© The Rockefeller University Press, 0022-1007/1997/12/1923/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 11, December 1, 1997 1923-1931
CD19-Regulated Signaling Thresholds Control Peripheral Tolerance and Autoantibody Production in B Lymphocytes
Makoto Inaoki*,
Shinichi Sato*,
Bennett C. Weintraub
,
Christopher C. Goodnow
, and
Thomas F. Tedder*
From the * Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710; and
Department of Microbiology and Immunology and Howard Hughes Medical Institute, Beckman Center, Stanford University School of Medicine, Stanford, California 94305
The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity. Increasing the density of CD19 expression renders B lymphocytes hyper-responsive to transmembrane signals, and transgenic mice that overexpress CD19 have increased levels of autoantibodies. The role of CD19 in tolerance regulation and autoantibody generation was therefore examined by crossing mice that overexpress a human CD19 transgene with transgenic mice expressing a model autoantigen (soluble hen egg lysozyme, sHEL) and high-affinity HEL-specific IgMa and IgDa (IgHEL) antigen receptors. In this model of peripheral tolerance, B cells in sHEL/IgHEL double-transgenic mice are functionally anergic and do not produce autoantibodies. However, it was found that overexpression of CD19 in sHEL/IgHEL double-transgenic mice resulted in a breakdown of peripheral tolerance and the production of anti-HEL antibodies at levels similar to those observed in IgHEL mice lacking the sHEL autoantigen. Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance. Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.
Address correspondence to Thomas F. Tedder, Department of Immunology, Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-3578; Fax: 919-684-8982; e-mail: thomas.tedder{at}duke.edu
1. Abbreviations used in this paper: hCD19, human CD19; IgHEL, high-affinity HEL-specific IgMa and IgDa; sHEL, soluble 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:
-
Kochi, Y., Myouzen, K., Yamada, R., Suzuki, A., Kurosaki, T., Nakamura, Y., Yamamoto, K.
(2009). FCRL3, an Autoimmune Susceptibility Gene, Has Inhibitory Potential on B-Cell Receptor-Mediated Signaling. J. Immunol.
183: 5502-5510
[Abstract]
[Full Text]
-
Yoshizaki, A., Iwata, Y., Komura, K., Ogawa, F., Hara, T., Muroi, E., Takenaka, M., Shimizu, K., Hasegawa, M., Fujimoto, M., Tedder, T. F., Sato, S.
(2008). CD19 Regulates Skin and Lung Fibrosis via Toll-Like Receptor Signaling in a Model of Bleomycin-Induced Scleroderma. Am. J. Pathol.
172: 1650-1663
[Abstract]
[Full Text]
-
Chang, N.-H., McKenzie, T., Bonventi, G., Landolt-Marticorena, C., Fortin, P. R., Gladman, D., Urowitz, M., Wither, J. E.
(2008). Expanded Population of Activated Antigen-Engaged Cells within the Naive B Cell Compartment of Patients with Systemic Lupus Erythematosus. J. Immunol.
180: 1276-1284
[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]
-
Oliver, P. M., Vass, T., Kappler, J., Marrack, P.
(2006). Loss of the proapoptotic protein, Bim, breaks B cell anergy. JEM
203: 731-741
[Abstract]
[Full Text]
-
Kilmon, M. A., Rutan, J. A., Clarke, S. H., Vilen, B. J.
(2005). Cutting Edge: Low-Affinity, Smith Antigen-Specific B Cells Are Tolerized by Dendritic Cells and Macrophages. J. Immunol.
175: 37-41
[Abstract]
[Full Text]
-
Yan, J., Wolff, M. J., Unternaehrer, J., Mellman, I., Mamula, M. J.
(2005). Targeting antigen to CD19 on B cells efficiently activates T cells. Int Immunol
17: 869-877
[Abstract]
[Full Text]
-
Hibbs, M. L., Harder, K. W., Armes, J., Kountouri, N., Quilici, C., Casagranda, F., Dunn, A. R., Tarlinton, D. M.
(2002). Sustained Activation of Lyn Tyrosine Kinase In Vivo Leads to Autoimmunity. JEM
196: 1593-1604
[Abstract]
[Full Text]
-
Marchbank, K. J., Kulik, L., Gipson, M. G., Morgan, B. P., Holers, V. M.
(2002). Expression of Human Complement Receptor Type 2 (CD21) in Mice During Early B Cell Development Results in a Reduction in Mature B Cells and Hypogammaglobulinemia. J. Immunol.
169: 3526-3535
[Abstract]
[Full Text]
-
Fujimoto, M., Poe, J. C., Satterthwaite, A. B., Wahl, M. I., Witte, O. N., Tedder, T. F.
