Antigenic composition of heart tissue

Antigenic Composition of Heart Tissue*

ENRIQUE ESPINOSA, M.D., IRVING KUSHNER, M.D. and MELVIN H. KAPLAN, M.D.?

Cleveland, Ohio

Analysis of the antigenic composition of heart tissue is essential for assessing the role of immune mechanisms in cardiac disease, and, in addition, provides an approach to the further definition of the structural properties of heart tissue. Immunologic procedures for differentiation of cardiac antigens have depended on the use of (1) antisera prepared in animals to extractable and insoluble components of heart, (2) autoimmune sera derived from patients with cardiac disease, and (3) antisera to the group A streptococcus which are cross-reactive with myocardial tissue. Technical methods have included complement fixation, tanned cell hemagglutination, antiglobulin consumption, immunofluorescence and precipitin reaction.

In addition to the antigens common to all organs, heart tissue contains antigens with distribution either limited to heart alone or limited to the heart and a few other tissues. These include: (1) heart-specific antigens, including a particulate antigen localized to sites between myofibrils, and two or three saline-soluble constituents; (2) antigens found only in heart and skeletal muscle, including insoluble components of sarcolemma extractable in acid, antigens of cross-striations of myofibers and at least one saline-soluble component, identified as myoglobin; (3) insoluble antigens common to cardiac, skeletal and smooth muscle; and (4) a soluble antigen which has been found in heart and kidney and possibly liver tissues. The cardiac antigen cross- reactive with the group A streptococcus has been identified in sarcolemma and is extractable in acid.

Further progress in the definition of these antigens and in evaluating their possible relation to cardiac disease will depend on their isolation and chemical characterization.

I T IS SELF-EVIDENT that an assessment of the possible role of immune mechanisms in

cardiac disorders, such as rheumatic fever, post- cardiotomy and postinfarction syndromes, car- diomyopathies, pericarditis and cardiac trans- plantation rejection, will depend on the differentiation and immunochemical definition of cardiac antigens considered relevant to the pathologic process under consideration. Avail- able data on antigenic constituents of heart tissue have come from several different lines of investigation. Antiheart sera prepared in animals by immunization with heart tissue homogenates or with extracts of heart tissue have been analyzed for serologic specificity by such procedures as complement fixation, tanned cell hemagglutination, antiglobulin consumption,

immunofluorescence and precipitin reaction. Such immune sera have permitted differentiation of several cardiac antigens, some of which were restricted in distribution to the heart alone (organ-specific antigens) ; others were distributed in the heart and other organs. Autoimmune sera derived from patients with cardiac disease have been utilized for similar analysis of serologic specificity for cardiac and other tissue antigens. Further definition of cardiac antigens has been derived from the observation of cross reaction, of heart tissue constituents with constituents of the group A streptococcus. The data thus far accumulated are limited, but much work is now in progress. This presentation is a review of the published information.

*From the Department of Medicine, Case-Western Reserve University School of Medicine and Metropolitan General Hospital, Cleveland, Ohio.

t Research Career Awardee, U. S. Public Health Grant K6-HE-4576 and supported by U. S. Public Health Grant H-3726.

Address for reprints: Enrique Espinosa, M.D., Cleveland Metropolitan General Hospital, 3395 Scranton Rd., Cleve- iand, Ohio 44109.

508 THE AMERICAN JOURNAL OF CARDIOLOGY

Antigenic Composition of Heart Tissue 500

~.~RDIAC ANTIGENS WITH ORGAN-SPECIFICITY

FOR HEART OR WITH LIMITED DISTRIBUTION IN OTHER ORGANS,

DEFINED WITH ANTISERA TO HEART TISSUE

Soluble Antigens in Heart and Skeletal Muscle: In early studies, Bailey and Raffel,’ using passive anaphylaxis technics, demonstrated heat-stable, water-soluble antigens in both heart and skeletal muscle but not in other organs. Henle et a1.2 described antigenic reactivity characteristic of heart tissue only in a sedimentable particulate fraction of crude saline extracts of bovine and mouse heart. They reported that antisera to the heart induced agglutination of tissue particles from the myocardium, but antisera to other organs were nonreactive. Absorption of antiheart sera with heart particles abolished this serologic activity, but absorption with kidney, liver, or lung particles had little or no effect. However, studies with skeletal muscle were not included.

