Rheumatic fever is a sequela of group A streptococcal infection and although the exact mechanisms of pathogenesis are unknown, it has been suggested to be due to an autoimmune mechanism related to biological mimicry between the streptococcus and human tissues. Our work has focused on the identification of host and streptococcal antigens and their epitopes which react with autoantibodies against heart. Little is known about how these crossreactive autoantibodies or their corresponding T cell clones might be stimulated or regulated or how they may function in the pathogenesis of acute rheumatic fever (ARF) or rheumatic heart disease (RHD). The work proposed focuses on the goal to study the molecular and immunological basis of crossreactions between streptococci and tissue antigens, specifically myosin, and to study the potential of these crossreactions in the pathogenesis of the disease. The objectives are: 1). to continue to characterize and produce murine and human anti-streptococcal monoclonal antibody (mAb) probes which crossreact with myosin and other host tissue proteins that may be targets in rheumatic carditis or other post- streptococcal sequelae; to identify crossreactive antigens, their epitopes and structures by using murine and human Mab probes to streptococci and myosin; to produce mAbs against synthetic peptides of M protein and myosin, and to investigate crossreactive cytotoxic anti-streptococcal Mabs; 2) to analyze affinity purified, anti-M peptide antibodies from human sera from streptococcal diseases and sequelae; to determine their reaction with defined M protein and myosin peptide epitopes, host tissue autoantigens, and streptococcal components and to determine if they are cytotoxic in vitro; 3) to produce and characterize anti-idiotypic Mab reagents which recognize human and mouse anti-streptococcal/anti-myosin/anti-N- acetyl-glusosamine Mabs as well as identify idiotypes associated with certain anti-streptococcal and/or anti-N-acetyl-glucosamine responses in animals and in rheumatic and autoimmune diseases; to continue to investigate unique idiotypes associated with ARF and other post- streptococcal sequelae; 4) to further define the basis of the antibody crossreactivity by nucleotide sequence analysis of anti- streptococcal/anti-myosin/anti-N-acetylglucosamine antibody VH and VL region genes using PCR techniques; 5) to characterize and clone T cells responsive to streptococcal M protein and host tissue antigen targets myosin and laminin and to identify T cell crossreactive sequences. These studies will attempt to unravel the potential mechanisms of pathogenesis in rheumatic fever and rheumatic heart disease and will support the growing body of evidence that infectious agents play a role in the development of autoimmunity in man.
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