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1.
Depletion of B cells is beneficial in rheumatoid arthritis (RA) patients with autoantibodies to citrullinated proteins (ACPA) and/or the Fc portion of immunoglobulins (rheumatoid factor [RF]), suggesting a role for B cells in disease pathogenesis. To date, however, the identity of specifically pathogenic B cell subsets has not been discovered. One candidate population is identified by the low expression or absence of complement receptor 2 (CD21?/low B cells). In this study, we sought to determine whether there was any correlation between CD21?/low B cells and clinical outcome in patients with established RA, either ACPA+/RF+ (n = 27) or ACPA?/RF? (n = 10). Healthy donors (n = 17) were included as controls. The proportion of the CD21?/low CD27?IgD? memory B cell subset in peripheral blood (PB) was significantly increased in ACPA+/RF+ RA patients compared with healthy donors, and the frequency of this subset correlated with joint destruction (r = 0.57, P < 0.04). The levels of the chemokines CXCL‐9 and CXCL‐10 were higher in synovial fluid than in plasma, and PB CD21?/low cells expressed the receptor, CXCR3. In synovial fluid, most of the B cells were CD21?/low, approximately 40% of that population was CD27?IgD?, and a third of those expressed the pro‐osteoclastogenic factor receptor activator of the nuclear factor κB ligand (RANKL). This subset also secreted RANKL, in addition to other factors such as IL‐6, even in the absence of stimulation. We interpret these data as reason to propose the hypothesis that the CD27?IgD? subset of CD21?/low B cells may mediate joint destruction in patients with ACPA+/RF+ RA.  相似文献   

2.
So far all studies on the murine ageing process have been conducted on virgin mice. Immune ageing may be influenced by sex hormone differences related to sex or pregnancies. The aim of this study was to investigate whether pregnancies and gender influence the cell changes observed during ageing in a peripheral lymphoid compartment of C57Bl/6 mice. Using flow cytometry, changes in (Thy1.2+) T cell, (B220+) B cell and (CD11b/Mac-1) macrophage spleen populations were monitored in 2, 8 (3 months after last pregnancy) 15 and 23-month-old mice including males, virgin and multiparous females. The development of naive (CDCD44low), memory (CD44high), activated/memory (MEL-14, CD62L) cells were investigated in CD4+ and CE8+ T cell subsets. Both short term (at 8 months) and long term (at 15 and 23 months) effects of multiparity were obvious in the lymphocyte/macrophage population changes associated with the ageing process. Short-term effects included delayed appearance of CD4+CD44high memory lymphocytes and increased numbers of both CD4+MEL-14low activated/memory cells and Mac-1+ macrophages when compared with virgin control mice. Later effects of multiparity were increased CD8αdull populations and increased T/B cell ratios and the ratio of memory to naive CD4+ cells (CD44+high/CD44+low). A sex effect was noticed: males exhibited lower Mac-1+ levels and memory/naive ratio in CD4+ subset than virgin females throughout life. These results suggest that gender and/or pregnancies affect the age-related distribution of lymphoid and macrophage cell populations in the spleen of C57Bl/6 mice.  相似文献   

3.
Activation of naive CD4+ T cells is essential for the induction of primary immune responses. However, this subset is less responsive to signaling via T cell receptor/CD3 (TcR/CD3) complex than memory CD4+ cells. For mitogenic activation of T cells, in addition to triggering of the TcR/CD3 complex, costimulatory signals are required that can be generated by surface structures present on the antigen-presenting cells. We investigated here whether differences in responsiveness to TcR/CD3 stimulation of naive and memory cells can be overcome by the costimulatory pathway B7/CD28. Using a B7-dependent system we show that even in the presence of optimal CD28 costimulation, CD4+ naive cells still have more stringent TcR/CD3 activation requirements than memory cells. Furthermore, titration of the B7 signal revealed that for activation of naive CD4+ cells a higher level of cross-linking of CD28 molecules is required than for memory cells. Thus, our results show that at least two signals are required for activation of both CD4+ memory and naive cells, but that for activation of naive cells higher cross-linking of both CD3 and CD28 molecules is necessary.  相似文献   

