Indian J Pediat 49 : 849-862, 1982

Immunopathogenesis of rheumatic fever and rheumaticheart disease-current concepts

K.s. Reddy, D.M., P.S. Rao, M.D. and M.L. Bhatia, M.D.,D.M.

Key words: Rheumatic fever; rheumatic heart disease ; streptococcal antigens;humoral and cellular immunity; HLA.

Rheumatic heart disease (RHO) con­tinues to be a major scourge in thedeveloping countr~es. It howeverremains an engima, with the intricaciesof its aetiopathogenetic mechanisms asyet unravelled. While the occurrence ofacute rheumatic fever (RF) as a sequalof streptococcal sore throat is wellsubstantiated by three independent linesof enquiry (epidemiological, serologicaland prophylactic), the precise immunolo·gical mechanisms have not yet beenfully elucidated. Genetic susceptibilityhas been incriminated as a factor, butthe genetic markers of susceptibilityare still being investigated. RHD inIndia presents certain distinct features,most notable of which is a markedlyadvanced calendar with florid manifesta­tions of crippling valvular lesionsoccurring at a young age-an' entityidentified as "juvenile RHD".l Incontradistinction to this, acute rheuma­tic fever in adults has been considereda benign "post-streptococcal arthritis".2The clinical heterogenity of the diseasemay be due to variable severity of theunderlying immune mechanisms butthis too needs to be established. This

From the Department of Cardiology, AllIndia Institute of Medical Sciences, NewDe1hi·II0029

Reprint Requests: K.S. Reddy

review summaIises the available dataon the immunopathogenesis of RHOand outlines the possible mechanismsas currently conceived.

Humoral Immunity

It has been documented that the seraof patients with acute rheumatic feverand rheumatic heart disease containantibodies that react with constituentsof the human heart, blood vessel wall,skeletal muscle, and the subthalamicand caudate nuclei of the brain.3

However, their precise role in thecausation of rheumatic carditis. choreaor valvular damage is not certain.

Coons and Kaplan4 initially notedthat group A streptococci containedantigen(s) which were cross-reactivewith cardiac and skeletal muscle andthe smooth muscle of blood vesselwalls. Further investigations5 revealedthat these antibodies (i) are not speciesspecific (ij) are, however, organ specificand bind only to muscle containingtissues and (iii) display no difference inavidity for staining rheumatic andnon-rheumatic tissues. This antigenwas noted in majority of group Astreptococci but was absent in othergroups of haemolytic streptococci. Thelocalisation of this cross-reactive antig~n

in the streptococcus is not yet clear.

850 THE INDIAN JOURNAL OF PEDIATRICS

There appear to be two cross-reactiveantigens, one associated with the surfaceM protein and the other with thestreptococcal cell membranes.

Heart - reactive antibodies have beendemonstrated in 25-73% of RHD casesdepending on the presence or absenceof active carciitis.6 '7 Majority of patientswith a recent streptococcal infectionand its sequelae have been noted tohave the cross-reactive, heart stainingantibody in their sera.3 In somepatients, the titre of the autoantibodycorrelated well with the severity ofrheumatic activity. In general, a posi­tive reaction was more in patients withactive rheumatic fever than in patientswho were clinically inactive. Amongpatients with clinically active disease.positive tests were more frequent inthose with carditis than in those with­out carditis. Temporal studies byRead et al3 indicate that a directrelationship exists between the presenceof beart reactive antibody and the onsetof rheumatic fever. They suggest thatrepeated streptococcal infections maybe necessary to stimulate the productionof heart reactive anibodies and thatthe full blown disease complex wouldappear only when the titres of theseautoreactive antibodies are sufficientlyelevated They also observed that,in cases of rheumatic recurrences,elevated heart reactive antibodies werepresent at the time of or just beforethe second attack.

In uncomplicated streptococcalinfections, little or no heart-reactiveantibodies are present, while in patientswith acute rheumatic fever these

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antibodies are detectable at a tenfolddilution of their sera.3 Bright floures­cent staining of cardiac tissue at dilutionsof serum greater than I: lOis consideredindicative of acute rheumatic fever,since such titres have not been seen inuncomplicated streptococcal infections.s

Heart-reactive antibodies have alsobeen detected in patients followingacute myocardial infarction and patientswith postpericardiatomy syndrome.However these antibodies do notcross-react with streptococcal membranes.s

Whether the heart reactive antibodiesin RF and RHD are the causalmechanisms of cardiac damage or aresecondary to cardic ti!>sue damagewith release of cardiac antigens thatare cross-reactive with streptococcalantigens is, however, stilI open toquestion and needs further elucidation.

N-acetyl glucosamine residues con­fer antigenic specificity to group Acarbohydrate, and this substance isalso a common constituent of mamma­lian tissues.s Dudding and Ayoub ll

observed that sera of a number ofpatients with RF and RHD demonstratedantibodies that bind to N -acetyl glu­cosamine. They also observed thatpatients with valvular disease havehigher titres than those without valvulardisease and that these antibodies persistfor years after the initial attack in pati­ents with valvular disease in contrast tothose without valvular disease in whomthese antibody titres rapidly falloff afterthe initial rheumatic attack. Duddingand Ayoub suggest that the persistence ofthese titers in patients with rheumaticvalvular disease may bp related to the

REDDY ET AL : IMMUNOPATHOGENESIS OF RF AND RHD 851

slow and sustained release of valvularcross-reactive glycoproteins, thus perpe­tuating the valve damage. The specifi­city of these antibodies to rheumaticvalvular disease has yet to be demonstra­ted.

