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Chronic infantile neurological cutaneous articular syndrome: CD10 over-expression in neutrophils is a possible key to the pathogenesis of the disease.

UNLABELLED: Chronic, Infantile, Neurological, Cutaneous and Articular Syndrome (CINCA) or Neonatal/Infantile Onset Multisystem Inflammatory Disease (NOMID/IOMID) is a rare, multisystem inflammatory disease characterised by neonatal onset of urticarial symptoms, persistent rash, ocular inflammatory lesions, progressive articular and neurological involvement and associated with characteristic overgrowth of the ossification nucleus of the patella. The tissues involved are extensively infiltrated by inflammatory cells, mostly neutrophils. This paper describes the clinical features of three new cases as well as a study of activation markers in neutrophils and search for mutations of the CIAS1gene in these patients. Clinical records of three cases of CINCA are reported. For genetic analysis, exon 3 of the CIAS1gene was amplified and sequenced. Immunophenotype, oxidative burst and phagocytosis were analysed in neutrophils obtained from all the three CINCA patients as well as from eight juvenile idiopathic arthritis (JIA) patients and eight healthy controls. Functional assays in neutrophils were normal in all three patients with CINCA syndrome and did not differ from those of JIA patients and healthy controls. The surface density of CD10 was significantly higher on neutrophils from CINCA patients as compared to those of JIA and controls (P<0.0005). In one subject a new missense mutation in the CIAS1gene was identified. CONCLUSION: the hyper expression of the activation antigen CD10/NEP in neutrophils from these three cases of CINCA, as compared to JIA patients and healthy controls, irrespective of the presence of mutations in CIAS1, could be a marker of the inflammatory disorder typical of some patients with CINCA syndrome.

Adolescent↗

Measurement of the growth parameters of precursor B-acute lymphoblastic leukaemic cells in co-culture with bone marrow stromal cells; detection of two cd10 positive populations with different proliferative capacities and survival.

A new assay system using the fluorescent probe PKH 26 GL was employed to investigate the regulation of precursor B-cell acute lymphoblastic leukaemic (ALL) cell growth. PKH 26 GL is a lipophilic fluorescent probe which becomes incorporated into the plasma membrane upon the staining of cells. As the amount of probe per cell reduces at each cell division, the fluorescence can be used to measure cell proliferation. Bone marrow derived ALL cells from seven newly diagnosed cases were stained with PKH 26 GL, and cultured for 14 days in control cultures without stimulus, or in cultures with preformed human bone marrow stromal cell layers. Viable leukaemic cells from these cultures were identified on the basis of forward light scatter, 90 degrees light scatter, propidium iodide exclusion, PKH 26 GL staining and CD10 expression by flow cytometry at the beginning of the culture period and on days 2, 6, 10 and 14. The growth parameters of these leukaemic cells were determined by analysis of their pattern of PKH 26 GL fluorescence. A higher rate of proliferation and survival of cells was observed in cultures with stromal cells compared with control cultures, without stromal cells. In the presence of stromal cells, survival and proliferation continued throughout the culture period; in contrast in five of seven control cultures no viable cells could be detected after 6-10 days. Interestingly, two populations of leukaemic cells were distinguished on the basis of their different rates of proliferation, when co-cultured with stromal cells. The results indicate that this technique provides a means for studying and quantitating leukaemic cell growth within a complex stroma-dependent system.

Acute Disease↗

Expression of the human homologue of rat NG2 in adult acute lymphoblastic leukemia: close association with MLL rearrangement and a CD10(-)/CD24(-)/CD65s(+)/CD15(+) B-cell phenotype.

