Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Published Online May 18, 2006
Science DOI: 10.1126/science.1124978

Reports

Submitted on January 17, 2006
Accepted on May 3, 2006

Autoreactive B Cell Responses to RNA-Related Antigens Due to TLR7 Gene Duplication

Prapaporn Pisitkun 1, Jonathan A. Deane 1, Michael J. Difilippantonio 2, Tatyana Tarasenko 1, Anne B. Satterthwaite 3, Silvia Bolland 1*

1 Lab. of Immunogenetics, NIAID/NIH, Rockville, MD 20852, USA.
2 Section of Cancer Genomics, Genetics Branch/CCR/NCI/NIH, Bethesda, MD 20892, USA.
3 Dept. of Internal Medicine, UT Southwestern, Dallas, TX 75390, USA.

* To whom correspondence should be addressed.
Silvia Bolland , E-mail: sbolland{at}nih.gov

Antibodies against nuclear self antigens are characteristic of systemic autoimmunity, although mechanisms promoting their generation and selection are unclear. Here we report that B cells containing the Y-linked autoimmune accelerator (Yaa) locus are intrinsically biased towards nucleolar antigens due to increased expression of TLR7, an ssRNA-binding innate immune receptor. The TLR7 gene is duplicated in Yaa mice due to a 4 Mb expansion of the pseudoautosomal region. These results reveal high divergence in mouse Y-chrosomomes and represent a good example of gene copy number qualitatively altering a polygenic disease manifestation.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir.
G. B. Beck-Engeser, D. Eilat, T. Harrer, H.-M. Jack, and M. Wabl (2009)
PNAS 106, 20865-20870
   Abstract »    Full Text »    PDF »
Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity.
Y. J. Crow and J. Rehwinkel (2009)
Hum. Mol. Genet. 18, R130-R136
   Abstract »    Full Text »    PDF »
Genetic Complementation Results in Augmented Autoantibody Responses to Lupus-Associated Antigens.
D. L. Sim, H. Bagavant, Y. M. Scindia, Y. Ge, F. Gaskin, S. M. Fu, and U. S. Deshmukh (2009)
J. Immunol. 183, 3505-3511
   Abstract »    Full Text »    PDF »
Long-term follow-up after non-myeloablative transplant of bone and marrow in BXSB mice.
O. Jones, A Lacson, X Zeng, J. Jones, K Katti, R. Cahill, and A. Ahmed (2009)
Lupus 18, 813-821
   Abstract »    PDF »
Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus.
D. H. Kono, M. K. Haraldsson, B. R. Lawson, K. M. Pollard, Y. T. Koh, X. Du, C. N. Arnold, R. Baccala, G. J. Silverman, B. A. Beutler, et al. (2009)
PNAS 106, 12061-12066
   Abstract »    Full Text »    PDF »
Selective Up-Regulation of Intact, but Not Defective env RNAs of Endogenous Modified Polytropic Retrovirus by the Sgp3 Locus of Lupus-Prone Mice.
K. Yoshinobu, L. Baudino, M.-L. Santiago-Raber, N. Morito, I. Dunand-Sauthier, B. J. Morley, L. H. Evans, and S. Izui (2009)
J. Immunol. 182, 8094-8103
   Abstract »    Full Text »    PDF »
Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing.
R. Fukui, S.-i. Saitoh, F. Matsumoto, H. Kozuka-Hata, M. Oyama, K. Tabeta, B. Beutler, and K. Miyake (2009)
J. Exp. Med. 206, 1339-1350
   Abstract »    Full Text »    PDF »
Therapeutic Targeting of Toll-Like Receptors for Infectious and Inflammatory Diseases and Cancer.
L. A. J. O'Neill, C. E. Bryant, and S. L. Doyle (2009)
Pharmacol. Rev. 61, 177-197
   Abstract »    Full Text »    PDF »
Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus-prone B6.Sle1.Yaa animals.
K. Maeda, A. Malykhin, B. N. Teague-Weber, X.-H. Sun, A. D. Farris, and K. M. Coggeshall (2009)
Blood 113, 4534-4540
   Abstract »    Full Text »    PDF »
Onset of autoimmune glomerulonephritis derived from the telomeric region of MRL-chromosome 1 is associated with the male sex hormone in mice.
