An arthritogenic T-cell specific epitope on cyanogen bromide fragment 11 (CB 11) of type II collagen can behave as a specific toleragen when administered intraperitoneally or intravenously in a genetically-defined, T-cell dependent mouse model of collagen-induced arthritis. Tolerance is associated with a reduction in signs of arthritis and reduced titers of anti-collagen antibodies. This arthritogenic epitope on CB 11 is mimicked structurally and immunologically by a naturally occurring collagen-like protein domain (of the platelet aggregation-associated protein, PAAP) expressed on the surface of the early colonizing oral bacterium, Streptococcus sanguis. By repeated swallowing from the time of acquisition in infancy, the collagen-like immunodeterminant on cells of S. sanguis is hypothesized to stimulate the systemic. immune system transmucosally. Since type II collagen will induce arthritis, this project will test the novel hypothesis that a 2.7 kDa, collagen-like peptide from S. sanguis will modulate the (i) development of T-cell dependent experimental arthritis in mice or (ii) protect by inducing specific systemic immune tolerance. To test these hypotheses, this proposal will compare features of CB 11 of type II collagen to a 2.7 kDa collagen-like peptide from S. sanguis. Specifically, this project will (i) partially characterize the structure of the 2.7 kDa collagen-like fragment from S. sanguis. After purification, the primary sequence of amino acids will be determined and compared to CB II of type II collagen. The extent of homology will be determined for key residues. Since it contains a structural motif that is homologous to the tolerogenic domain of type H collagen, the 2.7 kDa peptide will be used to (ii) tolerize mice. The 2.7 kDa peptide and CB II will he inoculated into separate mice either through intraoral or intraperitoneal routes to induce tolerance and the (a) time of onset, (b) incidence, and (c) severity of type II collagen-induced arthritis in each case will be compared. Since type II collagen-induced arthritis is T-cell dependent, the project will (iii) isolate T-cells from Peyer's patches and spleens from mice tolerized with the 2.7 kDa peptide to show adoptive transfer of tolerance to naive mice. Data from this project may suggest that commensal oral streptococci express an important environmental antigen that may contribute to the pathogenesis of rheumatoid arthritis in humans. Novel tolerogenic peptides will also be identified that may be useful for prevention and treatment.
| Costalonga, Massimo; Hodges, James S; Herzberg, Mark C (2002) Streptococcus sanguis modulates type II collagen-induced arthritis in DBA/1J mice. J Immunol 169:2189-95 |