The expression of the chondroitin sulfate proteoglycan neuron-glial antigen 2 (NG2) has been demonstrated in association with rearrangement of the mixed lineage leukemia (MLL) gene in acute leukemia, but the frequency of NG2 expression in adult acute lymphoblastic leukemia (ALL) is yet unknown. We evaluated NG2 expression in 313 adult ALL patients by flow cytometry and simultaneously determined MLL rearrangement in 120 adult patients out of them with B-precursor ALL by reverse transcription-polymerase chain reaction and fluorescence in situ hybridization. A total of 57% of pro-B ALL, 2% of common ALL and 20% of pre-B ALL were NG2 positive, but NG2 was absent in T-ALL and mature B-ALL. In B-precursor ALL, NG2 expression was significantly associated with a CD10(-)/CD34(-)/CD24(-)/CD65s(+)/CD15(+)/CD13(-)/CD33(-) phenotype and showed a sensitivity, specificity and positive predictive value of 0.89, 0.89, and 0.93 for MLL rearrangement, respectively. NG2 was positive in three patients without detectable MLL rearrangement and negative in eight patients with MLL-AF4 transcripts. However, NG2 predicted with a 100% accuracy MLL rearrangement among patients disclosing a CD65s(+) and/or CD15(+) immunophenotype. In summary, NG2 adds to a more precise identification of high-risk adult ALL and should therefore be included into diagnostic marker panels. As NG2 is negative in non-malignant hematopoietic cells, this novel antigen might also serve in future studies as a powerful marker in monitoring minimal residual disease.

Adolescent↗

Coexpression of Bcl-6 and CD10 in diffuse large B-cell lymphomas: significance of Bcl-6 expression patterns in identifying germinal center B-cell lymphoma.

Most follicular lymphomas (FLs) transform to diffuse lymphoma eventually, comprising a significant proportion of diffuse large B-cell lymphoma (DLBCL). Judging by bcl-2 rearrangement (bcl-2R), one third of DLBCLs are believed to be of FL derivation in the Western population. However, bcl-2R is not specific and is not detectable in every case of FL. In East Asia, FL is uncommon but DLBCL is not. The proportion of tumors of FL origin in DLBCL is not known in this region. The coexpression of Bcl-6 and CD10 proteins, a reliable marker to identify germinal center (GC) B-cell lymphoma including FL, was analyzed in primary nodal DLBCLs (n = 104) diagnosed at major hospitals in Seoul during a recent 2-year period, along with well-defined cases (n = 17) of nodal FL as controls. Bcl-2 protein expression (n = 77) was also studied along with bcl-2R (n = 64), by polymerase chain reaction. Formalin-fixed archival specimens were used in all these assays. The Bcl-6/CD10 coexpression was observed in 35 DLBCLs (34%) and 14 FLs (82%), and most of them showed a pattern of Bcl-6 expression similar to that of the GC. Bcl-2 expression or bcl-2R did not correlate with Bcl-6/CD10 coexpression. Histologically, compartmentalizing sclerosis was associated with a high rate of the coexpression (8 of 10). In conclusion, to detect GC B-cell lymphoma in routine biopsy specimens, a pattern of Bcl-6 staining similar to the GC must be identified. Bcl-6+/CD10+ GC B-cell lymphomas thus defined comprised one third of primary nodal DLBCLs in Korea. The incidence rate is similar to that in the West. The reasons for the discrepancy between the incidence of GC B-cell lymphoma and the paucity of the follicular pattern in East Asian subjects warrant further studies.

Adolescent↗

Significance of increased proportion of CD10-positive cells in nonmalignant bone marrows of children.

An immunophenotypic pattern characterized by increased proportions of CD10, CD19, and HLA-DR+ cells is observed in the bone marrow of some children with nonmalignant hematologic diagnoses. The purpose of this study was to ascertain the clinical and pathologic significance of this immunophenotype. The morphologic and immunophenotypic results of bone marrow specimens from 23 children with nonmalignant hematologic conditions are presented. In 11 children, an increased percentage of immature B-cell precursors was observed, suggesting the presence of B-lineage malignancy. None of the children have developed malignant lymphoproliferative disease in as long as 4 years of follow-up, despite the demonstration of a clonal lymphocyte proliferation in one patient. Although the biologic significance of the bone marrow immunophenotype is not yet understood, it is important to recognize that this lymphocyte pattern occurs commonly in children with nonmalignant hematologic conditions, and may reflect an increase in normally occurring lymphoid precursor cells.