4.
The atypical chemokine receptor CXCR7 binds the chemokines CXCL12 and CXCL11. The receptor is widely expressed and was shown to tune CXCR12‐induced responses of CXCR4. Here, the function of CXCR7 was examined at late stages of human B‐cell maturation, when B cells differentiate into Ab‐secreting plasmablasts. We identified two populations of CXCR7+ cells in tonsillar lymphocytes, one being presumably memory B cells or early plasmablasts (FSClowCD19+CD38mid) and the other being plasmablasts or early plasma cells (FSChighCD19+CD38+). CXCR7 is expressed on CD19+CD27+ memory B cells, on CD19+CD38+CD138? and intracellular immunoglobulin high plasmablasts, but not on CD19+CD138+icIghigh plasma cells. The differential expression pattern suggests a potential contribution of the scavenger receptor in final B‐cell maturation. On in vitro differentiating B cells, we found a marked inverse correlation between CXCR7 and CXCR5 cell surface levels, whereas expression of CXCR4 remained almost constant. Migration assays performed with tonsillar mononuclear cells or in vitro differentiated cells revealed that inhibition of CXCR7 markedly increases chemotaxis toward CXCL12, especially at late stages of B‐cell maturation. Chemotaxis was attenuated in the presence of CXCR4 antagonists, confirming that migration is CXCR4 mediated. Our findings unequivocally demonstrate a novel role for CXCR7 in regulating the migration of plasmablasts during B‐cell maturation.  相似文献   

5.

Introduction

Selective deficiency IgA (IgAD) is the most common primary abnormality of immunoglobulin production with unknown pathophysiology. It is genetically related to common variable immunodeficiency (CVID), where besides IgA also IgG and frequently IgM serum levels are decreased. In this study we focused on determination of B-lymphocyte developmental stages and searching for similarities between CVID and IgAD.

Materials and Methods

Using flow cytometry we determined major lymphocyte subpopulations and B-lymphocyte subsets: na?ve (CD27-IgD+), marginal zone cells (CD27+IgD+), class-switched memory cells (CD27+IgD-), ??double-negative?? B cells (CD27-IgD-), transitional cells (IgM++CD38++), plasmablasts (CD38+++IgM+ or IgM-), and CD21lowCD38low cells in 80 patients with IgAD, 48 patients with CVID, and 80 control persons.

Results

Compared to healthy controls, a decrease in the absolute number and frequency of CD4+ cells (both?P?P?=?0.035) as well as plasmablasts (P?lowCD38low subset (P?=?0.007) was observed in IgAD patients compared to control persons. No significant differences were observed in the remaining B-cell developmental subsets. A decrease in CD27+IgD- (<0.4% of peripheral blood lymphocytes), frequently observed in CVID patients and also previously reported in IgAD, was found in only five patients (6%) with IgAD, two of them being first-degree relatives of CVID patients.

Conclusion

Our results show a decrease of terminally differentiated B-lymphocyte subsets in patients with IgAD, similar as previously found in patients with CVID, but these results are less expressed than in CVID patients.  相似文献   

6.
CD27, which belongs to the tumor necrosis-factor receptor family, is expressed on germinal center (GC) but not on naive B cells, suggesting an important function of this molecule in the regulation of the GC reaction. We described here the expression of CD70, which is the ligand for CD27. We observed that in most tonsils, CD70 is only expressed on part of the IgD?, CD38? B cell population, which have been described as memory B cells. However, in 10 % of the tonsils tested, CD70+ IgD+ GC were found. The CD70+ GC B cells were small cells that also expressed CD44 and CD39, but were CD10? and CD38?, suggesting that they represent very recent immigrants that are in the process of forming a GC. The concordant expression of CD27 and its ligand CD70 on this primordial subset of GC B cells suggests an important role for CD27/CD70 interaction at this stage of GC formation.  相似文献   

