BREAKING OF B-CELL TOLERANCE TOWARD A HIGHLY CONSERVED SELF PROTEIN

Self proteins are processed and presented by APCs in the same way as f oreign proteins, Presentation of fragments derived from self proteins does not, however, lead to Th cell stimulation because of T cell toler ance, In this study, a novel approach was used to investigate whether B cell tolerance toward a self Ag could be due to the absence of this Th cell recognition. The highly conserved nonimmunogenic protein ubiqu itin was used as a model protein, Two modified ubiquitin molecules wer e constructed with ubiquitin segments exchanged either with the T cell epitope, OVA(325-336), which binds to the mouse A(d) MHC class II mol ecule, or with the T cell epitope, hen egg lysozyme(50-61), which bind s to the A(k) molecule. Mice were immunized with the resulting protein s. Both modified proteins elicited strong autoantibody responses towar d soluble native ubiquitin, demonstrating that insertion of a single f oreign T cell epitope can overcome the B cell nonresponsiveness. The T cell regulatory role of one of the inserted foreign T cell epitopes i n ubiquitin was studied, and at least two different Th cell specificit ies were found to operate in the response, The T cells were directed a gainst: 1) the inserted epitope, and 2) a combination of the inserted epitope and parts of the neighboring ubiquitin regions, Therefore, the absence of T cell help seems to be an important reason for B cell tol erance toward self proteins.