scholarly journals Increased Expression of B Lymphocyte Induced Maturation Protein 1 (BLIMP1) in Patients with Common Variable Immunodeficiency (CVID)

2020 ◽  
Author(s):  
Shockrollah Farrokhi ◽  
Faezeh Abbasi-rad ◽  
Nafiseh Esmaeil ◽  
Roya Sherkat ◽  
Reza Yazdani ◽  
...  
Keyword(s):  
B Cells ◽  
Protein Expression ◽  
B Cell ◽  
Common Variable Immunodeficiency ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Healthy Controls ◽  
Maturation Protein ◽  
Mrna And Protein Expression ◽  
Common Variable

Common variable immunodeficiency (CVID) is a primary immune deficiency disorder characterized by a failure in B cell differentiation, impaired immunoglobulin production, and defect in response to vaccines. As a result of defective B cell maturation and differentiation in CVID, the affected patients commonly present with reduced numbers of memory B cell and antibody-secreting plasma cells. B-cell lymphoma 6 protein (BCL6) and B lymphocyte induced maturation protein 1 (BLIMP1) molecules are two important transcription factors that have key roles in the maturation of B cells to plasma cells. Hence, in the current survey, we aimed to evaluate the mRNA and protein expression levels of BCL6 and BLIMP1 in B lymphocytes isolated from peripheral blood in CVID patients. We collected blood samples from 12 CVID patients and 12 healthy controls. We isolated peripheral blood mononuclear cells (PBMCs) using Ficoll density gradient separation. Then, CD19+ B cells were purified using MACS. The protein expression and transcriptional level of BCL6 and BLIMP1 were respectively measured using flow cytometry and real-time PCR. Our results showed that the BLIMP1 mRNA expression, as well as BLIMP1 protein expression, were significantly higher in CVID patients compared to control subjects (p=0.009 and p=0.007, respectively). However, we found no significant difference in mRNA and protein expression of BCL6 between patients and healthy controls. According to our findings, increased mRNA and protein expression levels of BLIMP1 could be involved in defective maturation of B cells in patients with CVID and elucidate mechanistic insights into the pathogenesis of this disorder.

scholarly journals B lymphocytes express and lose syndecan at specific stages of differentiation.

1989 ◽  
Vol 1 (1) ◽  
pp. 27-35 ◽  
Author(s):  
R D Sanderson ◽  
P Lalor ◽  
M Bernfield
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Receptor Expression ◽  
Cell Stage ◽  
Precursor B Cells

Lymphopoietic cells require interactions with bone marrow stroma for normal maturation and show changes in adhesion to matrix during their differentiation. Syndecan, a heparan sulfate-rich integral membrane proteoglycan, functions as a matrix receptor by binding cells to interstitial collagens, fibronectin, and thrombospondin. Therefore, we asked whether syndecan was present on the surface of lymphopoietic cells. In bone marrow, we find syndecan only on precursor B cells. Expression changes with pre-B cell maturation in the marrow and with B-lymphocyte differentiation to plasma cells in interstitial matrices. Syndecan on B cell precursors is more heterogeneous and slightly larger than on plasma cells. Syndecan 1) is lost immediately before maturation and release of B lymphocytes into the circulation, 2) is absent on circulating and peripheral B lymphocytes, and 3) is reexpressed upon their differentiation into immobilized plasma cells. Thus, syndecan is expressed only when and where B lymphocytes associate with extracellular matrix. These results indicate that B cells differentiating in vivo alter their matrix receptor expression and suggest a role for syndecan in B cell stage-specific adhesion.