In studies of the organ-specificity of the mammalian heart, Kaplan and Meyeserian3-5 imtnunized rabbits with homogenates from bovine and rat heart and examined the cross reactivity of such antisera with rabbit heart. By this cross-reactive autoimmune technic, it was possible to eliminate from consideration antigens with species-specific properties. Anti- sera to bovine or rat heart reacted with saline extracts of rabbit heart by capillary floc- culation tests and complement fixation, and with sections of heart tissue by immunofluorescence. These serologic reactions were abolished after absorption of sera with heart tissue but not after absorption with skeletal muscle or other rabbit tissue extracts. High speed centrifugation of heart extracts indicated that the reactive antigen in these tests was capable of being sedi- mcnted. Immunofluorescent staining of sections of rabbit heart tissue with these antiheart sera rel.ealed intense staining of myofibers in both intermyofibrillar and sarcolemmal-subsarcolem- ma1 sites. When antisera were absorbed with washed rabbit heart homogenate, staining was abolished completely; but when antisera were absorbed with rabbit skeletal muscle, only the sarcolemmal-subsarcolemmal staining was elim- inated and the intermyofibrillar pattern per- sisted. Absorption with other organ homogenates had no effect on these two patterns of staining. Antisera to skeletal muscle were reactive with sarcolemma of both heart and skeletal muscle. These data indicated (1) the presence of a particulate organ-specific antigen of heart in

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intermyofibrillar sites, capable of being sedimented by high speed centrifugation, possibly related to sarcoplasmic reticulum, and (2) the presence of antigen common to heart and skeletal muscle in sarcolemmal-subsarcolemmal sites.

Gery and Davies,” employing the tamred cell hemagglutination technic, reported that antisera to saline extracts of dog or rat heart cx- hibited serologic reactivity with heart extracts of a variety of animal species but failed to react with lung, liver, or kidney extracts of these species. Unfortunately, skeletal muscle extracts were not tested. In later studies, Grry et al7 demonstrated that the heart antigen common to the different mammalian species differed from that described by Kaplan since it was not capable of being sedimented by high speed centrifugation. Thus, occurrence of a saline- soluble antigen with apparent organ specificity for the heart was suggested by these data.

Antigenic analysis of soluble cardiac antigens in saline extracts of human heart was next undertaken by Kushner and Kaplan,” who em- ployed immunodiffusion and immunoelectro- phoresis. Goat antiserum to hotnogenate of human heart demonstrated reaction by gel diffusion with an antigen present in saline extracts of both myocardial and skeletal rnusclc. This antigen was not detected in saline extracts of other human organs but was present in the heart of all species tested. It was identified as ~nyo- globin by the pattern of identity which it gave with purified myoglobin in immunodiffusion plates, as well as by similarity of physicochemical behavior in gel filtration and gradient ultracentrifugation. A soluble cardiac antigen with strict organ-specific properties could not be demonstrated in these studies.

A second antigen common to the heart and kidney was demonstrated by gel diffusion. This antigen, present in primate species only, was not detected in extracts of fetal or newborn human hearts.

Insoluble Antigens in Heart and Skeletal Muscle: As noted previously, insoluble antigen(s) common to the heart and skeletal muscle were localized to sarcolemmal-subsarcolemmal sites by Kaplan and Meyeserian.j These antigens could be solubilized in dilute acid, and a sys- tematic antigenic analysis of such acid extracts of heart tissue was carried out by Espinosa and Kaplan.g Soluble constituents of human heart tissue were first removed by homogenization in saline and distilled water, and the remaining residue extracted in 0.05 M citric acid, pH 2.5.

510 Espinosa et al.

Such acid extracts of the heart and other organs were analyzed by immunodiffusion and immunofluorescence employing rabbit antisera to acid extracts of human myocardium. Analy- sis by immunodiffusion of the precipitin lines given by these antisera indicated that the cardiac antigens extracted by acid were multiple. Two antigens common to heart and skeletal muscle were differentiated by direct precipitation and by specific absorption tests. Both were localized to sarcolemmal-subsarcolemmal structures of myofibers, as determined by immunofluorescent studies. One of these antigens was found widely distributed among mammalian species ; the other was found in primate species only. Both antigens were susceptible to trypsin and pepsin digestion, relatively thermolabile and insoluble in organic solvents. Absorption and inhibition experiments excluded any relation of these antigens to myoglobin or other saline-soluble components of heart. Some degree of purification of these antigens was obtained by ion exchange chromatography and gel filtration. Other antigens common to heart and skeletal muscle have been differentiated more recently. In addition, such acid extracts of heart contained antigens of reticulin and basement mem- branes common to all organs. Evidence of antigen in sarcolemma related to basement membrane and reticulin in all other organs was suggested previously by the work of Cruickshank and HilLlo Scott11*‘2 presented evidence of an anti- genie relation of sarcolemma of muscle, media of arteries and reticulin in liver and spleen.

