A Balance between B Cell Receptor and Inhibitory Receptor Signaling Controls Plasma Cell Differentiation by Maintaining Optimal Ets1 Levels (original) (raw)
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Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy
Frontiers in Immunology, 2018
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.
Defective negative regulation of antigen receptor signaling in Lyn-deficient B lymphocytes
Current Biology, 1998
To elucidate the role of the Src family kinase Lyn in B cell receptor (BCR) signaling, we and others previously generated lyn -/mice and analyzed their B cell responses. Although the initiation of BCR signaling in lyn -/-B cells is delayed, BCR-induced ERK2 activation and proliferation are enhanced. As the co-receptors FcγRIIb1 and CD22 have been shown to be negative regulators of BCR signaling, we have now examined their functional roles in lyn -/-B cells.
B cell receptor signaling and autoimmunity
The FASEB Journal, 2001
The immune receptors of lymphocytes are able to sense the nature of bound ligands. Through coupled signaling pathways the generated signals are appropriately delivered to the intracellular machinery, allowing specific functional responses. A central issue in contemporary immunology is how the fate of B lymphocytes is determined at the successive developmental stages and how the B cell receptor distinguishes between signals that induce immune response or tolerance. Experiments with mice expressing transgenes or lacking signal transduction molecules that lead to abnormal lymphocyte development and/or response are providing important clues to the mechanisms that regulate signaling thresholds at different developmental stages. The studies are also revealing novel potential mechanisms of induction of autoimmunity, which may have a bearing on the understanding of human diseases.-Hasler, P., Zouali, M. B cell receptor signaling and autoimmunity. FASEB J. 15, 2085-2098 (2001)
Signaling mechanisms regulating B-lymphocyte activation and tolerance
Journal of Molecular Medicine, 2015
It is becoming more and more accepted that, in addition to producing autoantibodies, B lymphocytes have other important functions that influence the development of autoimmunity. For example, autoreactive B cells are able to produce inflammatory cytokines and activate pathogenic T cells. B lymphocytes can react to extracellular signals with a range of responses from anergy to autoreactivity. The final outcome is determined by the relative contribution of signaling events mediated by activating and inhibitory pathways. Besides the B cell antigen receptor (BCR), several costimulatory receptors expressed on B cells can also induce B cell proliferation and survival, or regulate antibody production. These include CD19, CD40, the B cell activating factor receptor, and Toll-like receptors. Hyperactivity of these receptors clearly contributes to breaking B-cell tolerance in several autoimmune diseases. Inhibitors of these activating signals (including protein tyrosine phosphatases, deubiquitinating enzymes and several adaptor proteins) are crucial to control Bcell activation and maintain B-cell tolerance. In this review, we summarize the inhibitory signaling mechanisms that counteract B-cell activation triggered by the BCR and the coreceptors.
Altered B cell signalling in autoimmunity
Nature Reviews Immunology, 2017
Recent work has provided new insights into how altered B cell-intrinsic signals-through the B cell receptor (BCR) and key co-receptors-function together to promote the pathogenesis of autoimmunity. These combined signals affect B cells at two distinct stages: first, in the selection of the naive repertoire; and second, during extrafollicular or germinal centre activation responses. Thus, dysregulated signalling can lead to both an altered naive BCR repertoire and the generation of autoantibody-producing B cells. Strikingly, high-affinity autoantibodies predate and predict disease in several autoimmune disorders, including type 1 diabetes and systemic lupus erythematosus. This Review summarizes how, rather than being a downstream consequence of autoreactive T cell activation, dysregulated B cell signalling can function as a primary driver of many human autoimmune diseases. Despite the established importance of B cells in the pathogenesis of human autoimmunity, the immune mechanisms that underlie initial breaks in B cell tolerance have not been completely defined. In addition to clonally rearranged B cell receptors (BCRs), B cells express innate pattern recognition receptors (including Toll-like receptors (TLRs)), costimulatory molecules (including CD40, CD80 and CD86) and cytokine receptors. Both the establishment of the naive B cell repertoire and B cell activation during an immune response depend on the coordinated, synergistic activation of these receptor families. Genome-wide association studies (GWAS) have identified hundreds of gene polymorphisms that are associated with an increased risk of developing auto-immunity 1-5. Importantly, the vast majority of these genetic changes are predicted to affect immune function. Most are located in non-coding elements that probably have an effect on gene expression, whereas only a limited number result in altered protein structures. Despite this increasingly robust genetic dataset, there is only a limited amount of mechanistic data with respect to the cell lineage-specific and stage-specific effects of candidate risk variants. Notably, autoimmunityassociated variants identified by GWAS are highly enriched for signalling programmes that may affect B cell function, including in genes that encode receptors, signalling effectors and Correspondence to: D.J.R.
Sustained Activation of Lyn Tyrosine Kinase In Vivo Leads to Autoimmunity
Journal of Experimental Medicine, 2002
Genetic ablation of the Lyn tyrosine kinase has revealed unique inhibitory roles in B lymphocyte signaling. We now report the consequences of sustained activation of Lyn in vivo using a targeted gain-of-function mutation (Lyn up/up mice). Lyn up/up mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. Lyn up/up B cells are characterized by the constitutive phosphorylation of negative regulators of B cell antigen receptor (BCR) signaling including CD22, SHP-1, and SHIP-1, and display attributes of lymphocytes rendered tolerant by constitutive engagement of the antigen receptor. However, exaggerated positive signaling is also apparent as evidenced by the constitutive phosphorylation of Syk and phospholipase C ␥ 2 in resting Lyn up/up B cells. Similarly, Lyn up/up B cells show a heightened calcium flux in response to BCR stimulation. Surprisingly, Lyn up/up mice develop circulating autoreactive antibodies and lethal autoimmune glomerulonephritis, suggesting that enhanced positive signaling eventually overrides constitutive negative signaling. These studies highlight the difficulty in maintaining tolerance in the face of chronic stimulation and emphasize the pivotal role of Lyn in B cell signaling.
Positive and negative roles of the tyrosine kinase Lyn in B cell function
Seminars in Immunology, 1998
The function of Lyn in B cell activation has been studied recently by examining the properties of B cells from mice in which the lyn gene has been inactivated by gene targeting. These mice show evidence of B cell hyperreactivity in vivo, as the number of B lymphoblastoid cells greatly increase with age, IgM levels increase by 10-fold or more, and autoantibodies to double-stranded DNA and other nuclear antigens become apparent. B cells from lyn yry mice also exhibit enhanced BCR-induced activation of MAP kinases, intracellular calcium elevation and proliferative responses in vitro. These phenomena may relate to participation of Lyn in events that serve to decrease B cell responses to antigen. Among the leading candidates for these suppressive events are the inhibition of B cell antigen receptor function by Fc␥ RIIb1 and by CD22. Although Lyn also participates positively in the initial events of B cell antigen receptor signal transduction, this function can also be supplied by other tyrosine kinases, presumably other Src-family kinases. In contrast, some aspects of inhibition by CD22 appear to be almost completely dependent upon Lyn and Fc␥ RIIb1 inhibition is also diminished in the absence of Lyn. Thus, the net effect of Lyn action is negative rather than positive for B cell activation. Key words: autoimmunity r CD22 r Fc␥ RIIb r Lyn r Src-family kinases ᮊ1998 Academic Press ACTIVATION OF B lymphocytes is initiated by contact Ž . of the B cell antigen receptor BCR with antigen and proceeds if the B cell receives additional stimulatory signals, which can include cytokines, membranebound molecules of helper T cells, such as CD40L, or polyclonal B cell activator molecules from bacterial cell walls. The extent and nature of required additio-From The George Williams Hooper Foundation,
Arthritis & Rheumatology, 2015
Objective. Systemic lupus erythematosus (SLE) is associated with hyperactivity of B cells and abnormalities of B cell receptor (BCR) signaling. To address the linkage between dysregulated BCR signaling and increased B cell function, we assessed immediate phosphorylation events in lupus B cells. Methods. B cells from SLE patients and healthy donors were analyzed by flow cytometry to assess phosphorylated CD22, Syk, and Akt as well as the basal expression of the BCR coreceptors CD22 and CD19. Confocal microscopy studies determined the recruitment of CD22 and the tyrosine phosphatase SH2 domain-containing phosphatase 1 to the activated BCR complex. Additionally, phosphatase activity in SLE versus healthy donor B cells was measured. Results. B cells from SLE patients showed diminished Syk phosphorylation and reduced intracellular calcium release after BCR activation as compared to B cells from healthy donors. This was related to an enhanced activity of tyrosine, but not serine/threonine, phosphatases and was corrected by inhibition of tyrosine phosphatase activity. In contrast to reduced Syk phosphorylation after BCR activation, phosphorylation of Akt was significantly increased in SLE B cells. The disturbed balance between Syk and Akt phosphorylation was significantly correlated with B cell survival following BCR engagement. Furthermore, CD272, but not CD271, B cells from SLE patients displayed increased expression and phosphorylation of the inhibitory BCR coreceptor CD22. Conclusion. These results indicate that an imbalance between serine and tyrosine phosphatases in SLE contributes to an intrinsically disturbed balance of BCR-initiated signaling pathways, resulting in enhanced survival of lupus B cells and differentiation into plasma cells. The development, maturation, and selection of B cells are tightly regulated by the affinity and activation threshold of the B cell receptor (BCR). Besides its important role during B cell differentiation and survival, the BCR plays a pivotal role in avoiding autoreactivity by initiating a variety of negative-selection events (1,2). After BCR crosslinking, conformation changes induced by cytoskeleton reorganization lead to a Lyn-dependent phosphorylation of the intracellular Iga/b immunoreceptor tyrosine-based activation motif (ITAM) of the BCR and its coreceptors (e.g., CD19 and CD22), followed by the recruitment and activation of the spleen tyrosine kinase (Syk). Subsequently, signaling molecules, such as Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K) and phospholipase Cg2 (PLCg2) accumulate in a signalosome to initiate internalization, antigen processing, calcium release, and a specific gene expression profile (3). Even though Syk can directly activate PI3K (4), a Syk-independent PI3K/ Akt activation has been described (5), subdividing the BCR-associated signaling pathway into two axes: Syk activation linked to PLCg2 phosphorylation and calcium influx, and CD19 phosphorylation followed by activation Supported by the DFG (SFB 650 project TP12, SFB 650 project TP16, SFB 633 A14, SPP ImmunoBone [Do491/8-2], and project Do491/7-3).