Matrix metalloproteinases as targets for the immune system during experimental arthritis.
Novel therapies for rheumatoid arthritis aiming at intervention in the inflammatory process by manipulation of autoreactive T and B lymphocytes receive major interest. However, the development of such therapies is largely hampered by the lack of knowledge of self-Ags recognized during the disease process. Recently, we predicted putative T cell self-epitopes based on a computer search profile. In the present study, the predicted self-epitopes were tested for T cell recognition in two experimental arthritis models, and their arthritogenic capacity was analyzed. Fourteen of n = 51 predicted self-epitopes were recognized during experimental arthritis of which six were able to actively induce arthritis. Interestingly, three of these six peptides were derived from matrix metalloproteinases (MMP), and only T cells responsive to MMP-derived epitopes were able to passively transfer arthritis to naive rats. Moreover, we demonstrate the presence of Abs to MMP-3 during the course of adjuvant arthritis. Together these data indicate that MMPs play a pivotal role as target for T and B cells during the development of inflammatory arthritis. This finding sheds new light on the pathophysiological role of MMPs during arthritis and opens novel possibilities for Ag-specific immunotherapy.
van Bilsen
Jolanda H M
JH
Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Wagenaar-Hilbers
Josée P A
JP
Grosfeld-Stulemeijer
Mayken C J T
MC
van der Cammen
Maarten J F
MJ
van Dijk
Mariska E A
ME
van Eden
Willem
W
Wauben
Marca H M
MH
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002358:Cartilage, Articular / Q000201:enzymology / Q000276:immunology; D003959:Diamines / Q000008:administration & dosage; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000201:enzymology*; D008198:Lymph Nodes / Q000201:enzymology / Q000276:immunology; D019278:Matrix Metalloproteinase 3 / Q000008:administration & dosage / Q000276:immunology; D020782:Matrix Metalloproteinases / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000201:enzymology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D001324:Autoantigens; D003959:Diamines; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D000644:Quaternary Ammonium Compounds; C015831:dimethyldioctadecylammonium; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; C006270:avridine