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In Kawasaki Syndrome Anti-Human Cardiac Myosin Autoantibodies Anti-Human Cardiac Myosin Autoantibodies in Kawasaki Syndrome Madeleine W. Cunningham, H. Cody Meissner, Janet S. Heuser, Biagio A. Pietra, David K. Kurahara and Donald Y. This information is current as M. Leung2 of September 29, 2021. J Immunol 1999; 163:1060-1065; ; http://www.jimmunol.org/content/163/2/1060 Downloaded from References This article cites 34 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/163/2/1060.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Anti-Human Cardiac Myosin Autoantibodies in Kawasaki Syndrome1 Madeleine W. Cunningham,* H. Cody Meissner,† Janet S. Heuser, * Biagio A. Pietra,§ David K. Kurahara,‡ and Donald Y. M. Leung2¶ Kawasaki syndrome (KS) is the major cause of acquired heart disease in children. Although acute myocarditis is observed in most patients with KS, its pathogenesis is unknown. Because antimyosin autoantibodies are present in autoimmune myocarditis and rheumatic carditis, the purpose of the current study was to determine whether anticardiac myosin Abs might be present during the acute stage of KS. Sera from KS patients as well as age-matched febrile controls and normal adults were compared for reactivity with human cardiac myosin in ELISAs and Western blot assays. A total of 5 of 13 KS sera, as compared with 5 of 8 acute rheumatic fever sera, contained Ab titers to human cardiac myosin that were significantly higher than those found in control sera. Both cardiac and skeletal myosins were recognized in the ELISA by KS sera, although stronger reactivity was observed to human Downloaded from cardiac myosin. Only IgM antimyosin Abs from KS sera were significantly elevated relative to control sera. KS sera containing antimyosin Abs recognized synthetic peptides from the light meromyosin region of the human cardiac myosin molecule and had a different pattern of reactivity than acute rheumatic fever sera, further supporting the association of antimyosin Ab with KS. These Abs may contribute to the pathogenesis of acute myocarditis found in patients with KS. The Journal of Immunology, 1999, 163: 1060–1065. http://www.jimmunol.org/ awasaki syndrome (KS)3 is an acute febrile illness that the appearance of circulating Abs that are cytotoxic against vas- occurs primarily in infants and young children (1, 2). KS cular endothelial cells prestimulated with IL-1b (10), TNF-a (11), K and rheumatic fever are the two leading causes of ac- or IFN-g (12) but not against unstimulated endothelial cells. quired heart disease in children (3). Myocarditis occurs in over half Therefore, it has been postulated that immune reactivity to vascu- the patients with acute KS (4, 5). In a review of endomyocardial lar endothelium may contribute to the vasculitis associated with biopsies from 201 patients with KS obtained 1 mo to 11 years after acute KS. onset of disease, Yutani et al. reported changes consistent with The etiology of immune activation in acute KS is not certain, myocarditis (6). Manifestations may include: mild mitral regurgi- although evidence supports an infectious etiology. Microbiologic tation, depressed myocardial function, and increased end systolic data suggest a role for staphylococcal and streptococcal superan- by guest on September 29, 2021 and end diastolic dimensions, which do not correlate with the pres- tigens (13, 14). Furthermore, the clinical symptoms of KS share a ence of coronary artery lesions (7). The myocarditis of KS is as- number of features with staphylococcal and streptococcal diseases, sociated with clinical features of tachycardia disproportionate to such as toxic shock syndrome and scarlet fever. Superantigens the degree of fever, gallop rhythm, murmur, and electrocardiogram have also been reported to induce the production of autoantibodies changes, including prolonged PR, QT intervals and diffuse low such as rheumatoid factor (15). voltage, ST-T wave changes, as well as the described echocardio- Autoantibodies against myosin have been implicated in the graphic findings. Although myocarditis is a well-known feature of pathogenesis of rheumatic carditis and autoimmune myocarditis, acute KS, little is known about its pathogenesis (7, 8). Immune diseases which also affect heart valve tissue and myocardium (16, activation associated with polyclonal B cell