O Ichii, A Konno, N Sasaki, D Endoh, Y Hashimoto, and Y Kon (2009)
Lupus 18, 491-500
   Abstract »    PDF »
Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus.
C. O. Jacob, J. Zhu, D. L. Armstrong, M. Yan, J. Han, X. J. Zhou, J. A. Thomas, A. Reiff, B. L. Myones, J. O. Ojwang, et al. (2009)
PNAS 106, 6256-6261
   Abstract »    Full Text »    PDF »
The roles of TLRs, RLRs and NLRs in pathogen recognition.
T. Kawai and S. Akira (2009)
Int. Immunol. 21, 317-337
   Abstract »    Full Text »    PDF »
CXCR4/CXCL12 Hyperexpression Plays a Pivotal Role in the Pathogenesis of Lupus.
A. Wang, A.-M. Fairhurst, K. Tus, S. Subramanian, Y. Liu, F. Lin, P. Igarashi, X. J. Zhou, F. Batteux, D. Wong, et al. (2009)
J. Immunol. 182, 4448-4458
   Abstract »    Full Text »    PDF »
Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7.
T. Hayashi, C. S. Gray, M. Chan, R. I. Tawatao, L. Ronacher, M. A. McGargill, S. K. Datta, D. A. Carson, and M. Corr (2009)
PNAS 106, 2764-2769
   Abstract »    Full Text »    PDF »
A Defect in Marco Expression Contributes to Systemic Lupus Erythematosus Development via Failure to Clear Apoptotic Cells.
N. J. Rogers, M. J. Lees, L. Gabriel, E. Maniati, S. J. Rose, P. K. Potter, and B. J. Morley (2009)
J. Immunol. 182, 1982-1990
   Abstract »    Full Text »    PDF »
A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice.
J. A. Bubier, T. J. Sproule, O. Foreman, R. Spolski, D. J. Shaffer, H. C. Morse III, W. J. Leonard, and D. C. Roopenian (2009)
PNAS 106, 1518-1523
   Abstract »    Full Text »    PDF »
Modified Adenine (9-Benzyl-2-Butoxy-8-Hydroxyadenine) Redirects Th2-Mediated Murine Lung Inflammation by Triggering TLR7.
A. Vultaggio, F. Nencini, P. M. Fitch, L. Fili, L. Maggi, P. Fanti, A. deVries, E. Beccastrini, F. Palandri, C. Manuelli, et al. (2009)
J. Immunol. 182, 880-889
   Abstract »    Full Text »    PDF »
TLR7-dependent and Fc{gamma}R-independent production of type I interferon in experimental mouse lupus.
P. Y. Lee, Y. Kumagai, Y. Li, O. Takeuchi, H. Yoshida, J. Weinstein, E. S. Kellner, D. Nacionales, T. Barker, K. Kelly-Scumpia, et al. (2008)
J. Exp. Med. 205, 2995-3006
   Abstract »    Full Text »    PDF »
Pivotal Advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis.
A. Andersson, R. Covacu, D. Sunnemark, A. I. Danilov, A. Dal Bianco, M. Khademi, E. Wallstrom, A. Lobell, L. Brundin, H. Lassmann, et al. (2008)
J. Leukoc. Biol. 84, 1248-1255
   Abstract »    Full Text »    PDF »
A single base mutation in the PRAT4A gene reveals differential interaction of PRAT4A with Toll-like receptors.
T. Kiyokawa, S. Akashi-Takamura, T. Shibata, F. Matsumoto, C. Nishitani, Y. Kuroki, Y. Seto, and K. Miyake (2008)
Int. Immunol. 20, 1407-1415
   Abstract »    Full Text »    PDF »
Glatiramer acetate treatment does not modify the clinical course of (NZB x BXSB)F1 lupus murine model.
P. Borel, M. Benkhoucha, M. S. Weber, S. S. Zamvil, M.-L. Santiago-Raber, and P. H. Lalive (2008)
Int. Immunol. 20, 1313-1319
   Abstract »    Full Text »    PDF »
Protection of Murine Systemic Lupus by the Ea Transgene without Expression of I-E Heterodimers.
E. Martinez-Soria, M.-L. Santiago-Raber, L. Ho, T. Moll, and S. Izui (2008)
J. Immunol. 181, 3651-3657
   Abstract »    Full Text »    PDF »
Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens.
M. Lech, O. P. Kulkarni, S. Pfeiffer, E. Savarese, A. Krug, C. Garlanda, A. Mantovani, and H.-J. Anders (2008)
J. Exp. Med. 205, 1879-1888
   Abstract »    Full Text »    PDF »