In an interesting study of patientswith chorea, Husby et al10 noted thepresence in their sera of another antibodythat cross-reacted with the antigens pre­sent in the neuronal cytoplasm of thecaudate and subthalamic nuclei in thebrain. This anti-neuronal antibody wasalso noted in patients with carditis,though the antibody titres were alwayshigher in those with chorea. In manypatients, a direct correlation was notedbetween the presence of this antibodyand the length and severity of the choreicattacks. Absorption experiments demo­nstrated these antineuronal antibodiescross-react with antigens present in groupA streptococcal cell membranes.

Anti-synovial antibodies have alsobeen demonstrated in the sera of patientswith RHO by Atal et al.1l Cross-reac­tivity between streptococcal teichoic acidand human heart tissue extract wasobserved by Khanna et al 12

High levels of circulating immunecomplexes (CIC) were found to be eleva­ted in patients with acute rheumatic feverby Read et aI.3 These immune complexeswere noted to persist for several weeksafter the initial appearance of the clinicalsymptoms. Wahi et al13 also noted thattwo different sizes of elC were formedin cases of acute rheumatic heart diseaseand that both the classical and alternatepathways of complement activation wereinvolved although there was an

increased synthesis of C' 3 complement.While elevated serum complementlevels during and following acuterheumatic fever were noted also byRead et als, the prognostic significanceof the elevated serum complement andthe precise a pathogenetic role of theCIC in RF and RHD remain to beelucidated.

Cellular Immunity

Several studies aimed at ascertainingthe nature of cellular reactivity tostreptococcal antigens in patients withrheumatic fever or rheumatic heartdisease have yielded conflicting resultsboth on the nature of the immuneresponse as also on its specificity.14-23This is attributable to the variablenature of the streptococcal antigen(s)used and the purity of the extract. Usingeither whole organisms or streptococcalsubstances in various stages of impurity,a depressed lymphyoproliferative res­ponse has been observed in RF andRHD. However, other workers havereported an elevated blastogenic responsein these disease states.

Read et al,19 using purified pre­parations of streptococcal cell walls andmembranes, tested the in vitroparameters of lymphocyte sensitivity,inhibition of leucocyte migration and14e thymidine incorporation by sensitizedcells in the presence of their sensitizingantigen. They observed a markedcellular reactivity in patients withrheumatic fever to streptococcal cellmembrane, a structure previously shownto have cross-reactivity with heartsarcolemma. This increased reactivity

852 THE INDIAN JOURNAL OF PEDIATRICS

persists in rheumatic patients upto fiveyears after the initial attack withoutany clinical or laboratory evidence ofan intercurrent streptococcal infectionor rheumatic recurrence during thisperiod. After five years the majorityof rheumatic patients lose this alteredsensitivity. Patients with uncomplicatedstreptococcal infections react to mem­brane antigens in the same manneras normal controls. Read et a13 '19

also demonstrated the specificity ofthis altered response to group Astreptococcal cell membranes. Theyalso noted that antigen-antibody com­plexes did not appear to play a directrole in this heightened cellular response.While the nature of streptococcalantigen(s) responsible for the observedcellular hyper reactivity was not clear,their study excluded M protein as anactive participant in that reaction.

Gray et al23 recently reported astudy of lymphocyte transformationresponses to purified preparations oftwo extracellular products of group Astreptococci (blastogen A and nucleaseB), phytohaemagglutinin and candidaalbicans antigen. when tonsillar andperipheral bloed lymphyocytes frompatients of RHO and non-rheumaticcontrols were exposed to these antigens.The RHO patients clearly had adepressed cellular immune responseto the two purified streptococcalextracellular antigens. The equal fre­quency in recovery of group A strepto­cocci from tonsils and the absenceof a consistent difference in titres ofhumoral antobodies to streptococcalextracellular antigens, particularly nu-

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clease B, suggest that this differentialre&ponse is not due to a lower level ofstim ulation by absence of repeatedexposure to group A streptococcal pro"ducts in RHO patients on pencillin prO'"phplaxis. The reactivity to phytohaemag"glutinin, a polyclonal T cell mitogen, washowever no different in RHO and controlsubjects, indicating that the decreasedT cell response in RHO subjects isprobably specific to streptococcal anti­gens and is not part of a generaldecrease in T cell responsiveness. Anon streptococcal antigen, C-albicans,stimulated little or no blastogenicactivity in the assay system used.Thus it is not established whether thelowered response in RHO patientsis associated only with streptococcalantigens.

