Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 650K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Phan, T. G. Articles by Brink, R. Search for Related Content PubMed PubMed Citation Articles by Phan, T. G. Articles by Brink, R. Pubmed/NCBI databases Gene GEO Profiles UniGene Substance via MeSH Social Bookmarking                            What's this?

B Cell Receptor–independent Stimuli Trigger Immunoglobulin (Ig) Class Switch Recombination and Production of IgG Autoantibodies by Anergic Self-Reactive B Cells

Tri Giang Phan¹, Michelle Amesbury¹, Sandra Gardam¹, Jeffrey Crosbie¹, Jhagvaral Hasbold², Philip D. Hodgkin², Antony Basten¹ and Robert Brink¹

¹ Centenary Institute of Cancer Medicine and Cell Biology, Newtown NSW 2042, Australia
² Walter and Eliza Hall Institute for Medical Research, Parkville VIC 3050, Australia

Address correspondence to Robert Brink, Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag Number 6, Newtown NSW 2042, Australia. Phone: 61-2-95656-136; Fax: 61-2-95656-105; E-mail: r.brink{at}centenary.usyd.edu.au

In both humans and animals, immunoglobulin (Ig)G autoantibodies are less frequent but more pathogenic than IgM autoantibodies, suggesting that controls over Ig isotype switching are required to reinforce B cell self-tolerance. We have used gene targeting to produce mice in which hen egg lysozyme (HEL)-specific B cells can switch to all Ig isotypes (SW_HEL mice). When crossed with soluble HEL transgenic (Tg) mice, self-reactive SW_HEL B cells became anergic. However, in contrast to anergic B cells from the original nonswitching anti-HEL x soluble HEL double Tg model, self-reactive SW_HEL B cells also displayed an immature phenotype, reduced lifespan, and exclusion from the splenic follicle. These differences were not related to their ability to Ig class switch, but instead to competition with non-HEL–binding B cells generated by V_H gene replacement in SW_HEL mice. When activated in vitro with B cell receptor (BCR)-independent stimuli such as anti-CD40 monoclonal antibody plus interleukin 4 or lipopolysaccharide (LPS), anergic SW_HEL double Tg B cells proliferated and produced IgG anti-HEL antibodies as efficiently as naive HEL-binding B cells from SW_HEL Ig Tg mice. These results demonstrate that no intrinsic constraints to isotype switching exist in anergic self-reactive B cells. Instead, production of IgG autoantibodies is prevented by separate controls that reduce the likelihood of anergic B cells encountering BCR-independent stimuli. That bacteria-derived LPS could circumvent these controls may explain the well-known association between autoantibody-mediated diseases and episodes of systemic infection.

