Understanding of the Pathogenesis of Spontaneous Autoimmune Disease by the Deletion of the Dominant Autoantigen

It is not known whether pathogenic autoimmune responses that arise spontaneously are initiated and driven by autoantigen, or by environmental agents. This question will be addressed in the study by disrupting the AE1 gene to prevent expression of the dominant red blood cell (RBC) autoantigen, Band 3 in autoimmune hemolytic anemia (AIHA) of NZB mice. We have previously shown that the major target of the pathogenic RBC autoantibodies is Band 3 and that CD4+ T-cells from NZB mice respond to this autoantigen. The recent work has demonstrated that a band 3 peptide, which is the predominant sequence 861-874 recognized by NZB T cells in vitro, bears a dominant helper epitope able to modulate the AIHA in vivo. Therefore, the goal of the current work is to determine which, if any, of the responses to Band 3 in NZB AIHA are initiated and driven by the autoantigen itself. The study started last year, and the approach stands at by comparing the autoreactive Th and autoantibody responses in gene disrupted AE1-/- NZB mice from wild type NZB. It showed that splenic Th-cells from AE1-/- NZB mice failed to proliferate in vitro to the many sub-dominant Band 3 determinants that are stimulatory in wild-type NZB mice. However, partial responsiveness was retained to the dominant helper epitope, which shows high homology with numerous bacterial sequences. Therefore, from this year, we will explore the role of autoantigen in eliciting the autoreactive immune responses by supplement of Band 3 in AE1-/- NZB mice. Most importantly, we will identify the possible microbial agents involved in initiating the pathogenic autoimmune responses against Band 3 by immunizing the candidate microbial derived peptides containing the similar epitope of Band 3 862-870 or by DNA vaccination of the sequence derived from the candidate microbial.

Project ID:PC9706-0151
External Project ID:NSC95-2320-B182-026-MY3