T and B lymphocyte abnormalities in bone marrow biopsies of common variable immunodeficiency

Blood ◽  
2011 ◽  
Vol 118 (2) ◽  
pp. 309-318 ◽  
Author(s):  
Manuella L. Gomes Ochtrop ◽  
Sigune Goldacker ◽  
Annette M. May ◽  
Marta Rizzi ◽  
Ruth Draeger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cell ◽  
Common Variable Immunodeficiency ◽  
Plasma Cells ◽  
Cell Development ◽  
B Cell Development ◽  
Bone Marrow Biopsies ◽  
Cell Counts ◽  
Common Variable

Abstract In common variable immunodeficiency (CVID) defects in early stages of B-cell development, bone marrow (BM) plasma cells and T lymphocytes have not been studied systematically. Here we report the first morphologic and flow cytometric study of B- and T-cell populations in CVID BM biopsies and aspirates. Whereas the hematopoietic compartment showed no major lineage abnormalities, analysis of the lymphoid compartment exhibited major pathologic alterations. In 94% of the patients, BM plasma cells were either absent or significantly reduced and correlated with serum immunoglobulin G levels. Biopsies from CVID patients had significantly more diffuse and nodular CD3+ T lymphocyte infiltrates than biopsies from controls. These infiltrates correlated with autoimmune cytopenia but not with other clinical symptoms or with disease duration and peripheral B-cell counts. Nodular T-cell infiltrates correlated significantly with circulating CD4+CD45R0+ memory T cells, elevated soluble IL2-receptor and neopterin serum levels indicating an activated T-cell compartment in most patients. Nine of 25 patients had a partial block in B-cell development at the pre-B-I to pre-B-II stage. Because the developmental block correlates with lower transitional and mature B-cell counts in the periphery, we propose that these patients might form a new subgroup of CVID patients.

Delayed Redistribution of CD27, CD40 and CD80 Positive B Cells and the Impaired In Vitro Immunoglobulin G Production in Patients with Non-Hodgkin Lymphoma Treated with Rituximab.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 938-938
Author(s):  
Mitsufumi Nishio ◽  
Katsuya Fujimoto ◽  
Satoshi Yamamoto ◽  
Toshiya Sakai ◽  
Kohki Kumano ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Healthy Controls ◽  
Immunoglobulin Production ◽  
Significant Difference ◽  
Healthy Control ◽  
Delayed Recovery

Abstract Rituximab (RT) has been proven to be very effective in depleting normal and malignant B lymphocytes in vivo and it is widely used for the treatment of B cell malignancies, particularly B cell non-Hodgkin’s lymphoma (NHL). RT alone does not appear to cause severe hypogammaglobulinemia according to initial clinical trials. However, recent studies revealed that patients who received RT as an adjuvant to stem cell transplantation (SCT) demonstrated an increased risk of developing severe hypogammaglobulinemia. We have found such hypogammaglobulinemia to be due to the delayed recovery of CD27 positive memory B cells and an impaired isotype expression. (Nishio et al. Eur J Haematol, 2006). This finding suggests that RT can influence not only the quantity, but also the quality of B-cell redistribution. Nevertheless, to our knowledge, precisely how the B-cell repertoire regenerates after anti-CD20-mediated transient B-cell depletion in patients with NHL remains to be elucidated. To clarify this, we performed a phenotypical analysis of B cells. A total of 22 patients with NHL who received RT combined with autologous SCT (n=17) or CHOP (n=5) were evaluated to identify their immunophenotype. The median period after the last administration of RT was 33.5 months (range from 12 to 56 months). We investigated the expression of various markers, including CD27, CD38, CD40, CD80, CD86 and CD95 on B cells by immunofluorescence staining with a flowcytometry analysis. A statistically significant difference was noted in three of the six surface antigens when the expressions of those antigens were compared with those in the healthy control populations (N=14). The most striking differences we found was the expression levels of CD27. The healthy control group had a much higher expression of CD27 in comparison to those of the patients treated with RT (28.1±14.1% vs 8.2±6.1%, p<0.001). In addition, significant differences in the expression of CD40 and CD80 were also noted. While the positive rates of CD80 and CD40 on B cells from healthy controls were 21.5±10.8% and 80.5±16.7%, those of patients treated with RT were 9.9±6.9% and 49.7±33.5%, respectively (p<0.01 and p<0.05). Since CD40-CD40L and CD80-CD28 pathways between B and T cells are necessary for the development of CD27 positive polyclonal B-cell activation and immunoglobulin production, we hypothesized that the B cells from patients treated with RT thus had a reduced ability to differentiate into plasma cells and immunoglobulin production in vitro. To test this hypothesis, we purified the B cells from ten patients with NHL treated with RT and then cultured them upon the engagement of immunoglobulin receptor and CD40 in the presence of IL-2 and IL-10. After eight days of stimulation, the supernatants of the culture were harvested and the concentrations of immunoglobulin were measured by ELISA. As a result, the IgG production was found to be significantly impaired in patients with NHL in comparison to those from the healthy controls. The observation of a delayed recovery of the memory B cells with an abnormal cell marker expression and function demonstrates that naive B cells may therefore be responsible for their failure to differentiate into plasma cells after RT therapy.

