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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The lupus-susceptibility locus, Sle3, mediates enhanced resistance to bacterial infections
B Mehrad, SJ Park, G Akangire, TJ Standiford, T Wu, J Zhu, C Mohan |
Journal of immunology (Baltimore, Md. : 1950) | 2006 |
Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus
AK Stanic, CM Stein, AC Morgan, S Fazio, MR Linton, EK Wakeland, NJ Olsen, AS Major |
Proceedings of the National Academy of Sciences | 2006 |
Development and Selection of Edited B Cells in B6.56R Mice
DR Sekiguchi, L Yunk, D Gary, D Charan, B Srivastava, D Allman, MG Weigert, ET Prak |
Journal of immunology (Baltimore, Md. : 1950) | 2006 |
Role of TLR9 in Anti-Nucleosome and Anti-DNA Antibody Production in lpr Mutation-Induced Murine Lupus
A Lartigue, P Courville, I Auquit, A François, C Arnoult, F Tron, D Gilbert, P Musette |
Journal of immunology (Baltimore, Md. : 1950) | 2006 |
A Tlr7 translocation accelerates systemic autoimmunity in murine lupus
S Subramanian, K Tus, QZ Li, A Wang, XH Tian, J Zhou, C Liang, G Bartov, LD McDaniel, XJ Zhou, RA Schultz, EK Wakeland |
Proceedings of the National Academy of Sciences | 2006 |
Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes
ME Haywood, SJ Rose, S Horswell, MJ Lees, G Fu, MJ Walport, BJ Morley |
Genes and Immunity | 2006 |
Dynamics of Bone and Cartilage Metabolism
JE Mulder, CA Kulak, E Shane |
Dynamics of Bone and Cartilage Metabolism | 2006 |
A signal adaptor SLAM-associated protein regulates spontaneous autoimmunity and Fas-dependent lymphoproliferation in MRL-Faslpr lupus mice
H Komori, H Furukawa, S Mori, MR Ito, M Terada, MC Zhang, N Ishii, N Sakuma, M Nose, M Ono |
Journal of immunology (Baltimore, Md. : 1950) | 2006 |
Effects of arginine-vasopressin and parathyroid hormone-related protein (1–34) on cell proliferation and production of YKL-40 in cultured chondrocytes from patients with rheumatoid arthritis and osteoarthritis
M Petersson, E Bucht, B Granberg, A Stark |
Osteoarthritis and Cartilage | 2006 |
Environment versus genetics in autoimmunity: a geneticist's perspective
C Mohan |
Lupus | 2006 |
Regulation of B Cell Tolerance by the Lupus Susceptibility Gene Ly108
KR Kumar, L Li, M Yan, M Bhaskarabhatla, AB Mobley, C Nguyen, JM Mooney, JD Schatzle, EK Wakeland, C Mohan |
Science | 2006 |
Hypercalcemia in rheumatoid arthritis: relationship with disease activity and bone metabolism
P Oelzner, G Lehmann, T Eidner, S Franke, A Müller, G Wolf, G Hein |
Rheumatology International | 2006 |