Regnase-1 is essential for B cell homeostasis to prevent immunopathology

Regnase-1 is an emerging regulator of immune responses with essential roles in the posttranscriptional control of immune cell activation. Regnase-1 is expressed in B cells; however, its B cell–specific functions remain unknown. Here, we demonstrate that Regnase-1 prevents severe autoimmune pathology and show its essential role in maintaining B cell homeostasis. Using Cre driver mice for ablation of Regnase-1 at various stages of B cell development, we demonstrate that loss of Regnase-1 leads to aberrant B cell activation and differentiation, resulting in systemic autoimmunity and early morbidity. The basis of these findings was informed by gene expression data revealing a regulatory role for Regnase-1 in the suppression of a transcriptional program that promotes B cell activation, survival, and differentiation. Overall, our study shows that Regnase-1 exerts critical control of B cell activation, which is required for prevention of immunopathology.

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Deep Phenotyping of CD11c+ B Cells in Systemic Autoimmunity and Controls

Frontiers in Immunology ◽

10.3389/fimmu.2021.635615 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hector Rincon-Arevalo ◽

Annika Wiedemann ◽

Ana-Luisa Stefanski ◽

Marie Lettau ◽

Franziska Szelinski ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Activation ◽

B Cell Activation ◽

Membrane Expression ◽

Ki 67 ◽

Inflammatory Conditions ◽

Systemic Autoimmunity ◽

Enhanced Expression

Circulating CD11c+ B cells are a key phenomenon in certain types of autoimmunity but have also been described in the context of regular immune responses (i.e., infections, vaccination). Using mass cytometry to profile 46 different markers on individual immune cells, we systematically initially confirmed the presence of increased CD11c+ B cells in the blood of systemic lupus erythematosus (SLE) patients. Notably, significant differences in the expression of CD21, CD27, and CD38 became apparent between CD11c− and CD11c+ B cells. We observed direct correlation of the frequency of CD21−CD27− B cells and CD21−CD38− B cells with CD11c+ B cells, which were most pronounced in SLE compared to primary Sjögren's syndrome patients (pSS) and healthy donors (HD). Thus, CD11c+ B cells resided mainly within memory subsets and were enriched in CD27−IgD−, CD21−CD27−, and CD21−CD38− B cell phenotypes. CD11c+ B cells from all donor groups (SLE, pSS, and HD) showed enhanced CD69, Ki-67, CD45RO, CD45RA, and CD19 expression, whereas the membrane expression of CXCR5 and CD21 were diminished. Notably, SLE CD11c+ B cells showed enhanced expression of the checkpoint molecules CD86, PD1, PDL1, CD137, VISTA, and CTLA-4 compared to HD. The substantial increase of CD11c+ B cells with a CD21− phenotype co-expressing distinct activation and checkpoint markers, points to a quantitative increased alternate (extrafollicular) B cell activation route possibly related to abnormal immune regulation as seen under the striking inflammatory conditions of SLE which shows a characteristic PD-1/PD-L1 upregulation.

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Absence of surface IgD does not impair naive B cell homeostasis and memory B cell formation in humans

10.1101/332361 ◽

2018 ◽

Author(s):

J. Nechvatalova ◽

S.J.W. Bartol ◽

Z. Chovancova ◽

L. Boon ◽

M. Vlkova ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Activation ◽

Genetic Defect ◽

Memory B Cells ◽

Cell Homeostasis ◽

Human B Cells ◽

B Cell Homeostasis

One Sentence SummaryHuman B cells with a genetic defect in IGHD develop normally in vivo, and do not have a competitive disadvantage to IgD-expressing B cells for developing into memory B cells.AbstractSurface immunoglobulin D (IgD) is co-expressed with IgM on naive mature B cells. Still, the role of surface IgD remains enigmatic even 50 years after its initial discovery. We here examined the in vivo role of surface IgD in human B-cell homeostasis and antibody responses in four individuals with heterozygous nonsense mutations in IGHD. All IGHD heterozygous individuals had normal numbers of B cells and serum immunoglobulins, and did not show signs of immunodeficiency or immune dysregulation. IgD+ and IgD– naive mature B cells were present in equal numbers and showed similar immunophenotypes, except for decreased expression of CD79b in the IgD– subset. Furthermore, both IgD+ and IgD– naive mature B cells had normal replication histories, similar capacities to differentiate into plasma cells upon in vitro stimulation, and Ig switched memory B cells showed similar levels of somatic hypermutations. Thus human B cells lacking IgD expression develop normally and generate immunological memory in vivo, suggesting that surface IgD might function more restricted in regulating of B-cell activation to specific antigenic structures.

