scholarly journals Decreased B lymphocytes subpopulations are associated with higher atherosclerotic risk in elderly patients with moderate-to-severe chronic kidney diseases

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jieshan Lin ◽  
Bin Tang ◽  
Zhanwu Feng ◽  
Wenke Hao ◽  
Wenxue Hu
Keyword(s):  
Regression Analysis ◽  
B Cells ◽  
Elderly Patients ◽  
B Cell ◽  
B Lymphocytes ◽  
Subclinical Atherosclerosis ◽  
Intima Media Thickness ◽  
Cox Regression Analysis ◽  
Media Thickness ◽  
B Cell Subsets

Abstract Aim Cardiovascular diseases (CVD) are the leading cause of death in patients with chronic kidney disease (CKD), and the risk of CVD increases with reductions in renal function. This study aims to investigate the potential roles of B lymphocyte populations in subclinical atherosclerosis (measured by intima-media thickness, IMT) and prognosis in elderly patients with moderate-to-severe CKD. Methods In this study, a total of 219 patients (143 moderate-to-severe CKD patients with stage 3–4 and 76 non-CKD controls) were recruited. B cell subsets: CD19(+)CD5(+) and CD19(+)CD5(−) B cells were analyzed by flow cytometry. Intima-media thickness (IMT) was measured by ultrasound. Correlations between the B cell subsets with IMT and clinical outcome was analyzed. Results CKD patients showed increased IMT (P = 0.006). The level of CD19(+)CD5(+) and CD19(+)CD5(−) B cells were decreased in CKD patients. Correlation analysis showed that IMT was positively correlated with systolic blood pressure, protein/creatinine ratio and diabetes (P < 0.05), and were negatively correlated with CD19(+)CD5(+) and CD19(+)CD5(−) B lymphocytes (P < 0.05). Stepwise multiple regression analysis showed that CD19(+)CD5(−) B cells had a significant independent association with IMT (P < 0.05). IMT was increased in lower level of total CD19(+) B cells (≤ 0.06 × 109 /L) and CD19(+)CD5(−) B cells (≤ 0.05 × 109 /L) (P < 0.05). Kaplan-Meier analysis showed that patients with lower levels of CD19(+)CD5(+) and CD19(+)CD5(−) B cells exhibited worse survival (P < 0.05). Cox regression analysis showed that patients with lower CD19(+)CD5(+) and CD19(+)CD5(−) B cells counts have a higher risk of all-cause mortality (P < 0.05). Conclusions Our results showed that decreased CD19(+)CD5(+) and CD19(+)CD5(−) B lymphocytes were correlated with atherosclerosis and worse survival, which indicates that B lymphocytes might involve in atherosclerosis and associated the prognosis of elderly patients with moderate-to-severe CKD.

scholarly journals Decreased B Lymphocytes Subpopulations Are Associated With Higher Atherosclerotic Risk in Elderly Patients With Moderate-to-severe Chronic Kidney Diseases

2021 ◽  
Author(s):  
Jieshan Lin ◽  
Bin Tang ◽  
Zhanwu Feng ◽  
Wenke Hao ◽  
Wenxue Hu
Keyword(s):  
Elderly Patients ◽  
B Cell ◽  
B Lymphocytes ◽  
B Lymphocyte ◽  
Kidney Diseases ◽  
Subclinical Atherosclerosis ◽  
Intima Media Thickness ◽  
Media Thickness ◽  
Kaplan Meier ◽  
B Cell Subsets