Jaffe et a1.t3 described an organ-specific antigen of heart in extract preparations of rabbit heart with the use of gel diffusion technics. However, in two of nine positive sera, reaction against skeletal muscle could also be shown.

Recently Halbert et a1.14 reported that precipitating autoantibodies to rabbit heart could be induced by hyperimmunization of rabbits with homogenates of homologous and heterologous heart tissue including tissue of rabbit, human, rat and guinea pig heart, in Freund’s adjuvant. From three to five precipitating sys- tems were differentiated by immunodiffusion when these antisera were tested against saline- soluble extracts of rabbit heart. Direct tests and absorption tests with other extracts of rabbit organs, including skeletal muscle, indicated that these sera contained organ-specific antibodies for at least two and possibly three soluble antigens of heart tissue. These antigens were common to several mammalian species.

In summary, the fallowing antigens of heart have

been dz$ferentiated by analysis of antiheart sera:

1. An organ-specific insoluble particulate antigen, present in cardiac myofibers and localized to sites between myofibrils.

2. Insoluble antigens common to heart and skeletal muscle, present in sarcolemmal-subsarcolemmal sites in myofibers and solubilized by dilute acid.

3. Organ-specific soluble antigens, two or possibly three in number.

4. Soluble antigen(s) common to heart and skeletal muscle, including myoglobin and heat- stable haptens.

5. Soluble antigen common to heart and kidney and possibly liver tissue.

6. Antigens of reticulin, basement membrane, connective tissue and vessels common to all organs.

In addition, antisera to striated muscle con- tractile proteins, myosin, heavy meromyosin, light meromyosin and actin have been used for differentiation of these proteins and for their cytologic Iocalization in the sarcomere of myofibrils.15j16

HEART ANTIGENS REVEALED BY HUMAN SERA CONTAINING AUTOANTIBODIES

TO HEART TISSUE

Antigen preparations that have been em- ployed in serologic tests for demonstrating autoantibodies to heart tissue have included heart homogenates, saline and ethanol extracts of heart, and tissue sections. Test procedures have included complement fixation, collodion particle agglutination, tanned cell hemagglutination, antiglobulin consumption and immunofluorescence. The use of an immunofluorescent technic has permitted differentiation of serologic reactions by the histologic distribution of the reactant within sections of cardiac tissue.

Kaplan et a1.i7 examined the reactive properties of sera from patients with rheumatic fever and from patients recovering from cardiac surgery and myocardial infarction. They demonstrated by immunofluorescent technic three patterns of reaction : subsarcolemmal, intermyofibrillar and diffuse sarcoplasmic staining. The most frequent staining pattern was of the subsarcolemmal rim of sarcoplasm, with a fainter mottled reaction of the remaining sarcoplasm. Immunofluorescent absorption tests indicated that the cardiac antigen related to this subsarcolemmal pattern of staining was also

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present in skeletal muscle but not in other organs. l7 Hess et al.ls and Van der Geld,lg utilizing immunofluorescent methods, confirmed the specificity of such reactive sera for both myocardial and skeletal muscle.