(2002). Complementary Roles for CD19 and Bruton's Tyrosine Kinase in B Lymphocyte Signal Transduction. J. Immunol.
168: 5465-5476
[Abstract]
[Full Text]
-
HASLER, P., ZOUALI, M.
(2001). B cell receptor signaling and autoimmunity. FASEB J.
15: 2085-2098
[Abstract]
[Full Text]
-
Hasegawa, M., Fujimoto, M., Poe, J. C., Steeber, D. A., Tedder, T. F.
(2001). CD19 Can Regulate B Lymphocyte Signal Transduction Independent of Complement Activation. J. Immunol.
167: 3190-3200
[Abstract]
[Full Text]
-
Hasegawa, M., Fujimoto, M., Poe, J. C., Steeber, D. A., Lowell, C. A., Tedder, T. F.
(2001). A CD19-Dependent Signaling Pathway Regulates Autoimmunity in Lyn-Deficient Mice. J. Immunol.
167: 2469-2478
[Abstract]
[Full Text]
-
Sato, S., Hasegawa, M., Fujimoto, M., Tedder, T. F., Takehara, K.
(2000). Quantitative Genetic Variation in CD19 Expression Correlates with Autoimmunity. J. Immunol.
165: 6635-6643
[Abstract]
[Full Text]
-
Mary, C., Laporte, C., Parzy, D., Santiago, M.-L., Stefani, F., Lajaunias, F., Parkhouse, R. M. E., O'Keefe, T. L., Neuberger, M. S., Izui, S., Reininger, L.
(2000). Cd22a PRE-mRNA Dysregulated Expression of the Cd22 Gene as a Result of a Short Interspersed Nucleotide Element Insertion in Cd22a Lupus-Prone Mice. J. Immunol.
165: 2987-2996
[Abstract]
[Full Text]
-
Ratanatharathorn, V., Carson, E., Reynolds, C., Ayash, L. J., Levine, J., Yanik, G., Silver, S. M., Ferrara, J. L.M., Uberti, J. P.
(2000). Anti-CD20 Chimeric Monoclonal Antibody Treatment of Refractory Immune-Mediated Thrombocytopenia in a Patient with Chronic Graft-versus-Host Disease. ANN INTERN MED
133: 275-279
[Abstract]
[Full Text]
-
Brauweiler, A., Tamir, I., Dal Porto, J., Benschop, R. J., Helgason, C. D., Humphries, R. K., Freed, J. H., Cambier, J. C.
(2000). Differential Regulation of B Cell Development, Activation, and Death by the Src Homology 2 Domain-Containing 5' Inositol Phosphatase (Ship). JEM
191: 1545-1554
[Abstract]
[Full Text]
-
, , , , , , , , , , , , , , , , , , ,
(2000). Human Anti-Thyroid Peroxidase Single-Chain Fragment Variable of Ig Isolated from a Combinatorial Library Assembled In-Cell: Insights into the In Vivo. J. Immunol.
164: 4162-4169
[Abstract]
[Full Text]
-
Hippen, K. L., Tze, L. E., Behrens, T. W.
(2000). Cd5 Maintains Tolerance in Anergic B Cells. JEM
191: 883-890
[Abstract]
[Full Text]
-
Cornall, R. J., Cheng, A. M., Pawson, T., Goodnow, C. C.
(2000). Role of Syk in B-cell development and antigen-receptor signaling. Proc. Natl. Acad. Sci. USA
97: 1713-1718
[Abstract]
[Full Text]
-
Fujimoto, M., Poe, J. C., Jansen, P. J., Sato, S., Tedder, T. F.
(1999). CD19 Amplifies B Lymphocyte Signal Transduction by Regulating Src-Family Protein Tyrosine Kinase Activation. J. Immunol.
162: 7088-7094
[Abstract]
[Full Text]
-
Oliver, A. M., Martin, F., Kearney, J. F.
(1999). IgMhighCD21high Lymphocytes Enriched in the Splenic Marginal Zone Generate Effector Cells More Rapidly Than the Bulk of Follicular B Cells. J. Immunol.
162: 7198-7207
[Abstract]
[Full Text]
-
O'Keefe, T. L., Williams, G. T., Batista, F. D., Neuberger, M. S.
(1999). Deficiency in CD22, a B Cell-specific Inhibitory Receptor, Is Sufficient to Predispose to Development of High Affinity Autoantibodies. JEM
189: 1307-1313
[Abstract]
[Full Text]
-
Theofilopoulos, A N
(1998). Effector and predisposing genes in murine lupus. Lupus
7: 575-584
[Abstract]