The differences in the observationsin the studies of Read et al19 andGray et a123 are probably explainedby the fact that the former studyemployed particulate components ofthe streptococcal cell membrane whilethe latter study employed purifiedsoluble extracellular products that areapparently not found in significantamounts in association with strepto·coccal cellular constituents. Sincethe precise nature of streptococcalantigens which are responsible for thealtered immune response leading tocardiac tissue damage is not as yetascertained, such variance in resultsemploying different antigens is perhapsinescapable at present. How suchaltered cellular immune responses todiffering streptococcal antigens fit intothe grand design of immunopathogenesis

REDDY ET AL: IMMUNOPATHOGENESIS OF RF AND RHD 853

of rheumatic .carditis and valvulardisease is yet to be clearly delineated.

Recent experimental evidencesupports a role for altered cellularimmune response in the pathogenesisof RHD. Yang et al24 reported thatguineapigs immunised with group Astreptococci or streptococcal cellmembranes have cytotoxic T cellscapable of damaging cultured heart cellsfrom guineapig embryos but not othercell types, such as skeletal muscle cellsor fibroblasts. They suggest thatimmunisation with streptococcal group-Amembranes primes the cytotoxic T cellsthat recognise normal heart membranesas a specific antigen. Hutto andAyoub26 have also noted that peripheralblood lymphocytes obtained from twopatients with acute rheumatic carditiswere cytotoxic for beating heart cellsin vitro. They also noted that auto­logous serum decreased the cytotoxicity.While these results suggest that sensitizedlymphocytes induced by streptococcalimmunization are cytotoxic to thecardiac tissue, more evidence is requiredfor a dominant cytopathogenetic roleof these cells in RF and RHD.

Reported results of two studies onlymphocyte subpopulation in the peri­pheral blood in patients with acuterheumatic fever or 'activity' have been atvariance with each other. Williams etal26 observed a decrease in bothpercent and absolute numbers ofcytotoxic!~uppressor cells during theacute process. They suggest that thismay reflect a fundamental lack ofresidual immunoregulatory or suppressorcontrol at the onset of the rheumatic

process itself. Similar defects havebeen suggested in peripheral blood Tcell subpopulations in systemic lupuserythematosus also. Khanna et al17

however noted a reduction in helperT cell population and an increasein cytotoxic or suppressor T cell popu­lation in patients of rheumatic heartdisease with 'activity' as compared tothose with chronic rheumatic heartdisease.

The role of altered cellular immuneresponse in causing the valvular damageof RHD has been investigated byRaizada et al28 who studied freshcardiac valvular tissues and atrialappendages, removed at surgery, from106 Indian patients and 21 Americanpatients. Twenty-five percent of theIndian rheumatic heart valves andone-third of the American heart valvesshowed significant interstitial lymphoidinfiltrates. Precise identification of thephenotypic profiles of inflammatorymononuclear cells revealed that theseinfiltrates contained a predominance ofT cells (70-80 percent) and onlyoccasional B cells. Most of the Tcells were helper/inducer T cells, withonly a minor representation ofsuppressor/cytotoxic T cells. In manyinstances, helper T cell collections wereseen in close juxtaposition to fibroblastsand collagen fibrils. These findingssuggest that the chronic rheumaticscarring process may involve helper!inducer T cells as an ancillary factorin the indolent contracture and fibrosisof deformed cardiac valvular structures.Attempts to demonstrate residualstreptococcal antigens by indirect

854 THE INDIAN JOURNAL OF PEDIATRICS

immunoflourescence techniques revealedthat there was no clearly demonstrablestreptococcal membrane or group Acarbohydrate antigen detectable withinthe monoucJear celIs or macrophage - likecells in cardiac valvular structures manyyears after initial rheumatic attacks.This finding refutes the suggestion ofCromartie et a129 '80 that the lack ofbiodegradibility of mucopeptide struc·tures within the group A streptococcalceIl wall may be related to thepersistence of the rheumatic inflamma­tory process, However, the persistent in­flammatory process of chronic RHD mayrepresent cell mediated immunitygenerated By auto-reactive T ce)]ssequestrated in the cardiac tissues, as

suggested by the findings of Raizadaet a1.

Immunogenetics of RheumaticFever and Rheumatic Heart Disease

While a high familial incidence ofrheumatic fever has been reported inseveral studies, these clinical studiesprovided no satisfactory proof ofheritable susceptibility as distinct fromcommon environmental factors.a'81'52

The mode of inheritance and themethods of its expression were notclearly delineated. Taranta32 concluded,from a study of rheumatic fever inmonozygotic and dizygotic twins thatif genetic factors are operative, theyhave a limited penetrance.

The discovery of the human leucocyteantigen (HLA) system in man, thedelineation of its immunoregulatoryfunction through linkage with theimmune response (Ir) genes, and the

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identification of human leucocyteantigens as useful genetic markers forseveral diseases has renewed the searchfor genetic markers of susceptibility torheumatic fever and rheumatic heartdil1ease.33'34

HLA system in man is the analogueof the major histoco,npatibility complex(MHC) of the mouse which has beenextensively studied and shown to beassociated with a high susceptibilityto the development of gross virusinduced leukemia.31i Apart from itsknown role in determining the responseto tissue transplantation, the HLAsystem which is located on the sixthchromosome, also plays an importantrole in determining the immuneresponse, production of certain com~

ponents of the complement system anddetermining the genetic prediliction toseveral diseases. The serologically deter­mined A, Band C loci antigens and thelymphocyte determined D locus antigens(inclusive of the B- lymphocyte al1o­antigens or DR antigens) constitutethis immunoregulatory gene complex.