Abstract Aim: Cardiovascular diseases (CVD) are the leading cause of death in patients with chronic kidney disease (CKD), and the risk of CVD increases with reductions in renal function. This study aims to investigate the potential roles of B lymphocyte populations in subclinical atherosclerosis (measured by intima-media thickness, IMT) and prognosis in elderly patients with moderate-to-severe CKD.Methods: In this study, a total of 219 patients (143 moderate-to-severe CKD patients with stage 3-4 and 76 non-CKD controls) were recruited. B cell subsets: B1 cells (CD19+CD5+) and B2 cells (CD19+CD5–) were analyzed by flow cytometry. Intima-media thickness (IMT) was measured by ultrasound. Correlations between the B cell subsets with IMT and clinical outcomes were analyzed.Results: CKD patients showed increased IMT (P=0.006). The level of B, B1 and B2 cells were decreased in CKD patients. Correlation analysis showed that IMT was positively correlated with systolic blood pressure, protein/creatinine ratio and diabetes (P<0.05), and were negatively correlated with B, B1 and B2 lymphocytes (P<0.05). IMT was increased in lower level of B (≤ 0.06 × 109 /L) and B2 cells (≤ 0.05 × 109 /L) (P<0.05). Kaplan-Meier analysis showed that patients with lower level of B, B1 and B2 cells exhibited worse survival (P<0.05).Conclusions: Our results showed that decreased B1 and B2 lymphocytes were correlated with atherosclerosis and worse survival, which indicates that B lymphocytes might involve in atherosclerosis and associated the prognosis of elderly patients with moderate-to-severe CKD.

Different Expression of FcgammaRIIb in Chronic Lymphocytic Leukemia and Human Normal B Lymphocytes

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3134-3134
Author(s):  
Carol Moreno ◽  
Rajendra Damle ◽  
Sonia Jansa ◽  
Gerardo Ferrer ◽  
Pau Abrisqueta ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Lymphocytes ◽  
Surface Membrane ◽  
Memory B Cells ◽  
Lymphocytic Leukemia ◽  
Cd38 Expression ◽  
B Cell Subsets

Abstract The Fcgamma receptors (FcγRs) are a family of molecules that modulate immune responses. FcγRIIb is an inhibitory FcγR that bears immunoreceptor tyrosine-based inhibitory motifs which transduce inhibitory signals on coligation with the surface membrane Ig of the B-cell antigen receptor (BCR). The role of FcγRIIb in controlling B cell activation through inhibition of BCR signaling has been extensively studied in animal models. Nevertheless, data on FcγRIIb are scant in human normal and neoplastic B cells, this being due to the lack of a specific antibody for human FcγRIIb. Consequently, there is little information on this receptor in chronic lymphocytic leukemia (CLL). Considering the activated nature of CLL cells and the central role of the BCR in the biology of the disease, studies of FcγRs are warranted. We used a novel specific mAb directly conjugated with Alexa 488 fluorophore that solely reacts with the human FcγRIIb (MacroGenics, Inc.) to investigate the receptors expression on CLL and normal human B cells. The study population included 84 patients with CLL and 24 age- and sex-matched controls. FcγRIIb expression was assessed as the mean fluorescence intensity (MFI) of surface membrane staining. In CLL cells, FcγRIIb was measured on CD19+CD5+ cells in combination with CD38, CD49d or CD69. Normal B cells were immunostained for CD19, CD5, IgD and CD38 expression and B cell subsets: naïve (IgD+CD38−), activated (IgD+CD38+) and memory B cells (IgD−CD38−) were studied for their relative expression of FcγRIIb. FcγRIIb expression was found significantly higher in naïve B cells compared to activated and memory B cells [median MFI: 17420 (11960–21180) vs. 11.140 (7899–16970) and 11.830 (6984–17100); p&lt;0.001]. Significant differences were also observed between CD5− and CD5+ normal B cells. In contrast, FcγRIIb expression was lower in CLL cells than in CD5+ and CD5− normal B lymphocytes [median MFI: 6901(1034–42600), 10180 (5856–14820) and 12120 (7776–16040); p&lt;0.05)]. Interestingly, FcγRIIb expression was variable within individual CLL clones, this being higher in CD38+ and CD49d+ cells than in CD38− and CD49d− cells (p&lt;0.05). Furthermore, the highest density of FcγRIIb was observed on those cells which coexpressed CD38 and CD49d. In contrast, no significant differences were observed between FcγRIIb and the expression of the activation antigen CD69. Although CD69 and CD38 expression was significantly higher on unmutated IGHV cases, no correlation was found between FcγRIIb levels and IGHV mutational status. Similarly, there was no correlation between FcγRIIb and other poor prognostic variables such as ZAP-70 (≥20%), CD38 (≥ 30%) or high risk cytogenetics. Nevertheless, cases with ≥ 30% CD49d+ cells had higher FcγRIIb expression than those with &lt;30% CD49d+ cells (p=0.006). The findings presented in this study suggest a hierarchy of FcγRIIb expression in normal B-cells, CLL cells and their subpopulations: circulating normal CD5− B cells &gt; circulating normal CD5+ B cells &gt; circulating CD5+ CLL B cells. In addition, although FcγRIIb is present on all normal B cell subsets its expression is higher in naïve B cells. Furthermore, in CLL FcγRIIb density is greater in CD38+ and CD49d+ cells within the clone. Although CD49d and FcγRIIb on CLL clones is linked in a direct manner, there is no relationship with FcγRIIb density and IGHV mutations, ZAP-70, CD38 and unfavorable cytogenetic markers. Finally, the relationship between FcγRIIb expression on CLL cells and functional responses to BCR and other receptor-mediated signals deserve further investigation.

