Connection of BANK1, Tolerance, Regulatory B cells, and Apoptosis: Perspectives of a Reductionist Investigation

BANK1 transcript is upregulated in whole blood after kidney transplantation in tolerant patients. In comparison to patients with rejection, tolerant patients display higher level of regulatory B cells (Bregs) expressing granzyme B (GZMB+) that have the capability to prevent effector T cells proliferation. However, BANK1 was found to be decreased in these GZMB+ Bregs. In this article, we investigated seven different transcriptomic studies and mined the literature in order to make link between BANK1, tolerance and Bregs. As for GZMB+ Bregs, we found that BANK1 was decreased in other subtypes of Bregs, including IL10+ and CD24hiCD38hi transitional regulatory B cells, along with BANK1 was down-regulated in activated/differentiated B cells, as in CD40-activated B cells, in leukemia and plasma cells. Following a reductionist approach, biological concepts were extracted from BANK1 literature and allowed us to infer association between BANK1 and immune signaling pathways, as STAT1, FcγRIIB, TNFAIP3, TRAF6, and TLR7. Based on B cell signaling literature and expression data, we proposed a role of BANK1 in B cells of tolerant patients that involved BCR, IP3R, and PLCG2, and a link with the apoptosis pathways. We confronted these data with our experiments on apoptosis in total B cells and Bregs, and this suggests different involvement for BANK1 in these two cells. Finally, we put in perspective our own data with other published data to hypothesize two different roles for BANK1 in B cells and in Bregs.

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B Cells and Antibodies as Targets of Therapeutic Intervention in Neuromyelitis Optica Spectrum Disorders

Pharmaceuticals ◽

10.3390/ph14010037 ◽

2021 ◽

Vol 14 (1) ◽

pp. 37

Author(s):

Jan Traub ◽

Leila Husseini ◽

Martin S. Weber

Keyword(s):

B Cells ◽

Neuromyelitis Optica ◽

Plasma Cells ◽

Treatment Options ◽

Treatment Strategies ◽

Therapeutic Interventions ◽

Complement Factor ◽

Major Subset ◽

Spectrum Disorders

The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.

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P0523PROTECTIVE ROLE OF REGULATORY B CELLS ON THE RENAL TISSUE REPAIRMEN AFTER ISCHEMIA REPERCUSSION INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0523 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Yokota Yunosuke ◽

Goh Kodama ◽

Sakuya Itou ◽

Yosuke Nakayama ◽

Nobukazu Komatsu ◽

...

Keyword(s):

Flow Cytometry ◽

Renal Function ◽

B Cells ◽

Interleukin 10 ◽

Renal Tissue ◽

Protective Role ◽

Regulatory B Cells ◽

Tubulointerstitial Injury ◽

Iri Model

Abstract Background and Aims Acute kidney injury (AKI), even if followed by renal recovery, is a risk factor for the future development of chronic kidney disease (CKD) and end- stage renal disease. It has been postulated that interleukin-10 (IL-10)-producing Regulatory B cells (Breg) play an important role for the tissue repairment in several tissues and organs. Basically, protective role of Breg has been reported in inflammatory bowel disease. In the kidney, it has been shown that IL-10 suppresses renal function decline and improves renal prognosis in IRI model, a typical model of AKI. However, the identity of Breg in the kidney and their origin have not been clarified. Further, how the Breg works during the transition from AKI to CKD is not known. Therefore, first we investigated whether Breg existed in renal tissue on the progression from AKI to CKD in IRI model mice. Further, we performed splenectomy, and examined the renal injury, Breg, and plasma IL-10 levels in this model. Method To examine the existence of Breg in the kidney of IRI model, we used 8-10 weeks-old GFP / IL-10 mice based on C57BL / 6J mice. They are reporter mice for IL-10 producing cells, and can visualize IL-10 producing cells under a fluorescence microscope without fluorescent immunostaining. We prepared following three groups, sham, IRI (unilateral), and IRI + SN (splenectomy) groups. Mice were anesthetized with chloral hydrate (4 g/kg,, intraperitoneal). After making a midline incision, exposed a blood vessel of the left renal pedicles and clamped it for 30 min by clips. one day, 7 days, and 14 days after the surgery, mice were sacrificed, and renal function and plasma IL-10 levels as well as tissue damages by PAS and Masson’s Trichrome staining were assessed. Tissue IL-10-producing cells were detected by flow cytometry. Results There was no difference of plasma IL-10 levels and renal tubulointerstitial injury in IRI group and IRI+SN group on day 1 after IRI. However, on day 7 and day 14, plasma IL-10 levels became gradually higher in IRI group, and SN decreased the increase in IL-10 levels. Tubulointerstitial injury was induced by IRI and SN further worsened tubular damages. Serum Cr and BUN levels were not different in three groups due to normal right kidney. On day 1, number of IL-10-producing B cells increased in the spleen and renal medulla in IRI group confirmed by flow cytometry, which was completely diminished by SN, suggesting that origin of the infiltrated Breg might be spleen, thereby being involved in the protective role in IRI injury in the kidney. Conclusion We report for the first time that Breg might be recruited from spleen by AKI, which may be one of the mechanisms to prevent the progression to CKD.

