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 Development in the Spleen Takes Place in Discrete Steps and Is Determined by the Quality of B Cell Receptor–Derived Signals

1999 ◽  
Vol 190 (1) ◽  
pp. 75-90 ◽  
Author(s):  
By Florienne Loder ◽  
Bettina Mutschler ◽  
Robert J. Ray ◽  
Christopher J. Paige ◽  
Paschalis Sideras ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Receptor ◽  
Transitional B Cells ◽  
Spleen And Lymph Nodes

Only mature B lymphocytes can enter the lymphoid follicles of spleen and lymph nodes and thus efficiently participate in the immune response. Mature, long-lived B lymphocytes derive from short-lived precursors generated in the bone marrow. We show that selection into the mature pool is an active process and takes place in the spleen. Two populations of splenic B cells were identified as precursors for mature B cells. Transitional B cells of type 1 (T1) are recent immigrants from the bone marrow. They develop into the transitional B cells of type 2 (T2), which are cycling and found exclusively in the primary follicles of the spleen. Mature B cells can be generated from T1 or T2 B cells.

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 Changes in the T and B- Cell Subsets Following Treatment with a CD25-Antibody in Patients with Steroid Refractory GvHD

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2497-2497
Author(s):  
Geothy Chakupurakal ◽  
Maria Garcia- Marquez ◽  
Alexander Shimabukuro- Vornhagen ◽  
Hans Anton Schloesser ◽  
Udo Holtick ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Interleukin 2 ◽  
Unrelated Donors ◽  
B Cell Subsets ◽  
Regulatory Type ◽  
Steroid Refractory

Abstract Allogeneic stem cell transplantation is the therapeutic option for a variety of malignant and non-malignant haematological diseases. Graft versus Host Disease (GvHD) is a common post transplant complication. In 40% of these patients, GvHD is steroid refractory and associated with a mortality of around 60%. Basiliximab is a chimeric murine –human antibody also selective for interleukin -2 receptor (IL-2R) with a half life of 7 days. It is routinely used as part of the induction therapy in renal transplant recipients to prevent acute rejection following successful phase III studies. Phase 2 studies have demonstrated its superior efficacy in treating patients with steroid refractory GvHD (1). We administered Basiliximab in 14 patients with steroid refractory GvHD with a median age of 41 (range 20-69). M: F 7:7. All patients but one 13/14 received PBSC from unrelated donors and 6/13 had mismatched unrelated donors. Overall response was in the order of 12/14 (85%). One patient could not be assessed. 7/14 (50%) achieved a complete response to treatment. We aimed to study the in vivo T- and B-cell changes following Basiliximab administration as this would be an ideal platform to monitor the alterations in the regulatory T and B-cell compartment. PBMCs were obtained from all donors after informed consent, Immucan (Nr 11-116) approved by our local ethics committee, prior to and after weekly administration of Basiliximab 40mg for 4 weeks. Control samples were obtained from patients with steroid responsive acute GvHD. The total number of CD3+ as well as CD4+ and CD8+ T-cells remained constant during treatment and no change was observed on comparison with the controls. Gagliani et al (2) demonstrated that regulatory type 1 T-cells can be identified by the co-expression of CD49b and Lag3. No difference was observed between the % CD49d+, Lag3+ T-cells in the control cohort and the treatment cohort prior to therapy, ie day 0. The % CD49d+, Lag3+ T-cells decreased during the treatment period (statistically significant) in comparison to the control cohort. Despite the use of the CD25-antibody, a small population of CD25+, CD127+ cells could be detected and this population correlated to the % CD49d+, Lag3+ T-cells. Figure 1 Figure 1. Figure 2 Figure 2. The % CD19+, CD20+ B-cells were similar prior to treatment in the treatment group and control. Following the first administration a rise was observed followed by a decline over the next 3 weeks. No changes were seen in the activated (CD20+, CD86+) and anergic B-cell subsets (CD20+, CD21-) during the observation period. The % of CD24high, CD27+ regulatory B-cells were found to be twice that seen in the controls. With treatment a decrease was seen in this population. The CD24high, CD38high transitional B-cells were also found to be higher than that seen in the controls. No change was observed in this subset with treatment. Figure 3 Figure 3. This is the first attempt to study the in-vivo changes induced by a CD25 antibody in patients with steroid refractory GvHD. We conclude that this antibody not only depletes the alloreactive CD25+ T and B-cell population but also alters the regulatory T and B-cell subsets in comparison to patients with steroid responsive GvHD. Our clinical data supports the efficacy of this drug in patients with steroid refractory GvHD. Contrary to the current knowledge that regulatory T-cells are required for GvHD suppression our data suggests that Basiliximab facilitates regulatory T-cell depletion. The reduction of the regulatory T-cell subset observed in patients responding to anti CD25 treatment suggests a complex regulation and potential dichotomous role of these cells in acute GvHD. Schmidt-Hieber M, Fietz T, Knauf W, Uharek L, Hopfenmuller W, Thiel E, et al. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol. 2005 Aug;130(4):568-74.Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, et al.Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med. 2013 Jun;19(6):739-46 Disclosures No relevant conflicts of interest to declare.

scholarly journals Distinct functional phenotypes of cloned Ia-restricted helper T cells.

1985 ◽  
Vol 162 (1) ◽  
pp. 188-201 ◽  
Author(s):  
J Kim ◽  
A Woods ◽  
E Becker-Dunn ◽  
K Bottomly
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Activation ◽  
Functional Types ◽  
Precursor B Cells ◽  
Type 3

Analysis of activation of phosphorylcholine (PC)-specific B cells by a large number of different cloned, self Ia-specific helper T cell (Th) clones has permitted the classification of such T cells into four distinct functional types. Types 1 and 2 induce B cells to secrete anti-PC antibody in an antigen-specific, Ia-restricted fashion. Type 3 cells induce antigen-specific, Ia-restricted B cell proliferation, but do not lead to specific antibody formation, and have been shown previously to have suppressor functions. Type 4 cells are autoreactive, and induce antigen-independent B cell activation and antibody secretion. The distinction between type 1 and type 2 Th clones was analyzed in detail. In bulk cultures, type 1 cloned lines generate an idiotypically heterogeneous anti-PC antibody response, whereas type 2 cloned lines induce a larger response that is dominated by the T15 idiotype. In limiting-dilution analyses, type 2 cells induce fourfold more T15+, PC-specific precursor B cells than do type 1 cells, and in addition, induce larger burst sizes for T15+, PC-specific B cells. Type 4 clones can also be subdivided into cells that are type 1-like, and cells that are type 2-like. These differences in functional phenotype are seen over a broad range of antigen and cell doses. Detailed analysis of the behavior of these distinct functional types of Th should allow a better understanding of the functional properties of mixed populations of antigen-primed, Ia-restricted Th cells.

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.

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 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 &lt; 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 &lt; 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.

scholarly journals The impact of hypoxia on B cells in COVID-19

2021 ◽  
Author(s):  
Prasanti Kotagiri ◽  
Federica Mescia ◽  
Aimee Hanson ◽  
Lorinda Turner ◽  
Laura Bergamaschi ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Hypoxic Conditions ◽  
Transitional B Cells ◽  
Transcriptional Changes ◽  
B Cell Subsets ◽  
The Impact ◽  
Pronounced Reduction ◽  
Early Features

Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This brought to mind the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. We demonstrated the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes we also observed in B cell VHL-deficient mice. This was corroborated by hypoxia-related transcriptional changes in COVID-19 patients, and by similar B cell abnormalities in mice kept in hypoxic conditions, including reduced marginal zone and germinal center B cells. Thus hypoxia might contribute to B cell pathology in COVID-19, and in other hypoxic states. Through this mechanism it may impact on COVID-19 outcome, and be remediable through early oxygen therapy.

scholarly journals Establishment of an inbred line of mice that express a synergistic immune defect precluding in vitro responses to type 1 and type 2 antigens, B cell mitogens, and a number of T cell-derived helper factors.

1983 ◽  
Vol 158 (5) ◽  
pp. 1401-1414 ◽  
Author(s):  
J J Mond ◽  
G Norton ◽  
W E Paul ◽  
I Scher ◽  
F D Finkelman ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
C3h Mice ◽  
Immune Defect ◽  
T Cell Help

Introduction of the CBA/N X-linked gene into C3H mice has resulted in the establishment of a new strain of mice that has profound immunologic defects. B cells from these mice show significantly impaired in vitro immune responses to the T cell-independent type 1 antigen trinitrophenyl-Brucella abortus (TNP-BA) as well as markedly reduced proliferative responses to a number of B cell mitogens when compared with the responses of the parental control mice. The in vivo response of such mice to TNP-BA is, however, comparable to that of CBA/N mice. Furthermore, B cells from C3.CBA/N mice are unresponsive to the plaque-forming cell enhancing effects induced by EL4-derived supernatant in the presence of TNP-BA, unlike B cells obtained from CBA/N or C3H/Hen mice whose responsiveness to TNP-BA can be significantly enhanced in the presence of EL4-derived supernatant. The model we have presented to best explain these results suggests that B cells from C3.CBA/N mice can be stimulated only under conditions in which they can interact with carrier-specific T cell help and not under conditions where factor-dependent responses are dominant.

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.

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