scholarly journals Mitogen-reactive B cell subpopulations selectively express different sets of V regions.

1982 ◽  
Vol 156 (1) ◽  
pp. 181-190 ◽  
Author(s):  
D Primi ◽  
F Mami ◽  
C Le Guern ◽  
P A Cazenave
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Absolute Frequency ◽  
The Absolute ◽  
Cell Subpopulations ◽  
B Cell Subsets ◽  
Beta Galactosidase

The experiments presented here were designed to investigate whether the idiotypic repertoire is equally distributed among B cells subpopulations as defined by mitogen reactivity. To this end we used lipopolysaccharides (LPS) and Nocardia delipidated cell mitogens (NDCM), which are two mitogens that have been described to act on different B cell subsets. The repertoire can be defined in quantitative terms as the frequency of B cells that are precursors for clones secreting immunoglobulin with a given specificity or with a determinate idiotype. We determined, therefore, the absolute frequency of LPS- and NDCM-sensitive B lymphocytes secreting immunoglobulin molecules that bear three idiotopes originally found on a monoclonal anti-beta galactosidase antibody. Because the frequencies of B cells carrying one of these idiotypes are dramatically different in the LPS- and NDCM-sensitive B cells subsets, we conclude that the idiotypic repertoire is not randomly distributed among mitogen-reactive B cell subpopulations.

scholarly journals AB0140 BAFF NEUTRALIZATION HAS JANUS-FACED EFFECT ON ATHEROSCLEROSIS ASSOCIATED WITH SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1370.3-1370
Author(s):  
F. Saidoune ◽  
N. Charles ◽  
J. Chezel ◽  
B. Escoubet ◽  
T. Papo ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Intima Media Thickness ◽  
The Body ◽  
Systemic Lupus ◽  
Media Thickness ◽  
Cholesterol Levels