Antigens, CD↗

Multiple myeloma: the relationship between CALLA (CD10) positive lymphocytes in the peripheral blood and light chain isotype suppression.

This study describes the presence of small numbers of common acute lymphocytic leukaemia antigen (CALLA, CD10)-positive lymphocytes in the peripheral blood of patients with multiple myeloma. A significant correlation (0.001 less than P less than 0.01) was found between the lack of light chain isotype suppression (LCIS), which is characteristic of progressive myeloma, and the presence of CALLA-positive lymphocytes. Sixty patients with multiple myeloma, four with benign monoclonal gammopathy (BMG) and seven with solitary plasmacytoma (SP) were monitored in this study. Nineteen of the patients with multiple myeloma demonstrated LCIS, of which only three were found to have CALLA-positive lymphocytes. Of the 41 patients with multiple myeloma who did not have LCIS, 20 (49%) had CALLA-bearing lymphocytes. None of the patients with BMG or SP demonstrated LCIS or were found to have CALLA-bearing lymphocytes in their blood. Forty-four of the patients with multiple myeloma were also monitored for serum beta-2-microglobulin (SB2M levels. There was no correlation between the SB2M and either LCIS or CALLA-positivity. Detection of CALLA-positive lymphocytes in the blood of patients with multiple myeloma may be an early marker of the onset of progressive disease. The correlation of CALLA expression on lymphocytes with lack of LCIS provides further evidence for the operation of immunoregulatory systems in these patients.

Antigens, Neoplasm↗

Serum levels of inflammatory cytokines at diagnosis correlate to the bcl-6 and CD10 defined germinal centre (GC) phenotype and bcl-2 expression in patients with diffuse large B-cell lymphoma.

Circulating inflammatory cytokines have a prognostic impact independent of the information provided by the International Prognostic Index (IPI) in diffuse large B-cell lymphoma (DLBCL). The present study characterized prognostic cytokines in relation to stage-specific B-cell differentiation antigens and bcl-2 protein expression, assessed by immunohistochemistry in de novo DLBCL. Serum levels of interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) were found to be significantly lower in patients with a germinal centre (GC) phenotype (co-expression of bcl-6 and CD10) compared with the non-GC phenotype. IL-6 and TNF-alpha levels were significantly elevated in patients expressing bcl-2 protein. Serum levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were not associated with the GC phenotype. On the contrary, both VEGF and bFGF were strongly correlated to bcl-2 expression. In survival analysis, IPI score remained the most important independent prognostic factor. However, IL-6 and VEGF, combined with non-GC phenotype and bcl-2 positivity, respectively, had a similar independent prognostic power as the IPI. In conclusion, our data suggest that inflammatory cytokines are differently distributed in the GC and non-GC phenotypes and correlate to bcl-2 expression. Combining these biomarkers may add to the prognostic information given by clinical variables in the IPI alone.

Adult↗

Flow cytometric technique for determination of prostasomal quantity, size and expression of CD10, CD13, CD26 and CD59 in human seminal plasma.

Summary Prostasomes are prostate-derived organelles in seminal plasma exhibiting pluripotent properties to facilitate the fertilization process. Seminal prostasome concentration, size distribution and expression of the prostasomal surface antigens CD10, CD13, CD26 and CD59 were examined by flow cytometry. The study group consisted of 79 men with involuntary infertility. Very strong correlations existed between the prostasome expressions of the different CD markers. Significant correlations between prostasome concentration and CD molecules were weak or lacking. Further, no or weak relationships were observed between the prostasomal CD markers and sperm morphology, seminal fructose, neutral alpha-glucosidase activity, zinc and tumour necrosis factor alpha concentrations. Flow cytometry is a practical way to study prostasomes in seminal fluid without prior separation. This is a new technique for evaluation of the role of prostasomes and their functions in male reproductive physiology.

