ScienceDaily (Mar. 26, 2010) — Researchers at National Jewish Health have discovered a fundamental step in the development of the immune system, one that allows B cells to mature and fight disease by producing effective antibodies. Immunologist Roberta Pelanda, PhD, and her colleagues have demonstrated that immature B cells in the bone marrow must receive a positive signal before they can migrate to the spleen where they mature and are activated. In the March 15, 2010 issue of The Journal of Experimental Medicine, the researchers also reported that a protein known as Erk helps deliver that positive signal.
Humans make millions of B cells every day, each one equipped with its own unique B-cell receptor. Each receptor recognizes a specific protein fragment. Once the receptor recognizes that fragment, the B cell becomes activated and releases antibodies that attack the protein or the cell it is on.
B-cell receptors first appear on developing B cells in the bone marrow. Some of those receptors bind to proteins that are a normal part of the body, and could trigger an autoimmune attack. Other receptors can be non-functional. The selection process weeds out these dangerous and non-functional B cells to produce a population that can recognize a wide variety of foreign, potentially harmful invaders, but tolerate proteins that are a normal part of the organism.
Negative selection occurs in the bone marrow when potentially autoimmune B cells are detected, rejected and instructed to produce a different receptor.
The next step has been unclear. Do B cells that survive negative selection leave the bone marrow on their own? Or do they need a signal that tells them to leave the marrow and migrate to the spleen?
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doi:10.1084/jem.20091673
The Journal of Experimental Medicine, Vol. 207, No. 3, 607-621
The Rockefeller University Press, 0022-1007 $30.00
© Rowland et al.
Sarah L. Rowland, Corinne L. DePersis, Raul M. Torres, and Roberta Pelanda
Integrated Department of Immunology, National Jewish Health and University of Colorado Denver, Denver, CO 80206
CORRESPONDENCE Roberta Pelanda: pelandar@njhealth.org
B cell receptors (BCRs) generate tonic signals critical for B cell survival and early B cell development. To determine whether these signals also mediate the development of transitional and mature B cells, we examined B cell development using a mouse strain in which nonautoreactive immunoglobulin heavy and light chain–targeted B cells express low surface BCR levels. We found that reduced BCR expression translated into diminished tonic BCR signals that strongly impaired the development oftransitional and mature B cells. Constitutive expression of Bcl-2 did not rescue the differentiation of BCR-low B cells, suggesting that this defect was not related to decreased cell survival. In contrast, activation of the Ras pathway rescued the differentiation of BCR-low immature B cells both in vitro and in vivo, whereas extracellular signal-regulated kinase (Erk) inhibition impaired the differentiation of normal immature B cells. These results strongly suggest that tonic BCR signaling mediates the differentiation of immature into transitional and mature B cells via activation of Erk, likely through a pathway requiring Ras.
Abbreviations used: BAFF, B cell activating factor; Erk, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; MFI, mean fluorescence intensity; pErk, phosphorylated Erk; PI, propidium iodide.
© 2010 Rowland et al.
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