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Circulation. 1995;92:281-282

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(Circulation. 1995;92:281-282.)
© 1995 American Heart Association, Inc.

Articles

T-Cells and T-Cell Clones in Rheumatic Fever Valvulitis

Getting to the Heart of the Matter?

John B. Zabriskie, MD

From the Laboratory of Clinical Microbiology/Immunology, The Rockefeller University, New York, N.Y.

Correspondence to John B. Zabriskie, MD, Head of the Laboratory of Clinical Microbiology/Immunology, Rockefeller University, New York, NY 10021-6399.


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
In spite of almost sixty years of intensive investigation, the pathogenic mechanisms underlying the initiation of the disease rheumatic fever remain elusive. This is not to say we have not made any progress. The identification of the organism as a group A Streptococcus by Rebecca Lancefield,1 the pioneering work of the association of Group A streptococci with rheumatic fever by Collis,2 and Coburn,3 and the primary prevention of rheumatic fever by judicious use of penicillin by Rammelkemp and associates4 all represent milestones in our understanding of this host-parasite relationship.

What is missing is our understanding of the exact sequence of events starting with a preceding streptococcal pharyngitis, often so mild as to go unnoticed, through a clearly defined latent period and ending with one or more clinical manifestations of disease involving different organ systems.

Among the many hypotheses entertained to explain this sequence of events has been the concept that rheumatic fever is a streptococcal-induced autoimmune disease. Thus, there is an abnormal immune response (both at a humoral and cellular level) on the part of the host to those streptococcal antigens cross reactive with relevant mammalian antigens. Implicit in this concept is that the abnormal immune response on the part of the host is genetically programmed.

While still speculative, a mounting body of evidence is emerging to support this concept. At the humoral level, heart reactive antibodies are seen in ARF patients during the acute stages, decline over time after the attack, and are invariably seen in recurrences.5 The streptococcal-induced nature of these antibodies is attested to by the fact that both streptococcal antigens and cardiac antigens can abolish the binding to heart tissue.6 Heart reactive antibodies seen in the post pericardiotomy syndrome (PPS) are only inhibited by cardiac antigens.7 Similarly, antibodies cross reactive with M proteins and cytoskeletal proteins such as myosin and tropomyosin are also seen in ARF patients.8 9

In a second major manifestation of rheumatic fever, namely, Sydenham's chorea, antibodies to the cells of the caudate nucleus are also present in the vast majority of the sera of patients with this clinical presentation of the disease.10 Furthermore, this antibody was detected in the CSF specimens of five patients with active chorea (Zabriskie JB. Unpublished data). A direct role for this antibody in the disease state has recently been demonstrated in that repeated plasmorphoresis of these patients has markedly diminished their symptoms (Dr Henrietta Leonard. Personal communication). As in the case of the heart reactive antibodies, these antibodies can also be absorbed by streptococcal antigens. Sera of patients with SLE also stain the nucleus of caudate cells but are not absorbed by streptococcal antigens.10

While there is a vast amount of evidence implicating cross reactions between streptococcal antigens and relevant mammalian antigens at a humoral level, only recently has the question of the cellular response to these cross reactive antigens been addressed. Using peripheral blood mononuclear cell populations obtained from acute rheumatic fever patients. Read and co-workers11 12 and others13 demonstrated that there was a heightened cellular response to both streptococcal and mammalian antigens in these patients compared to controls and patients with poststreptococcal glomerulonephritis. The streptococcal cellular reactivity persisted for at least 2 years after the initial attack. Most interesting was the observation that this cellular reactivity was primarily directed to membrane antigens from rheumatic fever associated strains.11

Perhaps most relevant to the disease process has been the studies of the cell types in the cardiac lesions themselves. Raizada et al14 clearly demonstrated the presence of T-cell subsets in a series of valves removed 10 to 20 years after the attack. Kemeny and colleagues15 carried out a more extensive study of the cell types found in the valvular specimens some of which were obtained during acute rheumatic fever carditis. In these valves, approximately 50% of the cells were macrophages and the CD4 to CD8 ratios approached 4:1. The preponderance of CD4 cells in the lesions strongly supports a hypercellular/cytotoxic reaction to streptococcal and/or cross reactive mammalian antigens. Yoshinaga showed that T-cell lines derived from these same valvular specimens and primed with streptococcal membrane antigens reacted to cell walls and membranes of rheumatic fever associated strains. Surprisingly, no reactivity to M protein or cytoskeletal proteins was seen in their studies.16

The paper by Guilheme and co-workers in this issue of Circulation makes a significant contribution to our further understanding of the role of T cells in the disease process. First this studies were carried out with "virgin" T-cell clones expanded only with PHA and not previously primed with streptococcal antigens as described by Yoshinaga.16 Secondly, the T-cell clones were obtained by limiting dilution and therefore quite likely to be individual T-cell clones. Most importantly their clones primarily recognized only those epitopes of the M protein moiety that were specifically cross reactive with the cytoskeletal proteins such as myosin and vimentin and perhaps other mammalian antigens. Some of their clones did recognize other segments of the M protein moiety but did not simultaneously react to any mammalian antigens. These results are quite striking and suggest a more intimate role for these mammalian streptococcal cross reactions in the disease process. The restricted specificity of these T-cell clones is indicated by the observation that 4 of 5 clones were of the CD4+ phenotype implying that these cells might well display restricted Vß receptors. These studies are now in progress. Finally the fact that none of the T-cell clones obtained from patients with cardiac diseases other than rheumatic fever recognized the M protein moiety or mammalian antigens points to the rather unique specificity of the rheumatic fever valvular T-cell clones.