The primary immunoregulatoryfunction of the HLA-A, Band C geneproducts appears to be in determiniI1lthe number and specificity of thecytotoxic killer T cells which areproduced on immunisation with a givenantigen.36 The D locus gene productshave a complex set of immunologicfunctions. 36 These cell-surface antigensare the strongest antigens in elicitingthe mixed lymphocyte culture reactionand graft versus host reaction. Theyalso appear to influence the efficiencyof interaction between T cells and

REDDY ET AL: IMMUNOPATHOGENESIS OP RF AND RHD 855

macrophages, between T cells and Bcells and perhaps between B cells andmacrophages. The 0 locus geneproducts appear to regulate function ofhelper and suppressor T cells. Theprocessing of antigens and theirpresentation by the macrophages tothe T cells is a crucial step in immuneresponse which is under the regulationof the immune response genes associatedwith the D/DR locus antigens. Theantigen-specific activation of B lym­phocytes in T-cell dependent antibodyresponses has also been shown torequire recognition, by helper T cells,of the products of the major histo­compatibility complex (MHC) expressedby cells cooperating in these responses.Thus the immune response geneslinked to the HLA system functionas a "Supergene" regulating theimmune response by influencinginteractions between the various limbsof the immune response.

The need to identify specific geneticmarkers which can from the basis forthe d¢ranged immune response in acuterheumatic fever and rheumatic heart dise­ase led to the study of HLA patterns inthese discorders by several groups of in­vestigators. Falk et al37 reported a decr­eased frequency of HLA-A3 as well as ahigher degree of HLA antigen homozy­gosity in caucasian patients withrheumatic fever. Caughey et al3S

could not confirm these findings. Theyreported an increased frequency ofantigens A3 and B8 with a concomitantdecrease in the frequency of HLA Al,in their Maori patients. In the caucasianpatients, an increased frequency of

Bt 7 and decreased frequency of HLA­A28 was reported by them. The statisti­cal validity of these observations hasbeen challenged by Filice et al.s,Leirisalo et al40 initially reported anincreased frequency of BW35 inpatients with acute rheumatic feverand an increased frequency of B13in patients with acute carditis ascompared to those without carditis.They did not however find any significantassociation of HLA antigens in patientswith chronic rheumatic heart disease.The distinction between patients withacute carditirs (at the time of evaluation)and patients of established rheumaticvalvular disease (who must have hadcarditis in the past) appears to be anartificial one, when related to the studyof alleles which do not change duringthe life time. In a subsequent studyof children with acute rheumatic fever,Leirisalso et al41 did not find anysignificant association with the A andB locus antigens. Murray et a142 alsoreported the absence of any significantassociation of HLA antigens with theoccurrence of acute rheumatic feverin adult Maxican Americans. However,a study confined to acute rheumaticfever in an adult population and notencompassing patients with rheumaticvalvular heart disease is bound to bevery selective and its conclusions aretherefore not relevant to a completeunderstanding of the problem. Wardet aI43'44 reported an increased frequencyof HLA A29 and HLA AW30/AW3 I inpatients with mitral valve diseasepresenting at a young age without apreceding history of rheumatic feveror chorea. These authors ~~suggested a

856 THE INDIAN JOURNAL OP PEDI~TRICS

viral aetiology of these lesions includingmitral stanosis, conventionally regardedto be rheumatic in etiology. However,tbis postulation is not supported byknown pathological data aboutacquired mitral valvular diseasespecially mitral stenosis.

HLA-B5 antigen has been associatedwith an altered immune response tostreptococcal antigens. Greenberget al46 observed that lymphocytes fromHLA-B5 positive individuals were moreresponsive, in vitro, to certainstreptococcal antigens than were B5negative lymphocytes, as assessed bythe blastogenic response. Yoshinoyaand Pope46 reported that, using fiveradioimmunoassays for detection ofimmune complexes in patients withacute rheumatic fever, HLA-B5 positivepatients were noted to have asignificantly more pronounced immuneresponse as measured by the circulatingimmune complexes suggesting a geneticbasis for the development of immunecomplexes in these patients. Anincreased frequency of HLA-B5' inpatients with rheumatic heart diseasehas been reported by severalworkers37'38'42 and has been detectedin our ongoing study of HLA patternsin Indian patients with RHD but fellshort of statistical significance in allthe studies. On the contrary, a studycarried out in Trinida<i47 noted thatrheumatic families as a group had asignificantly lower incidence of HLA­B5 antigen than did the nephritic ornon-streptococcal control families.