CD13 Antigens↗

Re-evaluation of mucin phenotypes of gastric minute well-differentiated-type adenocarcinomas using a series of HGM, MUC5AC, MUC6, M-GGMC, MUC2 and CD10 stains.

We examined which, and how many, mucin markers are necessary to define the phenotypes of gastric cancers, and re-evaluated the incidence of their mucin phenotypes and whether minute gastric carcinomas arise as unclassified type. Well-differentiated-type minute gastric carcinomas (n = 33) measuring 0%, and was 33%, 33%, 3%, 30%, and 0%, respectively, when the percentage of positive mucin phenotype was set at >or=10%. Thus, a panel of MUC5AC (or HGM), MUC6, MUC2 and CD10 stains is indispensable for accurately determining the mucin phenotypes of gastric carcinomas, and the above-mentioned classification is important for studying changes in the histological types of well-differentiated-type adenocarcinomas during change to the poorly differentiated type, as well as corresponding genetic abnormalities.

Adenocarcinoma↗

Expression of endopeptidase-24.11 (common acute lymphoblastic leukaemia antigen CD10) in the sciatic nerve of the adult rat after lesion and during regeneration.

Endopeptidase-24.11, which is identical with the common acute lymphoblastic leukaemia antigen CD10 (CALLA), is a cell surface Zn2+ metalloprotease that regulates peptide-induced responses in different tissues, including the nervous and immune systems. In the peripheral nervous system, high levels of the enzyme are present in all neonatal and early postnatal Schwann cells, while as myelination proceeds it is gradually suppressed in the majority of cells that form myelin but retained in non-myelin-forming cells in the adult animal. In the present study we have investigated the effects of transection, crush and regeneration of the adult rat sciatic nerve on the expression of the endopeptidase by Schwann cells in situ. Endopeptidase-24.11 was monitored by immunocytochemistry using the monoclonal anti-endopeptidase antibody 23B11. For comparison, a parallel study was carried out with a monoclonal antibody directed against the rat nerve growth factor receptor. We found that (i) all Schwann cells of the distal segment re-expressed endopeptidase-24.11 as early as 4 days after axotomy, the level of immunostaining reaching a maximum after 2 weeks, (ii) axonal regeneration repressed Schwann cell expression of endopeptidase-24.11, and (iii) the induction of the nerve growth factor receptor followed a similar pattern to that of endopeptidase-24.11 in the transected and crushed nerve. Enzymatic amplification of endopeptidase-24.11 cDNA from normal and axotomized adult rat sciatic nerve confirmed the expression of endopeptidase-24.11 in these tissues. Our results show that the expression of endopeptidase-24.11 in Schwann cells, as is the case with the nerve growth factor receptor, is induced by the loss of the normal axon-Schwann cell contact. The significant increase in the expression of endopeptidase-24.11 by Schwann cells after axonal damage suggests that the enzyme could play a role in axonal regeneration.

Animals↗

Different reactivity of monoclonal antibodies against common acute lymphoblastic leukaemia antigen (CD10).

The reactivity of five monoclonal antibodies J5, OKB-cALLA, Nu-N1, Nu-N2 and VIL-A1 against the common acute lymphoblastic leukaemia (common-ALL) antigen (glycoprotein 100, CD10); was investigated by indirect immunofluorescence in cell suspensions, and by immunoperoxidase in cytocentrifuge slides of ALL, chronic B cell lymphoproliferative disorders, and plasma cell dyscrasias. The five monoclonal antibodies gave similar positive results with both techniques only in samples of ALL. J5 was positive in variable degrees by immunofluorescence in the majority of B cell disorders examined but this was not confirmed by immunoperoxidase. OKB-cALLA reacted in a similar way to J5 in both techniques, although with a lower percentage of cells by immunofluorescence. Nu-N1, Nu-N2, and VIL-A1 were mainly negative when tested by both immunofluorescence and immunoperoxidase in B cell disorders other than ALL and therefore seemed to be more specific for the diagnosis of common-ALL.

