This article was downloaded by:[National Institutes of Health Library (NIH)] On: 27 March 2008 Access Details: [subscription number 790459001] Publisher: Informa Healthcare Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK

Autoimmunity Publication details, including instructions for authors and subscription information: http://www.informaworld.com/smpp/title~content=t713453864 Streptococcal mimicry and antibody-mediated cell signaling in the pathogenesis of Sydenham's chorea Christine A. Kirvan a; Susan E. Swedo b; David Kurahara c; Madeleine W. Cunningham d a Department of Biological Sciences, California State University, Sacramento, CA, USA b Department of Health and Human Services, Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA c Department of Pediatrics, University of Hawaii, Honolulu, HI, USA d Department of Microbiology and Immunology, University of Oklahoma, HSC, Oklahoma City, OK, USA

Online Publication Date: 01 February 2006 To cite this Article: Kirvan, Christine A., Swedo, Susan E., Kurahara, David and Cunningham, Madeleine W. (2006) 'Streptococcal mimicry and antibody-mediated cell signaling in the pathogenesis of Sydenham's chorea', Autoimmunity, 39:1, 21 - 29 To link to this article: DOI: 10.1080/08916930500484757 URL: http://dx.doi.org/10.1080/08916930500484757

PLEASE SCROLL DOWN FOR ARTICLE

Full terms and conditions of use: http://www.informaworld.com/terms-and-conditions-of-access.pdf This article maybe used for research, teaching and private study purposes. Any substantial or systematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material. Downloaded By: [National Institutes of Health Library (NIH)] At: 18:41 27 March 2008 evcs eitisadDvlpetlNuoscityBac,Ntoa nttt fMna elh ainlIsiue of Institutes National Health, Mental of Institute USA, National MD, Branch, Bethesda, Health, Neuropsychiatry Developmental and Pediatrics Services, irbooyadImnlg,Uiest fOlhm,HC kaoaCt,O,USA OK, City, Oklahoma HSC, Oklahoma, of University Immunology, and Microbiology O:10.1080/08916930500484757 DOI: online 1607-842X print/ISSN 0891-6934 [email protected] ISSN E-mail: 2217. OK, 271 City, 405 Oklahoma 1 HSC, Fax: Oklahoma, 3128. of 271 University Immunology, 405 and 1 Microbiology Tel: of USA. Department Cunningham, W. M. Correspondence: mid- the the in resurgence Since unexplained an [1]. been has individuals there 1980s of susceptible symptoms in (Sydenham’s characteristic and ARF the brain produce marginatum that and/or chorea) (erythema nodules) and (carditis), skin subcutaneous inflammatory heart (arthritis), in the joint against resulting which responses events in autoimmune initiate disorders appears antigens to streptococcal inflammatory by activation of immune streptococcal represents collection morbidity ARF worldwide. of a significant children in sequela mortality produces rheumatic and delayed acute which a is pharyngitis, responses (ARF), The these humans. fever of in studied responses best post- of autoimmune development infectious the ( with associated streptococcus specifically A Group Introduction Keywords: with epitope, II streptococcal kinase A protein group dependent the calmodulin antibodies calcium and chorea The acute of disorder. lysoganglioside movement in induction the recognize to present to the lead Antibodies due disease may signal ganglia. which is in and release basal infection dopamine and cells present subsequent streptococcal brain and neuronal hydroxylase A the tyrosine of group infiltrate of surface elevation and following the infection chorea the with Sydenham’s to react of due pathogenesis develop the which antibodies that suggests evidence Recent Abstract 1 KIRVAN A. CHRISTINE chorea Sydenham’s of pathogenesis signaling the cell in antibody-mediated and mimicry Streptococcal Autoimmunity niois(As rmSdna’ hradmntae h iir ewe yoagisd n h ru A group the disorders and neuropsychiatric autoimmune lysoganglioside chorea. pediatric between in in observed antibodies mimicry present the antibodies to the identical of not demonstrated group but similar chorea A were (PANDAS) epitope. Sydenham’s carbohydrate from streptococcal (mAbs) antibodies .CUNNINGHAM W. eateto ilgclSine,Clfri tt nvriy armno A USA, CA, Sacramento, University, State California Sciences, Biological of Department tetcci uomuiy huai ee,chorea fever, rheumatic autoimmunity, Streptococci, eray20;3() 21–29 39(1): 2006; February , 4 3 tetccu pyogenes Streptococcus eateto eitis nvriyo aai oouu I S,and USA, HI, Honolulu, Hawaii, of University Pediatrics, of Department 1 UA .SWEDO E. SUSAN , q 06Tyo Francis & Taylor 2006 )is 2 AI KURAHARA DAVID , yehmscoe n R r eedn on dependent are ARF initiating of the and Diagnosis after chorea months [11,12]. Sydenham’s 6 pharyngitis as ARF streptococcal late of manifestation as only the of presenting be may 10–30% review and in cases develop (for ARF can chorea lability Sydenham’s [10]). emotional symptoms, and obsessive-compulsive hypersensitivity, including ances, disturb- neuropsychiatric and by movements characterized involuntary is disorder confounding This ARF. of ner- [4–9]. dysfunction central (CNS) postinfectious system streptococcal–induced vous the of recently concerning advances mechanisms only striking forthcoming has information seen been carditis, have rheumatic in pathogenesis years of mechanisms molecular 50 the ARF elucidating and last US While the the [2,3]. in nations developing cases in unabated ARF continues reported of number yehmscoe stenuooi manifestation neurologic the is chorea Sydenham’s N 2 eateto elhadHuman and Health of Department aey-lcsmn.Monoclonal -acetyl-glucosamine. 