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

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.

SUBMITTER: Huang H

PROVIDER: S-EPMC1450147 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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

Huang Haochu H Kearney John F JF Grusby Michael J MJ Benoist Christophe C Mathis Diane D

Proceedings of the National Academy of Sciences of the United States of America 20060227 10

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 ...[more]

PMID: 16505356

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Project description:Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3-5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets.

Dataset Information

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

Publications

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

Similar Datasets

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