Background:Cardiovascular diseases (CVD) are the leading cause of death in systemic lupus erythematosus (SLE). B cells play a key role in the pathogenesis of lupus and anti-BAFF therapy has been approved in SLE. Since mature B cells also promote atherosclerosis, BAFF neutralization is expected to have an atheroprotective effect in SLE.Objectives:The aim of our study was to test this hypothesis using a new mouse model with a mix susceptibility to lupus and atherosclerosis that received or not an anti-BAFF treatment, and in a cohort of SLE patients in whom we monitored carotid plaques, the B cell compartment and BAFF levels.Methods:The effect of BAFF on atherosclerosis associated with lupus was investigated in the atherosclerosis- and lupus-proneApoe°D227Kmouse model and in a cohort of SLE patients. Mice were treated with a blocking anti-BAFF monoclonal antibody (Ab), while fed with a standard chow diet. Carotid plaque and carotid intima media thickness were assessed by ultrasound at baseline and during follow-up in SLE patients asymptomatic for CVD.Results:Anti-BAFF Ab inApoe°D227Kmice i/ induced a B cell depletion, ii/ efficiently treated lupus, iii/improved atherosclerosis lesions in mice that had low plasma cholesterol levels but worsened the lesions in mice with high cholesterol levels. In that case, the atheroprotective effect of the BAFF-BAFFR signaling inhibition on B cells was counterbalanced by the proatherogenic effect of the BAFF-TACI signaling inhibition on macrophages. In SLE patients, BAFF blood levels were associated with subclinical atherosclerosis. Anti-BAFF Ab treatment had a differential effect on the intima media thickness progression in SLE patients depending on the body mass indexConclusion:Depending on the balance between metabolic- and B cell-induced proatherogenic conditions, anti-BAFF could be respectively detrimental or beneficial on atherosclerosis development in SLEAcknowledgments:Guillaume Even, Yasmine Lamri, Anh-Thu Gaston,Disclosure of Interests:Fanny Saidoune Grant/research support from: supported by a research partnerships between the academic and GlaxoSmithKline France.Anti-BAFF mAb (IgG1, clone 10F4B) in mice was provided by Glaxosmithkline, Nicolas Charles: None declared, Julie Chezel: None declared, Brigitte Escoubet: None declared, Thomas Papo: None declared, Antonino Nicoletti: None declared, karim sacre: None declared

scholarly journals The Expression of BTK/p-BTK Is Different between CD5+ and CD5- B Lymphocyte from Autoimmune Hemolytic Anemia/Evans Syndromes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4886-4886
Author(s):  
Limin Xing ◽  
Yingying Qu ◽  
Ningning Duan ◽  
Zonghong Shao
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
B Lymphocytes ◽  
Autoimmune Hemolytic Anemia ◽  
Bruton’S Tyrosine Kinase ◽  
Healthy Controls ◽  
Bruton's Tyrosine Kinase ◽  
Significant Difference ◽  
B Cell Subsets

Abstract Objective To investigate the expression level of Bruton's tyrosine kinase (Btk) on CD19+B lymphocytes in peripheral blood (PB) of autoimmune hemolytic anemia (AIHA)/Evans patients. Methods The expression of Btk and Phosphorylated Btk(p-Btk) on CD5+CD19+B and CD5-CD19+B lymphocytes were detected using flow cytometry in AIHA/ Evans patients with different disease states, healthy controls (HC) and chronic lymphocytic leukemia (CLL) patients and analyzed its correlation with clinical parameters. Results 36 AIHA/ES patients (16 hemolytic, 20 remission), 11 CLL patients and 15 healthy controls (HC) were enrolled in this study. The expression of Btk and p-Btk on CD5+B lymphocytes in AIHA/Evans patients were higher than those in HCs and CLL patients, the latter two groups had no significant difference, and were positively correlated with the quantity of IgE. The ratio of p-Btk to Btk on CD5+B lymphocytes of hemolytic group and remission group was obviously higher than that on CD5-B lymphocytes [(74.62±6.42)%, (29.63±10.19)%, P=0.001], [(77.95±9.57)%, (26.29±6.86)%, P=0.006]. The ratio of p-BTK to BTK on CD5+B lymphocytes [(54.89±9.56)%] and CD5-B lymphocytes [(30.86±12.47)%, P=0.109)] showed no significant difference in HCs. There was no significant difference of Btk on CD5+B and CD5- B lymphocytes in AIHA/Evans patients, but the expression of p-Btk on CD5+B lymphocytes significantly higher than that on CD5-B lymphocytes in AIHA/Evans patients. Conclusion The expression levels of p-BTK in different B cell subsets of AIHA/Evans patients were significantly different, the expression levels of p-BTK in CD5+B cells were obviously higher than that in CD5-B cells, and higher than that in CD5+ B cells in CLL patients, and positively correlated with the number of serum IgE. Key words: anemia hemolytic autoimmune; Bruton's tyrosine kinase, Phosphorylated Bruton's tyrosine kinase; B cell subsets Disclosures No relevant conflicts of interest to declare.

