Major peptide autoepitopes for nucleosome-centered T and B cell interaction in human and murine lupus

Syamal K. Datta*

*Corresponding author for this work

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

The potential cross-reactivity of normal T and B cells to nuclear antigens is vast, probably due to their "education" by apoptotic cell antigens in generative lymphoid organs. Despite this "nucleocentric repertoire," as we call it, the peripheral immune system normally remains tolerant or ignorant of the products of apoptosis. However, the T helper (Th) cells, and also B cells of lupus, have a regulatory defect in the expression of CD40 ligand (CD40L). A sustained hyper-expression of CD40L by lupus T cells can be triggered by subthreshold stimuli, and is associated with impaired phosphorylation of Cbl-b, a critical downregulatory molecule in T cell signal transduction. This CD40L hyper-expression abnormally prolongs co-stimulatory signals to autoimmune B cells, and it probably instigates APC (dendritic cells, resting anti-DNA B cells, and macrophages) to present apoptotic cell autoantigens in an immunogenic fashion. We have identified the dominant nucleosomal epitopes that are critical for cognate interactions between autoimmune Th cells and anti-DNA B cells in lupus. By scanning of overlapping synthetic peptides, and by mass spectrometry of naturally processed peptides, five major epitopes in nucleosomal histones were localized, namely H1′22-42, H2B10-33, H385-105, H416-39, and H471-94. The autoimmune T cells as well as B cells of lupus recognize these epitopes, and with age, autoantibodies against the peptide epitopes cross-react with nuclear autoantigens. Moreover, the peptide autoepitopes can be promiscuously presented and recognized by lupus T cells in the context of diverse MHC alleles. This cross-reactivity opens up the possibility of developing "universally" tolerogenic peptides for therapy of lupus in humans despite their MHC diversity. Indeed, tolerogenic therapy with a single histone peptide epitope can halt the progression of established glomerulonephritis in lupus-prone mice by "tolerance spreading" that inactivates a broad spectrum of autoimmune T and B cells in concert.

Original languageEnglish (US)
Pages (from-to)79-90
Number of pages12
JournalAnnals of the New York Academy of Sciences
Volume987
DOIs
Publication statusPublished - Jan 1 2003

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Keywords

  • Anti-DNA autoantibody
  • Apoptosis
  • Autoimmunity
  • CD40 ligand
  • Nucleosomes
  • Peptide epitopes
  • Systemic lupus erythematosus
  • T cell-B cell interaction
  • Tolerance therapy

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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