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Role of IL-10-producing regulatory B cells in control of cerebral malaria inPlasmodium bergheiinfected mice

European Journal of Immunology ◽

10.1002/eji.201343512 ◽

2013 ◽

Vol 43 (11) ◽

pp. 2907-2918 ◽

Cited By ~ 25

Author(s):

Yunfeng Liu ◽

Yue Chen ◽

Zhaotao Li ◽

Yingli Han ◽

Yanxia Sun ◽

...

Keyword(s):

B Cells ◽

Cerebral Malaria ◽

Regulatory B Cells

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The Role of Pregnancy-Associated Hormones in the Development and Function of Regulatory B Cells

Frontiers in Endocrinology ◽

10.3389/fendo.2014.00039 ◽

2014 ◽

Vol 5 ◽

Cited By ~ 25

Author(s):

DamiÃ¡n Muzzio ◽

Marek Zygmunt ◽

Federico Jensen

Keyword(s):

B Cells ◽

Regulatory B Cells ◽

And Function

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Role of effector and regulatory B cells in patients with systemic sclerosis: IL-6 producing effector B cells associated with skin fibrosis

10.26226/morressier.5d4980ca8fb7e44098e72b78 ◽

2019 ◽

Author(s):

Takashi Matsushita ◽

Tadahiro Kobayashi

Keyword(s):

Systemic Sclerosis ◽

B Cells ◽

Skin Fibrosis ◽

Regulatory B Cells

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Regulatory B cells (Bregs) inhibit osteoclastogenesis and prevent bone loss in osteoporotic mice model

10.1101/2021.03.10.434751 ◽

2021 ◽

Author(s):

Leena Sapra ◽

Asha Bhardwaj ◽

Pradyumna K. Mishra ◽

Bhupendra K. Verma ◽

Rupesh K. Srivastava

Keyword(s):

B Cells ◽

Bone Marrow Cells ◽

Dependent Manner ◽

Regulatory B Cells ◽

Mice Model ◽

Post Menopausal Osteoporosis ◽

Post Menopausal ◽

First Time

AbstractIncreasing evidences in recent years have suggested that regulatory B cells (Bregs) are crucial modulator in various inflammatory disease conditions. However, the role of Bregs in case of postmenopausal osteoporosis remains unknown. Also, no study till date have ever investigated the significance of Bregs in modulating osteoclastogenesis. In the present study, we for the first time examined the anti-osteoclastogenic potential of Bregs under in vitro conditions and we observed that Bregs suppressed RANKL mediated osteoclastogenesis in bone marrow cells in a dose dependent manner. We further elucidated the mechanism behind the suppression of osteoclasts differentiation by Bregs and found that Bregs inhibit osteoclastogenesis via IL-10 production. To further confirm the bone health modulating potential of Bregs we employed post-menopausal osteoporotic mice model. Remarkably, our in vivo data clearly suggest a significant reduction (p < 0.01) in both CD19+IL-10+ and CD19+CD1dhiCD5+IL-10+ B10 Bregs in case of osteoporotic mice model. Moreover, our serum cytokine data further confirms the significant reduction of IL-10 levels in osteoporotic mice. Taken together, the present study for the first time unravels and establish the unexplored role of regulatory B cells in case of osteoporosis and provide new insight into Bregs biology in the context of post-menopausal osteoporosis.

