Abstract
B cell antigen receptor (BCR) signaling is a tightly regulated process governed by both positive and negative mediators/regulators to ensure appropriate responses to exogenous and autologous antigens. Upon naïve B cell recognition of antigen CD79 [the immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling subunit of the BCR] is phosphorylated and recruits Src and Syk family kinases that then phosphorylate proximal intermediaries linked to downstream activating signaling circuitry. This plasma membrane localized signalosome activates PI3K leading to generation of PIP3 critical for membrane localization and activation of plecktrin homology domain-containing effectors. Conversely, in anergic B cells, chronic antigen stimulation drives biased monophosphorylation of CD79 ITAMs leading to recruitment of Lyn, but not Syk, which docks only to bi-phosphorylated ITAMS. In this context, Lyn appears to function primarily as a driver of inhibitory signaling pathways promoting the inhibition of the PI3K pathway by inositol phosphatases, SHIP-1 and PTEN, which hydrolyze PIP3 to PIP2. Lyn may also exert negative regulation of signaling through recruitment of SHP-1, a tyrosine phosphatase that dephosphorylates activating signaling molecules. Alleles of genes that encode or regulate expression of components of this axis, including SHIP-1, SHP-1, Csk/PTPn22, and Lyn, have been shown to confer risk of autoimmunity. This review will discuss functional interplay of components of this pathway and the impact of risk alleles on its function.
Highlights
The stochastic nature of lymphocyte repertoire diversification leads to production of many B cells that are autoreactive
If B cell antigen receptor (BCR) interactions with autoantigen are of high avidity and the cell is immature, antigen receptor signals activate receptor editing, wherein immunoglobulin light chain allele usage changes to an alternative allele [2, 3]
Naïve B lymphocyte recognition of antigen leads to transduction and propagation of signals that induce expression of activation markers and prepare the cell to interact productively with T cells
Summary
The stochastic nature of lymphocyte repertoire diversification leads to production of many B cells that are autoreactive. It is estimated up to 70% of newly generated B cells recognize selfantigens [1] These autoreactive cells must be silenced to prevent the production of pathogenic autoantibodies and presentation of autoantigen-derived peptides to potentially pathogenic T cells. If B cell antigen receptor (BCR) interactions with autoantigen are of high avidity and the cell is immature, antigen receptor signals activate receptor editing, wherein immunoglobulin light chain allele usage changes to an alternative allele [2, 3]. If this process eliminates BCR autoreactivity, harmless cell proceeds to the periphery where it can participate in protective immune responses. This review is focused on the molecular regulatory mechanisms that are uniquely induced in anergic cells and are involved in maintenance of their unresponsiveness
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