Petarrayo et al48 fpund that usinga single human serum (883) obtained

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from a multiparous woman in Columbiathey were able to identify an antigenon the B-cells of 80% of the rheumaticfever patients tested in New Yorkand Bogota, Columbia. As thefrequency of this antigen in the generalpopulation is approximately )5%, thepresence of this B-Jymphocyte alloantigen.883 appears to be a strong genetictmarker of increased susceptibility toacute rheumatic fever. The predictivevalue of this antigen in other popula­tions needs to be determined. Itsvalue in predicting risk of carditisand chronic rheumatic valvular heartdisease as distinct from the morebenign lesions of rheumatic fever witha more favourable natural historyalso needs to be determined by studying'a large number of patients with variousfacets of acute rheumatic fever andrheumatic valvular heart disease.

In an ongoing study in our institu'tion, HLA patterns of 113 NorthIndian Hindu patients with establishedrheumatic valvular disease have sofar been analysed and compared with118 ethnically similar normal controls.4t

A and B locus antigens were studiedin all patients, while DR locus antigenswere typed in 14 patients. A significantincrease in the frequency of antigens.A28 (P< 0.OU5. Relative risk= 1.66)and BW35 (P< 0,(12, Relative ris= 3.13) and a significant decrease inthe frequency of :813 (P< 0.02, Relativerisk = 0.23) were observed in patientswith RHD. Analysis of DR locusantigens revealed a 62.5% frequencyof DR3 antigen in the patient groupas compared to a frequency of 20%

REDDY ET AL : IMMUNOPATHOGENESIS OF Rf AND RHO 85/

in the normal control population(P< 0001 Relative risk = 6.6).No significant differences in HLA Aand B antigen association was notedbetween patients with mitral valvedisease and those with combined mitraland aortic disease. However, a signi­ficant association with HLA· A28 andBW35 antigens was present only inpatients with a history of rheumaticfever and in patients with onset ofsymptoms before the age of twenty years(juvenile RHD group). These resultssuggest that susceptibility to RHD isHLA associated and mediated throughan immune response gene linked toDR3. HLA A and B locus antigenprofiles suggest that clinical heterogenityof RHD may be influenced by the HLAsystem. A larger study of DR antigenprofile in RHO and its various sub­groups is now underway and is likelyto yield useful information regardingHLA associated genetic susceptibilityto RHD in the Indian population.

Thus, from the various studies sofar conducted on the genetics of RFand RHD, strong associations haveonly emerged with DR antigens (DR-883with RF in Patarrayo's study and

DR3 with RHD in our study). This isnot surprising in view of the fact that,of the various HLA antigens, the Dlocus antigens appear to be mostproximately linked to the immuneresponse (Ir) region and the largestcategory of HLA-associated diseasescontains those with a primary associa­tion with a particular HLA-D type.36

The precise mechanisms by which theHLA- D locus al1ligens inflclence the

pathogenesis of RF and RHD isnot clear. From the known immuno­regulatory function of the HLA systema model can be postulated (Fig. n.In this model, proposed by Dos Reisand Barcinski,50 a genetically controlledantigen presentation function ofmacrophages is proposed to explainthe induction phase of streptococcalcarditis. They suggest that antigenicdeterminants in strains of beta-hemolyticstreptococci causing rheumatic feverare selected by macrophages, throughthe operation of immune response (lr)genes, to be presented to the Tlymphocytes. Macrophages with asusceptible genotype are able to selectcardiac-like determinant (s), fromamongst the various streptococcalantigens, for presentation to the Tlymphocyte. Cross-reactivity betweenthe selected determinants and hearttissue generates clones of auto-reactiveT cells. Autoimumnity will develop if,coincidental with the presentation ofthe relevant antigenic determinant,regulation of T cell production, whichis also under the influence of the HLAsystem, is disturbed. These workersalso demonstrated that streptococcus­bearing macrophages were able to inducepancarditis in syngenic hosts and primeT cells in vitro against normal hearttissue. This hypothesis is attractiveand needs to be actively investigatedfurther. The deposition of these cross·reactive T lymphocytes into the valvulartissues, as suggested by the work ofRaizada et al,28 may lay the fieldfor persistence of the auto-reactiveimmune process in the cardiac tissueswith the distressing long term of sequelae

858 THE INDIAN 10UR.NAL OF PEDIATRICS Vol. 49, No. 401

IB- HAEMOLYTICSTREPTOCOCCUS

\HLA DR I

I-II

!

I

IIL PROPOSED PATHOGENESIS OF RH-D·-----_--.-:......::.~~-_-----...

Figure: A model of proposed pathogenesis of RF and RHD(modified from DOS REIS and BARCINSKI).IO See textfor explanation.

of deformed valves and cliniealmanifestations of heart disease.

