Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnuclesomes

Chandra Mohan, Elizabeth Alas, Laurence Morel, Ping Yang, Edward K. Wakeland

Research output: Contribution to journalArticle

235 Scopus citations

Abstract

One of the hallmarks of SLE is the loss of tolerance to chromatin. The genes and mechanisms that trigger this loss of tolerance remain unknown. Our genetic studies in the NZM2410 lupus strain have implicated genomic intervals on chromosomes 1 (Sle1), 4 (Sle2), and 7 (Sle3) as conferring strong lupus susceptibility. Interestingly, B6 mice that are congenic for Sle1 (B6.NZMc1) have elevated IgG antichromatin Abs. This study explores the antinuclear antibody fine specificities and underlying cellular defects in these mice. On the B6 background, Sle1 by itself is sufficient to generate a robust, spontaneous antichromatin Ab response, staining Hep-2 nuclei homogeneously, and reacting primarily with H2A/H2B/DNA subnucleosomes. This targeted immune response peaks at 7-9 mo of age, affects both sexes with equally high penetrance (> 75%), and interestingly, does not 'spread' to other subnucleosomal chromatin components. Sle1 also leads to an expanded pool of histone-reactive T cells, which may have a role in driving the anti- H2A/H2B/DNA B cells. However, these mice do not exhibit any generalized immunological defects or quantitative aberrations in lymphocyte apoptosis. We hypothesize that Sle1 may lead to the presentation of chromatin in an immunogenie fashion, or directly impact tolerance of chromatin-specific B cells.

Original languageEnglish (US)
Pages (from-to)1362-1372
Number of pages11
JournalJournal of Clinical Investigation
Volume101
Issue number6
StatePublished - Mar 15 1998

Keywords

  • Anti-DNA
  • Autoimmunity
  • Chromatin
  • Lupus
  • Nucleosomes

ASJC Scopus subject areas

  • Medicine(all)

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