 Feb 14;66(3):373-7
16476935
PLoS Biol. 2007 Dec;5(12):e327
18092889
Gut. 2007 Mar;56(3):336-41
16935926
Hybridoma. 1985 Summer;4(2):179-86
2861155
Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11305-10
18685096
EMBO J. 2001 May 15;20(10):2413-23
11350930
Dig Dis Sci. 2000 Feb;45(2):398-402
10711458
Scand J Gastroenterol. 2009;44(2):162-7
18985542
Gastroenterology. 1996 Nov;111(5):1252-62
8898639
Bioorg Med Chem Lett. 2008 Oct 15;18(20):5559-62
18812257
Histochem Cell Biol. 2004 Jul;122(1):17-25
15221408
Gut. 2004 May;53(5):641-8
15082580
Gastroenterology. 2007 Jul;133(1):195-206
17631142
J Pediatr Gastroenterol Nutr. 2008 Mar;46(3):253-61
18376241
PLoS One. 2008 Mar 26;3(3):e1861
18365016
Gut. 2006 Dec;55(12):1746-53
16571636
Clin Exp Immunol. 2008 Apr;152(1):111-9
18279443
Nat Med. 1997 Jul;3(7):797-801
9212111
J Biol Chem. 2003 Aug 1;278(31):28793-8
12754211
J Exp Med. 1999 May 3;189(9):1373-82
10224277
Gut. 2002 Aug;51(2):177-81
12117875