The occurrence of yet another specificity of autoantibody was indicated by the observation that sera of some patients with myasthenia gravis exhibited reaction with antigens of cross striations of both voluntary and cardiac muscle fibers.“” Autoantibody reactive with cross striations has also been observed in sera of patients with cardiac disease.21

rls determined by the immunojluorescent technic, the serologic staining reactions with heart sections ob- serned in this laboratory and others with the use of human pathologic sera are directed to the following antigens:

1. Antigens distributed in sarcolemmal and subsarcolemmal sites, present in skeletal muscle as well as the heart.

2. Reactants localized between myofibrils, giving an intermyofibrillar pattern of staining.

3. Sarcoplasmic antigen(s) giving a diffuse sarcoplasmic pattern of staining.

4. Constituents of cross striations of myofibers, present also in skeletal muscle.

5. Antigen(s) of smooth muscle of vessel walls and of subendocardium.

6. Components in focal sites associated with collagenous connective tissue, and as yet not further defined.

Serologic tests for autoantibodies to heart tissue by other technics, such as complement fixation, collodion particle agglutination, tanned cell hemagglutination, antiglobulin consumption, or precipitation, and using as test antigens crude saline extracts of heart tissue, alcoholic extracts, or washed homogenates of heart tissue, could conceivably be related to one or more of these reactants revealed by immunofluorescent staining.

Little is known of the antigenic components of saline extracts of heart tissue which have been found reactive with autoantibodies in pathologic sera, in, for example, tanned cell hemagglutination tests. Reactive antigens in saline-soluble extracts of heart tissue have been differentiated from antigens of spleen, kidney and liver tissue but not as yet from antigen in skeletal muscle. Hemagglutination tests have shown that sera from patients with myasthenia gravis may react with saline extracts of both heart and skeletal muscle.22 It also remains to be determined whether saline extracts of heart tissue contain

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multiple autoantigenic components reactive with human sera.

ANTIGENS OF HEART TISSUE REI.ATED w THE CROSS REACTION OF GROUP A STREPTOCOCCI AND HEART TISSUE

The cross reaction of rabbit antistreptococcal serum with human heart tissue was first demonstrated by complement fixation and immunofluorescence.23 ,24 Immunofluorescent reaction was shown with antigen in sarcolemmal- subsarcolemmal sites in both heart and skeletal muscle as well as in smooth muscle fibers of vessel walls and endocardium. Reaction with smooth muscle was found to vary with specimens of heart tissue from different individuals, since only 14 of 40 different human heart specimens showed reactivity with antiserum.24 In these studies, cross reactive sera were prepared by immunization with group A streptococcal cells, cell walls, or acid extracts of cells and cell walls. Serologic reaction with striated and smooth muscle appeared attributable to the same antigen present in these different structures, since specific absorption test with either streptococcal or heart extract fractions abolished serologic reactivity for both sites simultaneously. The antigen was present also in heart and skeletal muscle of the rabbit; however, the extent of species distribution was not further studied. Absorption tests indicated that the antigen was not present in saline extracts of heart but was associated with the fraction of homogenates of heart tissuez3 that is particulate or capable of being sedimented. Recent evidence has indicated that this antigen is solubilized by acid extraction of washed human heart homogenates.25 As noted previously, such acid extracts of heart contained antigens localized in sarcolemmal-subsarcolem- ma1 sites in both heart and skeletal muscle.g

Evidence for the existence of antigen common to cardiac, skeletal and smooth muscle was also provided by Zabriskie and Freimer,2fi who demonstrated cross reaction with human cardiac and skeletal muscle and smooth muscle of vessel walls with rabbit antisera to streptococcal groups A and C and with antisera to cell mem- branes of these streptococcal groups. ‘The cardiac antigen appeared to be present in “sarcolemmal sheaths” prepared from heart tissue and was extractable with dilute hydro- chloric acid.

Nakhla and Glynn2’ also described cross-reactive antibodies to heart tissue after immunization of rabbits with group A streptococci. By

512 Espinosa et al.

immunofluorescence, complement fixation and passive hemagglutination, antisera to 9 of 10 group A streptococcal strains of different types and antiserum to a group C strain reacted with heart tissue of man, rabbit and guinea pig. Reactive antigen was localized in sarcolemmal and subsarcolemmal sites of cardiac and skeletal muscle. No reaction with other organs was observed. Although staining was sometimes noted in the smooth muscle fibers of the media of cardiac blood vessels, such staining of vessel walls or of smooth muscle was not observed in other organs. It was suggested that the antigen was also present in saliva and was related to blood group substances.

