Signaling mechanisms regulating B-lymphocyte activation and tolerance (original) (raw)
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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)
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.
Intracellular B Lymphocyte Signalling and the Regulation of Humoral Immunity and Autoimmunity
Clinical reviews in allergy & immunology, 2017
B lymphocytes are critical for effective immunity; they produce antibodies and cytokines, present antigens to T lymphocytes and regulate immune responses. However, because of the inherent randomness in the process of generating their vast repertoire of antigen-specific receptors, B cells can also cause diseases through recognizing and reacting to self. Therefore, B lymphocyte selection and responses require tight regulation at multiple levels and at all stages of their development and activation to avoid diseases. Indeed, newly generated B lymphocytes undergo rigorous tolerance mechanisms in the bone marrow and, subsequently, in the periphery after their migration. Furthermore, activation of mature B cells is regulated through controlled expression of co-stimulatory receptors and intracellular signalling thresholds. All these regulatory events determine whether and how B lymphocytes respond to antigens, by undergoing apoptosis or proliferation. However, defects that alter regulated ...
Toll-like receptor driven B cell activation in the induction of systemic autoimmunity
Seminars in Immunology, 2011
Studies over the past decade have demonstrated a key role for pattern recognition receptors in the activation of autoreactive B cells. Self reactive B cells that manage to escape negative selection often express relatively low affinity receptors for self antigens (ignorant B cells), and can only be activated by integrating a relatively weak BCR signal with signals from additional receptors. Members of the toll-like receptor (TLR) gene family, and especially the nucleic acid binding receptors TLR 7, 8 and 9, appear to play a key role in this regard and promote the production of autoantibodies reactive with DNA-or RNA-associated autoantigens. These autoantibodies are able to form immune complexes with soluble or cell-bound ligands, and these immune complexes can in turn activate a second round of proinflammatory cells that further contribute to the autoimmune disease process. Recent data have emerged showing a pathogenic role for TLR7, with an opposing, protective role for TLR9. Targeting these disregulated pathways offers a therapeutic opportunity to treat autoimmune diseases without crippling the entire immune system. Further understanding of the role of specific receptors, cell subsets, and inhibitory signals that govern these TLR-associated pathways will enable future therapeutics to be tailored to specific categories of autoimmune disease.
Entry of B Cell Receptor Into Signaling Domains is Inhibited In Tolerant B Cells
The Journal of …, 2000
Signal transduction through the B cell antigen receptor (BCR) is altered in B cells that express a receptor that recognizes self-antigen. To understand the molecular basis for the change in signaling in autoreactive B cells, a transgenic model was used to isolate a homogeneous population of tolerant B lymphocytes. These cells were compared with a similar population of naive B lymphocytes. We show that the BCR from naive B cells enters a detergent-insoluble domain of the cell within 6 s after antigen binding, before a detectable increase in BCR phosphorylation. This fraction appears to be important for signaling because it is enriched for lyn kinase but lacks CD45 tyrosine phosphatase and because the BCR that moves into this domain becomes more highly phosphorylated. Partitioning of the BCR into this fraction is unaffected by src family kinase inhibition. Tolerant B cells do not efficiently partition the BCR into the detergent-insoluble domain, providing an explanation for their reduced tyrosine kinase activation and calcium flux in response to antigen. These results identify an early, regulated step in antigen receptor signaling and self-tolerance.
Molecular Immunology, 2017
Antibodies produced by B-cells provide protection from infectious agents. However, impaired cell death signaling pathways in B-cells can lead to cancer, immunodeficiency or autoimmune diseases. B-cell signaling molecules such as CD20, CD19, Btk, and BAFF-R are targeted by therapeutic drugs and used to treat B-cell derived lymphomas or autoimmune diseases. Nevertheless, B-cells could develop resistance to these therapeutic drugs or the therapeutic drugs may have off-target effects. For instance, repeated rituximab (anti-CD20 antibody) treatment may lead to the loss of its target cell surface molecule, CD20. In addition, in B-cell malignancies, loss of CD19 expression has been observed. Another target molecule, Btk is expressed not only in B-cells but also in mast cells, macrophages, and dendritic cells. Thus, targeting Btk could negatively regulate the functions of innate immunity. The expression of BAFF-R is thought to be restricted to B-cells but it is also expressed on Tcells. Targeting BAFF-R, therefore, may lead to depletion of T-cells in addition to B-cells. B cell receptor (BCR) expression and signaling, however, are critically important for development, differentiation and survival of Bcells. Moreover, BCR is exclusively expressed on B-cells, which makes it an excellent target to avoid off-target effects. B-lymphocytes (B-cells) are core components of adaptive immunity. The main functions of B-cells include antigen presentation and antibody production. However, defects in B-cell growth, development and selection can result in malignancy, immunodeficiency, and autoimmunity (Yanaba et al., 2008; Basso and Dalla-Favera, 2015; Ahn and Cunningham-Rundles, 2009). B cell receptor (BCR) is a transmembrane receptor protein located on the surface of B-cells. Signaling through BCR is required for normal progression of B-cell development. In humans, B-cells are produced in the bone marrow from hematopoietic precursor cells and they migrate to secondary lymphoid organs (periphery) where they encounter antigens. In the bone marrow, the VDJ recombination process produces BCR repertoires that are able to recognize a large array of antigens. In the periphery, B-cells can be activated by a variety of infectious agents through BCR. This phenomenon leads to the formation of germinal centers (GCs) (Pieper et al., 2013). In GCs, B-cells undergo somatic hypermutation (SHM), which increases BCR diversity and thereby increases chances of producing B-cells with high affinity to antigens. However, the SHM process can also lead to the production of autoreactive-B cells (Mackay and Rose, 2001). The BCR complex consists of an antigen-binding subunit and a signaling subunit. The antigen binding subunit is a membrane-bound immunoglobulin (mIg) which lacks any signaling motif. The mIg part consists of two heavy and two light chains combined to each other by disulfide bonds. The signaling subunit consists of the accessory proteins CD79a (Igα) and CD79b (Igβ) which transmit the activating signals to the celĺs interior. The recognition of specific antigens by the mIg, therefore, leads to the activation of a number of kinases such as Brutońs tyrosine kinase (Btk), phosphatidyl-inositol-3-kinase (PI3K) and extracellular signal-regulated kinases (ERKs) (Niiro and Clark, 2002; Treanor, 2012). As we demonstrate in our previous work, the early activation of ERK1 and ERK2 following BCR stimulation results in short-term survival of GC Bcells. However, in the late phase, BCR stimulation leads to inhibition of ERK1 and ERK2, which correlates with cell death (Adem et al., 2015, Fig. 1). Interestingly, BCR-mediated apoptosis of GC B-cells is reversed by CD40 signaling (Adem et al., 2015, Fig. 4). These findings indicate that B-cells which overexpress ERK1 and ERK2 might bypass the selection process. Thus, B-cells which overexpress ERK1/2 and possess memory or plasma cell transcription signatures may transform into self-reactive memory B-cells or auto-antibody producing plasma cells. In addition, it is also possible that B cells which overexpress ERK1/2 but lack differentiation specific signatures may transform into lymphoma cells. Overexpression of Rasgrf-1 amplifies the Ras-ERK pathway in chronic lymphocytic leukemia cells, thereby enhancing B-cell survival. This indicates that malignant B-cells utilize ERKs for their survival (Liao et al., 2014). Moreover, changes in the activation of Ras-ERKs pathway may lead to autoimmune manifestations (Teodorovic et al., 2014). Thus, targeting ERKs may have therapeutic benefits against these B-cell derived diseases. However, because of the critical role of ERKs in various cellular functions, the use of ERK inhibitors can lead to severe cellular toxicity. It is, therefore, imperative to selectively target B-cells in order to avoid the side-effects which could result from off-target inhibition. Rituximab is a chimeric monoclonal antibody which targets CD20, the cell surface differentiation antigen on B-cells. CD20 has a role in B-cell activation and differentiation. It is expressed in mature B-cells but not in hematological stem cells, pro-B cells, normal plasma cells or other tissues. This unique characteristic of CD20 expression makes it the suitable target to treat B-cell derived lymphomas or autoimmune diseases (Du et al., 2007). However, rituximab does not deplete autoreactive antibody-producing plasma cells, because these cells do not express CD20. Nevertheless, rituximab depletes B-cells, thereby decreasing the production of autoreactive antibody and malignant B-cells. The loss of CD20 expression, however, after repeated rituximab treatment may contribute to B-cells' resistance against rituximab (Haidar et al., 2003). A study on CD20 −/− (knockout) mouse has shown normal development and function in CD20 deficient B-cells (Uchida et al., 2004). This data further strengthen the fact that CD20 is not a critical cell surface molecule for the survival and development of B cells. CD19 is another pan B-cell marker used to target and deplete B-cell
Innate pathways to B-cell activation and tolerance
Annals of The New York Academy of Sciences, 2010
B cells represent an important link between the adaptive and innate immune systems as they express both antigenspecific B-cell receptors (BCRs) as well as various Toll-like receptors (TLRs). Several checkpoints in B-cell development ensure that self-specific cells are eliminated from the mature B-cell repertoire to avoid harmful autoreactive responses. These checkpoints are controlled by BCR-mediated events but are also influenced by TLR-dependent signals from the innate immune system. Additionally, B-cell-intrinsic and extrinsic TLR signaling are critical for inflammatory events required for the clearance of microbial infections. Factors secreted by TLR-activated macrophages or dendritic cells directly influence the fate of protective and autoreactive B cells. Additionally, naive and memory B cells respond differentially to TLR ligands, as do different B-cell subsets. We review here recent literature describing intrinsic and extrinsic effects of TLR stimulation on the fate of B cells, with particular attention to autoimmune diseases.
Immunity, 2008
On the lupus-prone MRL-lpr/lpr (MRL-lpr) background, AM14 rheumatoid factor (RF) B cells are activated, differentiate into plasmablasts, and undergo somatic hypermutation outside of follicles. Using multiple strategies to impair T cells, we found that such AM14 B cell activation did not require T cells but could be modulated by them. In vitro, the signaling adaptor MyD88 is required for IgG anti-chromatin to stimulate AM14 B cell proliferation when T cells are absent. However, the roles of Toll-like receptors (TLRs) in AM14 B cell activation in vivo have not been investigated. We found that activation, expansion, and differentiation of AM14 B cells depended on MyD88; however, mice lacking either TLR7 or TLR9 displayed partial defects, indicating complex roles for these receptors. T cell-independent activation of certain autoreactive B cells, which gain stimuli via endogenous TLR ligands instead of T cells, may be the initial step in the generation of canonical autoantibodies.
Recent Progress in the Understanding of B-Cell Functions in Autoimmunity
Scandinavian Journal of Immunology, 2001
Our early concepts of the normal role of B cells in immunity focused on their ability to produce antibodies (Ab) and in the case of autoimmune diseases autoAbs, some of which were pathogenic. Over the past 10 years, it has became apparent that B cells display a variety of characteristics, other than Ab production, which could contribute to autoimmunity. They normally play a role in the development of lymphoid architecture, regulating T-cell subsets and dendritic cell (DC) function through cytokine production, and in activation of T cells. Receptors editing is also important in B cells which aids in immunity to infection and, possibly, prevention of autoimmunity. Transgenic animal models have now shown that B cells are necessary for many autoimmune diseases although their Ab products are not required in some cases. Negative signalling by CD5 and other molecules, such as CD22, in maintaining tolerance through recruitment of src-homology two domaincontaining protein tyrosine phosphatase-1 has also been documented. In fact, we have now reached a new era whereby the B cell has returned as an important contributor to autoimmune disorders, so that the race is on to characterize signalling regulation via the B-cell receptor and coreceptors. Identification of such molecules and their potential defects should lead to effective ways of controlling the immune response and in particular preventing the development of autoimmune states. The classical view of B cells in the biology of immune responses to infectious and self-antigens (Ag) that they promote immunity primarily by producing Ab turns out to be rather naõ Ève. Indeed, studies over the last few years indicate that this view is far from complete, and suggest that B lymphocytes have extraordinarily diverse functions within the immune system. Furthermore, it is becoming increasingly clear that the pathogenesis of autoimmune diseases cannot solely be accounted for by T cells, and intrinsic abnormalities of B cells have been described in such conditions. In this brief review we highlight some recent observations in the context of B lymphocyte in pathophysiology, and focus on their revival as pivotal players the pathophysiology in autoimmune diseases. Yet, it remains difficult to provide a model of how important B cells are in immunity and autoimmunity.