7.
We have shown that human CD20+25+ B cells display immunomodulatory properties. The aim of this study was to investigate if CD25+ B cells are found within the CD27 memory B cell population, and to analyse pattern of their cytokine production. B cells isolated from healthy subjects, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients were analysed regarding the frequency of CD25+ B cells within certain B cell subsets. Purified CD25+ B cells from healthy subject were used in vitro to evaluate their production of immunomodulatory cytokines. In healthy subjects the majority (60%) of memory B cells (CD20+27+) also co‐expressed CD25 while only 10–20% of the naïve B cells (CD20+27) and plasmablasts (CD20–27+) expressed CD25. In RA and SLE patients, we found that 51% and 48%, respectively, co‐expressed CD25 in the memory population, whereas only 11% and 9% co‐expressed CD25 in the naïve B cell population. Phenotypic analysis of the CD20+25+27+ and CD20+25+27 cells using CD10, CD24, CD38, CD45, CD71, CD80, CD86, CD95, CD138, BAFF‐R, TACI, IgA, IgD, IgG and IgM showed that CD20+25+27+ B cells preferentially represent highly activated, Ig class switched memory B cells. Cytokine profile analysis showed that CD25+ B cells secreted significantly higher levels of IL‐10 versus CD25 B cells. In contrast, TGF‐β1 secretion was similar between the CD25+ and CD25 sub‐populations. In conclusion, CD20+25+ B cells constitute a unique subpopulation preferentially occurring among CD20+27+ memory B cells. We suggest that CD25 can be used as a marker for a memory B cell subset.  相似文献   

8.
An antibody reactive with CD38 revealed both phenotypic and functional heterogeneity amongst CD45RBlow cells. Functional analysis of the CD38+ and CD38 fractions showed that the latter contained T cells which responded to recall antigens and produced high levels of cytokine in response to polyclonal stimulation. In contrast, the CD38+ population failed to proliferate or to produce detectable levels of cytokines. Despite appearing unresponsive, the CD38+ population significantly inhibited anti-CD3-induced proliferation and cytokine secretion by the reciprocal CD38 population. Immune suppression required stimulation through the TCR and was dependent on a physical interaction between regulatory and responding CD4+ populations. It did not involve killing of the responding T cells or secretion of IL-10 or TGF-β. Despite some similarities there is no direct correlation between the in vitro suppression characteristic of the CD38+ CD45RBlow subset and in vivo suppression which has been shown to be mediated by unseparated CD45RBlow CD4+ T cells. However, these results demonstrate that two functionally distinct subsets of T cells reside within the antigen-exposed or CD45RBlow CD4+ T cell population and are thus generated in vivo: (1) conventional memory T cells which proliferate and secrete cytokines in response to activation and (2) a population of regulatory T cells which inhibit T cell activation in vitro. Antibodies reactive with CD38 may provide a useful tool with which to study the role of these T cell subsets in the induction and regulation of the immune response.  相似文献   

9.
10.
11.
Mixed connective tissue disease (MCTD) is a systemic autoimmune disorder, characterized by the presence of antibodies to U1-RNP protein. We aimed to determine phenotypic abnormalities of peripheral B cell subsets in MCTD. Blood samples were obtained from 46 MCTD patients, and 20 controls. Using anti-CD19, anti-CD27, anti-IgD and anti-CD38 monoclonal antibodies, the following B cell subsets were identified by flow cytometry: (1) transitional B cells (CD19 + CD27-IgD + CD38high); (2) naive B cells (CD19 + CD27-IgD + CD38low); (3) non-switched memory B cells (CD19 + CD27 + IgD+); (4) switched memory B cells (CD19 + CD27 + IgD-); (5) double negative (DN) memory B cells (CD19 + CD27-IgD-) and (6) plasma cells (CD19 + CD27highIgD-). The proportion of transitional B cells, naive B cells and DN B lymphocytes was higher in MCTD than in controls. The DN B cells were positive for CD95 surface marker. This memory B cells population showed a close correlation with disease activity. The number of plasma cells was also increased, and there was an association between the number of plasma cells and the anti-U1RNP levels. Cyclophosphamide, methotrexate, and corticosteroid treatment decreased the number of DN and CD27high B cells. In conclusion, several abnormalities were found in the peripheral B-cell subsets in MCTD, which reinforces the role of derailed humoral autoimmune processes in the pathogenesis.  相似文献   

12.
Acute respiratory distress syndrome (ARDS) is a rapid onset life-threatening condition involving uncontrolled propagation of inflammatory responses. Here, we observed that ARDS patients that survived presented significantly higher frequencies of TIM-1+ B cells, especially the CD27+TIM-1+ B cells, than the ARDS patients who succumbed to the condition. We then found that using BCR/CD40 antigen-dependent stimulation or Staphylococcus aureus Cowan (SAC) antigen-independent stimulation, TIM-1+ B cells presented significantly higher IL-10 secretion and/or TGF-β1 secretion, with SAC stimulation being more effective. CD4+ T cells that incubated with TIM-1+ B cells presented significantly elevated IL-10 secretion, TGF-β1 secretion, and Foxp3 expression, than CD4+ T cells that incubated with TIM-1? B cells, suggesting TIM-1+ B cells promoted the in vitro development of Foxp3+ Treg cells. Interestingly, this TIM-1+ B cell-mediated promotion of Foxp3 expression was mostly dependent on TGF-β1 but not IL-10, since neutralization of TGF-β1, but not IL-10, resulted in the suppression of Foxp3 expression. We further showed that in TIM-1+ B cells, the CD27+ classical memory B cell subset demonstrated more regulatory potency than the CD27? subset. Together, our results suggested that the TIM-1+ B cells, especially those that expressed CD27, could promote Foxp3 expression. Their clinical efficacy in treating ARDS should be examined in in vivo experiments.  相似文献   

13.
Vertical transmission of human immunodeficiency virus (HIV) represents an important world-wide health problem although the incidence in developed countries has been drastically reduced by the extensive use of highly active antiretroviral therapy. Vertically HIV-infected subjects have been exposed to the virus during the maturation of their immune systems and have suffered a persistent chronic activation throughout their lifetime; the consequences of this situation for their immune system are not fully understood. The objective of this study was to analyse immunosenescence-related parameters in different CD4 T-cell subsets. Fifty-seven vertically HIV-infected subjects and 32 age-matched healthy subjects were studied. Activation (HLA DR+), senescence (CD28 CD57+) and proliferation (Ki67+) were analysed on different CD4 T-cell subsets: naive (CD45RA+ CD27+), memory (CD45RO+ CD27+), effector memory (CD45RO+ CD27) and effector memory RA (CD45RA+ CD27). Compared with healthy subjects, vertically HIV-infected subjects showed increased naive and memory CD4 T-cell frequencies (p 0.035 and p 0.010, respectively) but similar frequencies of both effector subsets. Whereas naive CD4 T cells were not further altered, memory CD4 T cells presented increased levels of senescence and proliferation markers (p <0.001), effector memory CD4 T cells presented increased levels of activation, senescence and proliferation markers (p <0.001) and effector memory RA CD4 T cells presented increased levels of activation and senescence (p <0.001) compared with healthy subjects. Despite long periods of infection, vertically HIV-infected subjects show specific patterns of immunosenescence, revealing a preserved CD4 T-cell homeostasis for subset differentiation and distribution. Nevertheless, excepting the naive subpopulation, all subsets experienced some immunosenescence, pointing to uncertain consequences of the future aging process in these subjects.  相似文献   

14.
Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinaemia and recurrent infections. Although the underlying cause is unknown, B cells from most CVID patients fail to differentiate to memory or plasma cells. We investigated if increased apoptosis could influence the fate of B cells. For this purpose we activated purified B lymphocytes of CVID patients with a surrogate T‐dependent (anti‐CD40) or T‐independent [cytosine–phosphate–guanosine oligodeoxynucleotides (CpG‐ODN) or anti‐immunoglobulin (Ig)M)] stimulus with or without interleukin (IL)‐21. We found that CD27+ B cells were more sensitive than CD27 B cells to spontaneous apoptosis and less sensitive to rescue from apoptosis. The addition of IL‐21 down‐modulated the protective effect of all the stimuli on CD27 B cells and the protective effect of CpG‐ODN and anti‐IgM on CD27+ B cells. In contrast, IL‐21 rescued unstimulated CD27 B cells and improved the rescue of anti‐CD40‐stimulated CD27+ B cells. When we compared patients and controls, mainly CD27+ B cells from MB0 patients were less sensitive to rescue from apoptosis than those from MB1 patients and controls after activation, irrespective of the IL‐21 effect. Increased apoptosis during an immune response could result in lower levels of immunoglobulin production in these patients.  相似文献   

15.
The composition of the peripheral blood lymphocyte compartment underlies developmental changes during ontogeny. Recently, several new B cell populations have been characterized which were suggested to develop in an age‐dependent manner. However, age‐dependent reference values for distinct B cell populations have rarely been reported. Therefore, we have characterized developmental changes in peripheral B cell populations from infancy to adulthood in order to define age‐dependent reference values. Using a flow cytometric approach we analysed the frequencies as well as the absolute counts of naive, switched and non‐switched memory B cells, CD27‐negative memory B cells, transitional B cells as well as CD21lowCD38low B cells from neonates up to the age of 50 years. Most of the B cell subsets showed age‐dependent developmental changes: while the peripheral B cell pool during infancy is characterized predominantly by transitional and naive B cells, the fraction of switched and non‐switched memory B cells increases gradually with age. CD21lowCD38low B cells as well as plasmablasts do not exhibit developmental changes. In summary, we could demonstrate particular changes in the peripheral blood B cell compartment during ontogeny. This study provides reference values of different B cell subpopulations offering comparability for studies addressing disturbed peripheral B cell development in immunodeficiency, autoimmunity or B cell reconstitution following cell‐depleting therapies.  相似文献   

16.
Vaccination with antigen‐pulsed CD40‐activated B (CD40‐B) cells can efficiently lead to the in vivo differentiation of naive CD8+ T cells into fully functional effectors. In contrast to bone marrow‐derived dendritic cell (BMDC) vaccination, CD40‐B cell priming does not allow for memory CD8+ T‐cell generation but the reason for this deficiency is unknown. Here, we show that compared to BMDCs, murine CD40‐B cells induce lower expression of several genes regulated by T‐cell receptor signaling, costimulation, and inflammation (signals 1–3) in mouse T cells. The reduced provision of signals 1 and 2 by CD40‐B cells can be explained by a reduction in the quality and duration of the interactions with naive CD8+ T cells as compared to BMDCs. Furthermore, CD40‐B cells produce less inflammatory mediators, such as IL‐12 and type I interferon, and increasing inflammation by coadministration of polyriboinosinic‐polyribocytidylic acid with CD40‐B‐cell immunization allowed for the generation of long‐lived and functional CD8+ memory T cells. In conclusion, it is possible to manipulate CD40‐B‐cell vaccination to promote the formation of long‐lived functional CD8+ memory T cells, a key step before translating the use of CD40‐B cells for therapeutic vaccination.  相似文献   

17.
Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by exocrine gland dysfunction, mainly causing sicca symptoms. B cells have a prominent role in SS, and the T follicular helper (TFH) cells provide B cells with survival and specialization signals in germinal centres. Here, we investigate peripheral TFH cells in pSS. Sixteen pSS patients and healthy controls were enrolled in the study, with 13 women and 3 men in each group. Whole blood was collected and separated into PBMC and plasma, followed by cryopreservation. Plasma samples were analysed for Ro52, Ro60 and La48 autoantibodies by indirect ELISA. For flow cytometric analysis, we defined 4 subsets of TFH‐like cells within the CD3+CD4+CXCR5+ population, namely the ICOSPD‐1, ICOSPD‐1+, ICOS+PD‐1 and ICOS+PD‐1+ (“TFH”) cells. We also investigated 4 CD19+ B cell subsets, the CD20+CD27+CD38 memory B cells, CD20+CD27+CD38+ memory B cells, CD20CD27+CD38++CD138 plasmablasts and CD20CD27+CD38++CD138+ plasma cells. We observed higher fractions of ICOS+PD‐1 cells, ICOS+PD‐1+ (“TFH”) cells and plasmablasts in pSS patients compared to controls, and lower frequencies of both types of memory B cells. The number of TFH cells correlated positively with the levels of plasmablasts and plasma cells in the pSS patients, but not in the controls. The pSS patients were stratified according to Ro52/Ro60/La48 serology, and a positive association was found between autoantibody levels and increased level of TFH cells, plasmablasts and plasma cells and lowered levels of memory B cells. We observed a higher response to Ro/La stimulation in pSS patients compared to controls of the memory B cells, although only significantly for the CD38 memory B cells. Overall, a pathological relation between the ICOS+ T follicular‐like helper cells and B cells in pSS was observed, but further work should be conducted to explore their overall impact upon disease progression.  相似文献   

18.
Activation of naive CD8+ T cells in the presence of interleukin‐4 modulates their CD8 co‐receptor expression and functional differentiation, resulting in the generation of CD8low cells that produce type 2 cytokines and display poor cytolytic and anti‐tumour activity. Although this CD8low phenotype becomes stable after about a week and can persist with further stimulation in vitro, it is not known whether it can be maintained long term in vivo. Here we report that CD8low cells derived from oval‐bumin257–264‐specific T‐cell receptor‐transgenic CD8+ T cells activated in the presence of interleukin‐4 could be detected in the spleen for at least 4 months after adoptive transfer into normal mice. A significant proportion of the long‐term surviving cells retained their CD8low phenotype in vivo and after clonal re‐activation in vitro. Although long‐term surviving CD8low cells lacked detectable cytolytic activity or perforin expression, they showed some anti‐tumour function in vivo. The persistence of functional cells with a CD8low phenotype in vivo raises the possibility that such cells can contribute to effector or regulatory responses to tumours or pathogens.  相似文献   

19.
In DNA vaccines, the gene of interest is cloned into a bacterial plasmid that is engineered to induce protein production for long periods in eukaryotic cells. Previous research has shown that the intramuscular immunization of BALB/c mice with a naked plasmid DNA fragment encoding the Mycobacterium leprae 65-kDa heat-shock protein (pcDNA3-Hsp65) induces protection against M. tuberculosis challenge. A key stage in the protective immune response after immunization is the generation of memory T cells. Previously, we have shown that B cells capture plasmid DNA-Hsp65 and thereby modulate the formation of CD8+ memory T cells after M. tuberculosis challenge in mice. Therefore, clarifying how B cells act as part of the protective immune response after DNA immunization is important for the development of more-effective vaccines. The aim of this study was to investigate the mechanisms by which B cells modulate memory T cells after DNA-Hsp65 immunization. C57BL/6 and BKO mice were injected three times, at 15-day intervals, with 100 µg naked pcDNA-Hsp65 per mouse. Thirty days after immunization, the percentages of effector memory T (TEM) cells (CD4+ and CD8+/CD44high/CD62Llow) and memory CD8+ T cells (CD8+/CD44high/CD62Llow/CD127+) were measured with flow cytometry. Interferon γ, interleukin 12 (IL-12), and IL-10 mRNAs were also quantified in whole spleen cells and purified B cells (CD43) with real-time qPCR. Our data suggest that a B-cell subpopulation expressing IL-10 downregulated proinflammatory cytokine expression in the spleen, increasing the survival of CD4+ TEM cells and CD8+ TEM/CD127+ cells.  相似文献   

20.
Toll‐like receptors (TLRs) recognize specific pathogen‐associated molecular patterns (PAMPs), which subsequently trigger innate immunity. Recent data also suggest a role for TLRs in the direct activation of adaptive immune cells. In the present study, the expression and function of TLR1–TLR10 were characterized in purified human tonsillar B cells, focusing on differences among CD19+ CD38 CD27 (naïve B cells), CD19+ IgD CD27[germinal centre (GC) B cells] and CD19+ CD38 CD27+ (memory B cells) cells. The study was also designed to compare the TLR expression in B cells obtained from infected and hyperplastic tonsils that served as controls. The results demonstrated a distinct repertoire of TLRs, in which TLR1, TLR2, TLR7, TLR9 and TLR10 predominated. No differences were found among naïve, GC and memory B cells. Tonsillar infection did not substantially alter the TLR expression profile in ex vivo‐isolated B‐cell subsets. Purified CD19+ B cells stimulated with Pam3CSK4, R‐837 and CpG oligodeoxynucleotide (ODN) 2006, via TLR1/TLR2, TLR7 and TLR9, respectively, showed an induction of interleukin‐6 secretion and an up‐regulated expression of human leucocyte antigen (HLA)‐DR. Collectively, the present study demonstrates that B cells exhibit constitutively high levels of specific TLRs, which are not developmentally regulated during the B‐cell differentiation process. Ongoing microbial infections, such as chronic tonsillitis, do not appear to affect the TLR profile in B cells. Furthermore, the distinct expression of TLRs allows B cells to respond directly to the cognate PAMPs. This further emphasizes the role of TLRs in directly activating adaptive immune cells.  相似文献   

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