In studies of cross-reactive antibodies to heart tissues induced by immunization of rabbits with type 5, group A streptococci, Lyampert et a1.28 and Danilova,2g using the immunofluorescent procedure, demonstrated reactivity of antisera with antigens of guinea pig cardiac and skeletal muscle in sarcolemmal and subsarcolemmal sites. Identical reactions with human, rabbit, rat and mouse heart sections were also noted, thereby indicating wide distribution of this antigen among various species. Absorption experiments confirmed the specificity of this reaction for heart and skeletal muscle. Serologic reaction of the type 5 antiserum was abolished by extracts of the homologous type only, The antigen detected was not found in smooth muscle, liver, kidney, or adrenal tissues. A similar reaction was noted with antiserum to a type 29 strain. However, antiserum to a type 1 strain reacted with intercalated disc of human myocardium.

The reverse cross reaction, that is, reaction of antiheart sera with extracts of group A streptococci, has also been observed by precipitin reaction in immunodiffusion plates.14r30 These cross reactions have not yet been shown to be related to cardiac autoantibody responses. Evidence of a cross reaction between a structural glycoprotein of heart valves and the group A carbohydrate of the streptococcus has been reported recently.31

Tissue Antigen Involved in Cross Reactions: Al- though there is not as yet complete agreement among the investigators cited with respect to the components of the streptococcal cell which contain the cross-reactive antigen(s), it seems probable that the same or closely related tissue antigen is involved in the observed cross reactions. There is agreement that this antigen is localized in cardiac and striated muscle, and

evidence has been presented that it is also present in smooth muscle of vessel walls, but may vary with respect to localization in this site in hearts of different individuals.24 Other investigators have failed to observe reaction with smooth muscle of vessel walls. Whether the dif- ferences observed may be related to individual variation of the heart specimens examined or to a difference of the reactive antigen itself remains to be resolved.

With respect to cross-reactive properties of human sera with heart antigen and with constituents of group A streptococci, such antibodies have been observed in sera of the majority of patients with rheumatic fever, rheumatic heart disease and glomerulonephritis, and in the sera from a lesser number of patients with uncompli- cated streptococcal infection. Kaplan and Svec,32 using immunofluorescent-absorption technics, observed such cross reactivity to in- volve sarcolemma of human heart. Immuno- fluorescent cross reaction of rheumatic sera with sarcolemma was also noted by Zabriskie.33 Reaction of rheumatic fever sera with heart tissue was found complicated by the presence of multiple autoantibodies to heart tissue.

CONCLUDING COMMENT

Several cardiac antigens with limited organ distribution have been identified with the use of different immunologic methods. Because of lack of chemical definition of most of the reported antigens, an accurate evaluation of their relation is not yet possible.

Knowledge of the antigenic composition of heart tissue will be considerably enhanced by chemical characterization of specific antigenic constituents. Such knowledge may then be ap- plied to many of the questions raised about the role of autoimmunity or autosensitization in cardiac disease, and possibly also to the de- velopment of methods for detecting specific cardiac antigens in blood or other biologic fluids. Recent developments in cellular frac- tionation procedures, technics of solubilizing water-insoluble tissue components and methods for purification and physicochemical analysis of tissue constituents should permit accelerated investigation in the future.

REFERENCES

1. BAILEY, G. H. and RAFFEL, S. Organ specificity of tissues of the dog and man as shown by passive anaphylaxis in guinea pigs. J. Exper. Meal., 73:617, 1941.

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2. HENLE, W., CHAMBERS, L. A. and GROUPE, W. The serological specificity of particulate components derived from various normal mammalian organs. J. &per. Med., 74~495, 1941.

3. KAPLAN, M. H. Immunologic studies of heart tissue. I. Production in rabbits of antibodies reactive with an autologous myocardial antigen following immunization with heterologous heart tissue. J. Zmmunol., 80:254, 1958.

4. KAPLAN, M. H. Immunologic studies of heart tissue. II. Differentiation of a myocardial sarcoplasmic antigen and cardiolipin. J. Zmmunol., 80: 268, 1958.

5. KAPLAN, M. H. and MEYESERIAN, M. Immunologic studies of heart tissue. v. Antigens related to heart tissue revealed by cross-reaction of rabbit antisera to heterologous heart. J. Immunol., 88 :450, 1962.

6. GERY, I. and DAVIES, A. M. Organ specificity of the heart. I. Animal immunization with heterologous heart. J. Zmmunol., 87:351, 1961.

7. GERY, I., DAVIES, A. M. and LAZAROV, E. Im- munity and immunotolerance to bovine heart antigens in the rat. Immunolo~, 7~192, 1964.