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Immunosuppressive Mechanisms of Regulatory B Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.611795 ◽

2021 ◽

Vol 12 ◽

Author(s):

Diego Catalán ◽

Miguel Andrés Mansilla ◽

Ashley Ferrier ◽

Lilian Soto ◽

Kristine Oleinika ◽

...

Keyword(s):

B Cells ◽

Immune Responses ◽

Metabolic Diseases ◽

Inflammatory Responses ◽

Surface Proteins ◽

Regulatory B Cells ◽

Cell Surface Proteins ◽

The Past ◽

And Function

Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.

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SWAP-70 deficiency causes high-affinity plasma cell generation despite impaired germinal center formation

Blood ◽

10.1182/blood-2007-07-102822 ◽

2008 ◽

Vol 111 (5) ◽

pp. 2714-2724 ◽

Cited By ~ 21

Author(s):

Laurence Quemeneur ◽

Veronique Angeli ◽

Michael Chopin ◽

Rolf Jessberger

Keyword(s):

B Cells ◽

Plasma Cell ◽

Cell Activation ◽

Plasma Cells ◽

Actin Binding ◽

B Cell Activation ◽

Interacting Protein ◽

Memory Response ◽

High Affinity

Germinal centers (GCs) are lymphoid tissue structures central to the generation of long-lived, high-affinity, antibody-forming B cells. However, induction, maintenance, and regulation of GCs are not sufficiently understood. The F-actin–binding, Rac-interacting protein SWAP-70 is strongly expressed in activated B cells like those in B follicles. Recent work suggests that SWAP-70 is involved in B-cell activation, migration, and homing. Therefore, we investigated the role of SWAP-70 in the T-dependent immune response, in GC formation, and in differentiation into plasma and memory B cells. Compared with wt, sheep red blood cell (SRBC)–, or NP-KLH–immunized SWAP-70−/− mice have strongly reduced numbers of GCs and GC-specific B cells. However, SWAP-70−/− NP-specific B cells accumulate outside of the B follicles, and SWAP-70−/− mice show more plasma cells in the red pulp and in the bone marrow, and increased NP-specific Ig and antibody-forming B cells. Yet the memory response is impaired. Thus, SWAP-70 deficiency uncouples GC formation from T-dependent antibody and long-lived plasma cell production and causes extrafollicular generation of high-affinity plasma cells, but does not adequately support the memory response.

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Crucial Role of Tumor Necrosis Factor Receptor 1 Expression on Nonhematopoietic Cells for B Cell Localization within the Splenic White Pulp

Journal of Experimental Medicine ◽

10.1084/jem.187.4.469 ◽

1998 ◽

Vol 187 (4) ◽

pp. 469-477 ◽

Cited By ~ 45

Author(s):

Maria Tkachuk ◽

Stephan Bolliger ◽

Bernhard Ryffel ◽

Gerd Pluschke ◽

Theresa A. Banks ◽

...

Keyword(s):

B Cells ◽

Tumor Necrosis ◽

Plasma Cells ◽

Tumor Necrosis Factor Receptor ◽

White Pulp ◽

Splenic White Pulp ◽

Initial Activation ◽

Deficient Mice ◽

Necrosis Factor

During immune responses the initial activation of B cells takes place in T cell zones of periarteriolar lymphoid sheaths (PALS) of the splenic white pulp. After initial activation, B cells migrate into the primary follicles and, in association with follicular dendritic cells (FDCs), undergo clonal expansion and differentiation giving rise to germinal centers (GCs). Peanut agglutinin binding (PNA+) cells of the GC differentiate further into memory or plasma cells. Here we report that in tumor necrosis factor receptor 1–deficient mice (TNFR1−/−), the location of B cells was altered and that plasma cells were abnormally distributed in the splenic PALS. In contrast to lymphotoxin α–deficient mice (LTα−/−), bone marrow or fetal liver transplantation did not correct the abnormal organization of the spleen, location of B cells, the lack of an FDC network, nor the antibody response in TNFR1−/− mice. These results argue for a crucial role of TNFR1 expression on nonhematopoietic cells for the maintenance of the splenic architecture and proper B cell location. In addition, the lack in development of an FDC network after adoptive transfer suggests that either FDCs are not of bone marrow origin or that they depend on signals from nonhematopoietic cells for maturation.

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