3 MADELEINE & , 4 eatetof Department Downloaded By: [National Institutes of Health Library (NIH)] At: 18:41 27 March 2008 h eodcosratv nie dnie was identified antigen cross-reactive N second [16,29–31]. (HCM), laminin mammalian The and myosin keratin an many cardiac actin, tropomyosin, protein, human with including M homology proteins sequence streptococcal structural shares that and the factor virulence is antiphagocytic first [13,14,17,29]. streptococci The A group to ARF unique for are that antigens in cross-reactive two (mAb) antibody identified responses monoclonal studies 1980s, immune early the In cross-reactive ARF. of generation of presence episodes the chorea Sydenham’s [25–28]. choreic in confirm ganglia basal of against studies antibodies duration with Recent and associated [23,24]. titers severity cross-sections antibody both ganglia anti-neuronal basal human with in neur- antigens with onal chorea reactivity showed which Sydenham’s responses autoantibody chorea antibodies in Sydenham’s of by characterizations pathology Early [21,22]. are to insults and contribute ganglia suggesting data basal observations (MRI) that clinical imaging resonance by magnetic responses as poststreptococcal implicated of immune targets is cortical ganglia primary the basal of in one The determinants [14,20]. brain neuronal the against directed humoral similar response cross-reactive a by of mediated production through is events chorea is Sydenham’s it that and [6,8], likely and carditis rheumatic streptococci to leads A antigens host group crossreactive against that responses shown immune has evidence [7,17–19]. Considerable carbohydrate and conformational protein antibodies or as such chemical multireactive structure dissimilar (2) with react and that [16] antigens and poly- host streptococcal distinct or (1) on chemical structures similar specificity: conformation recognize molecular that antibodies classified their reactive be to can antibodies [13– according antigens cross-reactive host Such antibodies with 15]. cross-reactive mimicry well of molecular are through inducers streptococci postinfec- as A of established group exacerbation autoimmunity, or induction tious the diagnosis in cated make can chorea delayed Sydenham’s difficult. the however, of titers, B onset DNase or (ASO) anti-streptoly- O elevated sin with symptoms of correlation nteban[7,37]. brain the antigens in neuronal against anti-heart cross-reactive directed induce responses and antigens immune of these carditis that probable rheumatic generation is to it the contribute have that GAC in and antibodies protein implicated M the anti- been Both GAC-specific [33–36]. by bodies recognized moieties GlcNAc by backbone rhamnose a polymer to bound are residues (GAC) GlcNAc carbohydrate [18,19,32]. A group the of epitope dominant 22 -acetyl- tetcca ufc niesaeipiae nthe in implicated are antigens surface Streptococcal impli- been have agents infectious several While .A ivne al. et Kirvan A. C. b - D guoaie(lNc,teimmuno- the (GlcNAc), -glucosamine b 13lnae ihterminal with linkages -1,3 otifciu eul 3,0.I a ensuggested been has It [39,40]. in sequela and post-infectious infection streptococcal active during responses a [18,19]. anti-GlcNAc skin is the which in human epitopes keratin, against of antibodies to characteristic reactivity pronounced no chorea the showed Interestingly, cross-reactive [6]. mAbs from laminin strongly and mAbs were HCM with that GlcNAc-specific carditis human rheumatic to demon- direct and in contrast antigens 6 cardiac for and reactivity minimal 5 strated serotypes protein 2). M rheumatogenic the (Figure from of recognition epitope no GlcNAc showed significant mAbs the Chorea demonstrated only with mAbs reactivity When chorea [38]. mammalian and antigens, antigens streptococcal of panel cross-reactive a against tested of identity uncover a to the employed from were patient derived in chorea is Sydenham’s mAbs response Recently, antibody antigens chorea. polyclonal Sydenham’s neuronal the by and complicated streptococcal able between be future, may the brain issue. and protein this In protein clarify M to anti-M study. the of against further mAbs cross-reactivity requires the and antibodies M chorea, role Sydenham’s streptococcal with suggest exact the associated data are against the of protein directed severity Although, 1). diminishing antibodies during with (Figure present decreased symptoms patient were of and levels antibodies matched illness elevated protein-specific did that M indicating than sera, pepM5 convalescent Acute greater to disorder. significantly by reactivity the showed sera of (pepM5) chorea phase Sydenham’s protein symptomatic associated the M was with antibodies streptococcal serum chorea 5 Sydenham’s in type fragment response of digestion extracellular the antibody of recognition revealed that laboratory cross-reactive our in Studies develop- a chorea. Sydenham’s the to of antigens ment streptococcal first link the clearly were studies to were pioneering antigens These neuronal identified. not the however, protein human antigens, M of recognition brain the antisera of protein regions M repeat inhibit could B and epitopes A Conserved multiple in [23]. contained recognizing brain human of cross- from proteins capable induced antibodies serotypes M reactive with rheumatogenic in animals of experimental antigens protein of demonstrated streptococcal immunization Dale and that of Bronze chorea, role Sydenham’s the Toelucidate components antibodies. wall anti-neuronal cross-reactive cell evoke bacterial may that indicating M 6, strain type streptococcal by rheumatogenic of cross-sections with absorbed membranes was nuclei antibodies sera chorea subthalamic [24]. human Sydenham’s fixed and antibodies in antigens caudate chorea cytoplasmic of Sydenham’s Recognition of reactivity lNci aal fgnrtn toghumoral strong generating of capable is GlcNAc specificities cross-reactive of Determination CNS characterize to first the were al. et Husby Downloaded By: [National Institutes of Health Library (NIH)] At: 18:41 27 March 2008 hramb togyratwt eai hc characterizes which keratin with skin. did react with reactive nor mAbs carditis, strongly GlcNAc-specific rheumatic mAbs with patients chorea from characteristic is produced which mAbs HCM, recognize with of to than failed laminin. also GAC and mAbs tropomyosin the Chorea myosin, with skeletal actin, greater Chorea collagen, significantly dsDNA, (rM6). was protein or reactivity M6 (pepM5) mAb streptococcal protein M recombinant streptococcal length of full fragment the either to bind ptp GcA)o ru tetccu ncmaio to comparison in streptococcus two-tailed A by tested group antigens other of (GlcNAc) epitope iue2 eciiyo hramb ihsrpoocland streptococcal significant with showed mAbs mAbs ( chorea Chorea reactivity of autoantigens. Reactivity mammalian 2. Figure patient. individual an Sydenham’s from separate sera four convalescent in illness and of acute phase symptomatic matched ( the represents acute with chorea graph associated Sydenham’s are Each matched IgG of patients. M5-specific dilutions chorea pep Serial of chorea. levels Sydenham’s elevated in significantly antibody show protein-specific sera M 1. Figure p , .5 ihteimndmnn carbohydrate immunodominant the with 0.05) t et h hramb i not did mAbs chorea The test. htso pcfi eeomna n differential and developmental glycolipids specific of show family gangliosides diverse that a mammalian are with Gangliosides [38]. cross-react to found chorea. an Sydenham’s and play of symptoms immunopathogenesis clinical antibodies may the GAC mediating that in the role and important indicate GlcNAc data abatement against the directed These with with symptoms. decreased elevated patients that of significantly GlcNAc from to showed sera titers chorea acute we that Sydenham’s Recently, observed [40,43]. have patients in chorea demonstrated of the been Sydenham’s levels to have Elevated antibodies antibodies GAC-specific [40]. of levels carbohydrate high streptococcal shown persistently were disease have heart to valvular with pro- [17,42]. patients myosin ARF cytoskeletal cardiac and to keratin particularly teins, responses antibody cell- T to dependent rise gives GlcNAc anti- with animals of experimental murine Immunization cross-reactivity [7,19,41]. proteins and specific mammalian with human host demonstrate of host with mAbs variety GlcNAc studies many a GAC and recognizing the to of tissues capable for similarity found specific were structural Antibodies be its glycoconjugates. may to residues antibodies due cross-reactive of GlcNAc induction the in O-linked important terminal that yehmscoe AsseicfrGcA were GlcNAc for specific mAbs chorea Sydenham’s nioysgaigadmimicry and signaling Antibody B n ovlset( convalescent and ) 23 A ) Downloaded By: [National Institutes of Health Library (NIH)] At: 18:41 27 March 2008 nue ySdna’ hraaue u not but acute, chorea was activation Sydenham’s II by [49–52]. kinase induced release CaM and and behavior Antibody-mediated influence synthesis that CNS to neurotransmitter due the of interest in multi- spectrum particular functions a of its broad was is a and II targets with neuronal kinase kinase CaM protein shown). chorea functional control not above as (data kinase ions levels protein calcium cAMP-dependent kinase not or of protein C activate and influx significantly not 3) general did antibodies (Figure a to induction due due antibody be to specific Antibody- appeared to activation [38]. II kinase catecholamine-secreting SK-N-SH CaM induced the line cell in neuroblastoma activation to shown II were kinase sera (CaM) protein and calcium/calmodulin-dependent trigger signal mAbs of chorea alteration Sydenham’s [47,48]. cells through neuroblastoma in cells pathways transduction neuronal homeo- of physiologic anti- the stasis cell that affect suggested neuronal antibodies have ganglioside alter reports might Previous function. binding Sydenham’s that antibody suggested sera chorea and mAbs chorea by human to reactivity tissue. antibody brain inhibitor chorea specific Sydenham’s and caudate-putamen potent of human is it to that indicating binding tissue sera acute and g ncmaio ocnrlCF niaigthat indicating CSF, control G G to anti-lysoganglioside lysoganglioside comparison of in levels IgG elevated found have matched were acute to samples (CSF) in with fluid Sydenham’s cerebrospinal patients not Acute chorea chorea. from Sydenham’s but sera without ARF or sera sera Syden- acute in convalescent found chorea also ham’s were concentrations antibody the of subunits recognized DNA- a also N lupus that mAb systemic demonstrated specific of (SLE) disorders erythematosus in ARF. neuropyschiatric responses to antibody the limited cross-reactive not of which is Investigation epitopes antibodies, [17–19]. dissimilar cross-reactive recognize structures of peptide Identification and as GlcNAc classified mimicry between been of studies has in previously including defined epitope as “dissimilar” GlcNAc surface, the and cell sides ganglio- the between Mimicry [44,45]. at transduction signal mediated multiple to contribute functions and brain the within expression rs-eciewt yoagisd G lysoganglioside with strongly