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Active Inhibition of Plasma Cell Development in Resting B Cells by Microphthalmia-associated Transcription Factor

Journal of Experimental Medicine ◽

10.1084/jem.20040612 ◽

2004 ◽

Vol 200 (1) ◽

pp. 115-122 ◽

Cited By ~ 59

Author(s):

Ling Lin ◽

Andrea J. Gerth ◽

Stanford L. Peng

Keyword(s):

Transcription Factor ◽

B Cells ◽

B Cell ◽

Plasma Cell ◽

Cell Activation ◽

Terminal Differentiation ◽

B Cell Activation ◽

Autoantibody Production ◽

B Cell Homeostasis ◽

Antibody Secretion

B cell terminal differentiation involves development into an antibody-secreting plasma cell, reflecting the concerted activation of proplasma cell transcriptional regulators, such as Blimp-1, IRF-4, and Xbp-1. Here, we show that the microphthalmia-associated transcription factor (Mitf) is highly expressed in naive B cells, where it antagonizes the process of terminal differentiation through the repression of IRF-4. Defective Mitf activity results in spontaneous B cell activation, antibody secretion, and autoantibody production. Conversely, ectopic Mitf expression suppresses the expression of IRF-4, the plasma cell marker CD138, and antibody secretion. Thus, Mitf regulates B cell homeostasis by suppressing the antibody-secreting fate.

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Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice

Blood ◽

10.1182/blood-2011-12-397919 ◽

2012 ◽

Vol 119 (16) ◽

pp. 3744-3756 ◽

Cited By ~ 108

Author(s):

Laurens P. Kil ◽

Marjolein J. W. de Bruijn ◽

Menno van Nimwegen ◽

Odilia B. J. Corneth ◽

Jan Piet van Hamburg ◽

...

Keyword(s):

B Cells ◽

Transgenic Mice ◽

B Cell ◽

Cell Activation ◽

Systemic Autoimmune Disease ◽

B Cell Activation ◽

Autoantibody Production ◽

Autoreactive B Cells ◽

Autoimmune Pathology

Abstract On antigen binding by the B-cell receptor (BCR), B cells up-regulate protein expression of the key downstream signaling molecule Bruton tyrosine kinase (Btk), but the effects of Btk up-regulation on B-cell function are unknown. Here, we show that transgenic mice overexpressing Btk specifically in B cells spontaneously formed germinal centers and manifested increased plasma cell numbers, leading to antinuclear autoantibody production and systemic lupus erythematosus (SLE)–like autoimmune pathology affecting kidneys, lungs, and salivary glands. Autoimmunity was fully dependent on Btk kinase activity, because Btk inhibitor treatment (PCI-32765) could normalize B-cell activation and differentiation, and because autoantibodies were absent in Btk transgenic mice overexpressing a kinase inactive Btk mutant. B cells overexpressing wild-type Btk were selectively hyperresponsive to BCR stimulation and showed enhanced Ca2+ influx, nuclear factor (NF)–κB activation, resistance to Fas-mediated apoptosis, and defective elimination of selfreactive B cells in vivo. These findings unravel a crucial role for Btk in setting the threshold for B-cell activation and counterselection of autoreactive B cells, making Btk an attractive therapeutic target in systemic autoimmune disease such as SLE. The finding of in vivo pathology associated with Btk overexpression may have important implications for the development of gene therapy strategies for X-linked agammaglobulinemia, the immunodeficiency associated with mutations in BTK.

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THU0499 Hm71224, A Novel Oral BTK Inhibitor, Inhibits Human Immune Cell Activation: New Drug Candidate to Treat B-Cell Associated Autoimmune Diseases

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2014-eular.2783 ◽

2014 ◽

Vol 73 (Suppl 2) ◽

pp. 355.4-356 ◽

Cited By ~ 5

Author(s):

J.K. Park ◽

J.A. Park ◽

Y.J. Lee ◽

J. Song ◽

J.I. Oh ◽

...