Streptococcal Vaccine

Since the discovery of streptococcalM protein by Lancefield more than50 years ago, this typespecific proteinhas been known to confer resistanceto phagocytosis.51 Until recentlyattempts to purify type-specific Mdeterminants and produce a multivalentvaccine were unsuccessful. Beachey etal recently identified a method thatgreatly helps to separate the type­specific surface determinants from therest of the proteins that make up thesurface structure of the streptococcus.52-55The purified "pep M" prepared froma strain of type 24 streptococci (arheumatogenic strain) proved to beantigenic in animals and men. These

peptide fragments, covalently coupled

with a polylysine carrier, become highly

immunogenic, producing type-specificopsonic antibodies against group Astreptococci in rabbits. This grouprecently reported production of a setof monoclonal antibodies against apurified fragment of type 24 stre­ptococcus M protein, using hybridomatechnology.56 If precise type-specificsurface determinants are identified andsynthesised by such techniques, it ispossible in near future to produce apolyvalent vaccine composed of smallpeptides effective against a variety ofstreptococcal M types. StolJerman51

suggests that a polyvalent vaccinecontaining the prevalent rheumatogenicstrains in a given population might bevaluable in protecting those at risk ofdeveloping RF. This is indeed an

REDDY ET AL : IMMUNOPATHOGENESIS OF RF AND RHO 859

interesting method of secondary pro­phylaxis against RF and potentiallyuseful in the primary prophylaxis ofthose with a definite genetic susceptibility(if such genetic markers are identifiedin each population). However, thesuperiority in terms of ease, efficacyand cost-effectiveness which penicillinprophylaxis is likely to have over thepotential polyvalent streptococcalvaccines is unlikely to make the vaccinea major agent of mass prophylaxis. Itwill be of use, however, in patientswho are sensitive to penicillin or againstrare strains of penicillin-resistantstreptococci which are rheumatogenic.

Non-streptococcal Etiology of"RheumaticH Heart Disease

Interest in exploring the possibilityof a non-streptococcal etiology of lesionsidentified with classical rheumatic feveror rheumatic heart disease has arisenfrom recent studies suggesting a viraletiology or Yersinia enterocolitica car­ditis Chandy et al57 reported that in theirstudy of 29 patients with mitral stenosishigher titres of antibodies againstcoxsackie B virus (CBV) types 3 and 4and a higher prevalence of the antibodyagainst type 3 CBV was noted inpatients without a history of rheumaticfever as compared to those with sucha history. A clinical overlap of acuterheumatic fever and yersinia arthritisas assessed by the Jones' criteria wasreported by Liatinen et al58 fromFinland. Whether Yersinia enterocali­tica carditis leads to valvular afflictionllimilar to classical RHD is not yetknown. These studies, suggestirg a

non-streptococcal etiology of RHOor a mimicry of the lesions associatedwith streptococcus related RF and RHOby other agents, are very preliminaryand need further corroboration andpathological proof before the hypothesescan be accepted.

Perspective

Abnormalities of both cellular andhumoral responses to streptococcalantigens which are cross-reactive withcardiac tissue have been demonstratedin patients with RF and RHO. Howeither or both of these lead to rheumaticcarditis with progression to valvularheart disease has to be clearly defined.A genetic susceptibility to RF andRHO has been suggested by studiesof human leucocyte antigen profiles insome patients. The demonstration ofan important immunoregulatory func­tion for the HLA system and itsassociated "Ir" genes strongly suggeststhat a genetically mediated abnormalityof the immune mechanisms predisposesto the development of a cardiac-reactiveimmune response on exposure of thesusceptible host to streptococcalantigens which have cardiac cross­reactive determinants. Future researchneeds to identify each link of thisabnormal immune response that leadsto RF and RHD and also delineate thefactors that determine the severity andclinical heterogenity of these disorders. Ifthese mechanisms are fully unravelled, itmay be possible to provide effective pri­mary and secondary prophylaxis againstrheumatic fever by manipulating crucialevents in the microcosmos of the

860 THE INDIAN JOURNAL OF PEDIATRICS

immune system rather than strugglein vain to salvage the burnt embers ofhearts ravaged by rheumatic heartdisease.

References

1. Roy S B. Bhatia M L, Lazaro E J. Rama­liogaswami V : Juvenile mitral stenosis inIndia. Lancet ii : 1193, 1963

2. McDonald EC and Weisman M M : Arti­cular manifestations of rheumatic feverin adults. Ann Intern Mtd 89:1002,1978

3. Read S, Zabriskie J B : Immunologic con­cepts in rheumatic fever. In Zabriskie J B(editor): Clinical Immunology of theHeart. Jobn Wiley and Sons, New York,PP 51, 1981

4. Ksplsm M H: Multiple nature of crossreactive relationship between antigensof group A streptococci and mammaliantissue. In Trenti JJ (editor): Cross reac­ting antigens and neoantigens. Williamsand Wilkins Co, pp 48,. 1967

5. Kaplea MH, Frangley J D: Autoimmu­nity to the heart in cardiac disease. Cur­ren t concept of the relation of autoimmu­nity to rheumatic ftJver, post cardiotomyand post infarction syndromes and cardio­myopathies. Am J Cardiol 24:459, 1969

6. Kaplen MH, Meyeserian M, Kushner I:Immunologic studies of heart tissue. II.Serologic reactions with human hearttissue as revealed by immunoflourescencemethod. J Exp Med 113:17, 1961

7. Hess EV. Fink C W, Taranta A: Heartmuscle antibodies in rheumatic fever andother disease. J Clin Invest 43:886. 1964

8. Goldstein I, Rebeyrotte P, Parlebas J, Hal­pern B: Isolation from heart valves ofglycoproteins which share immunologicalproperties with streptococcal hemolyticusgroup A polYsaccharide. Nature 219:886,1968