scholarly journals B-1 B lymphocytes require Blimp-1 for immunoglobulin secretion

2006 ◽  
Vol 203 (10) ◽  
pp. 2305-2314 ◽  
Author(s):  
David Savitsky ◽  
Kathryn Calame
Keyword(s):  
B Cells ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Influenza Infection ◽  
Cell Lineage ◽  
Adaptive Responses ◽  
Common Pathway ◽  
Viral Pathogens ◽  
Self Renewal ◽  
Maturation Protein

B-1 B cells produce circulating natural antibodies that provide “innate-like” protection against bacterial and viral pathogens. They also provide adaptive responses to blood and air-borne pathogens. B lymphocyte–induced maturation protein 1 (Blimp-1) is a transcriptional repressor that is required for the formation of B-2–derived antibody-secreting plasma cells. In this study, we used mice lacking Blimp-1 in the B cell lineage to show that Blimp-1 is not necessary for the formation or self-renewal of B-1 B cells but that Blimp-1 is required for normal immunoglobulin (Ig) secretion by B-1 cells. B-1 cells lacking Blimp-1 do not repress Pax5 mRNA and do not induce X-box binding protein 1, and μ secreted mRNA normally, showing that B-1 and B-2 cells both use a common pathway for Ig secretion. Blimp-1–deficient B-1 B cells are also defective in providing early protection against influenza infection.

scholarly journals Evaluation of MicroRNA-125b-5p and Transcription Factors BLIMP1 and IRF4 Expression in Unsolved Common Variable Immunodeficiency Patients

2021 ◽  
Author(s):  
Zahra Hamidi Esfahani ◽  
Reza Yazdani ◽  
Sepideh Shahkarami ◽  
Fateme Babaha ◽  
Hassan Abolhassani ◽  
...  
Keyword(s):  
Transcription Factors ◽  
B Cells ◽  
B Lymphocytes ◽  
Common Variable Immunodeficiency ◽  
Regulatory Protein ◽  
Genetic Defect ◽  
Genetic Diagnosis ◽  
Healthy Controls ◽  
Gene Expressions ◽  
Common Variable

Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary humoral immunodeficiencies characterized by failure in the final differentiation of B lymphocytes. The majority of CVID cases have no identified genetic defect, and epigenetic alteration could be involved in the pathogenesis of CVID. Hence, we aimed to evaluate the expression of hsa-miR-125b-5p -and, B lymphocyte-induced maturation protein-1(BLIMP-1) and interferon regulatory protein-4 (IRF-4) in a group of CVID patients with no definitive genetic diagnosis in comparison with healthy individuals. Ten CVID patients (all known genes excluded) and 10 age and sex-matched healthy controls participated in the study. B lymphocytes were isolated and expression of miR-125b-5p, IRF4, and BLIMP1 were evaluated by real-time polymerase chain reaction (RT-PCR). Moreover, B cell subsets were analyzed by flow cytometry. The results showed that the relative expression of miR-125b-5p in CVID patients was increased while it was decreased for the BLIMP1 and IRF4 transcription factors compared with the healthy controls. Although a reduction was observed in switched and non-switched memory B cells among all high-miR patients, these subsets were decreased in patients with normal miR expression (71.0% and 85.0%, respectively). Our results suggest that overexpression of miR-125b-5p affects the terminal differentiation of B cells in a selected group of CVID patients by downregulating the BLIMP-1 gene and more intensively for the IRF-4 gene expressions.  

