HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jane-wit, D. Articles by Tuohy, V. K. Search for Related Content PubMed PubMed Citation Articles by Jane-wit, D. Articles by Tuohy, V. K.

A Novel Class II-Binding Motif Selects Peptides That Mediate Organ-Specific Autoimmune Disease in SWXJ, SJL/J, and SWR/J Mice¹

Daniel Jane-wit^*,, Min Yu^2,*, Andrea E. Edling^*, Seiko Kataoka^*, Justin M. Johnson^*, Linda B. Stull^3,, Christine S. Moravec and Vincent K. Tuohy^4,*

^* Department of Immunology, Lerner Research Institute, and Center for Anesthesiology Research, Cleveland Clinic Foundation, Cleveland, OH 44195; and Department of Pathology, Case Western Reserve University, Cleveland, OH 44106

Idiopathic dilated cardiomyopathy (DCM) is responsible for 25% of all cases of congestive heart failure. We have recently shown that immunization of autoimmune-susceptible SWXJ mice with whole cardiac myosin leads to T cell-mediated experimental autoimmune myocarditis (EAMC) and DCM. We have now identified two disease-inducing peptides from cardiac -myosin heavy chain (CAMHC). Our approach involved the use of a novel MHC class II-binding motif contained in several peptides known to be immunogenic in SWXJ (H-2^q,s) mice or in the parental SJL/J (H-2^s) or SWR/J (H-2^q) mouse strains. Two of four CAMHC peptides containing the -KXXS- peptide motif were found to be immunogenic. Immunization of SWXJ or parental SJL/J and SWR/J mice with CAMHC peptides p406–425 or p1631–1650 resulted in EAMC and DCM, characterized by inflammation, fibrosis, and decompensated right-sided ventricular dilatation. Despite mediating high incidences of severe disease, both peptides were found to be cryptic determinants, thereby providing further evidence for the importance and perhaps predominance of self crypticity in autoimmunity. Both peptides showed dual parental I-A^q and I-A^s restriction and mediated passive transfer of disease with activated CD4⁺ T cells. An intact motif was necessary for antigenicity because loss of activity occurred in peptides containing nonconservative substitutions at the motif’s terminal lysine and serine residues. Our studies provide a new model for EAMC and DCM in strains of mice widely used in autoimmune studies. Moreover, the -KXXS- motif may be particularly useful in implicating previously overlooked proteins as autoimmune targets and in facilitating the development of new organ-specific autoimmune mouse models for human diseases.

This article has been cited by other articles:

				D. Jane-wit, C. Z. Altuntas, J. Monti, J. M. Johnson, T. G. Forsthuber, and V. K. Tuohy Sex-Defined T-Cell Responses to Cardiac Self Determine Differential Outcomes of Murine Dilated Cardiomyopathy Am. J. Pathol., January 1, 2008; 172(1): 11 - 21. [Abstract] [Full Text] [PDF]

				D. Jane-wit, C. Z. Altuntas, J. M. Johnson, S. Yong, P. J. Wickley, P. Clark, Q. Wang, Z. B. Popovic, M. S. Penn, D. S. Damron, et al. {beta}1-Adrenergic Receptor Autoantibodies Mediate Dilated Cardiomyopathy by Agonistically Inducing Cardiomyocyte Apoptosis Circulation, July 24, 2007; 116(4): 399 - 410. [Abstract] [Full Text] [PDF]

				Y. Matsumoto, Y. Tsukada, A. Miyakoshi, H. Sakuma, and K. Kohyama C Protein-Induced Myocarditis and Subsequent Dilated Cardiomyopathy: Rescue from Death and Prevention of Dilated Cardiomyopathy by Chemokine Receptor DNA Therapy J. Immunol., September 1, 2004; 173(5): 3535 - 3541. [Abstract] [Full Text] [PDF]