| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Australian Cancer Research Foundation Genetics Laboratory and Medical Genome Centre, John Curtin School of Medical Research, Australian Phenomics Facility, Australian National University, Canberra, Australia
Differentiation of B cells into plasma cells represents a critical immunoregulatory checkpoint where neutralizing Abs against infectious agents must be selected whereas self-reactive Abs are suppressed. Bacterial LPS is a uniquely potent bacterial immunogen that can bypass self-tolerance within the T cell repertoire. We show here that during LPS-induced plasma cell differentiation, the ERK intracellular signaling pathway serves as a pivotal switch integrating opposing inputs from Ag via BCR and from the two best characterized B cell differentiation factors made by T cells, IL-2 and IL-5. Continuous Ag receptor signaling through the RAS/MEK/ERK pathway, as occurs in self-reactive B cells, inhibits LPS induction of Blimp-1 and the plasma cell differentiation program. Differentiation resumes after a transient pulse of Ag-ERK signaling, or upon inactivation of ERK by IL-2 and IL-5 through induction of dual-specificity phosphatase 5 (Dusp5). The architecture of this molecular switch provides a framework for understanding the specificity of antibacterial Ab responses and resistance to bacterially induced autoimmune diseases such as Guillain-Barré syndrome.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Project Grant 224264 from the National Health and Medical Research Council.
2 L.R. and J.I.H. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Christopher C. Goodnow, Australian Cancer Research Foundation Genetics Laboratory and Medical Genome Centre, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia. E-mail address: Chris.Goodnow{at}anu.edu.au
4 Abbreviations used in this paper: HEL, hen egg lysozyme; PdBu, phorbol dibutyrate; EGFP, enhanced GFP; AFC, Ab-forming cell; cIg, cytoplasmic Ig.
This article has been cited by other articles:
|
|
 |
|
  R. Diz, S. K. McCray, and S. H. Clarke B Cell Receptor Affinity and B Cell Subset Identity Integrate to Define the Effectiveness, Affinity Threshold, and Mechanism of Anergy J. Immunol., September 15, 2008; 181(6): 3834 - 3840. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Turner, E. D. Hawkins, and P. D. Hodgkin Quantitative Regulation of B Cell Division Destiny by Signal Strength J. Immunol., July 1, 2008; 181(1): 374 - 382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. E. Kovanen, J. Bernard, A. Al-Shami, C. Liu, J. Bollenbacher-Reilley, L. Young, C. Pise-Masison, R. Spolski, and W. J. Leonard T-cell Development and Function Are Modulated by Dual Specificity Phosphatase DUSP5 J. Biol. Chem., June 20, 2008; 283(25): 17362 - 17369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. D. Hondowicz, S. T. Alexander, W. J. Quinn III, A. J. Pagan, M. H. Metzgar, M. P. Cancro, and J. Erikson The role of BLyS/BLyS receptors in anti-chromatin B cell regulation Int. Immunol., April 1, 2007; 19(4): 465 - 475. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