were cross-reactive mAbs chorea Sydenham’s that revealed [46]. hippocampus hra infiatyhge nilsgnloieG anti-lysoganglioside higher Significantly chorea. nteCSdrn ciedsae Lysoganglioside disease. active during G CNS the in 24 rndcin[84] nrae eeso anti-lyso- signal of G neuronal levels ganglioside Increased influence [38,44]. to transduction shown ganglioside -methyl- M1 eonto fnuoa elsraedeterminants surface cell neuronal of Recognition opttv niiinsuiswt GlcNAc with studies inhibition Competitive a lofudt lc yehmscoe mAb chorea Sydenham’s block to found also was .A ivne al. et Kirvan A. C. D satt ND)rcpo nthe in receptor (NMDA) aspartate M1 M1 nioiscreae ihactive with correlated antibodies seicatbde eepresent were antibodies -specific M1 ,aCNS M1 M1 iaeI ciiydrcl orltdwt vdt for avidity with correlated G directly lysoganglioside activity II kinase transduction signal a trigger cascade. to which binding by gangliosides, receptors Sydenham’s indirectly neuronal or of gangliosides in aggregation to cause CNS bind antibodies directly the may Pathogenic in chorea present 3). of was (Figure alteration events that transduction demonstrating signal CaM activation of Syden- levels II from significant kinase directed antibody CSF disease Intrathecal chorea active ham’s 3). the CaM with (Figure associated increased state is that activity II suggesting kinase sera, convalescent aa ae yehmscoe S nue a iaeI while II kinase CaM not. did induced CSF the CSF control of chorea 98–116% Sydenham’s was II rate. sera kinase acute basal CaM induced of in induction found NHS serum for that range activity convalescent The enzyme Matched of levels II. lower significantly ( kinase significantly CaM chorea and Sydenham’s sera activated chorea from Sydenham’s by sera kinase CaM Acute of CSF. Induction 3. Figure n/rcnetainmytigrcl inln events. signaling cell trigger may concentration and/or hrnii,wihhv infiatylwrlvl of levels ARF lower G active significantly anti-lysoganglioside have streptococcal from which acute sera and pharyngitis, chorea by Sydenham’s induced without was II kinase activation CaM Lower to samples. comparison convalescent in matched concentration have and/or to shown avidity were acute higher CSF from general and Antibody sera surface in II. chorea kinase Sydenham’s gangliosides cell CaM of induce strong not binding does that or suggesting alone binding II kinase CaM yoagisd G lysoganglioside vdt fSdna’ hramb2.. for 24.3.1 mAb chorea higher G The Sydenham’s lysoganglioside signaling. of cell of be avidity induction may antibody for specific required of concentration threshold nioyrcgiino elsraegangliosides G activation. surface lysoganglioside II cell than kinase of other CaM recognition mediating Antibody of capable hraauesr n S ugssta anti- that suggests CSF and G sera lysoganglioside acute chorea h ihs vdt o yoagisd G lysoganglioside for avidity highest demonstrated which 24.3.1, the mAb chorea only tested, h blt fcoe nioist nueCaM induce to antibodies chorea of ability The M1 M1 M1 M1 fteSdna’ hramAbs chorea Sydenham’s the Of . nioypeeti Sydenham’s in present antibody M1 nioyaiiy specificity, avidity, antibody n ihrlvl fanti- of levels higher and nioisidctn hta that indicating antibodies M1 i o activate not did M1 p , was , 0.05) Downloaded By: [National Institutes of Health Library (NIH)] At: 18:41 27 March 2008 51 eawscpbeo vkn infiatlvl of levels significant evoking of control acute capable chorea isotype was Sydenham’s to sera addition, In contrast 4(a)). in (Figure cells neuroblastoma n S eeasse o yooi oeta by potential cytotoxic for assessed were CSF complement- sera and chorea antibody-induced, Sydenham’s Acute cytotoxicity. of indicated mediated sera membrane potential cell chorea neuronal the Sydenham’s the to syndrome of antibodies motor Guillian-Barre Localization of with loss nerve [54–56]. the associated motor to contribute function the may which at terminal cytotoxicity lement-mediated ertasitrrlae[06] norstudies, mAb our elicited chorea regulate Sydenham’s 24.3.1 In that shows that of data [60–62]. preliminary phosphorylation proteins release II vesicle neurotransmitter be kinase synaptic can CaM exocytosis synapsins, Dopamine by [59]. mediated slices lines brain cell neuronal and in release associated dopamine been increased recently with has activation that II chorea kinase Sydenham’s CaM in importance is and It interest neurotransmitters. of excitatory of may release that the transduction to data lead signal such promote chorea, 24.3.1, Clinical Sydenham’s mAb as in chorea. antibodies that Sydenham’s suggests in dysfunction the [58]. antibody in serum the of with reversal patients removal chorea rapid Sydenham’s of plasma show course clinical which complements studies also exchange cytotoxicity chorea antibody Sydenham’s of been lack rarely The has [22,57]. demonstrated brain the physical to of lesions, evidence including damage, ganglia, basal MRI cytotoxic the While of than enlargement disorder. rather the studiesofSydenham’schoreapatientsshowed to brain, contribute the antibodies, the chorea of change which Sydenham’s physiology antibodies that sup- hypothesis of lysis the ports complement-mediated inability direct to in The antibodies antibodies [7]. are anti-GlcNAc there ARF of that suggesting populations cells, different endothelial mediated of complement killing directing of carditis capable rheumatic was which from derived contrast mAb in anti-GlcNAc is to mAbs complement- anti-GlcNAc of direct chorea nature to Sydenham’s non-destructive ability The the cytotoxicity. lack mediated were Additional to mAbs major found chorea I). a also Sydenham’s be (Table that to revealed pathogenesis studies appear of not did mechanism cell neuronal human G between antibody- jejuni mimicry molecular post-infectious, initiated be through to a thought disorder Guillian- is neurological mediated disorders. syndrome neurologic Barre other to contribute aecn ape n oldnra ua sera human con- normal matched pooled to and samples comparison valescent in release dopamine rrlaeasy opeetdpnetkligof killing Complement-dependent assay. Cr-release M1 ti nla o nioismdaeneurologic mediate antibodies how unclear is It nignloieatbde aebe eotdto reported been have antibodies Anti-ganglioside 5] rs-ecieatbde ietcomp- direct antibodies Cross-reactive [53]. iooyacaieadmonosialoganlioside and lipopolysaccharide 3 -oaierlaefo SK-N-SH from release H-dopamine Campylobacter 3 H- h lNceioeo h tetcca A and GAC streptococcal the with G of reacted lysoganglioside epitope IgG we GlcNAc serum Recently, PANDAS the that [70,71]. shown pathogenesis have of antibody-directed similar a mechanism clinical PANDAS through mediated of and be chorea may development Sydenham’s that in manifestations possibility PANDAS the in been demonstrated Anti-neuronal raising has been [68,69]. also etiology have disorders antibodies infectious both common for proposed a symp- and neuropsychiatric similar toms chorea share PANDAS Sydenham’s and [66,67]. A infection Group a of streptococcal by exacerbation preceded and is onset symptoms OCD the neuropsychiatric childhood that in of disorders cases tic other and Pediatric from sub- distinct The is as (PANDAS). group infections known Streptococcal with Associated disorders Disorders Neuropsychiatric tic disorder Autoimmune and obsessive-compulsive of (OCD) subgroup onset new relatively clinical Increased a childhood on similar chorea. focused has Sydenham’s attention share in with interest which growing manifestations a disorders witnessed has neurologic decade last The PANDAS and Sydenham’s movement the of the in chorea. to characteristics dopamine contribute neuropyschiatric of may levels synapse Elevated tyrosine of hydroxylase. activation through and synthesis dopamine the II of in exocytosis kinase increase the an CaM to to leads triggers that Sydenham’s binding activation antigen surface antibody for cell Chorea neuronal pathogenesis 5). antibody- (Figure an of chorea of recent model development Our the mediated to [65]. led chorea have studies Sydenham’s the of in haloperidol treatment as such of blockers efficacy neurotrans- receptor the dopamine alter explain may to release and antibodies synthesis chorea mitter chorea of Sydenham’s ability synthesis that The basal catecholamine suggest the increase of data antibodies part the the as identified of ganglia, have conclusively level not been hydroxylase that and tyrosine not neurons in cerebrum increase While an inset). the showed 4(c), seen of (Figure was cerebellum neurons level in hydroxylase in tyrosine 4(c)). hydroxylase only in (Figure tyrosine control increase isotype The of than neurons 24.3.1 levels cerebral mAb higher Chorea induced determined was immunohistochemistry. brain hydroxylase rat tyrosine by of into level transferred the passively and chorea was Sydenham’s 24.3.1 synthesis, mAb increased stimulating hydroxylase of capable tyrosine were mAbs chorea determine To if [63,64]. enzyme the II of kinase tyrosine CaM phosphorylation by and increased be synthesis can activity dopamine hydroxylase in rate enzyme the is limiting hydroxylase Tyrosine 4(b)). (Figure (NHS) nioysgaigadmimicry and signaling Antibody M1 si yehmscoe [72]. chorea Sydenham’s in as nvivo in 25 . Downloaded By: [National Institutes of Health Library (NIH)] At: 18:41 27 March 2008 ct eaidcdsgicnl oe3-oaierlaeta ace ovlsetsr rpoe H.()Sdna’ hramAb chorea Sydenham’s (c) NHS. pooled hydroxylase or sera tyorsine convalescent of matched than Values levels counting. release two-tailed scintillation increased 3H-dopamine by by more performed 24.3.1induced measured analysis significantly was Statistical 3H-dopamine induced release. and sera basal collected 3H-dopamine acute were of supernatants percentage incubation, as min 30 expressed a were After wells. the to added A 431wr eni otclnuos u o ncrbla eun (inset). chorea by neruons induced cerebellar hydroxylase in tyrosine The not of cross-sections. but levels Elevated neurons, brain control. hematoxylin. cortical and whole isotype with in removed the counterstained on seen than were and were hydroxylase immunohistochemistry substrate, Brains tyrosine 24.3.1 red of by mAb days. Fast levels with consecutive assessed higher developed induced antibody, five were hydroxylase-specific 24.3.1 for hydroxylase tyrosine mAb a day tyrosine with every probed of were Inc.) levels sections Animals, Comparative Lab fixed. (Hilltop formalin rats Lewis cannulated intracerebroventricular oie rbsrne ufrwt Mdprdn,1 Mnmfnie 0 Mnsxtn,10n uxtn,01m sobcacid, ascorbic mM 0.1 fluoxetine, nM 100 nisoxetine, nM 100 nomifensine, uM 10 doperidone, control. uM isotype 1 that CaCl cells with mM SK-N-SH 2 from buffer 3H-dopamine of ringer release 1 Kreb’s percentage higher at modified a plated induced 24.3.1 were mAb cells chorea Sydenham’s SK-N-SH (a) 4. Figure 26 .A ivne al. et Kirvan A. C. 2 MKlad02m MgCl mM 0.2 and KCl mM 3 , £ 0 el/el o aiatv oaieutk,clswr nuae ih3-oaiefr9 i in min 90 for 3H-dopamine with incubated were cells uptake, dopamine radioactive For cells/well. 106 2 ne tnadtsu utr odtos el eete hruhywse n nioywas antibody and washed thoroughly then were Cells conditions. culture tissue standard under nvivo in hramb2.. rioyecnrlwr asvl rnfre into transferred passively were control isotype or 24.3.1 mAb Chorea . t ts.