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Novel B-lymphocyte-deleting agents for the treatment of autoimmune diseases: induction of the mitochondrial pathway of apoptosis

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Background

To develop new approaches for the targeted deletion of pathogenic autoimmune B lymphocytes, we have studied a bacterial product, protein A of Staphylococcus aureus (SpA). We have previously discovered that SpA has the properties of a B-cell superantigen, enabling interactions with conserved variable region framework subdomains of the antigen receptors of lymphocytes rather than the complementarity determining region involved in the binding of conventional antigens [1]. Exposure to SpA can induce immune tolerance affecting a supraclonal set of lymphocytes [2].

Objective

To evaluate the outcome of in vivo SpA treatment.

Results

Within hours, a sequence of events is initiated only in targeted B cells, with rapid downregulation of B-cell antigen receptor and the coreceptors CD19 and CD21, the induction of an activation phenotype, and limited rounds of proliferation. Massive B-cell-specific apoptosis then occurs through a process heralded by the dissipation of mitochondrial membrane potential, followed later by the induction of the caspase pathway and DNA fragmentation. Post exposure, B-cell apoptotic bodies are deposited in the spleen, the lymph nodes and Peyers patches. While in vivo apoptosis does not require a death receptor, such as Fas, recent studies have demonstrated that apoptosis is linked to an induced imbalance in the members of the Bcl-2 family. By microfluorimetry and deconvoluted confocal microscopy, SpA induced a rapid depletion of Bcl-XL. There was also increased expression and translocation of a pro-apoptotic BH3-only member, which can form heterodimers resulting in Bax/Bak-mediated death.

References

  1. 1.

    Graille M, et al: Proc Natl Acad Sci USA. 2000, 97: 5399-5404. 10.1073/pnas.97.10.5399.

  2. 2.

    Silverman GJ, et al: J Exp Med. 2000, 192: 87-98. 10.1084/jem.192.1.87.

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Silverman, G., Goodyear, C. Novel B-lymphocyte-deleting agents for the treatment of autoimmune diseases: induction of the mitochondrial pathway of apoptosis. Arthritis Res Ther 5, 97 (2003) doi:10.1186/ar898

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Keywords

  • Mitochondrial Membrane Potential
  • Bacterial Product
  • Mitochondrial Pathway
  • Antigen Receptor
  • Post Exposure