Key Words: self-tolerance • autoimmunity • LPS • CD40 • hen egg lysozyme

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Chan, T. D., Gatto, D., Wood, K., Camidge, T., Basten, A., Brink, R. (2009). Antigen Affinity Controls Rapid T-Dependent Antibody Production by Driving the Expansion Rather than the Differentiation or Extrafollicular Migration of Early Plasmablasts. J. Immunol. 183: 3139-3149 [Abstract] [Full Text]  
• Eckl-Dorna, J., Batista, F. D. (2009). BCR-mediated uptake of antigen linked to TLR9 ligand stimulates B-cell proliferation and antigen-specific plasma cell formation. Blood 113: 3969-3977 [Abstract] [Full Text]  
• Linterman, M. A., Rigby, R. J., Wong, Raphael. K., Yu, D., Brink, R., Cannons, J. L., Schwartzberg, P. L., Cook, M. C., Walters, G. D., Vinuesa, C. G. (2009). Follicular helper T cells are required for systemic autoimmunity. JEM 206: 561-576 [Abstract] [Full Text]  
• Peters, A. L., Plenge, R. M., Graham, R. R., Altshuler, D. M., Moser, K. L., Gaffney, P. M., Bishop, G. A. (2008). A novel polymorphism of the human CD40 receptor with enhanced function. Blood 112: 1863-1871 [Abstract] [Full Text]  
• Turner, M. L., Hawkins, E. D., Hodgkin, P. D. (2008). Quantitative Regulation of B Cell Division Destiny by Signal Strength. J. Immunol. 181: 374-382 [Abstract] [Full Text]  
• Barral, P., Eckl-Dorna, J., Harwood, N. E., De Santo, C., Salio, M., Illarionov, P., Besra, G. S., Cerundolo, V., Batista, F. D. (2008). B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo. Proc. Natl. Acad. Sci. USA 105: 8345-8350 [Abstract] [Full Text]  
• Chackerian, B., Durfee, M. R., Schiller, J. T. (2008). Virus-Like Display of a Neo-Self Antigen Reverses B Cell Anergy in a B Cell Receptor Transgenic Mouse Model. J. Immunol. 180: 5816-5825 [Abstract] [Full Text]  
• de Andres, B., Cortegano, I., Serrano, N., del Rio, B., Martin, P., Gonzalo, P., Marcos, M. A. R., Gaspar, M. L. (2007). A Population of CD19highCD45R /lowCD21low B Lymphocytes Poised for Spontaneous Secretion of IgG and IgA Antibodies. J. Immunol. 179: 5326-5334 [Abstract] [Full Text]  
• Kilmon, M. A., Wagner, N. J., Garland, A. L., Lin, L., Aviszus, K., Wysocki, L. J., Vilen, B. J. (2007). Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and interleukin-6. Blood 110: 1595-1602 [Abstract] [Full Text]  
• Phan, T. G., Paus, D., Chan, T. D., Turner, M. L., Nutt, S. L., Basten, A., Brink, R. (2006). High affinity germinal center B cells are actively selected into the plasma cell compartment. JEM 203: 2419-2424 [Abstract] [Full Text]  
• Nishikawa, Y., Hikida, M., Magari, M., Kanayama, N., Mori, M., Kitamura, H., Kurosaki, T., Ohmori, H. (2006). Establishment of Lymphotoxin beta Receptor Signaling-Dependent Cell Lines with Follicular Dendritic Cell Phenotypes from Mouse Lymph Nodes. J. Immunol. 177: 5204-5214 [Abstract] [Full Text]  
• Kamperschroer, C., Dibble, J. P., Meents, D. L., Schwartzberg, P. L., Swain, S. L. (2006). SAP Is Required for Th Cell Function and for Immunity to Influenza. J. Immunol. 177: 5317-5327 [Abstract] [Full Text]  
• Acevedo-Suarez, C. A., Kilkenny, D. M., Reich, M. B., Thomas, J. W. (2006). Impaired Intracellular Calcium Mobilization and NFATc1 Availability in Tolerant Anti-Insulin B Cells. J. Immunol. 177: 2234-2241 [Abstract] [Full Text]  
• Watson, L. C., Moffatt-Blue, C. S., McDonald, R. Z., Kompfner, E., Ait-Azzouzene, D., Nemazee, D., Theofilopoulos, A. N., Kono, D. H., Feeney, A. J. (2006). Paucity of V-D-D-J Rearrangements and VH Replacement Events in Lupus Prone and Nonautoimmune TdT-/- and TdT+/+ Mice. J. Immunol. 177: 1120-1128 [Abstract] [Full Text]  
