title: Identification of T cell autoepitopes that cross-react with the C-terminal segment of the M protein of group A streptococci.
abstract: Rheumatic fever (RF) follows a throat infection with different M-serotypes of beta-hemolytic group A streptococci (GAS) and can affect different tissues, predominantly the heart. It is thought to be an autoimmune illness. Although histological examination of affected heart shows an infiltrate consisting mainly of T cells, antigens or epitopes that could be putative targets of autoimmune T cells have not been identified. We have examined the T cell response to the conserved C-terminal region of the M protein--a streptococcal surface coiled-coil protein which is the target of opsonic antibodies and antibodies which cross-react with human heart tissue. Australian Aborigine, Caucasian and Thai patients, controls and mice were studied to define regions of the protein immunogenic for T cells, and T cell lines and clones were tested for cross-reactivity to myosin as well as an extract of RF-diseased mitral heart valve. Murine (B10, B10.D2, B10.BR) M peptide-specific T cells were often cross-reactive for other M peptides but did not cross-react with human heart antigens. Patients with RF or other heart diseases, or control subjects exposed more commonly to GAS were more likely to have T cell responses to the M protein, with many regions of the C-terminus being recognized. T cell lines and a clone specific for different M peptides were generated from five donors. Cross-reactivity could be shown between different M peptides, but unlike murine M peptide-specific T cells three of the human T cell lines reacted strongly to peptides representing homologous regions of cardiac and skeletal muscle myosins, and two of these lines also responded to porcine myosin and an extract of human rheumatic mitral valve. However, these last two lines were derived from a normal donor without history of RF or other heart disease. Our data demonstrate that regions of the M protein, including regions that are being considered as subunit vaccines, have the potential to stimulate pre-existing heart cross-reactive T cells, but that the ability of such T cells to cross-react (as measured in vitro) is not in itself sufficient to lead to disease.
authors.affiliation: Molecular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Pruksakorn
authors.forename: B
authors.initials: B
authors.lastname: Currie
authors.forename: E
authors.initials: E
authors.lastname: Brandt
authors.forename: C
authors.initials: C
authors.lastname: Phornphutkul
authors.forename: S
authors.initials: S
authors.lastname: Hunsakunachai
authors.forename: A
authors.initials: A
authors.lastname: Manmontri
authors.forename: J H
authors.initials: JH
authors.lastname: Robinson
authors.forename: M A
authors.initials: MA
authors.lastname: Kehoe
authors.forename: A
authors.initials: A
authors.lastname: Galbraith
authors.forename: M F
authors.initials: MF
authors.lastname: Good
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology*; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins / Q000737:chemistry / Q000276:immunology*; D001483:Base Sequence; D002352:Carrier Proteins; D002648:Child; D003429:Cross Reactions; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D008969:Molecular Sequence Data; D044469:Racial Groups; D012213:Rheumatic Fever / Q000276:immunology; D013297:Streptococcus pyogenes / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001324:Autoantigens; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002352:Carrier Proteins; C014689:streptococcal M protein