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 immunogenic fashion, or directly impact tolerance of chromatin-specific B cells.
C Mohan, E Alas, L Morel, P Yang, E K Wakeland
Title and authors | Publication | Year |
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Caspase-Activated DNase is Required to Maintain Tolerance to Lupus Nuclear AutoAntigens
NR Jog, L Frisoni, Q Shi, M Monestier, S Hernandez, J Craft, ET Prak, R Caricchio |
Arthritis & Rheumatism | 2011 |
Murine Models of Systemic Lupus Erythematosus
D Perry, A Sang, Y Yin, YY Zheng, L Morel |
Journal of Biomedicine and Biotechnology | 2011 |
A novel isoform of the Ly108 gene ameliorates murine lupus
M Keszei, C Detre, ST Rietdijk, P Muñoz, X Romero, SB Berger, S Calpe, G Liao, W Castro, A Julien, YY Wu, DM Shin, J Sancho, M Zubiaur, HC 3rd, L Morel, P Engel, N Wang, C Terhorst |
Journal of Experimental Medicine | 2011 |
Cutting Edge: An NK Cell-Independent Role for Slamf4 in Controlling Humoral Autoimmunity
DR Brown, S Calpe, M Keszei, N Wang, S McArdel, C Terhorst, AH Sharpe |
Journal of immunology (Baltimore, Md. : 1950) | 2011 |
A New Zealand Black-derived locus suppresses chronic graft-versus-host disease and autoantibody production through nonlymphoid bone marrow-derived cells
Z Xu, A Vallurupalli, C Fuhrman, D Ostrov, L Morel |
Journal of immunology (Baltimore, Md. : 1950) | 2011 |
Murine Lupus Susceptibility Locus Sle2 Activates DNA-Reactive B Cells through Two Sub-Loci with Distinct Phenotypes
L Zeumer, A Sang, H Niu, L Morel |
Genes and Immunity | 2011 |
Auto-antibody production and glomerulonephritis in congenic Slamf1−/− and Slamf2−/− [B6.129] but not in Slamf1−/− and Slamf2−/− [BALB/c.129] mice
M Keszei, YE Latchman, VK Vanguri, DR Brown, C Detre, M Morra, CV Arancibia-Carcamo, CV Arancibia, E Paul, S Calpe, W Castro, N Wang, C Terhorst, AH Sharpe |
International Immunology | 2011 |