()AueSdna’ chorea Sydenham’s Acute (b) -test. Downloaded By: [National Institutes of Health Library (NIH)] At: 18:41 27 March 2008 nioymdae inltasuto i CaM via transduction signal chorea, Sydenham’s disease in antibody-mediated antigen(s) the identified target definitively cell in not neuronal have important studies be While derived process. of to the brain appears mechanism and chorea, GAC ganglioside the the Sydenham’s between on in cross-reactivity studies pathogenesis of antibody a number only are limited there Although understood. chorea incompletely Sydenham’s is antigens in determinants streptococcal neurological and between mimicry Molecular Summary of immunopathogenesis the that in suggest role PANDAS. data play may influential new signaling an the cell clarified, neuronal antibody-mediated been not chorea. PANDAS of has Sydenham’s induction streptococci to of A group similar Although staining ganglia differential basal cell human neuronal demonstrated increase and serum. to signaling shown non-depleted was to CSF comparison PANDAS kinase in CaM activation abrogated serum II PANDAS Depletion from sera. IgG convalescent of in not in but during disease, sera increases PANDAS acute for significant found activity II with kinase CaM chorea seen Sydenham’s that to in SK- similar in cells neuroblastoma activity human II N-SH kinase CaM induced sera PANDAS chorea. Sydenham’s to with contribute associated may symptoms synapse the clinical dopamine in the enhanced dopamine to of levels leading Higher hydroxylase in release. increase tyrosine an of induce activity may activity the cell II II kinase kinase to CaM CaM of Increased bind levels activity. elevated antibodies triggering in antigen pathogenesis chorea neuronal surface antibody-mediated Sydenham’s of chorea. model Proposed Sydenham’s 5. Figure References potential a Syden- be of disorders. related immunopathogenesis and may chorea ham’s the release in neurotrans- and of mechanism disruption synthesis subsequent mitter and II kinase 1]Siha R resa S unnhmM.Cytoker- MW. Cunningham NS, Greenspan AR, Shikhman [18] 1]Siha S resa S unnhmM.Asbe of subset A MW. Cunningham NS, Greenspan AS, Shikhman [17] MK, Ho PG, Fenderson JM, McCormack MW, Cunningham [16] molecular and sequelae Streptococcal MW. Cunningham [15] between antistrep- of link Polyspecificity RA. A Swerlick MW, Myosin: Cunningham MW. [14] Cunningham K, Krisher Sydenham’s [13] of recurrences isolated of Relation A. Taranta [12] Sydenham’s of relationship The GH. Stollerman A, Taranta [11] P. Lombroso D, Tucker MT, Mercadante MJ, Marques-Dias [10] 9 oet ,KsneS aklwD ua M Cunningham CM, Duran D, Jankelow S, Kosanke S, Roberts [9] Cunningham SM, Factor VA, Fischetti S, Kosanke A, Quinn [8] Cytotoxic MW. Cunningham K, Ward ME, Hemric JE, Galvin [7] A, Quinn SM, Factor SD, Kosanke ME, streptococcal Hemric JE, A Galvin group [6] of Pathogenesis MW. Cunningham [5] MW. Cunningham NM, streptococcal Mertens EE, Adderson A SM, Antone group [4] of resurgence The EL. Kaplan rheumatic [3] acute of Persistence HR. Hill Clin LY, century. Tani 21st L, Veasy the [2] in fever Rheumatic GH. Stollerman [1] avlredteim netDs2001;183:507–511. Dis Infect on J Focus endothelium. carditis: valvular rheumatic in mechanisms Pathogenic MW. 2001; by Immun disease Infect heart protein. 69:4072–4078. valvular m streptococcal autoimmune recombinant of Induction and MW. valves heart 2000;106:217–224. recognizes Investig Clin carditis J laminin. 2002; rheumatic from Pathol mAb its J and Am Myosin carditis. cardiac of rheumatic 160:297–306. epitopes in different implications by in valvulitis rats and myocarditis lewis of Induction MW. Cunningham 2000;13:470–511. Rev Microbiol Clin infections. Immunol J laminin. 1997;159:5422–5430. protein surface cell 36.2.2 cytotoxic heart the encoding recognizs antibody that sequences monoclonal gene V anti-streptococcal/anti-myosin of analysis Molecular Pediatr J States. United the of 1994;124:9–16. area intermountain the in fever 2001;33:806–814. Dis Infect iei ecinwt nioisadlcis n induces and lectins, and antibodies with reaction in mine tnppieSGGGG mimics SFGSGFGGGY peptide atin rtisadgopAsrpooclMpoenrecognizes protein M streptococcal A N group and cytoskeletal proteins with cross-reactive antibodies monoclonal mouse protein. M in 1989;143:2677–2683. recognize Immunol GLN-LYS-SER-LYS-GLN J myosin and sequence protein cross- the antibodies M murine streptococcal and with Human reactive JB. Dale EH, Beachey Lippincott 2000. Philadelphia: Wilkins; system. and immune Williams the on Effects microbes editors. RS, of Fujinami MW, Cunningham In: mimicry. 1986;164:998–1012. Med Exp J implications autoimmunity. their in and antibodies monoclonal murine tococcal Med J Engl N infections. 