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.

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.

Impact Of The Number Of Prior Treatment Lines Received On The Distribution Of Peripheral Blood Leukocyte Subsets In Advanced-Stage B-Cell Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4158-4158
Author(s):  
Georgiana Grigore ◽  
Susana Barrena ◽  
Martin Perez-Andres ◽  
Miriam Fierro ◽  
Marcos González ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Advanced Stage ◽  
Absolute Count ◽  
Purine Analogues ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
The Absolute ◽  
B Cell Subsets

Abstract Introduction It is currently well-known that B-cell chronic lymphocytic leukemia (CLL) patients have an impaired immune function -particularly in advanced disease-, which significantly contributes to a higher risk of infections. The introduction of new effective therapeutic agents, such as the purine analogues (or alkylating agents with concomitant properties of purine analogues) plusanti-CD20 monoclonal antibodies, have significantly increased the rate of complete responses in CLL, but so far their impact on the overall immune function and the spectrum of infections occurring in CLL patients after therapy, remains to be fully understood. Aim To evaluate the effect of the number of treatment lines received on the different normal circulating leucocyte cell populations, including normal B-cell subsets, in advanced-stage treated CLL. Material and Methods The distribution of peripheral blood (PB) leukocytes was analyzed in 85 untreated CLL patients, and compared to that of 63 patients who had previously been treated with 1 line of treatment (n=39) or >1 line of treatment (n=24), and who failed to respond. Analysis was performed by 8-color flow cytometry with monoclonal antibodies against CD3, CD4, CD5, CD8, TCRgd, CD19, CD20, CD27, CD38, CD45, CD56, sIgM, sIgA, sIgG, sIgLambda and sIgKappa. Results The absolute count of circulating malignant B cells was not significantly different (p>0.05) in the untreated vs. previously treated patients who received 1 or >1 line of treatment (77,627±84,211 vs 67,994±72,087 vs 59,282±74,206 cells/uL; respectively). In contrast, as compared to untreated patients, PB normal B cells were found to be reduced in patients who had received either 1 line or >1 line of treatment (89±142 vs 36±57 and 23±32 cells/uL, p=0.004 and p<0.001, respectively), but at similar levels between the two groups of previously treated patients (p>0.05). When dissecting the normal B-cell subsets, therapy-related decreased B-cell numbers were mostly due to a reduced number of circulating memory B cells (67±98 vs 21±45 and 15±26 cells/uL; p=0.001 and p<0.001, respectively), including all memory isotypes: IgM (24±31 vs 5±13 and 5±6 cells/uL, p<0.001), IgG (25±59 vs 10±32 and 6±13 cells/uL; p=0.008) and IgA (18±30 vs 5±10 and 6±12 cells/uL; p=0.001 and p=0.003). No significant differences were found as regards the absolute count of immature (5±11 vs 8±26 and 3±11 cells/uL; p>0.05) and naïve (16±55 vs 6±18 and 4±8 cells/uL; p>0.05) B cells, nor for circulating plasma cells (3±18 vs 5±21 and 2±6 cells/uL; p>0.05), regardless of the therapy status. As compared to untreated patients, the absolute count of CD4+ T cells and CD4/CD8 double negative TCRαβ cells were significantly lower in patients with >1 line of treatment (1,836±1,340 vs 1,256±1,027 and 131±165 vs 56±97 cells/uL, p=0.03 and p=0.007 respectively) but not in those who had received only 1 line (1,477±1,349 and 201±747 cells/uL; p>0.05). In contrast, therapy did not show a significant impact on the absolute count of PB T CD8+ and TCRgd cells. No statistically significant differences were observed in the number of PB innate immune subpopulations including, neutrophils, eosinophils, basophils, monocytes, NK cells and dendritic cells. Conclusions While there are no differences regarding the number of leukemic cells, previously treated patients have significantly reduced counts of total and memory (all isotypes) normal B-cell subsets when compared to untreated patients. Together with this, CD4+ helper T cells could also be compromised after more than 1 line of treatment. Monitoring of these therapy-related immune defects could contribute to a better management of infectious complications in advanced-stage CLL patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals T- and B-lymphocytes subpopulations in the early and advanced rheumatoid arthritis

2021 ◽  
Vol 15 (2) ◽  
pp. 17-22
Author(s):  
A. V. Martynova ◽  
T. V. Popkova ◽  
A. P. Aleksankin ◽  
G. I. Gridneva ◽  
E. V. Gerasimova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Lymphocytes ◽  
B Lymphocyte ◽  
Relative Number ◽  
Memory B Cells ◽  
T And B Lymphocytes ◽  
The Absolute ◽  
Group 2 ◽  
Group 1

Objective: to evaluate changes in T- and B-lymphocyte subpopulations at different stages of rheumatoid arthritis (RA).Patients and methods. The study included 53 patients with a definite RA diagnosis according to the 2010 ACR/EULAR criteria (mean age 54.2 [47; 62] years). Group 1 included 27 patients (25 women and 2 men) without history of synthetic disease modifying anti-rheumatic drugs (sDMARDs) intake, group 2 included 26 patients (22 women and 4 men) receiving sDMARDs (methotrexate or leflunomide). The control group consisted of 29 healthy volunteers (23 women and 6 men), the median age was 58.5 [53; 62] years. In all participants flow cytofluorometry according to the standard technique with immunophenotyping of T- and B-lymphocytes was performed.Results and discussion. Compared to controls, patients in group 1 who had not previously received sDMARDs showed a transient increase in "switched" memory B-cells, transient B-cells, and plasmablasts, which was not observed in patients of group 2 (on sDMARDs therapy). Patients with advanced RA showed a statistically significant decrease in the absolute and relative number of memory B-cells, the absolute and relative number of "switched" B-lymphocytes, as well as the number of plasmablasts and transient cells. In RA patients, a statistically significant rela tionship was established between the number of swollen joints and the level of plasmablasts (r=0.51), memory cells (r=0.54), and "switched" B-cells (r=0.41), p< 0,05 in all cases. There were no statistically significant changes in other subpopulations of B-lymphocytes and the profile of T-lymphocytes.Conclusion. Changes in the B-lymphocyte profile are characteristic of different stages of RA. At an early stage, there is an increase in the number of transient B-lymphocytes, plasmablasts and plasmocytes, and in the advanced stage, a decrease in the level of certain populations of B-lymphocytes, such as memory B-cells and "switched" B-lymphocytes. It can be assumed that the ineffectiveness of sDMARDs is associated with a change in the population composition of B-lymphocytes, which requires further study.

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 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.

scholarly journals Complexity of the human memory B-cell compartment is determined by the versatility of clonal diversification in germinal centers

2015 ◽  
Vol 112 (38) ◽  
pp. E5281-E5289 ◽  
Author(s):  
Bettina Budeus ◽  
Stefanie Schweigle de Reynoso ◽  
Martina Przekopowitz ◽  
Daniel Hoffmann ◽  
Marc Seifert ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Clone ◽  
Human Memory ◽  
Memory B Cells ◽  
Sequencing Analysis ◽  
Cell Compartment ◽  
Memory B Cell ◽  
Cell Clones ◽  
B Cell Subsets

Our knowledge about the clonal composition and intraclonal diversity of the human memory B-cell compartment and the relationship between memory B-cell subsets is still limited, although these are central issues for our understanding of adaptive immunity. We performed a deep sequencing analysis of rearranged immunoglobulin (Ig) heavy chain genes from biological replicates, covering more than 100,000 memory B lymphocytes from two healthy adults. We reveal a highly similar B-cell receptor repertoire among the four main human IgM+ and IgG+ memory B-cell subsets. Strikingly, in both donors, 45% of sequences could be assigned to expanded clones, demonstrating that the human memory B-cell compartment is characterized by many, often very large, B-cell clones. Twenty percent of the clones consisted of class switched and IgM+(IgD+) members, a feature that correlated significantly with clone size. Hence, we provide strong evidence that the vast majority of Ig mutated B cells—including IgM+IgD+CD27+ B cells—are post-germinal center (GC) memory B cells. Clone members showed high intraclonal sequence diversity and high intraclonal versatility in Ig class and IgG subclass composition, with particular patterns of memory B-cell clone generation in GC reactions. In conclusion, GC produce amazingly large, complex, and diverse memory B-cell clones, equipping the human immune system with a versatile and highly diverse compartment of IgM+(IgD+) and class-switched memory B cells.

scholarly journals In VitroMeasles Virus Infection of Human Lymphocyte Subsets Demonstrates High Susceptibility and Permissiveness of both Naive and Memory B Cells

2018 ◽  
Vol 92 (8) ◽  
pp. e00131-18 ◽  
Author(s):  
Brigitta M. Laksono ◽  
Christina Grosserichter-Wagener ◽  
Rory D. de Vries ◽  
Simone A. G. Langeveld ◽  
Maarten D. Brem ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Immune Suppression ◽  
Peripheral Blood ◽  
Measles Virus ◽  
Memory B Cells ◽  
T And B Cells ◽  
B Cell Subsets

ABSTRACTMeasles is characterized by a transient immune suppression, leading to an increased risk of opportunistic infections. Measles virus (MV) infection of immune cells is mediated by the cellular receptor CD150, expressed by subsets of lymphocytes, dendritic cells, macrophages, and thymocytes. Previous studies showed that human and nonhuman primate memory T cells express higher levels of CD150 than naive cells and are more susceptible to MV infection. However, limited information is available about the CD150 expression and relative susceptibility to MV infection of B-cell subsets. In this study, we assessed the susceptibility and permissiveness of naive and memory T- and B-cell subsets from human peripheral blood or tonsils toin vitroMV infection. Our study demonstrates that naive and memory B cells express CD150, but at lower frequencies than memory T cells. Nevertheless, both naive and memory B cells proved to be highly permissive to MV infection. Furthermore, we assessed the susceptibility and permissiveness of various functionally distinct T and B cells, such as helper T (TH) cell subsets and IgG- and IgA-positive memory B cells, in peripheral blood and tonsils. We demonstrated that TH1TH17 cells and plasma and germinal center B cells were the subsets most susceptible and permissive to MV infection. Our study suggests that both naive and memory B cells, along with several other antigen-experienced lymphocytes, are important target cells of MV infection. Depletion of these cells potentially contributes to the pathogenesis of measles immune suppression.IMPORTANCEMeasles is associated with immune suppression and is often complicated by bacterial pneumonia, otitis media, or gastroenteritis. Measles virus infects antigen-presenting cells and T and B cells, and depletion of these cells may contribute to lymphopenia and immune suppression. Measles has been associated with follicular exhaustion in lymphoid tissues in humans and nonhuman primates, emphasizing the importance of MV infection of B cellsin vivo. However, information on the relative susceptibility of B-cell subsets is scarce. Here, we compared the susceptibility and permissiveness toin vitroMV infection of human naive and memory T- and B-cell subsets isolated from peripheral blood or tonsils. Our results demonstrate that both naive and memory B cells are more permissive to MV infection than T cells. The highest infection levels were detected in plasma cells and germinal center B cells, suggesting that infection and depletion of these populations contribute to reduced host resistance.

A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4500-4504 ◽  
Author(s):  
Nadia L. Bernasconi ◽  
Nobuyuki Onai ◽  
Antonio Lanzavecchia
Keyword(s):  
B Cells ◽  
B Cell ◽  
Constitutive Expression ◽  
Human Memory ◽  
Cell Receptor ◽  
Primary Response ◽  
Memory B Cells ◽  
Toll Like Receptors ◽  
Polyclonal Activation ◽  
B Cell Subsets

Abstract Toll-like receptors (TLRs) are pattern recognition receptors that trigger innate immunity. In this study we investigated the expression of 10 TLRs in human naive and memory B-cell subsets. We report that in human naive B cells most TLRs are expressed at low to undetectable levels, but the expression of TLR9 and TLR10 is rapidly induced following B-cell-receptor (BCR) triggering. In contrast, memory B cells express several TLRs at constitutively high levels. The differential expression of TLR9 correlates with responsiveness to its agonist, CpG DNA. Thus, human memory B cells proliferate and differentiate to immunoglobulin (Ig)–secreting cells in response to CpG, while naive B do so only if simultaneously triggered through the BCR. The BCR-induced expression of TLRs in human naive B cells prevents polyclonal activation in a primary response, because it restricts stimulation to antigen-specific B cells. In contrast, the constitutive expression of TLRs in memory B cells allows polyclonal activation of the entire memory pool. Thus, in human B cells TLRs are downstream of BCR and play a role both in the primary response and in the memory phase.

scholarly journals Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2150-2158 ◽  
Author(s):  
Magdalena A. Berkowska ◽  
Gertjan J. A. Driessen ◽  
Vasilis Bikos ◽  
Christina Grosserichter-Wagener ◽  
Kostas Stamatopoulos ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Phenotypic Diversity ◽  
Human Memory ◽  
Memory B Cells ◽  
Memory B Cell ◽  
Effector Cells ◽  
B Cell Subsets

Abstract Multiple distinct memory B-cell subsets have been identified in humans, but it remains unclear how their phenotypic diversity corresponds to the type of responses from which they originate. Especially, the contribution of germinal center-independent responses in humans remains controversial. We defined 6 memory B-cell subsets based on their antigen-experienced phenotype and differential expression of CD27 and IgH isotypes. Molecular characterization of their replication history, Ig somatic hypermutation, and class-switch profiles demonstrated their origin from 3 different pathways. CD27−IgG+ and CD27+IgM+ B cells are derived from primary germinal center reactions, and CD27+IgA+ and CD27+IgG+ B cells are from consecutive germinal center responses (pathway 1). In contrast, natural effector and CD27−IgA+ memory B cells have limited proliferation and are also present in CD40L-deficient patients, reflecting a germinal center-independent origin. Natural effector cells at least in part originate from systemic responses in the splenic marginal zone (pathway 2). CD27−IgA+ cells share low replication history and dominant Igλ and IgA2 use with gut lamina propria IgA+ B cells, suggesting their common origin from local germinal center-independent responses (pathway 3). Our findings shed light on human germinal center-dependent and -independent B-cell memory formation and provide new opportunities to study these processes in immunologic diseases.

scholarly journals B Lymphocyte Chemotaxis Regulated in Association with Microanatomic Localization, Differentiation State, and B Cell Receptor Engagement

1998 ◽  
Vol 187 (5) ◽  
pp. 753-762 ◽  
Author(s):  
Conrad C. Bleul ◽  
Joachim L. Schultze ◽  
Timothy A. Springer
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Messenger Rna ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Cxc Chemokine

Migration of mature B lymphocytes within secondary lymphoid organs and recirculation between these sites are thought to allow B cells to obtain T cell help, to undergo somatic hypermutation, to differentiate into effector cells, and to home to sites of antibody production. The mechanisms that direct migration of B lymphocytes are unknown, but there is evidence that G protein–coupled receptors, and possibly chemokine receptors, may be involved. Stromal cell– derived factor (SDF)-1α is a CXC chemokine previously characterized as an efficacious chemoattractant for T lymphocytes and monocytes in peripheral blood. Here we show with purified tonsillar B cells that SDF-1α also attracts naive and memory, but not germinal center (GC) B lymphocytes. Furthermore, GC B cells could be converted to respond to SDF-1α by in vitro differentiation into memory B lymphocytes. Conversely, the migratory response in naive and memory B cells was significantly reduced after B cell receptor engagement and CD40 signaling. The receptor for SDF-1, CXC chemokine receptor 4 (CXCR4), was found to be expressed on responsive as well as unresponsive B cell subsets, but was more rapidly downregulated on responsive cells by ligand. Finally, messenger RNA for SDF-1 was detected by in situ hybridization in a layer of cells surrounding the GC. These findings show that responsiveness to the chemoattractant SDF-1α is regulated during B lymphocyte activation, and correlates with positioning of B lymphocytes within a secondary lymphoid organ.

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