scholarly journals Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
Anthony Lau ◽  
Danielle T. Avery ◽  
Katherine Jackson ◽  
Helen Lenthall ◽  
Stefano Volpi ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Peripheral Tolerance ◽  
Gain Of Function ◽  
Autoantibody Production ◽  
Self Tolerance ◽  
A Cell ◽  
Phosphoinositide 3 Kinase ◽  
Self Antigen

Antibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding heterozygous Pik3cd activating mutation, self-reactive B cells exhibit a cell-autonomous subversion of their response to self-antigen: instead of becoming tolerized and repressed from secreting autoantibody, Pik3cd gain-of-function B cells are activated by self-antigen to form plasmablasts that secrete high titers of germline-encoded IgM autoantibody and hypermutating germinal center B cells. However, within the germinal center, peripheral tolerance was still enforced, and there was selection against B cells with high affinity for self-antigen. These data show that the strength of PI3K signaling is a key regulator of pregerminal center B cell self-tolerance and thus represents a druggable pathway to treat antibody-mediated autoimmunity.

scholarly journals Active PI3K abrogates central tolerance in high-avidity autoreactive B cells

2019 ◽  
Vol 216 (5) ◽  
pp. 1135-1153 ◽  
Author(s):  
Sarah A. Greaves ◽  
Jacob N. Peterson ◽  
Pamela Strauch ◽  
Raul M. Torres ◽  
Roberta Pelanda
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Peripheral Tolerance ◽  
High Avidity ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Central Tolerance ◽  
Autoreactive B Cells ◽  
Self Antigen

Autoreactive B cells that bind self-antigen with high avidity in the bone marrow undergo mechanisms of central tolerance that prevent their entry into the peripheral B cell population. These mechanisms are breached in many autoimmune patients, increasing their risk of B cell–mediated autoimmune diseases. Resolving the molecular pathways that can break central B cell tolerance could therefore provide avenues to diminish autoimmunity. Here, we show that B cell–intrinsic expression of a constitutively active form of PI3K-P110α by high-avidity autoreactive B cells of mice completely abrogates central B cell tolerance and further promotes these cells to escape from the bone marrow, differentiate in peripheral tissue, and undergo activation in response to self-antigen. Upon stimulation with T cell help factors, these B cells secrete antibodies in vitro but remain unable to secrete autoantibodies in vivo. Overall, our data demonstrate that activation of the PI3K pathway leads high-avidity autoreactive B cells to breach central, but not late, stages of peripheral tolerance.

scholarly journals A disease-related rheumatoid factor autoantibody is not tolerized in a normal mouse: implications for the origins of autoantibodies in autoimmune disease.

1996 ◽  
Vol 184 (4) ◽  
pp. 1269-1278 ◽  
Author(s):  
L G Hannum ◽  
D Ni ◽  
A M Haberman ◽  
M G Weigert ◽  
M J Shlomchik
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Rheumatoid Factor ◽  
Normal Mouse ◽  
Memory Cell ◽  
Cell Development ◽  
Cell Tolerance ◽  
Autoantibody Production ◽  
Self Antigen

We have analyzed B cell tolerance in a rheumatoid factor (RF) transgenic mouse model. The model is based on AM14, a hybridoma, originally isolated from an autoimmune MRL/lpr mouse that has an affinity and specificity typical of disease-related RFs from this strain. AM14 binds to immunoglobulin (Ig)G2a of the "a" allotype (IgG2aa) and not to IgG2ab. Thus, by crossing the transgenes onto an IgHa (BALB/c) background or to a congenic IgHb (CB.17) background, we could study the RF-expressing B cells when they were self-specific (IgHa) or when they were not self-specific (IgHb). These features make the AM14 model unique in focusing on a true autoantibody specificity while at the same time allowing comparison of autoreactive and nonautoreactive transgenic B cells, as was possible in model autoantibody systems such as anti-hen egg lysozyme. Studies showed that AM14 RF B cells can make primary immune responses and do not downregulate sIgM, indicating that the presence of self-antigen does not induce anergy of these cells. In fact, IgHa AM14 transgenic mice have higher serum levels of transgene-encoded RF than their IgHb counterparts, suggesting that self-antigen-specific activation occurs even in the normal mouse background. Since AM14 B cells made primary responses, we had the opportunity to test for potential blocks to self-reactive cells entering the memory compartment. We did not find evidence of this, as AM14 B cells made secondary immune responses as well. These data demonstrate that a precursor of a disease-specific autoantibody can be present in the preimmune repertoire and functional even to the point of memory cell development of normal mice. Therefore, immunoregulatory mechanisms that normally prevent autoantibody production must exert their effects later in B cell development or through T cell tolerance. Conversely, the data suggest that it is not necessary to break central tolerance, even in an autoimmune mouse, to generate pathologic, disease-associated autoantibodies.

scholarly journals Human lymphoma mutations reveal CARD11 as the switch between self-antigen–induced B cell death or proliferation and autoantibody production

2012 ◽  
Vol 209 (11) ◽  
pp. 1907-1917 ◽  
Author(s):  
Yogesh S. Jeelall ◽  
James Q. Wang ◽  
Hsei-Di Law ◽  
Heather Domaschenz ◽  
Herman K.H. Fung ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Antigen Receptors ◽  
Autoantibody Production ◽  
Molecular Change ◽  
Cell Responses ◽  
Self Tolerance ◽  
Human Lymphoma ◽  
Self Antigen

Self-tolerance and immunity are actively acquired in parallel through a poorly understood ability of antigen receptors to switch between signaling death or proliferation of antigen-binding lymphocytes in different contexts. It is not known whether this tolerance-immunity switch requires global rewiring of the signaling apparatus or if it can arise from a single molecular change. By introducing individual CARD11 mutations found in human lymphomas into antigen-activated mature B lymphocytes in mice, we find here that lymphoma-derived CARD11 mutations switch the effect of self-antigen from inducing B cell death into T cell–independent proliferation, Blimp1-mediated plasmablast differentiation, and autoantibody secretion. Our findings demonstrate that regulation of CARD11 signaling is a critical switch governing the decision between death and proliferation in antigen-stimulated mature B cells and that mutations in this switch represent a powerful initiator for aberrant B cell responses in vivo.

scholarly journals Bcl-x rather than Bcl-2 mediates CD40-dependent centrocyte survival in the germinal center

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1359-1364 ◽  
Author(s):  
JM Tuscano ◽  
KM Druey ◽  
A Riva ◽  
J Pena ◽  
CB Thompson ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Protein Levels ◽  
Staphylococcus Aureus Cowan ◽  
A Cell ◽  
Tonsil Tissue ◽  
Cell Fractions ◽  
Selection Of

Both rapid B-cell proliferation and programmed cell death (PCD) occur during the differentiation and selection of B cells within the germinal center. To help elucidate the role of Bcl-x in B-cell antigen selection and PCD within the germinal center, we examined its expression in defined B-cell populations and by immunochemistry of tonsil tissue. Purified B-cell fractions enriched for centrocytes express high amounts of Bcl-x and relatively low amounts of Bcl-2, whereas fractions enriched for centroblasts lack significant levels of both proteins. Consistent with this observation, immunocytochemistry localized Bcl-x within cells scattered throughout the germinal center. Stimulation of tonsil B cells with either CD40 or Staphylococcus aureus Cowan increase bcl-x mRNA and protein levels. Treatment of a cell line with a germinal center phenotype (RAMOS) or the tonsillar B-cell centroblast fraction with CD40 rapidly increased Bcl-x levels and partially rescued B cells from PCD. These data suggest that Bcl-x rather than Bcl-2 may rescue centrocytes during selection in the germinal center.

scholarly journals Excessive CD11c+Tbet+B cells promote aberrant TFHdifferentiation and affinity-based germinal center selection in lupus

2019 ◽  
Vol 116 (37) ◽  
pp. 18550-18560 ◽  
Author(s):  
Wenqian Zhang ◽  
Huihui Zhang ◽  
Shujun Liu ◽  
Fucan Xia ◽  
Zijian Kang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Molecular Mechanisms ◽  
Affinity Maturation ◽  
Antibody Affinity ◽  
Autoantibody Production ◽  
Cell Responses ◽  
Antigen Presenting

Excessive self-reactive and inadequate affinity-matured antigen-specific antibody responses have been reported to coexist in lupus, with elusive cellular and molecular mechanisms. Here, we report that the antigen-specific germinal center (GC) response―a process critical for antibody affinity maturation―is compromised in murine lupus models. Importantly, this defect can be triggered by excessive autoimmunity-relevant CD11c+Tbet+age-associated B cells (ABCs). In B cell-intrinsic Ship-deficient (ShipΔB) lupus mice, excessive CD11c+Tbet+ABCs induce deregulated follicular T-helper (TFH) cell differentiation through their potent antigen-presenting function and consequently compromise affinity-based GC selection. Excessive CD11c+Tbet+ABCs and deregulated TFHcell are also present in other lupus models and patients. Further, over-activated Toll-like receptor signaling in Ship-deficient B cells is critical for CD11c+Tbet+ABC differentiation, and blocking CD11c+Tbet+ABC differentiation in ShipΔB mice by ablating MyD88 normalizes TFHcell differentiation and rescues antigen-specific GC responses, as well as prevents autoantibody production. Our study suggests that excessive CD11c+Tbet+ABCs not only contribute significantly to autoantibody production but also compromise antigen-specific GC B-cell responses and antibody-affinity maturation, providing a cellular link between the coexisting autoantibodies and inadequate affinity-matured antigen-specific antibodies in lupus models and a potential target for treating lupus.

scholarly journals Peripheral tolerance checkpoints imposed by ubiquitous antigen expression limit antigen-specific B-cell responses under strongly immunogenic conditions

2020 ◽  
Author(s):  
Jeremy F. Brooks ◽  
Peter R. Murphy ◽  
James E.M. Barber ◽  
James W. Wells ◽  
Raymond J. Steptoe
Keyword(s):  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Affinity Maturation ◽  
Peripheral Tolerance ◽  
Cell Detection ◽  
Autoantibody Production ◽  
Cell Responses ◽  
Counter Selection ◽  
B Cell Responses

AbstractA series of layered peripheral checkpoints maintain self-reactive B cells in an unresponsive state. Autoantibody production occurs when these checkpoints are breached, however, when and how this occurs is largely unknown. In particular, how self-reactive B cells are restrained during bystander inflammation in otherwise healthy individuals is poorly understood. A weakness has been the unavailability of methods capable of dissecting physiologically-relevant B-cell responses, without the use of an engineered B-cell receptor. Resolving this will provide insights that decipher how this process goes awry during autoimmunity or could be exploited for therapy. Here we use a strong adjuvant to provide bystander innate and adaptive signals that promote B-cell responsiveness, in conjunction with newly developed B cell detection tools to study in detail the ways that peripheral tolerance mechanisms limit the expansion and function of self-reactive B cells activated under these conditions. We show that although autoreactive B cells are recruited into the germinal centre, their development does not proceed, possibly through rapid counter-selection. Consequently, differentiation of plasma cells is blunted, and autoantibody responses are transient and devoid of affinity maturation. We propose this approach and these tools can be more widely applied to track antigen-specific B cell responses to more disease relevant antigens, without the need for BCR transgenic mice, in settings where tolerance pathways are compromised or have been genetically manipulated to drive stronger insights into the biology underlying B cell-mediated autoimmunity.

scholarly journals A mechanism of T cell dependent selection of antigen engaged Germinal Center B cells

2016 ◽  
Author(s):  
Vinod Krishna ◽  
Kurtis E. Bachman
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Peripheral Tolerance ◽  
B Cell Tolerance ◽  
Germinal Center Reaction ◽  
Dark Zone ◽  
T Cell Help ◽  
Selection Of

A model of B cell affinity selection is proposed, and an explanation of peripheral tolerance mechanisms through antibody repertoire editing is presented. We show that affinity discrimination between B cells is driven by a competition between obtaining T cell help and removal of B cells from the light zone, either through apoptosis or by a return to the dark zone of germinal centers. We demonstrate that this mechanism also allows for the negative selection of self reactive B cells and maintenance of B cell tolerance during the germinal center reaction. Finally, we demonstrate that clonal expansion upon return to the germinal center dark zone amplifies differences in the antigen affinity of B cells that survive the light zone.

scholarly journals Positive Selection of Anti–Thy-1 Autoreactive B-1 Cells and Natural Serum Autoantibody Production Independent from Bone Marrow B Cell Development

2003 ◽  
Vol 197 (1) ◽  
pp. 87-99 ◽  
Author(s):  
Kyoko Hayakawa ◽  
Masanao Asano ◽  
Susan A. Shinton ◽  
Ming Gui ◽  
Li-Jun Wen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Positive Selection ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Immunoglobulin M ◽  
Autoantibody Production ◽  
Serum Autoantibody ◽  
Self Antigen

A natural serum autoantibody specific for the Thy-1 glycoprotein (anti–Thy-1 autoantibody [ATA]) is produced by B-1 cells that are positively selected by self-antigen. Here, using ATAμκ transgenic mice we show that cells with this B cell receptor are negatively selected during bone marrow (BM) development. In a Thy-1 null environment, BM ATA B cells progress to a normal follicular stage in spleen. However, in a self-antigen–positive environment, development is arrested at an immature stage in the spleen, concomitant with induction of CD5. Such cells are tolerant and short-lived, different from B-1. Nonetheless, ATA-positive selection was evident by self-antigen–dependent high serum ATA production, comprising ∼90% of serum immunoglobulin M in ATAμκ mice. Splenectomy did not eliminate ATA production and transfer of tolerant splenic B cells did not induce it. These findings demonstrate that B-1 positive selection, resulting in the production of natural serum ATA, arises independently from the major pathway of BM B cell development and selection.

scholarly journals The periphery is the dominant site of B-cell deletion in a polyclonal repertoire

2020 ◽  
Author(s):  
Jeremy F. Brooks ◽  
Raymond J. Steptoe
Keyword(s):  
B Cells ◽  
B Cell ◽  
Antigen Expression ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Peripheral Tolerance ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
T Cell Help ◽  
Self Antigen

AbstractThe concerted actions of multiple tolerance checkpoints limit the possibility of immune attack against self-antigens. For B cells, purging of autoreactivity from the developing repertoire has been almost exclusively studied using B-cell receptor transgenic models. Analyses have generally agreed that central and peripheral tolerance occurs in the form of deletion, receptor editing and anergy. However, when and where these processes occur in a normal polyclonal repertoire devoid of B-cell receptor engineering remain unclear. Here, employing sensitive tools that alleviate the need for B-cell receptor engineering, we track the development of self-reactive B cells and challenge whether deletion plays a meaningful role in B-cell tolerance. We find self-reactive B cells can mature unperturbed by ubiquitous self-antigen expression but, even in the presence of T-cell help, are robustly anergic in the periphery. These studies query the prominence attributed to central and peripheral deletion by most BCR transgenic studies and suggest that other mechanisms predominantly govern B cell tolerance.

scholarly journals B cell–intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice

Blood ◽  
2012 ◽  
Vol 119 (12) ◽  
pp. 2819-2828 ◽  
Author(s):  
Mike Recher ◽  
Siobhan O. Burns ◽  
Miguel A. de la Fuente ◽  
Stefano Volpi ◽  
Carin Dahlberg ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Autoantibody Production ◽  
Marginal Zone B Cells ◽  
Wiskott Aldrich Syndrome ◽  
Germinal Center B Cells

Abstract Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS gene that encodes for a protein (WASp) involved in cytoskeleton organization in hematopoietic cells. Several distinctive abnormalities of T, B, and natural killer lymphocytes; dendritic cells; and phagocytes have been found in WASp-deficient patients and mice; however, the in vivo consequence of WASp deficiency within individual blood cell lineages has not been definitively evaluated. By conditional gene deletion we have generated mice with selective deficiency of WASp in the B-cell lineage (B/WcKO mice). We show that this is sufficient to cause a severe reduction of marginal zone B cells and inability to respond to type II T-independent Ags, thereby recapitulating phenotypic features of complete WASp deficiency. In addition, B/WcKO mice showed prominent signs of B-cell dysregulation, as indicated by an increase in serum IgM levels, expansion of germinal center B cells and plasma cells, and elevated autoantibody production. These findings are accompanied by hyperproliferation of WASp-deficient follicular and germinal center B cells in heterozygous B/WcKO mice in vivo and excessive differentiation of WASp-deficient B cells into class-switched plasmablasts in vitro, suggesting that WASp-dependent B cell–intrinsic mechanisms critically contribute to WAS-associated autoimmunity.

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