scholarly journals Identification of a Subset of Common Variable Immunodeficiency Patients with Impaired B-Cell Protein Tyrosine Phosphorylation

1999 ◽  
Vol 6 (6) ◽  
pp. 856-860 ◽  
Author(s):  
Rivka Schwartz ◽  
Yael Ben-Anat Porat ◽  
Zeev Handzel ◽  
Zeev Sthoeger ◽  
Ben-Zion Garty ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
B Cells ◽  
B Cell ◽  
Tyrosine Phosphorylation ◽  
Common Variable Immunodeficiency ◽  
Cell Protein ◽  
Normal Donor ◽  
Protein Tyrosine Phosphorylation ◽  
Protein Tyrosine ◽  
Common Variable

ABSTRACT The mechanisms responsible for common variable immunodeficiency syndrome (CVID) are as yet unknown. In the present study, we show that the B-cell dysfunction in a subset of CVID patients is caused by defective protein tyrosine phosphorylation (PTP). We demonstrated that the PTP level and immunoglobulin (Ig) secretion malfunctions can be successfully repaired when normal plasma membrane components are implanted into these patients’ B cells. Stimulation of CVID patients’ peripheral blood mononucleated cells with anti-Ig antibody revealed that 7 of 11 patients had lower PTP levels than those found in the normal donor cells. Plasma membrane implantation to the cells of these patients resulted in elevated PTP levels which reached normal levels upon stimulation with anti-human Ig antibody. The results revealed two distinct groups of CVID patients. The first group included patients whose B cells expressed low PTP levels after Ig stimulation. In these patients the plasma membrane implantation restored the normal PTP level as well as the ability to secrete IgM and/or IgG after B-cell stimulation. In the second group, patients whose B cells expressed a normal PTP level after Ig stimulation, with no restoration of their ability to secrete Ig upon plasma membrane implantation and lipopolysaccharide stimulation. We conclude that the first group has an early signal transduction defect located in the B-cell plasma membrane, while in the second group the defect is located elsewhere.

scholarly journals B-cell populations discriminate between pediatric- and adult-onset multiple sclerosis

2016 ◽  
Vol 4 (1) ◽  
pp. e309 ◽  
Author(s):  
Alexander Schwarz ◽  
Bettina Balint ◽  
Mirjam Korporal-Kuhnke ◽  
Sven Jarius ◽  
Kathrin von Engelhardt ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Cross Sectional Study ◽  
Memory B Cells ◽  
Immunoglobulin M ◽  
Adult Onset ◽  
Cross Sectional

Objective:To comparatively assess the B-cell composition in blood and CSF of patients with pediatric-onset multiple sclerosis (pedMS) and adult-onset multiple sclerosis (adMS).Methods:In this cross-sectional study, we obtained blood and CSF samples from 25 patients with pedMS (8–18 years) and 40 patients with adMS (23–65 years) and blood specimens from 66 controls (1–55 years). By using multicolor flow cytometry, we identified naive, transitional, isotype class-switched memory, nonswitched memory, and double-negative memory B-cell subsets as well as plasmablasts (PB) and terminally differentiated plasma cells (PC). Flow cytometric data were compared to concentrations of B-cell-specific cytokines in serum and CSF as determined by ELISA.Results:Frequencies of circulating naive B-cells decreased with higher age in controls but not in patients with multiple sclerosis (MS). B-cell patterns in CSF differed between pedMS and adMS with an acute relapse: in pedMS-derived CSF samples, high frequencies of nonswitched memory B cells and PB were present, whereas class-switched memory B cells and PC dominated in the CSF of patients with adMS. In pedMS, PB were also elevated in the periphery. Accumulation of PB in the CSF correlated with high intrathecal CXCL-13 levels and augmented intrathecal synthesis of immunoglobulin G and immunoglobulin M.Conclusions:We demonstrate distinct changes in intrathecal B-cell homeostasis in patients with pedMS during active disease, which differ from those in adults by an expansion of plasmablasts in blood and CSF and similarly occur in prototypic autoantibody-driven autoimmune disorders. This emphasizes the particular importance of activated B-lymphocyte subsets for disease progression in the earliest clinical stages of MS.

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