activation as well as an 17). Furthermore, cardiac myosin is known to induce myocarditis increased number of activated T cells and macrophages is found in animal models (18). To date, there have been no studies exam- during the acute phase of KS (9). Acute KS is also associated with ining the occurrence of anticardiac myosin autoantibodies in acute KS. Sera were also obtained from eight children presenting with acute rheumatic fever (ARF). The purpose of the current study was *Department of Microbiology and Immunology, University of Oklahoma Health Sci- ences Center, Oklahoma City, OK 73190; †Department of Pediatrics, New England to seek evidence for antimyosin Abs in patients with acute KS. Medical Center, Boston, MA 02111; ‡Department of Tropical Medicine and Medical Microbiology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96822; §Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO 80262; and ¶Department of Pediatrics, National Jewish Medical and Materials and Methods Research Center, Denver, CO 80206 Sera Received for publication October 29, 1998. Accepted for publication May 10, 1999. The study was conducted on sera from 13 children in the acute phase of The costs of publication of this article were defrayed in part by the payment of page KS. These patients fulfilled the established clinical criteria for KS (19). charges. This article must therefore be hereby marked advertisement in accordance These criteria included a fever for $5 days and at least four of the five with 18 U.S.C. Section 1734 solely to indicate this fact. following symptoms: nonexudative conjunctival injection; changes in the 1 This work was supported by Grants HL35280 and HL56267 (to M.W.C.) and Grants oral pharynx, including mucosal erythema, dry fissured lips, and “straw- HL37260 and AR41256 (to D.Y.M.L.) from the National Institutes of Health. berry tongue”; changes in the extremities, characteristically erythema of 2 Address correspondence and reprint requests to Dr. Donald Y. M. Leung, Depart- the palms and soles, induration of the hands and feet, or perungual des- ment of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson quamation in the subacute phase of the disease; polymorphous rash; and Street, Room K926, Denver, CO 80206. E-mail address: [email protected] cervical adenopathy (one or more nodes of $1.5 cm in diameter). A total 3 Abbreviations used in this paper: KS, Kawasaki syndrome; ARF, acute rheumatic of 11 of the 13 KS patients had clinical evidence of myocarditis during the fever; LMM, light meromyosin. acute phase of their illness. Sera were also obtained from 12 age-matched Copyright © 1999 by The American Association of Immunologists 0022-1767/99/$02.00 The Journal of Immunology 1061 Table I. Sequences of LMM peptides Peptide Sequence Peptide Sequence LMM-1 KEALISSLTRGKLTYTQQ LMM-26 EGDLNEMEIQLSHANRMA LMM-2 TYTQQLEDLKRQLEEEVK LMM-27 ANRMAAEAQKQVKSLQSL LMM-3 EEEVKAKNALAHALQSAR LMM-28 SLQSLLKDTQIQLDDAVR LMM-4 LQSARHDCDLLREQYEEE LMM-29 RANDDLKENIAIVERRNN LMM-5 EQYEEETEAKAELQRVLSK LMM-30 IAIVERRNNLLQAELEEL LMM-6 RVLSKANSEVAQWRTKYE LMM-31 ELEELRAVVEQTERSRKL LMM-7 RTKYETDAIQRTEELEEA LMM-32 RSRKLAEQELIETSERVQ LMM-8 ELEEAKKKLQRLQEAEE LMM-33 SERVQLLHSQNTSLINQK LMM-9 QEAEEAVEAVNAKCSSLE LMM-34 LINQKKKMDADLSQLQTE LMM-10 CSSLEKTKHRLQNEIEDL LMM-35 TEVEEAVQESRNAEEKAKK LMM-11 EIEDLMVDVERSNAAAAA LMM-36 RNAEEKAKKAITDAAMMA LMM-12 AAAAALDKKQRNFDKILA LMM-37 AAMMAEELKKEQDTSAHL LMM-13 DKILAEWKQKYEESQSEL LMM-38 TSAHLERMKKNMEQTIKDL LMM-14 SQSELESSQKEARSLSTE LMM-39 TIKDLQHRLDEAEQIALK LMM-15 SLSTELFKLKNAYEESLE LMM-40 EQIALKGGKKQLQKLEARV LMM-16 EESLEHLETFKRENKNLQ LMM-41 LEARVRELENELEAEQKR LMM-17 NKNLQEEISDLTEQLGSS LMM-42 AEQKRNAESVKGMRKSER LMM-18 EQLGSSGKTIHELEKVRKQ LMM-43 RKSERRIKELTYQTEEDR Downloaded from LMM-19 KVRKQLEAEKMELQSALE LMM-44 TEEDRKNLLRLQDLVDKL LMM-20 LQSALEEAEASLEHEEG LMM-45 LVDKLQLKVKAYKRQAEE LMM-21 EEGKILRAQLEFNQIKAE LMM-46 RQAEEAEEQANTNLSKFR LMM-22 NQIKAEIERKLAEKDEEME LMM-47 LSKFRKVQHELDEAEERA LMM-23 DEEMEQEKRNHLRVVDSL LMM-48 AEERADIAESQVNKLRAK LMM-24 VVDSLQTSLDAETRSRNE LMM-49 KLRAKSRDIGTKGLNEE LMM-25 RSRNEALRVKKKMEGDLN http://www.jimmunol.org/ febrile children, 10 normal adults who had no known illness, and 14 chil- lent Igs conjugated with HRP. The blot was developed using chloronaph- dren presenting with ARF. All ARF patients demonstrated positive anti- thol as indicator with
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