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9. ESPINOSA, E. and KAPLAN, M. H. Antigenic analysis of human heart tissue. Identification of antigens with specificity restricted to heart and skeletal muscle in acid extracts of myocardium. J. Zmmunol., 100:1020, 1968.

10. CRUICKSHANK, B. and HILL, A. G. S. Histochemi- cal identification of connective tissue antigen in rat. J. Path. t?? Bact., 66:283, 1953.

11. SCOTT, D. G. A study of the antigenicity of basement membrane and reticulin. Brif. J. Exper. Path., 38: 178,1957.

12. SCOTT, D. G. An immune-histological study of connective tissue. Ann. Rheumat. Dis., 18 :207, 1959.

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14. HALBERT, S. P., HOLM, S. E. and THOMPSON, A. Cardiac autoantibodies. I. Immunodiffusion analysis of multiple responses evoked homologously and heterologously. J. Exper. Med., 127:613, 1968.

15. MARSHALL, J., HOLTZER, H., FINCK, H. and PEPE, F. The distribution of protein antigens in striated myofibrils. Exper. Cell Res., Suppl. 7:219, 1959.

16. SZENT-GYORCYI, A. G. and HOLTZER, H. Fixation of muscle proteins with antibodies. Biochim. et biophys. acta, 41:14, 1960.

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Heart muscle antibodies in rheumatic fever and other diseases. J. Clin. Iwest., 43 :886, 1964.

19. VAN DER GELD, H. Anti-heart antibodies in the post-pericardiotomy and the post-myocardial-infarction syndromes. Lancet, 2:617, 1964.

20. BEUTNER, E. Il., WITEBSKY, E., RICKEN. I>. and ADLER, R. H. Studies on autoantibodies in myasthenia gravis. J.A.M.A., 183,:46, 1962.

21. DUHEILLE, J. and PETITIER, H. Etudr immuno- histologique des auto-antig&nes myocardiques. Compt. rend. sot. biol., 161 ~419, 1967.

22. DJANIAN, .\. Y., BEUTNER, E. H. and WITEBSKY, E. Tanned-cell hemagglutination test for detection of antibodies in sera of patients with myasthc~nia gravis. J. Lab. G Clin. Med., 63:60, 1964.

23. KAPLAN, M. H. and MEYESBRIAN, M. An immuno- logical cross-reaction between group A streptococcal cells and human heart tissue. Lancrt, 1 :706, 1962.

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25. KAPLAN, M. H., ESPINOSA, E. and FRENGLEY, J. D. Properties of solubilized cross-reactive antigens of streptococcal cell walls and mammalian heart and heart valves (Abstr.). Fed. Proc., 26:701, 1967.

26. ZABRISKIE, J. B. and FREIMER, E. H. An immuno- logical relationship between the group A streptococcus and mammalian muscle. J. Exper. Med., 1241661, 1966.

27. NAKHLA, L. S. and GLYNN, L. E. Studies on the antigen in P-hemolytic streptococci that cross- reacts with an antigen in human myocardium. ImmunoloQ, 13 :209, 1967.

28. LYAMPERT, I. M., VVEDENSKAYA, 0. T. and DANI- LOVA, T. A. Study on streptococcus group A antigens common with heart tissue elements. Immunolou, 11:313, 1966.

29. DANILOVA, T. A. An immunofluorescent study of the antigen of group A streptococcus and heart tissue from human and experimental animals. Fed. Proc., 25 (Transl. Suppl.):lO99, 1966.

30. KAPLAN, M. H. and SUCHY, M. L. Immunologic relation of streptococcal and tissue antigens. II. Cross-reaction of antisera to mammalian heart tissue with a cell wall constituent of certain strains of group ,4 streptococci. J. Exper. Med., 119~643, 1964.

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32. KAPLAN, M. H. and SVEC, K. H. Immunologic relation of streptococcal and tissue antigens. III. Presence in human sera of streptococcal antibody cross-reactive with heart tissue. Association with streptococcal infection, rheumatic fever, and glomerulonephritis. J. Exper. Med., 119:651, 1964.

33. ZABRISKIE, J. B. Mimetic relationships between group A streptococci and mammalian tissues. Advances Immunol., 7~147, 1967.


End of Symposium

VOLl_?ME 24, OCTOBER 1969

Antigenic composition of heart tissue

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