Induction of tolerance in arthritogenic B cells with receptors of differing affinity for self-antigen.

Academic Article

Abstract

  • Multiple mechanisms of tolerance induction limit autoimmunity, but their relative contribution for lymphocytes recognizing self-antigens of differing availability is incompletely understood. The mechanisms applied to arthritogenic B cells expressing antigen-specific B cell receptors (BCRs) with different affinities for glucose-6-phosphate isomerase (GPI) were examined in the corresponding Ig gene knock-in mice. This ubiquitously expressed and blood-borne enzyme is the target autoantigen in the K/BxN model of inflammatory arthritis and perhaps in some humans with arthritis. Negative selection of B cells expressing high-affinity anti-GPI specificities, whose surface receptors were occupied by GPI, operated mainly at the transitional B cell stages in the spleen, preventing their final differentiation and entry into follicular areas. Receptor editing contributed to the purging of cells displaying anti-GPI BCRs, and significant numbers of autoreactive cells escaped through expression of an additional Ig light (L) chain, accumulating gradually in lymphoid organs. In contrast, low-affinity anti-GPI B cells, whose surface receptors did not carry GPI, matured normally. The "escaped" dual-L-chain cells and the "ignored" low-affinity cells are the likely precursors of cells that produce pathogenic autoantibodies once T cell help is provided. These studies portray, in a single system, the range of tolerance mechanisms applied to potentially pathogenic B cells, and serve as a base for dissecting where T cell help intervenes and where therapeutic agents impinge.
  • Keywords

  • Alleles, Animals, Arthritis, Experimental, B-Lymphocytes, Cell Differentiation, Gene Rearrangement, B-Lymphocyte, Glucose-6-Phosphate Isomerase, Humans, In Vitro Techniques, Lymphoid Tissue, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Antigen, B-Cell, Recombinant Proteins, Self Tolerance
  • Digital Object Identifier (doi)

    Author List

  • Huang H; Kearney JF; Grusby MJ; Benoist C; Mathis D
  • Start Page

  • 3734
  • End Page

  • 3739
  • Volume

  • 103
  • Issue

  • 10