A novel class II-binding motif selects peptides that mediate organ-specific autoimmune disease in SWXJ, SJL/J, and SWR/J mice

D Jane-wit, M Yu, AE Edling, S Kataoka… - The Journal of …, 2002 - journals.aai.org
D Jane-wit, M Yu, AE Edling, S Kataoka, JM Johnson, LB Stull, CS Moravec, VK Tuohy
The Journal of Immunology, 2002journals.aai.org
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 α-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 …
Abstract
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 α-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 pα406–425 or pα1631–1650 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 IA q and IA 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.
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