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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Development of murine lupus involves the combined genetic contribution of the SLAM and FcgammaR intervals within the Nba2 autoimmune susceptibility locus
TN Jørgensen, J Alfaro, HL Enriquez, C Jiang, WM Loo, S Atencio, MR Bupp, CM Mailloux, T Metzger, S Flannery, SJ Rozzo, BL Kotzin, M Rosemblatt, MR Bono, LD Erickson |
Journal of immunology (Baltimore, Md. : 1950) | 2009 |
CXCR4/CXCL12 hyperexpression plays a pivotal role in the pathogenesis of lupus
A Wang, AM Fairhurst, K Tus, S Subramanian, Y Liu, F Lin, P Igarashi, XJ Zhou, F Batteux, D Wong, EK Wakeland, C Mohan |
Journal of immunology (Baltimore, Md. : 1950) | 2009 |
The lupus susceptibility locus Sle3 is not sufficient to accelerate atherosclerosis in lupus-susceptible low density lipoprotein receptor-deficient mice
NS Wade, BG Stevenson, DS Dunlap, AS Major |
Lupus | 2009 |
Antigen receptor signaling in the rheumatic diseases
J Zikherman, A Weiss |
Arthritis Research & Therapy | 2009 |
The lupus-susceptibility gene kallikrein downmodulates antibody-mediated glomerulonephritis
QZ Li, J Zhou, R Yang, M Yan, Q Ye, K Liu, S Liu, X Shao, L Li, XJ Zhou, EK Wakeland, C Mohan |
Genes and Immunity | 2009 |
Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus
CO Jacob, J Zhu, DL Armstrong, M Yan, J Han, XJ Zhou, JA Thomas, A Reiff, BL Myones, JO Ojwang, KM Kaufman, M Klein-Gitelman, D McCurdy, L Wagner-Weiner, E Silverman, J Ziegler, JA Kelly, JT Merrill, JB Harley, R Ramsey-Goldman, LM Vila, SC Bae, TJ Vyse, GS Gilkeson, PM Gaffney, KL Moser, CD Langefeld, R Zidovetzki, C Mohan |
Proceedings of the National Academy of Sciences | 2009 |
Anti-nuclear antibody reactivity in lupus may be partly hard-wired into the primary B-cell repertoire
S Chang, L Yang, YM Moon, YG Cho, SY Min, TJ Kim, YJ Kim, W Patrick, HY Kim, C Mohan |
Molecular Immunology | 2009 |
Molecular hallmarks of anti-chromatin antibodies associated with the lupus susceptibility locus, Sle1
Z Liang, S Chang, MS Youn, C Mohan |
Molecular Immunology | 2009 |
The Lupus Susceptibility Locus Sle1 Breaches Peripheral B Cell Tolerance at the Antibody-Forming Cell and Germinal Center Checkpoints
R Vuyyuru, C Mohan, T Manser, ZS Rahman |
Journal of immunology (Baltimore, Md. : 1950) | 2009 |
Effects of the Sri Lankan medicinal plant, Salacia reticulata, in rheumatoid arthritis
Y Sekiguchi, H Mano, S Nakatani, J Shimizu, M Wada |
Genes & Nutrition | 2009 |
Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus-prone B6.Sle1.Yaa animals
K Maeda, A Malykhin, BN Teague-Weber, XH Sun, AD Farris, KM Coggeshall |
Blood | 2009 |
Activation-induced deaminase heterozygous MRL/lpr mice are delayed in the production of high-affinity pathogenic antibodies and in the development of lupus nephritis
C Jiang, ML Zhao, M Diaz |
Immunology | 2009 |
Three checkpoints in lupus development: central tolerance in adaptive immunity, peripheral amplification by innate immunity and end-organ inflammation
H Kanta, C Mohan |
Genes and Immunity | 2009 |
BLyS Ligands and Receptors
MP Cancro |
2009 | |
The MHC Haplotype H2b Converts Two Pure Nonlupus Mouse Strains to Producers of Antinuclear Antibodies
K Hannestad, H Scott |
Journal of immunology (Baltimore, Md. : 1950) | 2009 |