9. Dudding B A, Ayoub EM: Persistenceof streptococcal group A antibody inpatients with rheumatic valvular dlseaes.

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J Exp Med 128 : 1081, 196810. Husby G, Van de Rijn I, Zabriskie J B :

Antibody reacting with cytoplasm of sub.thalamic and caudate nuclei neurons i~chorea and acute rheumatic fever. J ExpMed 144: 1094, 1976

11. Atal P R, Mathur K S, Wahal P K, SinghM M, Hazra DK, Kumari J: Comparisonof tanded red cells haemagglutinin testand immunoflourescent technique fordetection of autoantibodies in rheumaticfever and rheumatic heart disease. Indian JPath Bacterioll3:87, 1970

12. Khanna A K, Ganguly N K, Anand ISChakravarti R N, Wahi P L: Immunogeni:city of group A streptococcal teichoic acidin relation to rheumatic heart disease.Indian heart J 34:315,1982

13. Wahi P L, Ganguly N K, Anand IS,Khanna A: Circulating immune complexesin cases of rheumatic heart disease.Indian Heart J 33: 158, 11)81

14. HiJschhorn K, Schraibman R R, Verbo S.Grushkin R H: The action of streptolysinS on peripheral lymphocytes of normalsubjects and patients with acute rheuma­tic fever. Proc Nat! Acad Sci 52:1151,1964

15. Gery I, Brand-Auraban A, Benezra D.Jacbo A, Davies A N: Transformationof lymphocytes from patients with rheU­matic fever by streptolysin S. Clin ExpImmunol 3:717, 1968

16. Francis J C. Oppeneim J J: Impairedlymphocyte stimulation by some strepto­coccal antigens in patients with recurrentaphthous stomatitis and rheumatic heartdisease. Clio Exp Immunol 6:573, 1970

17. Cuppari G, Quaglita F, Ieri A, TarantaA: Lymphocyte transformation with stre­ptolysin S by serum in rheumatic disease.J Lab Clin Med 80:165, 1972

18. Marie N, Berkal A J: Cellular immunityin children With acute rheumatic fever andrheumatic carditis. Pediatr Res 13: 16, 1979

19. Read S E, Fisanetti V A, Utermohlen V,Falk RE, Zabriskie J B: Cellular reactivity

REDDY ET AL : IMMUNOPATHOGENESIS OF RF AND RHD 861

studies to streptococcal antigens. Mig­ration inhibition studies in patients withstreptococcal infections and rheumaticfever. J Clin Invest 54:439. 1974

20. Lueker RD, Williams R CJr: Decreasedreactivity of lymphocyte in mixed leucocy­tes culture from patients with rheumaticfever. Circulation 46:655. 1972

21. Mihalcu F. Stefanescu M, TeodorescuM: The immune cellular response testedby lymphocyte transformation in strepto­coccal infections. In International sym­posium on Immunity to Infections of theRespiratory system in Man and AnimalsDevelopments in Biological standards.Karger S A. Basel 28:246. 1975

22. Sapru RP. Ganguly N K. Sharma S,Chandani RE, Gupta A K: Cellularreaction to group A bl'ta hemolytic strep­tococcal membrane antigen and its rela­tion to complement levels in patients withrheumatic heart disease. Br Med J 2:422.1977

23. Gray ED. Wannamaker L W, Ayoub BM, Kholy A E. Abdin Z H: Cellular

imm'Jne responses to extracellular strep­tococcal products in rheumatic heartdisease. J Clin Invest 68:665, 1981

24'. Yong LC, Soprey P R. Wittner M K.Fox B N: Streptococcal induced ceil-me­diated immune destruction of cardiacmyofibers in vitro. J Exp Med 146:344.1977

25. Hutto J H. Ayoub B M: Cytotoxicity oflymphocytes from patients with rheumaticcarditis to cardiac cells in vitro. In Zab­riskie J B. Read S E (editors) StreptococcalDiseases and Immune Response. NewYork. Academic press, 1979

26. Williams R C Jr. Raizada V. PrakashK. Van de Rijn I. Stobo JD, Sharma K B:Changes in T lymphocyte subsets duringacute rheumatic fever. J Clin ImmuneIn Press. 1982

27. Khanna A, Ganguly N K. Anand I S.Wahi P L: Lymphocyte subpopu1ationand cytotoxic reactions in cases of rheu-

matic heart disease. Indian Heart J 33:1441981

28. Raizada V. Williams RC, Chopra p. et al:Tissue distribution of lymphocytes inrheumatic heart valves as defined bymonoclonal anti·T cell antibodies. Am J

Med.In Press. 198229. Cromartie W J, Craddock J H: Rheumatic

like lesions in mice. Science 154:284, 196630. Cromartie W J. Craddock JG. Schwab

J H, nderle S K. Yang C H: Arthritisin rats after systemic injection of strepto·coccal cells or cell walls. J Exp Med146:1585. 1977

31. Glynn L E. Holborrow E J: Blood grollps.and their secretion in rheumatic fever.Rheumatology 2:113, 1969

32. Taranta • Torosdag S, Metrakos J D.Jegier W. Uchida I: Rheumatic fever inmanozygotic and dizygotic twins. Circu­lation 20:778. 1959

