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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Dysregulated Cytokine Production by Dendritic Cells Modulates B Cell Responses in the NZM2410 Mouse Model of Lupus
A Sang, YY Zheng, Y Yin, I Dozmorov, H Li, HC Hsu, JD Mountz, L Morel |
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Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus
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Germinal Center B Cell Depletion Diminishes CD4+ Follicular T Helper Cells in Autoimmune Mice
I Yusuf, J Stern, TM McCaughtry, S Gallagher, H Sun, C Gao, T Tedder, G Carlesso, L Carter, R Herbst, Y Wang |
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B Cell-Intrinsic TLR7 Signaling Is Essential for the Development of Spontaneous Germinal Centers
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Journal of immunology (Baltimore, Md. : 1950) | 2014 |
The Lupus Susceptibility Locus Sle1 Facilitates the Peripheral Development and Selection of Anti-DNA B Cells through Impaired Receptor Editing
SH Chang, TJ Kim, YJ Kim, Y Liu, SY Min, MJ Park, HS Park, SK Lee, KH Nam, HY Kim, C Mohan, HR Kim |
Journal of immunology (Baltimore, Md. : 1950) | 2014 |
Activation of Rheumatoid Factor-Specific B Cells Is Antigen Dependent and Occurs Preferentially Outside of Germinal Centers in the Lupus-Prone NZM2410 Mouse Model
A Sang, H Niu, J Cullen, SC Choi, YY Zheng, H Wang, MJ Shlomchik, L Morel |
Journal of immunology (Baltimore, Md. : 1950) | 2014 |
The Murine Pbx1-d Lupus Susceptibility Allele Accelerates Mesenchymal Stem Cell Differentiation and Impairs Their Immunosuppressive Function
S Lu, L Zeumer, H Sorensen, H Yang, Y Ng, F Yu, A Riva, B Croker, S Wallet, L Morel |
Journal of immunology (Baltimore, Md. : 1950) | 2014 |
Novel application of multi-stimuli network inference to synovial fibroblasts of rheumatoid arthritis patients
P Kupfer, R Huber, M Weber, S Vlaic, T Häupl, D Koczan, R Guthke, RW Kinne |
BMC Medical Genomics | 2014 |
Dysregulated Cytokine Production by Dendritic Cells Modulates B Cell Responses in the NZM2410 Mouse Model of Lupus
A Sang, YY Zheng, Y Yin, I Dozmorov, H Li, HC Hsu, JD Mountz, L Morel, MS Horwitz |
PloS one | 2014 |