As is so often true in science, this paper raises as many intriguing questions as it provides answers. The authors primarily confined their studies to the more terminal end of the M protein moiety. Yet, one of the major streptococcal vaccine candidates as proposed by Fischetti and co-workers17 is directed towards the conserved C repeat region of the M protein molecule, a region of the molecule much closer to the cell wall anchor. Whether or not significant streptococcal mammalian cross reactions are seen in this area needs to be addressed. Secondly, as both Barnett and Cunningham18 and Yoshinaga16 have pointed out, there appears to be other mammalian streptococcal cross reactions unrelated to the M protein moiety that was not explored in this paper. Finally, the exact nature of the mammalian antigens involved in these microbial host mutations needs to be more fully defined especially in the context of the T cell receptor.

What is true is that the cellular arm of the immune system appears to more initimately involved in the disease process than previously recognized. The authors have clearly opened up a path for what will be an area of future fruitful investigations.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Lancefield RC. Specific relationships of cell composition to biologic activity of hemolytic streptococci. Harvey Lectures. 1941;36:251-265.
  2. Collis WRF. Acute rheumatism and hemolytic streptococci. Lancet. 1931;1:1341-1345.
  3. Coburn AF. The Factor of Infection in Rheumatic State. Baltimore, Md: Williams and Wilkins; 1931.
  4. Rammelcarp CH, Denny FW, Wannamaker LW. Studies on the Epidermiology of Rheumatic Fever. Minneapolis, Minn: University of Minnesota Press; 1952:72-89.
  5. Zabriskie JB, Hsu KC, Seegal BC. Heart-reactive antibody associated with rheumatic fever: characterization and diagnostic significance. Clin and Exp Immunol. 1970;7:147-159.
  6. Zabriskie JB. Rheumatic fever: the interplay between host, genetics and microbe. Lewis A Conner Memorial Lecture. Circulation. 1985;71:1078-1086.
  7. Engle MA, Gay WA, Zabriskie JB, Senterfit LB. The postpericardiotomy syndrome: 25 years' experience. J Cardiovas Med. 1984;April:321-332.
  8. Dale JB, Beachey EH. Epitopes of streptococcal M proteins shared with cardiac myosins. JEM. 1985;162:583-591. [Abstract/Free Full Text]
  9. Cunningham ME, Krisher K, Graves DC. Murine monoclonal antibodies reactive with human heart and group A streptococcal membrane antigens. Infect and Immun. 1984;46:34-41. [Abstract/Free Full Text]
  10. Husby G, van de Rijn I, Zabriskie JB, Abdin ZH, Williams RC Jr. Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Exp Med. 1976;144:1094-1110. [Abstract/Free Full Text]
  11. Read SE, Zabriskie JB, Fischetti VA, Utermohlen V, Falk R. Cellular reactivity studies to streptococcal antigens in patients with streptococcal infections and their sequelae. JCI. 1974;54:439-450.
  12. Read SE, Reid HFM, Fischetti VA, Poon-King T, Rankissoon R, McDowell M, Zabriskie JB. Serial studies on the cellular immune response to streptococcal antigens in acute and convalescent rheumatic fever patients in Trinidad. J Clin Immunol. 1986;6:433-441. [Medline] [Order article via Infotrieve]
  13. Hutto JH, Ayoub EM. Cytotoxicity of lymphocytes from patients with rheumatic carditis to cardiac cells in vitro. In: Read SE, Zabriskie JB, eds. The Immune Response. New York: Academic Press; 1980:733-738.
  14. Raizada V, Williams RC Jr, Chopra P, Gopinath N, Prakash K, Sharma KB, Herian KM, Panday SP, Aurora R, Nigam M, Zabriskie JB, Husby G. Tissue distribution of lymphgocytes in rheumatic heart valves as defined by monoclonal anti-T cell antibodies. Amer J Med. 1983;74:90-96. [Medline] [Order article via Infotrieve]
  15. Kemeny E, Grieve T, Marcus R, Sarelli P, Zabriskie JB. Identification of mononuclear cells and T cell subsets in rheumatic valvulitis. Clin Immunol Immunopath. 1989;52:225-237. [Medline] [Order article via Infotrieve]
  16. Yoshinaga M, Figueroa F, Wahid MR, Marcus RH, Suh E, Zabriskie JB. Antigenic specificity of lymphocytes isolated from valvular specimens of rheumatic fever patients. J Autoimmunity. In press.
  17. Fischetti VA. Streptococcal M protein: molecular design and biological behaviour. Clin Microbiol Revs. 1989;2:285-314. [Abstract/Free Full Text]
  18. Barnett LA, Cunningham MW. A new heart cross-reactive antigen in streptococcus pyogene is not M protein. J Inf Dis. 1990;162:685-882.[Medline] [Order article via Infotrieve]



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