Homeostatic chemokines drive migration of malignant B cells in patients with non-Hodgkin lymphomas

Blood ◽  
2004 ◽  
Vol 104 (2) ◽  
pp. 502-508 ◽  
Author(s):  
Livio Trentin ◽  
Anna Cabrelle ◽  
Monica Facco ◽  
Davide Carollo ◽  
Marta Miorin ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Receptor Expression ◽  
Mantle Cell ◽  
B Cell Subsets ◽  
Almost All

Abstract This study investigated the role of several chemokines and their receptors on malignant B lymphocytes recovered from 13 patients with chronic lymphocytic leukemia (CLL), 9 with hairy cell leukemia (HCL), 5 with mantle cell lymphoma (MCL), 5 with marginal zone B-cell lymphoma (MZL), 6 with small lymphocytic lymphoma (SLL), and 5 with follicular cell lymphoma (FCL). Flow cytometry analysis demonstrated that CXCR4 and CXCR5 were expressed on all malignant and normal B cells. Considering CC receptors, CCR1 was expressed in 70% of patients with CLL and 40% of those with HCL but was lacking in patients with MCL, MZL, SLL, and normal B cells. CCR2 showed a heterogeneous pattern of expression. CCR3 was found in almost all patients with CLL and in the majority of those with HCL, whereas it was usually lacking in patients with MZL and SLL and in healthy subjects. CCR5 was expressed in patients with HCL and MCL. Migration assays showed that different chemokines, mainly CXCL12 and CXCL13, are able to trigger migration of malignant B lymphocytes. Some of these chemokines induce calcium mobilization. These data indicate that different patterns of chemokine receptor expression identify different malignant B-cell subsets and that these receptors are functional and might play a role in malignant B-cell circulation. (Blood. 2004;104:502-508)

scholarly journals B-lymphocyte subpopulations in patients with rheumatoid arthritis and the effect of an interleukin-6 receptor inhibitor on them.

2019 ◽  
Vol 56 (6) ◽  
pp. 731-738
Author(s):  
E. V. Gerasimova ◽  
T. V. Popkova ◽  
A. P. Aleksankin ◽  
A. V. Martynova ◽  
E. L. Nasonov
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Interleukin 6 ◽  
B Lymphocyte ◽  
Memory B Cells ◽  
Absolute Count ◽  
The Absolute ◽  
B Cell Subsets ◽  
Receptor Inhibitor

The clinical efficacy and safety of interleukin-6 (IL-6) receptor blockade have been well studied, but the data on the impact of therapeutic inhibition of IL-6 on B cells are scarce and contradictory. Preliminary reports have shown that B cell function and a humoral immune response may be modulated by an IL-6 receptor inhibitor.Objective: to assess the effect of 12-month tocilizumab (TCZ) therapy on B-cell phenotype and gene expression in RA and to analyze the association between B-cell subsets and RA activity.Subjects and methods. Examinations were made in 24 active RA patients (20 women and 4 men) (median age, 55 [49; 64] years; disease duration, 72 [24; 108] months; DAS28 5.8 [5.3; 6.3]; the patients were seropositive for rheumatoid factor (RF) (100%) and for anti-cyclic citrullinated peptide antibodies (87.3%). The patients received TCZ 8 mg/kg every 4 weeks. After 12 months of therapy, 54% of patients were categorized as good responders, 46% as moderate responders according to the EULAR response criteria. A control group consisted of 29 volunteers (21 women and 8 men; median age, 58.5 [53.0; 62.0] years). Peripheral blood lymphocytes were immunophenotyped at the time of enrollment and after 12 months. The absolute and relative counts of CD19+B lymphocytes, memory B cells (CD19+CD27+), non-switched memory B cells (CD19+IgD+CD27+), switched memory B cells (CD19+IgDCD27+), naive (CD19+IgD+CD27-), double-negative (CD19+IgD-CD27-), transitional (CD19+IgD+CD10+CD38++CD27) B cells, plasma cells (CD19+СD38+), and plasmablasts (CD19+СD38+++IgD-CD27+CD20-) were estimated using multicolor flow cytometry. Results and discussion. The relative and absolute counts of memory B cells (CD19+CD27+) (1.3 [0.9; 1.7]%, 0015 [0.001; 0.003]•109/l), switched memory B cells (CD19+IgD-CD27+) (6.8 [3.6; 11.6]%, 0.01 [0.005; 0.02]•109/l), and the absolute number of transitional B cells (CD19+CD38++CD10+IgD+CD27-) (0.00009 [0; 0.00028]•109/l) were found to be lower in RA patients than in donors: 2.2 [1.1; 3.0]%, 0.003 [0.001; 0.007]•109/l; 12.8 [9.3; 17.0]%, 0.02 [0.01; 0.04]•109/l; 0.0001 [0; 0.0003]•109/l, respectively (p<0.05 for all cases). After 12 months of TCZ therapy initiation, there were decreases in the relative and absolute counts of plasmablasts (CD19+CD38+++CD27+IgD-CD20-) from 0.15 [0.1; 0.3] to 0.1 [0.01; 0.1]% and from 0.0003 [0.00007; 0.004]•109/l to 0.0001 [0; 0.0003]•109/l, respectively (p<0.05). At the same time, the relative and absolute counts of memory B cells (CD19+CD27+) and switched memory B cells (CD19+CD27+IgD-) remained lower in RA patients than in donors: 1.0 [0.7; 1.2] and 2.2 [1.1; 3.0]%; 0.001 [0.006; 0.003]•109/l and 0.003 [0.001; 0.007]•109/l; 3.1 [1.1; 4.2] and 12.8 [9.3; 17.0]%; 0.003 [0.002; 0.006]•109/l and 0.02 [0.01; 0.04]•109/l, respectively (p<0.05 for all cases). Following 12 months of TCZ therapy, the numbers of other B-cell subpopulations were not considerably altered. When included in the study, the patients with RA showed correlations between the absolute count of memory B cells (CD19+CD27+) and the level of C-reactive protein (r=0.50; p<0.05); between the absolute count of plasmablasts (CD19+CD38+++CD27+IgD-CD20-) and the level of RF (r=0.41 and r=0.52; p<0.05). There were no correlations of B cell subsets with clinical and laboratory findings after 12 months of TCZ initiation.Conclusion. Immunophenotyping of peripheral blood B lymphocyte subsets showed the lower relative and absolute counts of memory B cells (CD19+CD27+) and switched memory B cells (CD19+CD27+IgD-) in RA patients than in healthy donors. The found correlations between the counts of memory B cells and plasmablasts and the values of laboratory parameters in patients with high RA activity may suggest that B lymphocytes are involved in the pathogenesis of RA. There was a decline in plasmablast levels after 12 months of TCZ therapy.

Lymphoproliferative disorders (LPD) involving lungs: T and B cell subsets within pulmonary infiltrates and in peripheral blood

1984 ◽  
Vol 42 ◽  
pp. 700-701
Author(s):  
Irene Stachura ◽  
Milton H. Dalbow ◽  
Michael J. Niemiec ◽  
Matias Pardo ◽  
Gurmukh Singh ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lymphoproliferative Disorders ◽  
Mixed Population ◽  
Lymphoid Cells ◽  
Lymphomatoid Granulomatosis ◽  
Cell Type ◽  
Cell Surface Antigens ◽  
Pulmonary Infiltrates ◽  
B Cell Subsets

Lymphoid cells were analyzed within pulmonary infiltrates of six patients with lymphoproliferative disorders involving lungs by immunofluorescence and immunoperoxidase techniques utilizing monoclonal antibodies to cell surface antigens T11 (total T), T4 (inducer/helper T), T8 (cytotoxic/suppressor T) and B1 (B cells) and the antisera against heavy (G,A,M) and light (kappa, lambda) immunoglobulin chains. Three patients had pseudolymphoma, two patients had lymphoma and one patient had lymphomatoid granulomatosis.A mixed population of cells was present in tissue infiltrates from the three patients with pseudolymphoma, IgM-kappa producing cells constituted the main B cell type in one patient. In two patients with lymphoma pattern the infiltrates were composed exclusively of T4+ cells and IgG-lambda B cells predominated slightly in the patient with lymphomatoid granulomatosis.

scholarly journals OP0005 ELEVATED STAT1 EXPRESSION BUT NOT PHOSPHORYLATION IN LUPUS B CELLS CORRELATES WITH DISEASE ACTIVITY AND INCREASED PLASMABLAST SUSCEPTIBILITY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 4-5
Author(s):  
A. Aue ◽  
F. Szelinski ◽  
S. Weißenberg ◽  
A. Wiedemann ◽  
T. Rose ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Autoimmune Diseases ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
B Cell Subsets

Background:Systemic lupus erythematosus (SLE) is characterized by two pathogenic key signatures, type I interferon (IFN) (1.) and B-cell abnormalities (2.). How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT).Objectives:JAK-STAT inhibition is an attractive therapeutic possibility for SLE (3.). We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared to other autoimmune diseases and healthy controls (HD) and related it to disease activity.Methods:Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T-cells of 21 HD, 10 rheumatoid arthritis (RA), 7 primary Sjögren’s (pSS) and 22 SLE patients was analyzed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs of SLE patients and HD after IFNα and IFNγ incubation were further investigated.Results:SLE patients showed substantially higher STAT1 but not pSTAT1 in B and T-cell subsets. Increased STAT1 expression in B cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker (4.). STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.Figure 1.Significantly increased expression of STAT1 by SLE B cells(A) Representative histograms of baseline expression of STAT1, pSTAT1, STAT3 and pSTAT3 in CD19+ B cells of SLE patients (orange), HD (black) and isotype controls (grey). (B) Baseline expression of STAT1 and pSTAT1 or (C) STAT3 and pSTAT3 in CD20+CD27-, CD20+CD27+ and CD20lowCD27high B-lineage cells from SLE (orange) patients compared to those from HD (black). Mann Whitney test; ****p≤0.0001.Figure 2.Correlation of STAT1 expression by SLE B cells correlates with type I IFN signature (Siglec-1, CD169) and clinical activity (SLEDAI).Correlation of STAT1 expression in CD20+CD27- näive (p<0.0001, r=0.8766), CD20+CD27+ memory (p<0.0001, r=0.8556) and CD20lowCD27high (p<0.0001, r=0.9396) B cells from SLE patients with (A) Siglec-1 (CD169) expression on CD14+ cells as parameter of type I IFN signature and (B) lupus disease activity (SLEDAI score). Spearman rank coefficient (r) was calculated to identify correlations between these parameters. *p≤0.05, **p≤0.01. (C) STAT1 expression in B cell subsets of a previously undiagnosed, active SLE patient who was subsequently treated with two dosages of prednisolone and reanalyzed.Conclusion:Enhanced expression of STAT1 by B-cells candidates as key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold promise to block STAT1 expression and control plasmablast induction in SLE.References:[1]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.[2]Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130-44.[3]Dorner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645-57.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136-45.Disclosure of Interests:Arman Aue: None declared, Franziska Szelinski: None declared, Sarah Weißenberg: None declared, Annika Wiedemann: None declared, Thomas Rose: None declared, Andreia Lino: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen

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