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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Defective B-cell response to T-dependent immunization in lupus-prone mice
H Niu, ES Sobel, L Morel |
European Journal of Immunology | 2008 |
How the study of children with rheumatic diseases identified interferon-alpha and interleukin-1 as novel therapeutic targets
V Pascual, F Allantaz, P Patel, AK Palucka, D Chaussabel, J Banchereau |
Immunological Reviews | 2008 |
Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens
M Lech, OP Kulkarni, S Pfeiffer, E Savarese, A Krug, C Garlanda, A Mantovani, HJ Anders |
Journal of Experimental Medicine | 2008 |
Yaaautoimmune phenotypes are conferred by overexpression of TLR7
AM Fairhurst, S Hwang, A Wang, XH Tian, C Boudreaux, XJ Zhou, J Casco, QZ Li, JE Connolly, EK Wakeland |
European Journal of Immunology | 2008 |
Systemic IFN‐α drives kidney nephritis in B6.Sle123mice
AM Fairhurst, A Mathian, JE Connolly, A Wang, HF Gray, TA George, CD Boudreaux, XJ Zhou, QZ Li, S Koutouzov, J Banchereau, EK Wakeland |
European Journal of Immunology | 2008 |
Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice
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Genes and Immunity | 2008 |
Accelerated atherosclerosis is independent of feeding high fat diet in systemic lupus erythematosus-susceptible LDLr(-/-) mice
N Braun, NS Wade, EK Wakeland, AS Major |
Lupus | 2008 |
Genetic variation in C-reactive protein (CRP) gene may be associated with risk of systemic lupus erythematosus and CRP concentrations
PB Shih, S Manzi, P Shaw, M Kenney, AH Kao, F Bontempo, MM Barmada, C Kammerer, MI Kamboh |
The Journal of rheumatology | 2008 |
Principles of Bone Biology
CJ Rosen, T Niu |
Principles of Bone Biology | 2008 |
Accelerated atherosclerosis is independent of feeding high fat diet in systemic lupus erythematosus–susceptible LDLr−/− mice
NA Braun, NS Wade, EK Wakeland, AS Major |
Lupus | 2008 |
A lupus-susceptibility C57BL/6 locus on chromosome 3 (Sle18) contributes to autoantibody production in 129 mice
Y Heidari, L Fossati-Jimack, F Carlucci, MJ Walport, HT Cook, M Botto |
Genes and Immunity | 2008 |