1959;260:1204–1210. streptococcal preceding to chorea 1956; Med J Am 20:170–175. streptococci. A group with 1997;20: infection to chorea Am North Clin Psychiatr 809–820. chorea. Sydenham’s Dis Infect Microbiol Clin J 1991;10:55–57. Eur sequelae. their and infections tetcciadhat cec 1985;227:413–415. Science heart. and streptococci -acetyl- b - D guoaie muo 1993;151:3902–3913. Immunol J -glucosamine. nioysgaigadmimicry and signaling Antibody N -acetyl- b - D -glucosa- 27 Downloaded By: [National Institutes of Health Library (NIH)] At: 18:41 27 March 2008 1]Siha R unnhmM.Imnlgclmimicry Immunological MW. Cunningham AR, Shikhman [19] 2]Sie A wd E Post- SE. Swedo LA, EJ, Snider Thompson [26] AJ, Lees RC, Dale F, Cardoso AJ, Church [25] RC. Williams ZH, Abdin JB, Zabriskie I, Rijn de van G, Husby [24] that protein M Streptococcal of Epitopes JB. Dale MS, Bronze [23] MB, Schapiro C, Parker MJP, Kruesi JL, Rapoport JN, Giedd [22] Mannheim BJ, Casey MB, Schapiro HL, Leonard SE, Swedo In: [21] fever. rheumatic and Streptococci MW. Cunningham [20] 3]ClgnJ,KntT,Kas M tutr fthe of Structure RM. Krause TJ, Kindt JE, Coligan [33] MW. Cunningham KE, Ward AR, Shikhman EE, Adderson [32] Tropomyosin MW. Cunningham VA, Fischetti PG, Fenderson [31] BA, McManus JM, Gulizia SM, Antone AM. MW, Cunningham Spanier [30] KK, Krisher NK, Hall MW, Cunningham [29] MT, Mercadante JF, Leckman S, Parveen SA, Morshed [28] Anti- FH. Grus MA, Garvey O, Lee CR, Loiselle HS, Singer [27] 3]SlaoiL,BaeM,MCryM a Y arsi JB. Zabriskie JY, Tai M, McCarty MS, Blake LG, Salvadori [35] IgG3 of Interaction JM. Davie WJ, Monafo NS, Greenspan [34] 28 between 1994;153:5593–5606. vivo in ivnoiG nibslgnlaatbde naueand acute in 2002;59:227–231. Neurology antibodies chorea. ganglia Sydenham’s persistent Anti-basal G. Giovannoni and fever. subthalamic rheumatic 1976;144:1094–1110. acute Med of and Exp chorea J in cytoplasm neurons nuclei with caudate reacting Antibodies Immunol J 1993;151:2820–2828. brain. human with cross-react that the antibodies evoke SE. of Swedo imaging 1995;45:2199–2202. SD, resonance Neurology ganglia. Hamburger Magentic basal AC, chorea: Vaituzis WL, Sydenham’s Marsh DP, PL, Dickstein D, Kozuch Kaysen HL, Leonard AJ, Allen Pediatrics dance. Vitus St of Physical 1993;91:706–713. symptoms chorea: Sydenham’s psychological DC. and Rettew MC, Lenane GB, 13. Plati- p. York: 1996. New Press; num disease. autoimmune antibody and Microorganisms anti-keratin driven microbially 1994;152:4375–4387. Immunol J a response. for Evidence ysnatbd eingns muo 1998;161: Immunol J genes. region V 2020–2031. anti- antibody Human myosin carditis: rheumatic from antibodies monoclonal polyreactive of analysis Molecular M streptococcal 1989;142:2475–2481. A Immunol group J proteins. with epitopes immunologic shares in role A 1993;68:118–123. Immunopathol molecules: Immunol Clin heart. coiled-coil the against autoimmunity Alpha-helical CJ. Gauntt 1986;136:293–298. Immunol antibodies J monoclonal myosin. streptococcal with A cross-reactive anti-group of study A disorders. autoimmune 2001;50:566–577. and Psychiatry and Tourette’sBiol cytoskeletal, with chorea, adults Sydenham’s nuclear, and syndrome, children neural, in epitopes against streptococcal Lombroso L, Antibodies Scahill RA, King PJ. H, Zhang BS, T, Peterson Fujii S, Y, Yazgan Paul A, Arman EC, Miguel MH, Kiss Bittencourt chorea. Sydenham in 2003;136:154–161. abnormalities Neuroimmunol J antibody ganglia basal h niois netDs1995;171:593–600. Dis Infect of J to capabilities antibodies. opsonophagocytic the titers and antibody polysaccharide A ELISA group streptococcus-liposome A Group anti- anti-idiotypic inhibiting and 1987;138:285–292. and Immunol anti-isotypic, J bodies. Enhancing anti-GAC, vaccine: of A effects group streptococcal with antibody (GAC) carbohydrate A group anti-streptococcal iodr ftecnrlnrossse.Cr pnNeurol Opin Curr system. nervous central 2003;16:359–365. the of disorders tetcca rusA -ain n carbohydrates. C and A-variant 1978;15:755–760. A, Immunochemistry groups streptococcal .A ivne al. et Kirvan A. C. N nicroyrt nioyrsos.JImmunol J response. antibody anti-carbohydrate -acetyl- b - D guoaieadctkrtnpeptides. cytokeratin and -glucosamine tetcca autoimmune streptococcal N -acetylglucosamine/anti- 5]Za ,LwnA gK.Cagsi hshrlto of phosphorylation in Changes KT. Ng Deficient A, Y. Lawen W, Wang Zhao S, [52] Tonegawa CF, Stevens AJ, Silva [51] 5]MrnA,AnkH rnegs M nioisinduced Antibodies MM. Prendergast H, Annuk AP, Moran [53] 5]Shla ,HitK rnvsnM eoigCa2 Decoding M. Srinivasan K, Heist H, Schulman [50] Abnormal S. Tonegawa RW, Greene DG, Rainnie C, Chen [49] A, Oohira H, Kaneko K, Takeuchi K, Watanabe K, Kasahara [48] SC, Previtali M, Corbo C, Sciorati I, Lorenzetti A, Quattrini [47] Volpe JA, Hardin SC, Lee KN, Konstantinov LA, DeGiorgio [46] a with technique immunohistochemical An T. Tai M, protein Kotani [45] inhibit Lysosphingolipids RM. Bell YA, Hannun [44] N, Augustine H, Hill JS, Heuser A, Beeker MW, Cunningham [43] T-Cell- B. Diamond MW, Cunningham L, Liao S, Malkiel [42] Isolation B. Halpern J, Parlebas P, Rebeyrotte I, Goldstein [41] A group streptococcal of Persistence EM. Ayoub BA, Dudding [40] JB. Zabriskie A, Khanna DR, MW. Buskirk A, Gibofsky Cunningham J, Froude JS, [39] Heuser SE, Swedo CA, streptococcal A Kirvan group [38] of Pathogenesis MW. Cunningham [37] of carbohydrate group-specific the in Variation M. McCarty [36] Ca2 Res Brain Prog kinase. 1995;105:95–104. CaM multifunctional by nucleus the to yganglioside-mimicking by 1999;55:557–568. Res Neurosci J passive learning. after avoidance memories long-term and short-term of processing hrdsrcgieeioe ttendso ave.J Ranvier. of nodes the at 2005;165:179–185. epitopes Neuroimmunol recognise charides o lh-acu-amdlnkns I cec 1994;266: Science II. 291–294. kinase Chem deficient alpha-calcium-calmodulin mice mutant Biol for in behavior aggressive J and response fear rafts. lipid in in gangliosides signaling 2000;275:34701–34709. of TAG-1 Involvement molecule adhesion Y. cell neuronal Sanai glycosylphosphatidylinositol-anchored T, Yamamoto E. Clementi Neuroimmunol R, J 2001;114:213–219. cells. Nemni neuroblastoma in homeostasis L, intracellular calcium modulate Wrabetz autoantibodies anti-GM1 N, IgM Human Canal ML, lupus Feltri systemic in receptor 2001;7:1189–1193. glutamate Med Nat NR2 erythematosus. the cross- with antibodies anti-DNA