Tissue transglutaminase-mediated formation and cleavage of histamine-gliadin complexes: biological effects and implications for celiac disease.
Celiac disease is an HLA-DQ2-associated disorder characterized by an intestinal T cell response. The disease-relevant T cells secrete IFN-gamma upon recognition of gluten peptides that have been deamidated in vivo by the enzyme tissue transglutaminase (transglutaminase 2 (TG2)). The celiac intestinal mucosa contains elevated numbers of mast cells, and increased histamine secretion has been reported in celiac patients. This appears paradoxical because histamine typically biases T cell responses in the direction of Th2 instead of the Th1 pattern seen in the celiac lesions. We report that histamine is an excellent substrate for TG2, and it can be efficiently conjugated to gluten peptides through TG2-mediated transamidation. Histamine-peptide conjugates do not exert agonistic effects on histamine receptors, and scavenging of biologically active histamine by gluten peptide conjugation can have physiological implications and may contribute to the mucosal IFN-gamma response in active disease. Interestingly, TG2 is able to hydrolyze the peptide-histamine conjugates when the concentrations of substrates are lowered, thereby releasing deamidated gluten peptides that are stimulatory to T cells.
Qiao
Shuo-Wang
SW
Institute of Immunology, Rikshospitalet, University of Oslo, Oslo, Norway. s.w.qiao@labmed.uio.no
Piper
Justin
J
Haraldsen
Guttorm
G
Oynebråten
Inger
I
Fleckenstein
Burkhard
B
Molberg
Oyvind
O
Khosla
Chaitan
C
Sollid
Ludvig M
LM
D000595:Amino Acid Sequence; D002446:Celiac Disease / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D016166:Free Radical Scavengers / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D005903:Gliadin / Q000737:chemistry / Q000378:metabolism*; D005983:Glutens / Q000378:metabolism; D006632:Histamine / Q000737:chemistry / Q000378:metabolism*; D017442:Histamine Agonists / Q000378:metabolism; D006633:Histamine Antagonists / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors; D016209:Interleukin-8 / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000378:metabolism; D013379:Substrate Specificity; D011503:Transglutaminases / Q000737:chemistry / Q000378:metabolism*
D018984:Epitopes, T-Lymphocyte; D016166:Free Radical Scavengers; D017442:Histamine Agonists; D006633:Histamine Antagonists; D016209:Interleukin-8; D010446:Peptide Fragments; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018664:Interleukin-12; D005983:Glutens; D006632:Histamine; D005903:Gliadin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins