Adult BM generates CD5+ B1 cells containing abundant N‐region additions
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Abstract The self‐renewing capacity of B1 cells infers homeostatic regulation; however, previous work suggests the low level of N‐region addition characterizing B1 cells early in life increases with age, which implies that the B1‐cell population is not a closed system. To explore this, we evaluated N‐region addition in CD5 + B1 cells generated from adult BM. Adult BM cells were marked with GFP introduced by mouse stem cell virus transduction, and were then adoptively transferred into lethally irradiated recipients. Within 2–3 months, we found GFP‐marked CD5 + B cells in the peritoneal cavities of recipients, which we demonstrate here meet a variety of criteria for B1‐cell traits including Mac‐1 surface expression; annexin, elfin, and Pax‐5 gene expression; mitogenic responsiveness to phorbol ester; and spontaneous immunoglobulin secretion. Notably, we found by single‐cell PCR that this population of BM‐derived CD5 + B1 cells expressed immunoglobulin with abundant N‐region addition (and little V H 11/V H 12 skewing), unlike CD5 + B1 cells obtained from unmanipulated animals but reminiscent of B2 cells. Further, we confirmed that native CD5 + B1 cells from older mice contain more N‐region additions than native CD5 + B1 cells from younger mice. These results suggest that adult BM progenitors contribute to the peritoneal CD5 + B1‐cell pool over time.Keywords:
CD5
Abstract Objective Treatment with rituximab depletes B cells from the peripheral blood (PB) and salivary glands (SGs) of patients with primary Sjögren's syndrome (SS). The purpose of this study was to track the repopulation of B cell subsets in PB as well as their subsequent homing into SGs in patients with primary SS treated with rituximab. Methods A series of 4‐color flow cytometry experiments delineated B cell subsets in 15 patients with primary SS. All were tested on days 8 and 15 of treatment. Nine of the patients were followed up monthly for 10 months, and the remaining 6 patients were followed up monthly for 24 months. Enzyme‐linked immunosorbent assays were developed to measure serum levels of BAFF and rituximab. SGs were biopsied at the start of the study and 4 months after treatment in 15 patients, 12 months after treatment in 3 patients, and 24 months after treatment in 2 patients. Results Baseline serum levels of BAFF correlated inversely (r = −0.92, P < 5 × 10 −4 ) with the duration of B cell depletion: the higher the BAFF levels, the shorter the duration of B cell depletion. Four B cell subsets repopulated the PB: plasmablasts (CD19+, CD5−,IgD−,CD38++), transitional type 1 (T1) B cells (CD19+,CD5+,IgD+,CD38++), mature Bm2 cells (CD19+,CD5+/−,IgD+,CD38+/−), and memory B cells (CD19+,CD5−,IgD−,CD38−). Increased numbers of Bm2 cells and decreased memory B cells reappeared with time. Sequential SG biopsies revealed that B cells were absent in these glands for 12 months: they were detected 24 months after rituximab treatment. Memory and T1 B cells were the first B cells identified locally. Conclusion The timing of B cell repopulation is modulated by BAFF and is followed by reconstitution of the preexisting abnormalities.
Immunoglobulin D
CD5
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The CD5 molecule is expressed on T cells and, at a lower density, on a minor B cell subset (CD5+ B cells). The pan-B Ag CD72 was recently identified as the CD5 counterstructure, and several data suggest the involvement of this ligand pair in T-B cell cognate interaction. However, the functional role of CD5 and CD72 molecules within the B cell compartment is still unknown. In this work we studied umbilical cord blood CD5+ B cells (B-1a), adult splenic CD5- B cells (B-2), and CD5+ B cells from patients with chronic lymphocytic leukemia. Flow cytometry analysis and proliferation assays were used to determine 1) the ability of B-1a and B-2 cells to coexpress functionally relevant counterligands other than CD5 and CD72, and 2) the signaling capacity of CD5 and CD72 in terms of B cell activation and proliferation. To this purpose, freshly isolated or preactivated normal and neoplastic B cells were cultured with agonistic anti-CD5 or anti-CD72 mAbs in the presence or the absence of cytokines equipped with B cell activity. Our data demonstrate that CD5 and CD72 molecules are coexpressed with other ligand pairs usually involved in T-B cell cognate interaction on B-1a cells, but not on B-2 cells. CD5 and/or CD72 engagement delivers critical costimulatory signals in B-1a, B-2, and B cells from patients with chronic lymphocytic leukemia, but with different requirements and patterns. Besides suggesting the potential involvement of B-1a lymphocytes in B-B cell interactions during T-independent B cell responses, our results indicate that CD5 and CD72 counterstructures play a functional role in the B cell compartment.
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Naive B cell
ZAP70
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B CLL is a monoclonal proliferation of lymphocytes which express the CD5 antigen (CD5+ CLL). Rare exceptions (less than 10%) are CD5-, as are the majority of B PLL. We have studied the clinical, cytological and immunophenotypic characteristics of a series of 12 CD5-CLL and have established a score which allows the distinction between CD5+ CLL, CD5- CLL and PLL. Among the CD5- CLL, there were significantly more cases with advanced stage (Rai and Binet) and splenomegaly. The cytological study found more mixed CLL according to FAB classification (more prolymphocytes). There were significantly more CD23-, FMC7+, SIg strong positive cases. A score from 0 to 6 was established based on clinical, cytological and immunophenotypic criteria. Typical CD5+ CLL was scored 0, score 6 corresponded to typical PLL. There were significantly more higher scores amongst CD5- CLL. It therefore appears that CD5- CLLs share certain features with B PLL. The use of this scoring system will allow determination of prognosis within these different categories, thus identifying groups which require specific therapy.
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CD23
Prolymphocytic leukemia
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Lymphocytes from patients affected by B-cell chronic lymphocytic leukemia (B-CLL) have frequently been shown to be positive for the multidrug resistance (MDR) phenotype. However, this phenotype does not seem to be responsible for the resistance to alkylating agents usually employed in the management of CLL.Lymphocytes from 42 patients were evaluated by flow cytometry for P-170 expression and by spectrophotometry for glutathione-S-transferase (GST) activity.Our findings show that GST is not related to any clinical parameter but is increased in treated patients. Conversely, 85% of patients were positive for P-170 and this was related to the percentage of CD5/CD19-positive lymphocytes. CD5/CD19-negative patients were also negative for P-170. MDR was not related to any clinical parameter evaluated nor to GST activity in lymphocytes.MDR is constitutively expressed in B-cell chronic lymphocytic leukemia and seems to be related to a CD5/CD19 B-CLL phenotype. The increase of GST activity in treated patients is statistically significant (p < 0.005).
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Immunophenotyping
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B cells in chronic lymphocytic leukaemia (CLL) usually express the CD5 antigen, which appears to participate in the pathogenesis of autoimmune phenomena. However, 7-20% of B-CLL patients are CD5-. The aim of this study was to assess whether CD5 expression could be used as a discriminating factor for two subgroups of B-CLL. Twenty-nine CD5- B-CLL patients were compared in terms of clinico-biological characteristics and survival with a control group of 29 sex- and age-matched, consecutive CD5+ B-CLL subjects. B-CLL was considered to be CD5- when less than 5% of mononuclear cells expressed CD5 after subtraction of the number of T cells. Splenomegaly, lymph node involvement, and haemolytic anemia were found in CD5+ patients in a significantly higher proportion than in their CD5- counterparts, who presented with an earlier stage of disease. CD5- patients had a median survival of 97.2 (22-130) months, exceeding CD5+ subjects significantly [84.0 (19-120) months, p = 0.0025]. CD5- patients seemingly present with milder disease and have a favourable prognosis compared with the vast majority of B-CLL patients who express CD5.
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Objective:To investigate the role of detecting t(11;14),CD5 and CD23 in diagnosis of chronic lymphocytic leukemia(CLL).Method:Flow cytometry(FCM) and conventional cytogenetics (CC) were performed in 45 patients who were firstly diagnosed as CLL,then interval fluorescence in situ hybridization(I-FISH) was performed in all patients.Result:All patients were negative with t(11;14) in CC.FCM results showed that 5 patients were CD5+CD23-and 40 patients were CD5+CD23+.Four patients with CD5+CD23-were positive with t(11;14) by I-FISH,but no patients with CD5+CD23+ were positive with t(11;14) by I-FISH.Conclusion:Examination of t(11;14),CD5 and CD23 plays an important role in diagnosing CLL.CLL shows features of t(11;14) negative and CD5+ CD23+.A few of mantle cell lymphoma(MCL) cases are misdiagnosed as CLL. MCL is identified as t(11;14) and CD5+ CD23-.
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CD23
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Chronic lymphocytic leukemia cell (CLL) usually (95%) express B-phenotype and the CD5 antigen which is usually present on the surface of normal T cells. However, among B CLL, 7 to 20% do not express CD5. The significance of the lack of CD5 expression remains unclear. We reviewed 42 consecutive CD5- B CLL seen in three French medical centers from 1985 to 1991 and compared them with 79 CD5+ B CLL. Immunophenotype studies were performed using indirect immunofluorescence under light microscopy as well as flow cytometry after 1988. B CLL was considered to be CD5 negative when less than 5% of mononuclear cells expressed CD5 after subtraction of the number of T-cells. Cases with CD5- B CLL had isolated splenomegaly more frequently (p = 2.10(-7)). They frequently expressed a higher level of surface immunoglobulin (S-Ig) or the switch mu/delta phenotype (p = 4.7 10(-2)). The median survival time was not reached but no significant difference between CD5 negative and positive B CLL was observed at the time of our data analysis (p = 0.97). Clinical presentation of CD5- B CLL seems to be different from other forms of B CLL. Although, no conclusion can be reached in terms of prognosis, CLL with low expression of CD5 should be regarded as a subtype of CLL with a different clinical presentation than CD5+ CLL.
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Immunophenotyping
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We demonstrate that, on average, greater than 90% of B lymphocytes in fetal spleen express CD5 at gestational ages of 17-23 weeks. Similarly, CD5+ B cells (B-1 cells) are the major B cell subset in umbilical cord blood. These findings depend on the optimization of fluorochrome conjugated anti-CD5 reagents for multiparameter fluorescent-activated cell sorter (FACS) analysis. From infancy through childhood the percentage of B-1 cells gradually diminishes in both spleen and peripheral blood. Stable adult levels, 25-35% of the total B cell population, are reached in late adolescence. The decrease in the percentage of B-1 cells in spleen is accompanied by an increase in conventional (CD5-) B cells, keeping the percentage of total B cells per mononuclear cells relatively constant. In contrast, in peripheral blood, the concentration of both B-1 cells and total B cells decreases, while T cells increase. At the functional level, we show that polyreactive IgM autoantibodies are produced by FACS-sorted CD5high B cells, but not by CD5- B cells from adolescent spleen. In contrast, fetal splenic CD5high and CD5- B cells appear functionally uniform, both producing IgM autoantibodies that are typical of B-1 cells. The apparent level of CD5- B cells in fetal spleen, on average 10% of total B cells, may still result from limitations of our reagent. The prominence of B-1 cells in fetal spleen and cord blood, the gradual reduction of B-1 cells with increasing age, and its characteristic repertoire, all suggest a role for this cell type in immunologically immature hosts.
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Cord blood
Immunoglobulin M
Regulatory B cells
Naive B cell
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The presence of the CD5 (67 kDa) molecule on the surface of B cells has been considered a marker for cells producing auto‐and polyreactive antibodies. Cord blood B lymphocytes (rich in CD5 + B cells) have been sorted into CD5 positive and negative populations by flow cytometry using monoclonal antibodies to CD20 and CD5. Clones of these populations were obtained by immortalization mill Epstein Barr virus. Clones derived from both CD5 + and CD5 − B cells produced IGM which was auto‐ and polyreactive with a higher frequency of these specificities in the CD5 + population. These data indicate Ihm expression of surface CD5 on cord blood B cells Is not a definitive marker of an auto/polyreactive population.
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Cord blood
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