33. SasazuPi T. Grument FC. McDevitt M C:The association of genes in the majorhistocompatibility complex and diseasesusceptibility. nn Rev Me d 28:425. 1977

34. Reddy K S. Bhatia M L: HLA system andcardiovascular disease. J ASloc PhysiciansIndia 29:615, 1981

35. Lilly F. Boyse E • Old L J: Genetic blSisof susceptibility to viral leukaemogenesis.Lancet ii:1207.1967

36. McDevitt H 0: Current concepts: Regu­lation of the immune response by themajor histocompatibility system. NI EngJ Med 303:1514. 1980

37. Falk J A. Fleischmann J L. ZabriskieJ B, Falk RE: A study of HLA antigenphenotype in rheumatic fever andrheumatic: heart disease patients. TissueAntigens 3:173, 1973

38. Caughey 0 B. Doughlas R. Wilson W,Hassal 1 B: HLA antigens in Europeansand Maoris with rheumatic fever andrheumatic heart disease. J Rheumatol2:319, 1975

39. Filic:e G A. Wingo P A: HLA antigen inEuropeans and Maoris. J Rheumatol3:437,1976

862 THE INDIAN JOURNAL OF PEDIATRICS

40. Leirisal0 M, Laitinen 0, Tizikainen: AHLA phenotypes in patients with rheuma­tic fever, rheumatic heart disease and yer­sinia arthritis. J Rheumatol 4: suppl 3:78,1977

41. Leirisalo M, Koiruranta P, Laitinen 0:Rheumatic fever and its sequelae inchildren-A follow up study with HLA.J Rheumatol 7:500, 1980

42. Murray MC, Montkiel M M, PersellinR M: A study of HLA antigens in adultswith acute rheumatic fever. ArthRheumatol 21:6,652

43. Ward C, Gelsthorpe K. Doughty RW:A relation between HLA antigens andclinical features in patients with valvularheart disease. Brt Med J 1:1499, 1976

44. Ward 0, Gelsthorpe K, Doughty R W,Hardisty C A: HLA antigens andacquired heart disease. Tissue Antigens7:221,1976

45. Greenberg L T, Gray ED, Yonis E J:Association of HLA·5 and immune­responsiveness in vitro to streptococcalantigens. J Exp Med 141:935,1975

46. Yoshinoya S, Pope R M: Detection ofimmune complexes in acute rheumaticfever and their relationship to IILA-B5.J Clin Invest 65:136, 1980

47. Read S E, Reid H, Poon-King T, FischettiVA. Zabriskie J B, Rapaport F T: HLAand predisposition to the non-suppurativesequelae of group A streptococcal infec­tions. Transplant Proc 9:543, 1977

48. Patarrayo M E, Winchester R J, VejeranoA, Gibofsky A, Chalem A, ZabriskieJ B, Kunkel H G: Association of a B-cellalloantigen with susceptibility to rheuma­tic fever. Nature 278:173,1979

49. Rao P S, Reddy K S, Mehra N K, VaidyaM C, Bhatia M L: HLA antigen patternsin Indian patients with rheumatic heartdisease with special reference to DR locus.Indian Heart J 34:298, 1982

Vol. 49, No. 401

50. Dos Reis G, Barcinski M A: Role ofmacrophage dependent determinant selec­tion in induction of strePtococcal carditis.Lancet ii:777, 1980

51. Stollerman G H: Streptococcal vaccinesand global strategies for prevention ofrheumatic fever. Am J Med 68:636. 1980

52. Beachey E H, Stollerman G H. ChiangE Y, Chiang T M, Seyer J M, Kang A H:Purification and properties of M proteinextracted from group A streptococciwith pepsin-covalent structure of theamino terminal region of type 24 Manti·gen. J Exp Med 145:1469, 1977

53. Beachey E H, Stollerman G H, JohnsonR H, Ofek I, Bisno A L: Human immuneresponse to immunization with a structur­ally defined polypeptide fragment of

streptococcal M protein. J Exp Med]50:862,1979

54. Beachey E H, Seyer J M, Kang A H:Primary structure of protective antigensof type 24 streptococcal M protein.J Biolchem 225:6284, 1980

55. Beachey E H, Seyer J M, Dale J B,Simpson W A, Kang A H: Type specificprotective immunity evoked by syntheticpeptide of streptococcus pyogenes Mprotein. Nature 292 : 457,198]

56. Harty D L, Beachey E H, Simpson W A,Dale J B: Hybridoma antibodies againstprotective arnd nonprotective antigenicdeterminants of a structurally definedpolypeptide fragment of streptococcal MProtein. J Exp Med 155: 1010,1982

57. Chandy K G, John J J, Cherian G C :Coxsackie viruses and chronic valvularheart disease. Am Heart J 100: 578,]980

58. Laitinen 0, LeirisaJo M, Allender E:Rheumatic fever and yersinia arthritis;criteria and diagnostic problems in achanging disease pattern. Scand JRheumatol4 : 145, 1975