Tissue transglutaminase enhances collagen type II-induced arthritis and modifies the immunodominant T-cell epitope CII260-270.
The calcium-dependent enzyme tissue transglutaminase (tTG) is associated with diverse biological functions, such as induction of apoptosis, modeling of the extracellular matrix, receptor-mediated endocytosis, cell growth and differentiation, cell adhesion and signal transduction. Also, it may deamidate glutamine residues to glutamic acid and catalyze cross-linking of proteins. In this study, we have investigated the impact of tTG for posttranslational modifications and cross-linking of the immunodominant T-cell epitope CII260-270 and their effects on the collagen-induced arthritis, an animal model for rheumatoid arthritis. By using mass spectrometry analysis and hybridoma assays, we have demonstrated that tTG could perform both types of modifications (deamidation and cross-link formation) on the immunodominant T-cell epitope CII259-273. Replacement of the glutamine at position 267 with glutamic acid leads to a decreased binding affinity to MHC II. T cells recognized both non-modfied (Q(267)) and modified (E(267)) CII259-273-peptides. We also show that administration of tTG leads to increased incidence, severity and histopathological manifestations of collagen-induced arthritis in mice. Moreover, we conclude that both processes, deamidation and cross-linking, are involved in the tTG-catalyzed reactions, and in vivo administration of tTG enhances arthritis severity and joint destruction in mice.
Dzhambazov
Balik
B
Department of Medical Biochemistry and Biophysics, Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.
Lindh
Ingrid
I
Engström
Ake
A
Holmdahl
Rikard
R
D000818:Animals; D000906:Antibodies / Q000097:blood; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D024043:Collagen Type II / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006168:Guinea Pigs; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011499:Protein Processing, Post-Translational; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D000906:Antibodies; D024043:Collagen Type II; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins