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

Lau, A.; Avery, Danielle T.; Jackson, Katherine; Lenthall, Helen; Volpi, Stefano; Brigden, Henry; Russell, Amanda J.; Bier, Julia; Reed, Joanne H.; Smart, Joanne; Cole, Theresa; Choo, Sharon; Gray, Paul; Berglund, Lucinda J.; Hsu, Peter; Wong, Melanie; O’Sullivan, Michael; Boztuğ, Kaan; Meyts, Isabelle; Uzel, Gülbû; Notarangelo, Luigi D.; Brink, Robert; Goodnow, Christopher C.; Tangye, Stuart G.; Deenick, Elissa K.

doi:10.1084/jem.20191336

Cited by 36 publications

(45 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another example of a PID with a B cell specific break in self-tolerance are patients with gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), who present with production of germline autoreactive IgM antibodies ( 119 ). PI3K expression has been shown to be increased in cGvHD patients ( 120 ).…”

Section: The Role Of B Cell Mediated Autoimmunitymentioning

confidence: 99%

Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease

Rozmus

2021

Front. Immunol.

View full text Add to dashboard Cite

Chronic graft-versus-host disease (GvHD) has become a leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT) and can burden patients with devastating and lifelong health effects. Our understanding of the pathogenic mechanisms underlying chronic GvHD remains incomplete and this lack of understanding is reflected by lack of clear therapeutic approaches to steroid refractory disease. Observations predominantly from mouse models and human correlative studies currently support a three phase model for the initiation and development of chronic GvHD: 1) early inflammation and tissue damage triggers the innate immune system. This leads to inflammatory cytokine/chemokine patterns that recruit effector immune cell populations; 2) chronic inflammation causes the loss of central and peripheral tolerance mechanisms leading to emergence of pathogenic B and T cell populations that promote autoimmune and alloimmune reactions; 3) the dysregulated immunity causes altered macrophage polarization, aberrant tissue repair leading to scarring and end organ fibrosis. This model has led to the evaluation of many new therapies aimed at limiting inflammation, targeting dysregulated signaling pathways and restoring tolerance mechanisms. However, chronic GvHD is a multisystem disease with complex clinical phenotypes and it remains unclear as to which cluster of patients will respond best to specific therapeutic strategies. However, it is possible to gain novel insights from immune-related monogenic diseases. These diseases either share common clinical manifestations, replicate steps from the three phase chronic GvHD model or serve as surrogates for perfectly targeted drugs being investigated in chronic GvHD therapy. In this review, we will summarize the evidence from these monogenic immune related diseases that provide insight into pathogenic pathways in chronic GvHD, rationales for current therapies and novel directions for future drug discovery.

show abstract

Section: The Role Of B Cell Mediated Autoimmunitymentioning

confidence: 99%

Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease

Rozmus

2021

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Most APDS patients present with an increase in circulating transitional B cells, as well as reduced numbers of class-switched B cells. In addition to clear B cell-intrinsic effects of APDS-associated mutations 45 – 47 , 55 , the defects in humoral immunity could also be due in part to the elevated numbers of Tfh cells and disorganized germinal centers found within the secondary lymphoid organs of APDS patients 56 . Within the germinal center, the signals that drive the Tfh program also initiate the expression of ICOS and migration towards the T-B border zone.…”

Section: Lessons From Activated Pi3kδ Syndromementioning

confidence: 99%

Control of T lymphocyte fate decisions by PI3K signaling

Murter

Kane

2020

F1000Res

View full text Add to dashboard Cite

Virtually all aspects of T and B lymphocyte development, homeostasis, activation, and effector function are impacted by the interaction of their clonally distributed antigen receptors with antigens encountered in their respective environments. Antigen receptors mediate their effects by modulating intracellular signaling pathways that ultimately impinge on the cytoskeleton, bioenergetic pathways, transcription, and translation. Although these signaling pathways are rather well described at this point, especially those steps that are most receptor-proximal, how such pathways contribute to more quantitative aspects of lymphocyte function is still being elucidated. One of the signaling pathways that appears to be involved in this “tuning” process is controlled by the lipid kinase PI3K. Here we review recent key findings regarding both the triggering/enhancement of PI3K signals (via BCAP and ICOS) as well as their regulation (via PIK3IP1 and PHLPP) and how these signals integrate and determine cellular processes. Lymphocytes display tremendous functional plasticity, adjusting their metabolism and gene expression programs to specific conditions depending on their tissue of residence and the nature of the infectious threat to which they are responding. We give an overview of recent findings that have contributed to this model, with a focus on T cells, including what has been learned from patients with gain-of-function mutations in PI3K as well as lessons from cancer immunotherapy approaches.

show abstract

“…Downstream of PI3K activation, FOXO factors are inactivated in developing B cells ( Fruman and Bismuth, 2009 ; Zhang et al, 2011 ). Therefore, RANK-mediated PI3K activation at B cell selection checkpoints could in theory prevent proper FOXO-mediated induction of the proapoptotic molecule Bim, which results in the survival of autoreactive B cells ( Arron et al, 2001 ; Enders et al, 2003 ; Lau et al, 2020 ; Wong et al, 1999 ). This is likely one mechanism by which forced RANK K240E signaling can disrupt B cell tolerance.…”

Section: Discussionmentioning

confidence: 99%

Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia

Alankus

Ecker

Vahl

et al. 2020

Journal of Experimental Medicine

View full text Add to dashboard Cite

Clinical evidence suggests alterations in receptor activator of NF-κB (RANK) signaling are key contributors to B cell autoimmunity and malignancy, but the pathophysiological consequences of aberrant B cell–intrinsic RANK signaling remain unknown. We generated mice that express a human lymphoma–derived, hyperactive RANKK240E variant in B lymphocytes in vivo. Forced RANK signaling disrupted B cell tolerance and induced a fully penetrant systemic lupus erythematosus–like disease in addition to the development of chronic lymphocytic leukemia (CLL). Importantly, RANKK240E transgenic CLL cells as well as CLL cells of independent murine and of human origin depend on microenvironmental RANK ligand (RANKL) for tumor cell survival. Consequently, inhibition of the RANKL–RANK axis with anti-RANKL antibodies killed murine and human CLL cells in vitro and in vivo. These results establish pathological B cell–intrinsic RANK signaling as a potential driver of autoimmunity and B cell malignancy, and they suggest the exploitation of clinically available anti-RANKL compounds for CLL treatment.

show abstract

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

Cited by 36 publications

References 67 publications

Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease

Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease

Control of T lymphocyte fate decisions by PI3K signaling

Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia

Contact Info

Product

Resources

About