reacts lupus of subset Res A B. Diamond Brain BT, cerebellum. Their rat gangliosides: 1997;1(2):152–156. the Protoc Res to in Brain antibodies distribution monoclonal differential of Science series sphingolipidoses. the for Implications 1987;235(4789):670–674. C: kinase TH1/TH2 the and cytotoxicity of study paradigm. A acute of fever: immunology the rheumatic into Insights EE. 2000;68: Adderson G, Veesy Immun Infect myosin. of cardiac 5803–5808. epitope with dominant reactive the to polysaccharide, streptococcal response antibody dependent 1968;219:866–868. Nature ides. immunological share with which properties glycopeptides of valves heart from Exp J disease. valvular rheumatic 1968;128:1081–1098. with Med patients in antibody Top Curr autoimmunity. and 1989;145:5–26. Immunol mimicry Microbiol A molecular tissue: of human model and streptococcus between Cross-reactivity 2000;13:472–511. Rev Microbiol Clin basis Med infections. Exp chemical J the carbohydrates. on the of Studies 1956;104:629–643. specificity II. serological streptococci. for A group ui iaeI uatmc.Sine1992;257:201–206. Science mice. mutant II kinase alpha-calcium-calmo-dulin in potentiation long-term hippocampal nSdna hra a e 2003;9:914–920. Med Nat signaling chorea. cell Sydenham in neuronal autoantibody-mediated and Mimicry + cloui-eedn rti iaeI CMI)in (CaMKII) II kinase protein /calmodulin-dependent tetccu haemolyticus Streptococcus aplbce jejuni Campylobacter N aey-lcsmn,i cross- is -acetyl-glucosamine, ru polysacchar- A group lipooligosac- + signals Downloaded By: [National Institutes of Health Library (NIH)] At: 18:41 27 March 2008 6]IaaS,HwetG,FrelS,Kno ,GeyME. Gnegy L, Kantor ST, Ferrell GH, Hewlett SI, Iwata [62] Racagni M, Gennarelli E, Iuliano E, and Tiraboschi E, dispersion Consogno Synapsin [61] TA. Ryan P, Greengard P, Chi [60] 5]Kno ,HwetG,GeyM.Ehne amphetamine- Enhanced ME. Gnegy GH, Hewlett L, Kantor [59] SE. Swedo R, Werden SF, Leitman LA, Snider MA, Garvey [58] showing case A chorea: Sydenham’s J. Byrne M, Pike Z, Traill [57] Schnaar JW, Griffin NR, Mehta CY, Li PH, Lopez G, Zhang [56] Wagner I, Morrison M, Chakrabarti JJ, Plomp GM, O’Hanlon [55] EG, Rowan CP, O’Leary GM, O’Hanlon K, Paparounas [54] nacddpmn ees n hshrlto fsnpi I synapsin and of phosphorylation and II release dopamine Enhanced kinase CaM presynaptic 2001;50:337–344. Psychiatry Biol in I. S-adenosylmethio- synapsin changes with induces treatment nine Long-term M. Popoli G, 2001;4: Neurosci Nat activity. 1187–1193. synaptic during reclustering synaptic and 1999;19:3801–3808. Neurosci J phosphorylation vesicles. calmodulin-dependent and n K and Neurol Child J prednisone. or 2005;20:424–429. exchange, immuno- plasma intravenous with globulin, chorea Sydenham’s of Treatment Med Dev MRI. and 1995;37:270–273. CT Neurol on Child abnormalities 2004; striatal reversible Brain neuropathies. immune for 127:1085–1100. immunoglobu- Implications intravenous by lin: protection its and cytotoxicity 2001; neuronal antibody-mediated Anti-ganglioside Brain KA. Sheikh RL, terminal. nreve Anti-GQ1b motor HJ. the 124:893–906. Willison of EG, medi destruction Rowan antibodies Molenarr S, J, ganglioside Conner BDT, Stewart Trapp X, PC, Yin CS, Goodyear ER, block conduction acute cascade 1999;122:807–816. complement inducing the activate and without Ranvier peripheral of bind nodes can nerve antibodies Anti-ganglioside HJ. Willison eetdapeaie ifrnilrqieet o Ca2 for requirements Differential amphetamine: repeated + mdae oaierlaei a titmafter striatum rat in release dopamine -mediated t complement-dependent ate nvitro in Brain . + - 7]Kra A ta.Atbd-eitdnuoa elsignaling cell neuronal Antibody-mediated al. et CA, Kirvan On [72] KK. Voeller EM, Ayoub WK, Goodman TK, Murphy [71] neuropsy- autoimmune Paediatric SE. Swedo HL, Leonard [70] for search The PANDAS: SE. Swedo childhood J, Giedd of MA, Garvey model [69] A chorea: Sydenham’s SE. Swedo [68] AJ, Allen B, Mittleman M, Garvey HL, on Leonard SE, Speculations Swedo LS. [67] Kiessling HL, Leonard SE, Swedo [66] Koller M, Hagerty LD, Bacon LA, Bieliauskas PA, Nausieda [65] Nagy-Felsobuki mice von PR, Dunkley in ME, Graham LR, Bevilaqua changes [64] Neurochemical K. Akiyama D, Sutoo [63] tdwt tetccu PNA)wt yehmschorea, Sydenham’s submitted. with (PANDAS) streptococcus with associ- ated disorders neuropsychiatric autoimmune pediatric links Biol line? the 2000;47:851–857. draw we Psychiatry do Where chorea: Sydenham’s defining infection streptococcal 2001;4:191–198. with Neuropsychopharmacol J associated Int (PANDAS). 1998;13: disorders Neurol chiatric Child J fever. rheumatic 413–423. from Lessons disorders. neuropsychiatric pediatric of triggers environmental 1998;155:264–271. first Psychiatry the J Am of BK. cases. description 50 Dubbert Clinical infections: J, associated streptococcal Zamkoff disorders with S, neuropsychiatric Dow autoimmune L, Pediatric Lougee S, Perlmutter 1994;93:323–326. Pediatrics childhood. of disorders neuropsychiatric after antibody-mediated antineuronal sensitivity dopaminergic 1983;33:750–754. Chronic Neurology chorea. RN. 2001;276: Sydenham’s Glantz Chem WC, Biol J rate the the Ser(40). alters increase of 40411–40416. to Ser(19) phosphorylation hydroxylase of of tyrosine Phosphorylation of PW. conformation Dickson EI, repeated after 1997;283:1445–1452. Ther synaptosomes Exp Pharmacol striatal J amphetamine. in neuromodulin and uomuenuosciti iodr.JM 1994;272: JAMA disorders. 1788–1791. neuropsychiatric autoimmune Behav exposures. stress 2002;134:347–354. Res psychological Brain or physical following nioysgaigadmimicry and signaling Antibody 29