| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
* Department of Pathology, Weill Medical College, and
Immunology Graduate Program, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021
TLRs are pattern recognition receptors that initiate innate immune responses. TLR9 detects microbial DNA with hypomethylated CpG motifs and in humans is preferentially expressed by IFN-
-producing plasmacytoid dendritic cells and B cells. In addition to favoring IFN- release, TLR9 signals B cell activation, proliferation, and IgM production. Recent findings suggest that CpG DNA-TLR9 interaction plays a key role in systemic lupus erythematosus and rheumatoid arthritis, two autoimmune disorders characterized by dysregulated production of DNA-reactive IgG. We show that CpG DNA initiates germline C
1, C2, and C3 gene transcription by activating B cells through a TLR9-mediated NF-
B-Rel-dependent innate pathway that cooperates with IL-10 through STAT proteins and IFN-responsive factors. This pathway is inhibited by chloroquine, a drug that attenuates the clinical manifestations of IgG-mediated autoimmune disorders. Germline C gene transcription is associated with up-regulation of activation-induced cytidine deaminase, a key element of the B cell class switch-inducing machinery, and is followed by class switch DNA recombination from Cµ to C1, C2, and C3. Subsequent IgG production requires additional signals from BCR and a B cell-activating factor of the TNF family (BAFF), produced by dendritic cells upon exposure to IFN-. Our findings suggest that CpG DNA-TLR9 interaction may be important to initiate or amplify early T cell-independent IgG responses against pathogens. This implies that CpG DNA released during infections may exacerbate autoimmunity by stimulating autoreactive B cells to switch from an IgM to a more pathogenic IgG isotype.
This article has been cited by other articles:
|
|
 |
|
  T. A. Barr, S. Brown, P. Mastroeni, and D. Gray B Cell Intrinsic MyD88 Signals Drive IFN-{gamma} Production from T Cells and Control Switching to IgG2c J. Immunol., July 15, 2009; 183(2): 1005 - 1012. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Fried and F. A. Bonilla Pathogenesis, Diagnosis, and Management of Primary Antibody Deficiencies and Infections Clin. Microbiol. Rev., July 1, 2009; 22(3): 396 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. S. Longo, P. L. Lugar, S. Yavuz, W. Zhang, P. H. L. Krijger, D. E. Russ, D. D. Jima, S. S. Dave, A. C. Grammer, and P. E. Lipsky Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting Blood, April 16, 2009; 113(16): 3706 - 3715. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang, S. A. Blozis, M. Lederman, A. Krieg, A. Landay, and C. J. Miller Enhanced Antibody Responses Elicited by a CpG Adjuvant Do Not Improve the Protective Effect of an Aldrithiol-2-Inactivated Simian Immunodeficiency Virus Therapeutic AIDS Vaccine Clin. Vaccine Immunol., April 1, 2009; 16(4): 499 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Miyazaki, C. H. Kuo, T. Tominaga, Y. Inoue, and S. J. Ono Regulatory Function of CpG-Activated B Cells in Late-Phase Experimental Allergic Conjunctivitis Invest. Ophthalmol. Vis. Sci., April 1, 2009; 50(4): 1626 - 1635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Nacionales, J. S. Weinstein, X.-J. Yan, E. Albesiano, P. Y. Lee, K. M. Kelly-Scumpia, R. Lyons, M. Satoh, N. Chiorazzi, and W. H. Reeves B Cell Proliferation, Somatic Hypermutation, Class Switch Recombination, and Autoantibody Production in Ectopic Lymphoid Tissue in Murine Lupus J. Immunol., April 1, 2009; 182(7): 4226 - 4236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Bekeredjian-Ding, A. Doster, M. Schiller, P. Heyder, H.