• Paus, D., Phan, T. G., Chan, T. D., Gardam, S., Basten, A., Brink, R. (2006). Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. JEM 203: 1081-1091 [Abstract] [Full Text]  
• Huang, H., Kearney, J. F., Grusby, M. J., Benoist, C., Mathis, D. (2006). Induction of tolerance in arthritogenic B cells with receptors of differing affinity for self-antigen. Proc. Natl. Acad. Sci. USA 103: 3734-3739 [Abstract] [Full Text]  
• Butler, J. E., Francis, D. H., Freeling, J., Weber, P., Krieg, A. M. (2005). 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. 175: 6772-6785 [Abstract] [Full Text]  
• Fields, M. L., Nish, S. A., Hondowicz, B. D., Metzgar, M. H., Wharton, G. N., Caton, A. J., Erikson, J. (2005). The Influence of Effector T Cells and Fas Ligand on Lupus-Associated B Cells. J. Immunol. 175: 104-111 [Abstract] [Full Text]  
• Yang, R., Murillo, F. M., Delannoy, M. J., Blosser, R. L., Yutzy, W. H. IV, Uematsu, S., Takeda, K., Akira, S., Viscidi, R. P., Roden, R. B. S. (2005). B Lymphocyte Activation by Human Papillomavirus-Like Particles Directly Induces Ig Class Switch Recombination via TLR4-MyD88. J. Immunol. 174: 7912-7919 [Abstract] [Full Text]  
• Phan, T. G., Gardam, S., Basten, A., Brink, R. (2005). Altered Migration, Recruitment, and Somatic Hypermutation in the Early Response of Marginal Zone B Cells to T Cell-Dependent Antigen. J. Immunol. 174: 4567-4578 [Abstract] [Full Text]  
• Acevedo-Suarez, C. A., Hulbert, C., Woodward, E. J., Thomas, J. W. (2005). Uncoupling of Anergy from Developmental Arrest in Anti-Insulin B Cells Supports the Development of Autoimmune Diabetes. J. Immunol. 174: 827-833 [Abstract] [Full Text]  
• Jin, H., Carrio, R., Yu, A., Malek, T. R. (2004). Distinct Activation Signals Determine whether IL-21 Induces B Cell Costimulation, Growth Arrest, or Bim-Dependent Apoptosis. J. Immunol. 173: 657-665 [Abstract] [Full Text]  
• Seagal, J., Edry, E., Naftali, H., Melamed, D. (2004). Generation and selection of an IgG-driven autoimmune repertoire during B-lymphopoiesis in Ig{micro}-deficient/lpr mice. Int Immunol 16: 905-913 [Abstract] [Full Text]  
• Steeves, M. A., Marion, T. N. (2004). Tolerance to DNA in (NZB x NZW)F1 Mice That Inherit an Anti-DNA VH as a Conventional {micro} H Chain Transgene but Not as a VH Knock-in Transgene. J. Immunol. 172: 6568-6577 [Abstract] [Full Text]  
• Ekland, E. H., Forster, R., Lipp, M., Cyster, J. G. (2004). Requirements for Follicular Exclusion and Competitive Elimination of Autoantigen-Binding B Cells. J. Immunol. 172: 4700-4708 [Abstract] [Full Text]  
• Silveira, P. A., Dombrowsky, J., Johnson, E., Chapman, H. D., Nemazee, D., Serreze, D. V. (2004). B Cell Selection Defects Underlie the Development of Diabetogenic APCs in Nonobese Diabetic Mice. J. Immunol. 172: 5086-5094 [Abstract] [Full Text]  
• Batten, M., Fletcher, C., Ng, L. G., Groom, J., Wheway, J., Laabi, Y., Xin, X., Schneider, P., Tschopp, J., Mackay, C. R., Mackay, F. (2004). TNF Deficiency Fails to Protect BAFF Transgenic Mice against Autoimmunity and Reveals a Predisposition to B Cell Lymphoma. J. Immunol. 172: 812-822 [Abstract] [Full Text]  
• Cook, A. J. L., Oganesian, L., Harumal, P., Basten, A., Brink, R., Jolly, C. J. (2003). Reduced Switching in SCID B Cells Is Associated with Altered Somatic Mutation of Recombined S Regions. J. Immunol. 171: 6556-6564 [Abstract] [Full Text]  
• Hangartner, L., Senn, B. M., Ledermann, B., Kalinke, U., Seiler, P., Bucher, E., Zellweger, R. M., Fink, K., Odermatt, B., Burki, K., Zinkernagel, R. M., Hengartner, H. (2003). Antiviral immune responses in gene-targeted mice expressing the immunoglobulin heavy chain of virus-neutralizing antibodies. Proc. Natl. Acad. Sci. USA 100: 12883-12888 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS