scholarly journals B Lymphocyte Subsets in Children With Steroid-Sensitive Nephrotic Syndrome: A Longitudinal Study

2021 ◽  
Vol 9 ◽  
Author(s):  
Chen Ling ◽  
Zhi Chen ◽  
Xiaolin Wang ◽  
Lin Hua ◽  
Jingang Gui ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Dynamic Changes ◽  
Steroid Administration ◽  
Transitional B Cells ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive ◽  
Cell Subpopulations ◽  
B Cell Subsets ◽  
Time Point

Background: B-cell subsets may be involved in the pathogenesis of childhood steroid-sensitive nephrotic syndrome (SSNS). Horizontal control studies have shown that homeostasis of B-cell subsets changes at different stages of the SSNS. However, there is a lack of longitudinal studies that have investigated dynamic changes in B cell subpopulations.Methods: Blood samples were collected at the following time points from 15 children with SSNS treated at our hospital: before administration of steroid and after 3 days, 1 week, and 3, 6, 9, and 12 months. The proportions of circulating total B cells (CD19+), transitional B cells (CD19+CD24highCD38high), mature B cells (CD19+CD24lowCD38intermediate), and memory B cells (CD19+CD24highCD38−) were monitored by flow cytometry.Results: The proportion of CD19+ B cells before steroid administration was significantly higher than that observed at any other time point or in the healthy control (HC) group (p < 0.001). However, this proportion was significantly lower than that in the HC group at 12 months (p = 0.031). Transitional B cells before (%BL 9.5 ± 4.4) and 3 days after steroid administration (%BL 10.6 ± 5.1) were significantly higher than at any other time point or in the HC group (p < 0.001). Although these cells declined after the 3rd day the percentage was still significantly lower than that of the HC group at 12 months (p = 0.029). Memory B cells increased gradually after steroid administration and decreased to the normal range after 9 months.Conclusions: B cell subpopulations show dynamic changes in children with SSNS, suggesting that they are involved in the pathogenesis of the disorder. Further studies are required to determine whether this change can guide individualized treatment.

Decreased Circulating Transitional B-Cell to Memory B-Cell Ratio Is a Risk Factor for Relapse in Children with Steroid-Sensitive Nephrotic Syndrome

Nephron ◽  
2020 ◽  
pp. 1-6
Author(s):  
Chen Ling ◽  
Zhi Chen ◽  
Jianfeng Fan ◽  
Qiang Sun ◽  
Xiaolin Wang ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Free Survival ◽  
Transitional B Cells ◽  
Kaplan Meier ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive ◽  
B Cell Subsets ◽  
Transitional B Cell ◽  
Relapse Group

<b><i>Introduction:</i></b> A significant proportion of children with SSNS (steroid-sensitive nephrotic syndrome) experience recurrence. Reliable biomarkers to predict flare are currently lacking because the pathogenesis of SSNS remains obscure. <b><i>Objective:</i></b> Since B cells may be involved in the pathogenesis of SSNS, we aimed to identify perturbations of B-cell subsets that might predict SSNS relapse. <b><i>Methods:</i></b> We measured levels of circulating B-cell subsets in 69 SSNS children by flow cytometry, between 2018 and 2019. We divided them into a relapse group and a nonrelapse group according to whether a relapse occurred within 1 year of follow-up. We used Cox survival analysis to assess correlations between B-cell subsets and relapse. In addition, recurrence-free survival curves were calculated using the Kaplan-Meier method. <b><i>Results:</i></b> The proportion of transitional B cells was significantly lower in the relapse group (5.3 ± 5.1% vs. 8.7 ± 4.3% in nonrelapse group, <i>p</i> = 0.007), while the proportion of memory B cells was significantly higher (8.4 ± 3.0% vs. 5.8 ± 3.3% in nonrelapse, <i>p</i> = 0.002). There was a significant decrease in the transitional B-cell to memory B-cell ratio (T/M) in the relapse group (<i>p</i> &#x3c; 0.001). Univariate analysis revealed that transitional B cells, memory B cells, and the T/M ratio were significantly correlated with relapse in SSNS patients (<i>p</i> &#x3c; 0.05). Multivariate analysis revealed that only T/M ratio (hazard ratio 0.278, 95% confidence interval 0.085–0.908, <i>p</i> = 0.034) was an independent risk factor for recurrence-free survival in SSNS patients. A cutoff value for the T/M ratio of 1.16 resulted in a sensitivity of 90% and specificity of 80% (area under the curve 0.909; <i>p</i> &#x3c; 0.001). Kaplan-Meier curves of cumulative relapse-free survival, stratified by this cutoff value, were constructed, which showed that the cumulative relapse-free rates for cutoff values of &#x3e;1.16 (<i>n</i> = 38) and ≤1.16 (<i>n</i> = 31) were 76.3 and 29.0%, respectively (χ<sup>2</sup> = 18.416, <i>p</i> &#x3c; 0.001). <b><i>Conclusions:</i></b> Decreased transitional B/memory B ratio is associated with SSNS recurrence in the reported cohort. Thus, it may prove to be a useful marker to predict SSNS relapse in children.

Monitoring of B Cell Subpopulations in Patients with Chronic Graft-Versus-Host Disease May Predict Response to Extracorporeal Photopheresis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 467-467
Author(s):  
Zoya Kuzmina ◽  
Winfried Pickl ◽  
Robert Knobler ◽  
Michal Kouba ◽  
Nina Worel ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Therapeutic Response ◽  
Extracorporeal Photopheresis ◽  
Graft Versus Host ◽  
Transitional B Cells ◽  
Cell Subpopulations ◽  
B Cell Homeostasis ◽  
B Cell Subsets ◽  
Transitional B Cell

Abstract Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HCT) requiring prolong immunosuppressive therapy and increasing non-relapse mortality. Immune mechanisms underlying cGVHD have remained elusive. Recently, we reported a severe disturbance in B cell homeostasis seen in a significant expansion of immature/transitional B lymphocytes (CD21−) and a significant decrease of non-class switched (CD19+/IgD+/CD27+) and class-switched memory B cells (CD19+/IgD−/CD27+) in patients with active chronic GVHD. In long-lasting cGVHD irreversible tissue damage cannot be distinguished from active cGVHD with certainty since no biomarkers for monitoring of cGVHD activity as well as for assessment of therapeutic response are available. We investigated serially every 3 to 6 months B cell subpopulations in the peripheral blood (PB) of 47 patients (median age 40 years, range 18–62 years) given extracorporeal photopheresis (ECP) as first line (n=13) or salvage therapy (n=34). Twenty-nine patients (64%) had more than 2 organs affected by cGVHD and in 21 patients (45%) severity of organ involvement was grade 3 according to the NIH Consensus. Duration of cGVHD before ECP was a median of 2.5 years. ECP was performed initially every two weeks on 2 consecutive days and monthly thereafter until improvement. The median duration of ECP was 30 (range, 8–50) cycles during a median of 13 (range, 3–36) months and ECP is still ongoing in 14 patients. A total of 257 samples with a median of 6 analyses per patient (range, 3 to 10) was assessed. PB leukocytes were analyzed by multiparameter flow cytometry after staining for CD19, CD27, CD21 and surface Ig. Patients were scored for cGVHD activity and response evaluation according to the NIH Consensus Development Project criteria at every sampling event. Thirty-five patients (75%) responded to ECP, including 22 with complete resolution, whereas 12 (25%) were nonresponders. Retrospective correlation of clinical response to ECP with B cell subpopulation numbers revealed that patients not responding to ECP had a significantly higher number of immature/transitional B cells (CD19+/CD21−) (mean 16.6%, range 0.8–57%) in PB samples taken prior to start of ECP compared to responders (mean 13%, range 1–54%, p 0.0001). The numbers of both non-class-switched and class-switched memory B cells were significantly higher in ECP-responders, mean 5.1% (range 1–21%) compared to a mean of 4.2% (range 0.3–14%) in nonresponders (p 0.041) The CD21−/CD27+ ratio was significantly higher in nonresponders with a mean of 8.6 (range 0.5–50) compared to a mean of 6.6 (range 0.3–89) in the responding group(p 0.0005). Three months after start of ECP patients responding to therapy had a decrease in their CD21−/CD27+ ratio (mean 3, range, 0.3–18, p=0.05) whereas in nonresponders B cell subpopulations were unchanged. After 6 months a significant decrease in immature/transitional B cell numbers (CD19+/CD21−) compared to baseline (p=0.03) values was observed in ECP responders whereas ECP nonresponders presented a further increase in immature/transitional B cell (CD19+/CD21−) numbers. One year after start of ECP 22 patients with durable complete responses had a further decrease of the CD21−/CD27+ ratio (mean 1.6, range 0.2–5.4) comparable to patients with resolved cGVHD as previously reported (Greinix et al, BBMT14:208–219, 2008). In contrast, nonresponders to ECP with persistent active cGVHD had a significantly higher CD21−/CD27+ ratio (mean 3.3, range, 0.1–11, p=0.08) in PB samples. In conclusion, determining the degree of disturbance of B cell homeostasis as seen in elevated numbers of immature/transitional B cells and decreased memory B cell subsets during active cGVHD could be used for predicting therapeutic response to ECP. Moreover, 3 to 6 months after start of ECP distribution of B cell subpopulations differed significantly between ECP responders and nonresponders. Thus, B cell subsets serially assessed could serve as possible biomarkers of response to ECP in cGVHD. Our preliminary findings should be confirmed in a larger prospective patient cohort receiving ECP.

scholarly journals The expansion of activated naive DNA autoreactive B cells and its association with disease activity in systemic lupus erythematosus patients

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Kittikorn Wangriatisak ◽  
Chokchai Thanadetsuntorn ◽  
Thamonwan Krittayapoositpot ◽  
Chaniya Leepiyasakulchai ◽  
Thanitta Suangtamai ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
Autoreactive B Cells ◽  
Dsdna Antibody ◽  
Cell Subpopulations ◽  
B Cell Subsets

Abstract Background Autoreactive B cells are well recognized as key participants in the pathogenesis of systemic lupus erythematosus (SLE). However, elucidating the particular subset of B cells in producing anti-dsDNA antibodies is limited due to their B cell heterogeneity. This study aimed to identify peripheral B cell subpopulations that display autoreactivity to DNA and contribute to lupus pathogenesis. Methods Flow cytometry was used to detect total B cell subsets (n = 20) and DNA autoreactive B cells (n = 15) in SLE patients’ peripheral blood. Clinical disease activities were assessed in SLE patients using modified SLEDAI-2 K and used for correlation analyses with expanded B cell subsets and DNA autoreactive B cells. Results The increases of circulating double negative 2 (DN2) and activated naïve (aNAV) B cells were significantly observed in SLE patients. Expanded B cell subsets and DNA autoreactive B cells represented a high proportion of aNAV B cells with overexpression of CD69 and CD86. The frequencies of aNAV B cells in total B cell populations were significantly correlated with modified SLEDAI-2 K scores. Further analysis showed that expansion of aNAV DNA autoreactive B cells was more related to disease activity and serum anti-dsDNA antibody levels than to total aNAV B cells. Conclusion Our study demonstrated an expansion of aNAV B cells in SLE patients. The association between the frequency of aNAV B cells and disease activity patients suggested that these expanded B cells may play a role in SLE pathogenesis.

scholarly journals AB0025 B-CELL SUBSETS AS ADDITIONAL DIAGNOSTIC TOOL FOR PRIMARY SJOGREN’S SYNDROME AND SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1315.1-1316
Author(s):  
S. Benevolenskaya ◽  
I. Kudryavtsev ◽  
M. Serebriakova ◽  
I. Grigor’eva ◽  
A. Budkova ◽  
...  
Keyword(s):  
B Cells ◽  
Discriminant Analysis ◽  
B Cell ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Transitional B Cells ◽  
B Cell Subsets ◽  
Sjögren‘S Syndrome

Background:Systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) are chronic complex disorders with an autoimmune background, multifactorial etiology, multiple circulating antinuclear antibodies and damage of various organs. SLE and pSS have several similar clinical and serological aspects; likewise, SLE and Sjögren’s syndrome may coexist (so-called secondary Sjögren’s syndrome). However, applied classification criteria do not differentiate SLE and pSS. It is known that humoral immunity plays significant part in pathogenesis of those diseases; hereby, we can expect imbalances in B cell subset frequencies during SLE and pSS.Objectives:To investigate clinical utility of B cell subsets in distinguish SLE and pSS during diagnosis.Methods:A total of 25 SLE patients, 25 SS patients and 49 healthy volunteers (HV) were included in the study. The diagnosis of SLE was performed according to the 2019 EULAR – ACR classification criteria, the diagnosis of pSS - according to the 2016 EULAR – ACR criteria. Phenotyping of blood B cell subsets was done using flow cytometry. Total peripheral blood B cells were identified using CD19 expression, distinct B cell subsets were characterized by IgD, CD38 and CD27 expression. All of the statistical analysis of data was performed with STATISTICA Version 12.0 Inc. (USA).Results:We evaluated the percentages of circulating B-cell subsets using three major classification schemes based on the relative co-expression of either IgD/CD38 (so-called “Bm1-Bm5” classification), IgD/CD27 and CD38/CD27. A discriminant analysis was performed for all B cell classifications. Analysis of CD38 and CD27 co-expression demonstrated most significant separation between patients with SLE and pSS (fig. 1). Moreover, discriminant analysis carried out by using a forward stepwise model demonstrated that the top significance was documented while assessing the percentage of plasmoblasts (CD27hiCD38hi), resting memory B-cells (CD27dimCD38low), mature active B-cells (CD27dimCD38dim), naive mature B-cells (CD27dimCD38low), as well as counting the absolute numbers of transitional B-cells (CD27lowCD38hi), model percent correct was 78,6% (p <0,05, tab.1).Figure 1.Graphic distribution of SLE and pSS patients as well as HV analyzed by discriminant analysis.Conclusion:B cell subsets might provide a useful diagnostic tool for distinction SLE and pSS. More research needed to investigate clinical value of B-cell subsets in autoimmune rheumatic diseases.Table 1.Peripheral B-cell subset composition in SLE and SS patients vs. HV group assessed by discriminant analysis.ParameterF-testp-levelPlasmoblasts (CD27hiCD38hi), %7,93<0.001Resting memory B-cells (CD27dimCD38low), %13,72<0.001Transitional B-cells (CD27lowCD38hi)29,74<0.001Mature active B-cells (CD27dimCD38dim), %5,20<0.001Naive mature B-cells (CD27dimCD38low), %3,100.049Double negative (CD27lowCD38low), %1,980,14Resting memory B-cells (CD27dimCD38low)1,020,36Double negative (CD27lowCD38low)2,320,10Plasmoblasts (CD27hiCD38hi)1,020,36Naive mature B-cells (CD27dimCD38low)1,030,36Mature active B-cells (CD27dimCD38dim)1,020,36Transitional B-cells (CD27lowCD38hi), %1,030,36Disclosure of Interests:None declared

scholarly journals Marginating transitional B cells modulate neutrophils in the lung during inflammation and pneumonia

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
John Podstawka ◽  
Sarthak Sinha ◽  
Carlos H. Hiroki ◽  
Nicole Sarden ◽  
Elise Granton ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Regulatory Networks ◽  
Vascular Inflammation ◽  
Transitional B Cells ◽  
Pulmonary Capillaries ◽  
Life Threatening ◽  
B Cell Subsets

Pulmonary innate immunity is required for host defense; however, excessive neutrophil inflammation can cause life-threatening acute lung injury. B lymphocytes can be regulatory, yet little is known about peripheral transitional IgM+ B cells in terms of regulatory properties. Using single-cell RNA sequencing, we discovered eight IgM+ B cell subsets with unique gene regulatory networks in the lung circulation dominated by transitional type 1 B and type 2 B (T2B) cells. Lung intravital confocal microscopy revealed that T2B cells marginate in the pulmonary capillaries via CD49e and require CXCL13 and CXCR5. During lung inflammation, marginated T2B cells dampened excessive neutrophil vascular inflammation via the specialized proresolving molecule lipoxin A4 (LXA4). Exogenous CXCL13 dampened excessive neutrophilic inflammation by increasing marginated B cells, and LXA4 recapitulated neutrophil regulation in B cell–deficient mice during inflammation and fungal pneumonia. Thus, the lung microvasculature is enriched in multiple IgM+ B cell subsets with marginating capillary T2B cells that dampen neutrophil responses.

scholarly journals B Cell Subsets as Severity-Associated Signatures in COVID-19 Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Víctor A. Sosa-Hernández ◽  
Jiram Torres-Ruíz ◽  
Rodrigo Cervantes-Díaz ◽  
Sandra Romero-Ramírez ◽  
José C. Páez-Franco ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Subset ◽  
Hierarchical Cluster ◽  
Specific Subset ◽  
Respiratory Parameters ◽  
Cell Subpopulations ◽  
Severity Of The Disease ◽  
B Cell Subsets ◽  
Relationship Of

BackgroundSARS-CoV-2 infection represents a global health problem that has affected millions of people. The fine host immune response and its association with the disease course have not yet been fully elucidated. Consequently, we analyze circulating B cell subsets and their possible relationship with COVID-19 features and severity.MethodsUsing a multiparametric flow cytometric approach, we determined B cell subsets frequencies from 52 COVID-19 patients, grouped them by hierarchical cluster analysis, and correlated their values with clinical data.ResultsThe frequency of CD19+ B cells is increased in severe COVID-19 compared to mild cases. Specific subset frequencies such as transitional B cell subsets increase in mild/moderate cases but decrease with the severity of the disease. Memory B compartment decreased in severe and critical cases, and antibody-secreting cells are increased according to the severity of the disease. Other non-typical subsets such as double-negative B cells also showed significant changes according to disease severity. Globally, these differences allow us to identify severity-associated patient clusters with specific altered subsets. Finally, respiratory parameters, biomarkers of inflammation, and clinical scores exhibited correlations with some of these subpopulations.ConclusionsThe severity of COVID-19 is accompanied by changes in the B cell subpopulations, either immature or terminally differentiated. Furthermore, the existing relationship of B cell subset frequencies with clinical and laboratory parameters suggest that these lymphocytes could serve as potential biomarkers and even active participants in the adaptive antiviral response mounted against SARS-CoV-2.

Distribution and Cytokine Profile of Peripheral B Cell Subsets Is Perturbed in Pediatric IBD and Partially Restored During a Successful IFX Therapy

2020 ◽  
Author(s):  
Alexander Schnell ◽  
Benedikt Schwarz ◽  
Mandy Wahlbuhl ◽  
Ida Allabauer ◽  
Merlin Hess ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Flow Cytometry ◽  
B Cells ◽  
B Cell ◽  
Crohn Disease ◽  
Transitional B Cells ◽  
Healthy Control ◽  
B Cell Subsets ◽  
Trough Levels ◽  
Pediatric Ibd

Abstract Background The role of B cells in inflammatory bowel disease (IBD) is ambiguous, as B cells may have both pathogenic and protective functions in IBD. We studied B cell subsets before and after initiation of an anti-tumor necrosis factor alpha (anti-TNFα) therapy in pediatric IBD. The aim of the study was to examine the behavior of B cells in pediatric IBD patients undergoing an anti-TNFα therapy and, more specifically, to clarify their association with a successful or an unsuccessful infliximab (IFX) treatment. Methods A total of N = 42 pediatric IBD patients (Crohn disease, n = 30; ulcerative colitis, n = 12) for whom an anti-TNFα therapy with and without a concomitant azathioprine (AZA) medication was administered were recruited. Fourteen healthy age-matched children served as control patients. Blood samples were collected before initiation of the anti-TNFα therapy, before the fourth infusion at the end of the induction phase, and after 6 and 12 months under therapy maintenance. Flow cytometry (CD20, CD27, CD38, CD138) and intracellular staining (interleukin 10 [IL10], TNFα, granzyme B) were performed. Responders to successful IFX therapy were classified exhibiting a fecal calprotectin level of below 100 µg/g or achieving levels of &lt;10% of the baseline value at initiation than at the end of the 12-month follow-up period. Results Before initiation of anti-TNFα therapy, flow cytometry revealed increased percentages of naïve B cells whereas transitional B cells were reduced compared with those in the healthy control patients. The IL10-producing B cells of both ulcerative colitis and Crohn disease patients were reduced at the initiation of IFX therapy, whereas TNFα-producing transitional CD24hiCD38hi B cells in ulcerative colitis patients were increased compared with those in healthy control patients. After 12 months of therapy, we detected a significant increase of IL10-producing transitional B cells in responding patients. The IFX trough levels in the responding patients showed a significant increase until 6 months after IFX initiation, attaining mean values of 9.9 µg/mL, whereas the IFX dosage was significantly lower than that in the nonresponding patients. The IFX trough levels in AZA-treated patients reached earlier therapeutic levels than in patients without AZA comedication, whereas during the course of the IFX therapy, comedication with AZA had no significant effect on the outcome. Conclusions Attaining a normalization of IL10 production among CD24hiCD38hi B cells after 12 months of therapy may represent additional information about the reconstitution of a patient’s immune system in responding patients. The achievement of an IFX trough level of ~10 µg/mL at 6 months of treatment is associated with a successful anti-TNFα therapy. In addition, AZA comedication supports an earlier achievement of therapeutic IFX trough levels.

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.

Reduced Circulating Memory B-Cells Account for Humoral Immune Defects in Multiple Myeloma, Associated with Infective Risk and Poor Vaccination Responses

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3393-3393
Author(s):  
Jonathan Carmichael ◽  
Clive R Carter ◽  
Christopher Parrish ◽  
Charlotte Kallmeyer ◽  
Sylvia Feyler ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Bacterial Infections ◽  
Memory B Cells ◽  
Antibody Responses ◽  
Progressive Reduction ◽  
Cell Numbers ◽  
Humoral Immune ◽  
Transitional B Cells ◽  
B Cell Subsets

Abstract Multiple myeloma (MM) is characterized by an increased risk of infection due to the immunosuppressive effect of the disease and conjointly of therapy. Furthermore, there is impaired responses to vaccination to counter the infection risk. The factors that underpin defective B-cell homeostasis and effective humoral immunity are not clear, nor are the extent of the defects. Also, the level of impaired humoral immunity in MGUS is not fully understood. The aim of this study was to delineate the circulating B-cell populations and recall antibody responses in patients with MGUS & MM, compared to age-matched controls, correlating with the responsiveness to vaccinations, incidence of infective complications and concomitant therapy. We performed comprehensive B-cell immunophenotyping by multi-parameter flow cytometry of peripheral blood samples from patients with MGUS (n=16), asymptomatic MM (n=18) and MM (n=108) with a median age of 63 years (range 38-94) comparing them to age-matched controls (n=9). B-cell subsets included naïve (CD19+CD27-), memory (CD19+CD27+; non-switch CD19+IgD+CD27+, switch CD19+IgD-CD27+), transitional (CD19+CD27-CD24hiCD38hi) & regulatory (CD19+CD27+CD24hi) B-cells. Serum uninvolved total IgG, IgM & IgA levels along with vaccine-specific antibody responses were analysed. There is a progressive decrease in the uninvolved immunoglobulin classes with significant reduction in total IgA (p=0.006) and IgM levels (p=0.007) in aMM/MM compared to MGUS & control (Figure 1). When anti-pneumococcal antibodies were measured, only 30% of aMM/MM patients had adequate protective levels compared to 79% of age-matched controls, with 40% of aMM/MM patients with inadequate levels experiencing recurrent respiratory tract infections compared to 25% of aMM/MM patients with adequate proactive antibodies. Patients with MGUS, aMM and MM have lower total B-cell numbers compared to controls (1-way ANOVA p=0.004; Figure 1). The reduction in B-cell numbers were primarily the consequence of reduced memory B-cells (percentage and absolute 1-way ANOVA p<0.0001), noted in both MGUS and aMM/MM but a progressive reduction with increasing disease activity (MGUS>aMM>MM). Furthermore, a correlation with total IgG levels & memory B-cell numbers is evident (r2=-0.053) & progressive reduction in memory B-cell numbers is seen with advancing cycles of therapy. The ratio of switch:non-switch memory B-cells is unaltered (control 1.05, MGUS 0.53, aMM 1.41 & MM 1.49; 1-way ANOVA p=ns). Conversely, there is a compensatory increase in the percentage of transitional B-cells when increasing disease stage is compared to controls (control 7.38% (95%ci 4.9,9.9) vs MGUS 14.0% (95%ci 7.4, 20.7) vs aMM 14.95% (95%ci 8, 21.9); 1-way ANOVA p<0.001) but a reduction is noted in MM (5.82%, 95%ci 4.5,7.2; p<0.0001), primarily being driven by sequential lines of therapy. As a consequence, the ratio of Memory:transitional B-cells is significantly reduced in aMM/MM compared to MGUS & controls (control 10.35, MGUS 20.46, aMM 7.74 & MM 4.57; 1-way ANOVA p=0.006), associated with increasing incidence of bacterial infections. A non-significant correlation is seen between transitional B-cells and total uninvolved immunoglobulin levels and with recall responses to vaccinations. There is a progressive decrease in the CD19+CD27+CD24hi B-cell subset between control and plasma cell dyscrasias (control 20.4% (95%ci 15.5,25.2), MGUS 14.0% (95%ci 7.4, 20.7), aMM 14.95% (95%ci 8, 21.9) & MM 5.82%, 95%ci 4.5,7.2; p<0.0001), primarily being driven by sequential lines of therapy and associated with increased incidence of infection. This study illustrates that patients with myeloma demonstrate reduced total circulating B-cells primarily as a consequence of reduced memory B-cells, associated with reduced immunoglobulin and recall antibody responses. This is associated with increased incidence of bacterial infections and is worsened by sequential exposure to lymphodepleting therapies. Of particular importance is the identified aberration in B-cell subsets seen in MGUS compared with age-matched control, indicative of humoral immune dysregulation highlighting that MGUS may not be an immunologically inert disorder. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Expression of Ia antigens on hapten-specific B cells. I. Delineation of B-cell subpopulations.

1976 ◽  
Vol 144 (2) ◽  
pp. 414-427 ◽  
Author(s):  
J L Press ◽  
N R Klinman ◽  
H O McDevitt
Keyword(s):  
B Cells ◽  
B Cell ◽  
Igg Antibody ◽  
B Cell Maturation ◽  
Cellular Expression ◽  
Ia Antigens ◽  
Express Cell ◽  
Switch Mechanism ◽  
Cell Subpopulations ◽  
B Cell Subsets

The nonimmune adult spleen contains at least two B-cell subpopulations. The majority of primary B cells express cell surface Ia determinants and have the capacity to give rise to IgG antibody-producing clones after T-cell dependent antigenic stimulation. There is also a small subpopulation of primary B cells which are, by definition, Ia negative, since their activity is not eliminated by negative selection with anti-Ia serum and complement. The Ia-negative B cells give rise to clones that produce only IgM antibody. These B-cell subsets may form a continuum in B-cell maturation, or they may exist as discrete B-cell lineages. Since the cellular expression of Ia antigens appears to correlate with the ability of the B cell to generate IgG-producing clones, it is speculated that Ia molecules may have a role in the IgM to IgG B-cell switch mechanism.

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