-M. Lorenz, B. Schraven, U. Bommhardt, and K. Heeg TLR9-Activating DNA Up-Regulates ZAP70 via Sustained PKB Induction in IgM+ B Cells J. Immunol., December 15, 2008; 181(12): 8267 - 8277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Chiron, I. Bekeredjian-Ding, C. Pellat-Deceunynck, R. Bataille, and G. Jego Toll-like receptors: lessons to learn from normal and malignant human B cells Blood, September 15, 2008; 112(6): 2205 - 2213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Porter, S. Vavassori, and L. R. Covey A Polypyrimidine Tract-Binding Protein-Dependent Pathway of mRNA Stability Initiates with CpG Activation of Primary B Cells J. Immunol., September 1, 2008; 181(5): 3336 - 3345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Xu, P. A. Santini, A. J. Matthews, A. Chiu, A. Plebani, B. He, K. Chen, and A. Cerutti Viral Double-Stranded RNA Triggers Ig Class Switching by Activating Upper Respiratory Mucosa B Cells through an Innate TLR3 Pathway Involving BAFF J. Immunol., July 1, 2008; 181(1): 276 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Gao, P. Jennings, and D. Yuan Requirements for the natural killer cell-mediated induction of IgG1 and IgG2a expression in B lymphocytes Int. Immunol., May 1, 2008; 20(5): 645 - 657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Capolunghi, S. Cascioli, E. Giorda, M. M. Rosado, A. Plebani, C. Auriti, G. Seganti, R. Zuntini, S. Ferrari, M. Cagliuso, et al. CpG Drives Human Transitional B Cells to Terminal Differentiation and Production of Natural Antibodies J. Immunol., January 15, 2008; 180(2): 800 - 808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Busconi, J. W. Bauer, J. R. Tumang, A. Laws, K. Perkins-Mesires, A. S. Tabor, C. Lau, R. B. Corley, T. L. Rothstein, F. E. Lund, et al. Functional Outcome of B Cell Activation by Chromatin Immune Complex Engagement of the B Cell Receptor and TLR9 J. Immunol., December 1, 2007; 179(11): 7397 - 7405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Montes, E. V. Acosta-Rodriguez, M. C. Merino, D. A. Bermejo, and A. Gruppi Polyclonal B cell activation in infections: infectious agents' devilry or defense mechanism of the host? J. Leukoc. Biol., November 1, 2007; 82(5): 1027 - 1032. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Bitsaktsis, B. Nandi, R. Racine, K. C. MacNamara, and G. Winslow T-Cell-Independent Humoral Immunity Is Sufficient for Protection against Fatal Intracellular Ehrlichia Infection Infect. Immun., October 1, 2007; 75(10): 4933 - 4941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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 BAFF and MyD88 signals promote a lupuslike disease independent of T cells J. Exp. Med., August 6, 2007; 204(8): 1959 - 1971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Krieg Antiinfective Applications of Toll-like Receptor 9 Agonists Proceedings of the ATS, July 1, 2007; 4(3): 289 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Darce, B. K. Arendt, S. K. Chang, and D. F. Jelinek Divergent Effects of BAFF on Human Memory B Cell Differentiation into Ig-Secreting Cells J. Immunol., May 1, 2007; 178(9): 5612 - 5622. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Guay, T. A. Andreyeva, R. L. Garcea, R. M. Welsh, and E. Szomolanyi-Tsuda MyD88 Is Required for the Formation of Long-Term Humoral Immunity to Virus Infection J. Immunol., April 15, 2007; 178(8): 5124 - 5131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Bekeredjian-Ding, S. Inamura, T. Giese, H. Moll, S. Endres, A. Sing, U. Zahringer, and G. Hartmann Staphylococcus aureus Protein A Triggers T Cell-Independent B Cell Proliferation by Sensitizing B Cells for TLR2 Ligands J. Immunol., March 1, 2007; 178(5): 2803 - 2812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Gourzi, T. Leonova, and F. N. Papavasiliou Viral induction of AID is independent of the interferon and the Toll-like receptor signaling pathways but requires NF-{kappa}B J. Exp. Med., February 19, 2007; 204(2): 259 - 265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Huggins, T. Pellegrin, R. E. Felgar, C. Wei, M. Brown, B. Zheng, E. C. B. Milner, S. H. Bernstein, I. Sanz, and M. S. Zand CpG DNA activation and plasma-cell differentiation of CD27- naive human B cells Blood, February 15, 2007; 109(4): 1611 - 1619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Chiu, W. Xu, B. He, S. R. Dillon, J. A. Gross, E. Sievers, X. Qiao, P. Santini, E. Hyjek, J.-w. Lee, et al. Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL Blood, January 15, 2007; 109(2): 729 - 739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Teleshova, J. Kenney, G. Van Nest, J. Marshall, J. D. Lifson, I. Sivin, J. Dufour, R. Bohm, A. Gettie, and M. Robbiani Local and Systemic Effects of Intranodally Injected CpG-C Immunostimulatory-Oligodeoxyribonucleotides in Macaques J. Immunol., December 15, 2006; 177(12): 8531 - 8541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Szodoray, P. Alex, M. B. Frank, M. Turner, S. Turner, N. Knowlton, C. Cadwell, I. Dozmorov, Y. Tang, P. C. Wilson, et al. A genome-scale assessment of peripheral blood B-cell molecular homeostasis in patients with rheumatoid arthritis Rheumatology, December 1, 2006; 45(12): 1466 - 1476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Butler and N. Wertz Antibody Repertoire Development in Fetal and Neonatal Piglets. XVII. IgG Subclass Transcription Revisited with Emphasis on New IgG3 J. Immunol., October 15, 2006; 177(8): 5480 - 5489. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Fecteau, G. Cote, and S. Neron A New Memory CD27-IgG+ B Cell Population in Peripheral Blood Expressing VH Genes with Low Frequency of Somatic Mutation J. Immunol., September 15, 2006; 177(6): 3728 - 3736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Minns, L. C. Menard, D. M. Foureau, S. Darche, C. Ronet, D. W. Mielcarz, D. Buzoni-Gatel, and L. H. Kasper TLR9 Is Required for the Gut-Associated Lymphoid Tissue Response following Oral Infection of Toxoplasma gondii. J. Immunol., June 15, 2006; 176(12): 7589 - 7597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Miller, J. E. Stadanlick, and M. P. Cancro Space, Selection, and Surveillance: Setting Boundaries with BLyS. J. Immunol., June 1, 2006; 176(11): 6405 - 6410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Han, S. Wang, Y. Fan, J. Yang, L. Jiao, H. Qiu, and X. Yang Chlamydia Infection Induces ICOS Ligand-Expressing and IL-10-Producing Dendritic Cells That Can Inhibit Airway Inflammation and Mucus Overproduction Elicited by Allergen Challenge in BALB/c Mice J. Immunol., May 1, 2006; 176(9): 5232 - 5239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Suarez, O. Lortholary, O. Hermine, and M. Lecuit Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation Blood, April 15, 2006; 107(8): 3034 - 3044. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. He, X. Qiao, P. J. Klasse, A. Chiu, A. Chadburn, D. M. Knowles, J. P. Moore, and A. Cerutti HIV-1 Envelope Triggers Polyclonal Ig Class Switch Recombination through a CD40-Independent Mechanism Involving BAFF and C-Type Lectin Receptors J. Immunol., April 1, 2006; 176(7): 3931 - 3941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Teleshova, J. Kenney, V. Williams, G. Van Nest, J. Marshall, J. D. Lifson, I. Sivin, J. Dufour, R. Bohm, A. Gettie, et al. CpG-C ISS-ODN activation of blood-derived B cells from healthy and chronic immunodeficiency virus-infected macaques J. Leukoc. Biol., February 1, 2006; 79(2): 257 - 267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cunningham-Rundles, L. Radigan, A. K. Knight, L. Zhang, L. Bauer, and A. Nakazawa TLR9 Activation Is Defective in Common Variable Immune Deficiency J. Immunol., February 1, 2006; 176(3): 1978 - 1987. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Guo, S. Garg, K. M. Hill, L. Jayashankar, M. R. Mooney, M. Hoelscher, J. M. Katz, J. M. Boss, and S. Sambhara A Distal Regulatory Region Is Required for Constitutive and IFN-{beta}-Induced Expression of Murine TLR9 Gene J. Immunol., December 1, 2005; 175(11): 7407 - 7418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Butler, D. H. Francis, J. Freeling, P. Weber, and A. M. Krieg Antibody Repertoire Development in Fetal and Neonatal Piglets. IX. Three Pathogen-Associated Molecular Patterns Act Synergistically to Allow Germfree Piglets to Respond to Type 2 Thymus-Independent and Thymus-Dependent Antigens J. Immunol., November 15, 2005; 175(10): 6772 - 6785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Riemekasten and B. H. Hahn Key autoantigens in SLE Rheumatology, August 1, 2005; 44(8): 975 - 982. [Full Text] [PDF]
|
|
|
|
|
|
R. Yang, F. M. Murillo, M. J. Delannoy, R. L. Blosser, W. H. Yutzy IV, S. Uematsu, K. Takeda, S. Akira, R. P. Viscidi, and R. B. S. Roden B Lymphocyte Activation by Human Papillomavirus-Like Particles Directly Induces Ig Class Switch Recombination via TLR4-MyD88 J. Immunol., June 15, 2005; 174(12): 7912 - 7919. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