Keyword(s):

Autoimmune Diseases ◽

B Cell ◽

Cell Activation ◽

Immune Cell ◽

Drug Candidate ◽

Immune Cell Activation ◽

New Drug ◽

Btk Inhibitor ◽

Human Immune

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Toll-like receptor driven B cell activation in the induction of systemic autoimmunity

Seminars in Immunology ◽

10.1016/j.smim.2011.01.016 ◽

2011 ◽

Vol 23 (2) ◽

pp. 106-112 ◽

Cited By ~ 122

Author(s):

Nathaniel M. Green ◽

Ann Marshak-Rothstein

Keyword(s):

B Cell ◽

Cell Activation ◽

B Cell Activation ◽

Toll Like Receptor ◽

Systemic Autoimmunity

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Normal B Cell Homeostasis Requires B Cell Activation Factor Production by Radiation-resistant Cells

Journal of Experimental Medicine ◽

10.1084/jem.20030789 ◽

2003 ◽

Vol 198 (6) ◽

pp. 937-945 ◽

Cited By ~ 181

Author(s):

Leonid Gorelik ◽

Kevin Gilbride ◽

Max Dobles ◽

Susan L. Kalled ◽

Daniel Zandman ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Survival ◽

Stromal Cells ◽

Cell Activation ◽

B Cell Activation ◽

B Cell Survival ◽

Activation Factor ◽

Radiation Resistant ◽

B Cell Homeostasis

The cellular source of B cell activation factor (BAFF) required for peripheral B cell survival/maturation is unknown. To determine the nature of BAFF-producing cells we established and analyzed reciprocal bone marrow (BM) chimeras with wild-type (WT) and BAFF-deficient mice. The results revealed that BAFF production by radiation-resistant stromal cells is completely sufficient to provide a necessary signal for B cell survival/maturation, as BAFF−/− BM cells transferred into lethally irradiated WT mice gave rise to normal numbers of follicular (FO) and marginal zone (MZ) B cell subpopulations. On the other hand, transfer of WT BM into BAFF−/− lethally irradiated mice resulted only in minimal reconstitution of mature FO B cells and no restoration of MZ B cells. Thus, in the absence of BAFF+/+ stromal cells, BAFF production by BM-derived cells, presumably by macrophages, dendritic cells, and/or neutrophils, was not at all sufficient to support normal B cell homeostasis. Interestingly, immunization of both types of chimeras stimulated high levels of antigen-specific antibody secretion, indicating that either stromal cell– or hematopoietic cell–derived BAFF is sufficient for B cell antibody responses.

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Longitudinally persistent cerebrospinal fluid B-cells resist treatment in multiple sclerosis

10.1101/490938 ◽

2018 ◽

Author(s):

Ariele L. Greenfield ◽

Ravi Dandekar ◽

Akshaya Ramesh ◽

Erica L. Eggers ◽

Hao Wu ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Variable Region ◽

B Cell Activation ◽

Cell Dynamics ◽

Autoimmune Pathology ◽

B Cell Subsets

AbstractB-cells are key contributors to chronic autoimmune pathology in multiple sclerosis (MS). Clonally related B-cells exist in the cerebrospinal fluid (CSF), meninges, and central nervous system (CNS) parenchyma of MS patients. Longitudinally stable CSF oligoclonal band (OCB) antibody patterns suggest some local CNS B-cell persistence; however, the longitudinal B-cell dynamics within and between the CSF and blood remain unknown. We sought to address this by performing immunoglobulin heavy chain variable region repertoire sequencing on B-cells from longitudinally collected blood and CSF samples of MS patients (n=10). All patients were untreated at the time of the initial sampling; the majority (n=7) were treated with immune modulating therapies 1.2 (+/−0.3 SD) years later during the second sampling. We found clonal persistence of B-cells in the CSF of five patients; these B-cells were frequently immunoglobulin (Ig) class-switched and CD27+. We identified specific blood B-cell subsets that appear to provide input into CNS repertoires over time. We demonstrate complex patterns of clonal B-cell persistence in CSF and blood, even in patients on high-efficacy immune modulating therapy. Our findings support the concept that peripheral B-cell activation and CNS-compartmentalized immune mechanisms are in part therapy-resistant.

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