Evidence for Genes in Addition to Tlr7 in the Yaa Translocation Linked with Acceleration of Systemic Lupus Erythematosus.
M.-L. Santiago-Raber, S. Kikuchi, P. Borel, S. Uematsu, S. Akira, B. L. Kotzin, and S. Izui (2008)
J. Immunol. 181, 1556-1562
   Abstract »    Full Text »    PDF »
A role for sex chromosome complement in the female bias in autoimmune disease.
D. L. Smith-Bouvier, A. A. Divekar, M. Sasidhar, S. Du, S. K. Tiwari-Woodruff, J. K. King, A. P. Arnold, R. R. Singh, and R. R. Voskuhl (2008)
J. Exp. Med. 205, 1099-1108
   Abstract »    Full Text »    PDF »
Biomarkers in newly diagnosed pediatric-extensive chronic graft-versus-host disease: a report from the Children's Oncology Group.
H. Fujii, G. Cuvelier, K. She, S. Aslanian, H. Shimizu, A. Kariminia, M. Krailo, Z. Chen, R. McMaster, A. Bergman, et al. (2008)
Blood 111, 3276-3285
   Abstract »    Full Text »    PDF »
A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses.
K. Takahashi, T. Shibata, S. Akashi-Takamura, T. Kiyokawa, Y. Wakabayashi, N. Tanimura, T. Kobayashi, F. Matsumoto, R. Fukui, T. Kouro, et al. (2007)
J. Exp. Med. 204, 2963-2976
   Abstract »    Full Text »    PDF »
Primary Development and Participation in a Foreign Antigen-Driven Immune Response of a Chromatin-Reactive B Cell Clonotype Are Not Influenced by TLR9 or Other MyD88-Dependent TLRs.
F. Coffey, X. Liu, and T. Manser (2007)
J. Immunol. 179, 6663-6672
   Abstract »    Full Text »    PDF »
Autoimmunity Stimulated by Adoptively Transferred Dendritic Cells Is Initiated by Both {alpha}beta and {gamma}{delta} T Cells but Does Not Require MyD88 Signaling.
D. A. Martin, K. Zhang, J. Kenkel, G. Hughes, E. Clark, A. Davidson, and K. B. Elkon (2007)
J. Immunol. 179, 5819-5828
   Abstract »    Full Text »    PDF »
BXSB/long-lived Is a Recombinant Inbred Strain Containing Powerful Disease Suppressor Loci.
M. E. K. Haywood, L. Gabriel, S. J. Rose, N. J. Rogers, S. Izui, and B. J. Morley (2007)
J. Immunol. 179, 2428-2434
   Abstract »    Full Text »    PDF »
BAFF and MyD88 signals promote a lupuslike disease independent of T cells.
J. R. Groom, C. A. Fletcher, S. N. Walters, S. T. Grey, S. V. Watt, M. J. Sweet, M. J. Smyth, C. R. Mackay, and F. Mackay (2007)
J. Exp. Med. 204, 1959-1971
   Abstract »    Full Text »    PDF »
Murine Dendritic Cell Type I IFN Production Induced by Human IgG-RNA Immune Complexes Is IFN Regulatory Factor (IRF)5 and IRF7 Dependent and Is Required for IL-6 Production.
K. Yasuda, C. Richez, J. W. Maciaszek, N. Agrawal, S. Akira, A. Marshak-Rothstein, and I. R. Rifkin (2007)
J. Immunol. 178, 6876-6885
   Abstract »    Full Text »    PDF »
Inhibition of Toll-Like Receptor-7 (TLR-7) or TLR-7 plus TLR-9 Attenuates Glomerulonephritis and Lung Injury in Experimental Lupus.
R. D. Pawar, A. Ramanjaneyulu, O. P. Kulkarni, M. Lech, S. Segerer, and H.-J. Anders (2007)
J. Am. Soc. Nephrol. 18, 1721-1731
   Abstract »    Full Text »    PDF »
The Bxs6 Locus of BXSB Mice Is Sufficient for High-Level Expression of gp70 and the Production of gp70 Immune Complexes.
J. Rankin, J. J. Boyle, S. J. Rose, L. Gabriel, M. Lewis, V. Thiruudaian, N. J. Rogers, S. Izui, and B. J. Morley (2007)
J. Immunol. 178, 4395-4401
   Abstract »    Full Text »    PDF »
Lupus Nephritis: Toll the Trigger!.
K. D. Smith (2006)
J. Am. Soc. Nephrol. 17, 3273-3275
   Full Text »    PDF »
Nucleic Acid-Sensing TLRs as Modifiers of Autoimmunity.
J. A. Deane and S. Bolland (2006)
J. Immunol. 177, 6573-6578
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)