Rheumatoid arthritis is a chronic autoimmune polyarthritis affecting approximately 1% of the Caucasian population. Collagen-induced arthritis (CIA) in DBA/1 mice shares features with rheumatoid arthritis in humans. In these mice, autoimmune arthritis is induced by immunization with type II collagen. When presented by the class II MHC molecule I-Aq, the 10-mer epitope I A G F K G E Q G P K within type II collagen primes autoreactive CD4+ T cells capable of initiating autoimmune arthritis. Partially homologous to the 10-mer T cell epitope, the P G E Q P K sequence is found within the platelet aggregation-associated protein (PAAP) expressed on the surface of Streptococcus sanguis strain 133-79. By repeated swallowing from the time of acquisition in infancy, the collagen-like immunodeterminant on S. sanguis cells is hypothesized to stimulate the immune system transmucosally and modulate the development experimental autoimmune arthritis. We first optimized the arthritis-induction protocol with primary and secondary type II collagen immunizations. The single immunization protocol stimulates rapid onset and induces greater levels of arthritis when compared to a multiple immunization protocol. In tolerization experiments, neonatal oral inoculation of live S. sanguis reduced the time of onset, rate of development and the final severity of arthritis when delivered at 6 days post-partum. It appears that the inhibitory effect is dependent on partial T cell cross reactivity between the 10-mer of type II collagen and the plateletinteractive domain on S. sanguis . Immunization with either type II collagen generates T cells that recognize heat killed PAAP+ S. sanguis. Alternatively, live S. sanguis in CFA cannot prime anti-type II collagen T cells. The oral tolerogenic effects therefore are challenged by the possibility that parenteral inoculation with S. sanguis may stimulate primed type III collagen-specific T cells, for example, in rheumatoid arthritis patients. Finally, Peyer's patch and spleen T cells appear responsible for the transmucosal anti-arthritic effect. Adoptive transfer of these T cells into recipient mice inhibits the development and the severity of arthritis. In conclusion, the tolerogenic effect elicited by S. sanguis suggests a novel symbiotic relationship between the host and the commensal microbiota expressing self-mimicking epitopes.
Streptococcus sanguis modulation of tolerance in murine arthritis
Massimo Costalonga
First
1999-01-01
Abstract
Rheumatoid arthritis is a chronic autoimmune polyarthritis affecting approximately 1% of the Caucasian population. Collagen-induced arthritis (CIA) in DBA/1 mice shares features with rheumatoid arthritis in humans. In these mice, autoimmune arthritis is induced by immunization with type II collagen. When presented by the class II MHC molecule I-Aq, the 10-mer epitope I A G F K G E Q G P K within type II collagen primes autoreactive CD4+ T cells capable of initiating autoimmune arthritis. Partially homologous to the 10-mer T cell epitope, the P G E Q P K sequence is found within the platelet aggregation-associated protein (PAAP) expressed on the surface of Streptococcus sanguis strain 133-79. By repeated swallowing from the time of acquisition in infancy, the collagen-like immunodeterminant on S. sanguis cells is hypothesized to stimulate the immune system transmucosally and modulate the development experimental autoimmune arthritis. We first optimized the arthritis-induction protocol with primary and secondary type II collagen immunizations. The single immunization protocol stimulates rapid onset and induces greater levels of arthritis when compared to a multiple immunization protocol. In tolerization experiments, neonatal oral inoculation of live S. sanguis reduced the time of onset, rate of development and the final severity of arthritis when delivered at 6 days post-partum. It appears that the inhibitory effect is dependent on partial T cell cross reactivity between the 10-mer of type II collagen and the plateletinteractive domain on S. sanguis . Immunization with either type II collagen generates T cells that recognize heat killed PAAP+ S. sanguis. Alternatively, live S. sanguis in CFA cannot prime anti-type II collagen T cells. The oral tolerogenic effects therefore are challenged by the possibility that parenteral inoculation with S. sanguis may stimulate primed type III collagen-specific T cells, for example, in rheumatoid arthritis patients. Finally, Peyer's patch and spleen T cells appear responsible for the transmucosal anti-arthritic effect. Adoptive transfer of these T cells into recipient mice inhibits the development and the severity of arthritis. In conclusion, the tolerogenic effect elicited by S. sanguis suggests a novel symbiotic relationship between the host and the commensal microbiota expressing self-mimicking epitopes.
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