Antibodies, Monoclonal↗

Transient erythroblastopenia of childhood with CD10, TdT, and cytoplasmic mu lymphocyte positivity in bone marrow.

Over three years, three children presented with anaemia, reticulocytopenia, and marrow erythroblastopenia. A pronounced lymphocytosis was also evident in two of the marrow aspirates, with increased numbers of cells bearing the immunophenotype TdT+, CD10+ HLA DR+, and cytoplasmic mu +, and reported to be compatible with acute lymphoblastic leukaemia (ALL). The clinical course of the illness was fully compatible with transient erythroblastopenia of childhood (TEC), and all three children remained well one to four years after initial presentation. It is concluded that increased numbers of lymphoid cells with a common or pre-B ALL phenotype may be found in bone marrow aspirates of children with TEC, and should not be misdiagnosed as acute leukaemia.

Anemia↗

Primary CD20+CD10+CD8+ T-cell lymphoma of the skin with IgH and TCR beta gene rearrangement.

Most cutaneous T-cell lymphomas are derived from mature postthymic T cells of the CD4 subtype. When other less common profiles are encountered, a diagnostic challenge is posed. Accurate categorization is critical because of the specificity of therapeutic regimens, including biologics. A 65-year-old woman was seen in 2001 because of a thigh mass manifesting an unusual phenotype eventually categorized as a mature postthymic CD8+ T-cell lymphoma with CD10 and weak CD20 expression. Molecular studies revealed T-cell receptor and heavy chain immunoglobulin rearrangement. Her cutaneous disease progressed despite several cycles of chemotherapy and radiation therapy. However, a therapeutic trial with denileukin diftitox resulted in a striking response. The importance of this case lies in the novel phenotype and dual T- and B-cell rearrangements. Rather than representing an aberrant phenotype, this tumor may represent the malignant counterpart of a benign population of weakly CD20+ T cells of the CD8 subset.

Aged↗

[CD5+ CD10+ extranodal B-cell lymphoma with tetraploid chromosomal abnormality].

An 84-year-old man was admitted with pleural lymphomatous effusion and bone marrow infiltration. The abnormal cells from the effusion showed abundant basophilic cytoplasm, large atypical nuclei, and small nucleoli with frequent mitosis. The abnormal cells were found to be CD5+, CD10+, CD19+, and CD20+ by flow cytometry, and had clonal rearrangements of the IgH-JH gene, indicating the existence of a clonal B-cell population. No bcl-1, bcl-2, bcl-6, or c-myc rearrangement was found. Neither human herpesvirus 8 (HHV-8) nor Epstein-Barr virus was detected in the abnormal cells. Tetraploid chromosomal abnormality was present. After administration of prednisolone, transient disappearance of the effusion was obtained.

Aged↗

[CD10(CALLA)-negative acute lymphoblastic leukemia. A group with a bad prognosis].

The results of 188 patients with acute lymphoblastic leukemia, studied between 1985 and 1990, showed that 8 cases were CD10 negative, Dr, and CD19 positive. These findings indicate cell dedifferentiation and poor prognosis. The patients age ranged from 2 to 30 years, with a mean of 11 years. The male/female ratio was 5/3. Lymph node enlargement and splenomegaly were found in the 8 patients. With the exception of one patient in whom leucopenia was present, the white cell counts were always higher than 30,000/dl. The karyotype was studied in four cases, and all of them were hyperdiploid. This is the first report in Venezuela of cases with acute lymphoblastic leukemia - CD 10 negative.

Adolescent↗

Murine common acute lymphoblastic leukemia antigen (CD10 neutral endopeptidase 24.11). Molecular characterization, chromosomal localization, and modeling of the active site.

To further analyze CD10/NEP function in lymphoid and nonlymphoid cells using well characterized murine systems, we isolated the murine CD10/NEP homologue, determined its chromosomal location, and modeled the enzyme's active site. The murine CD10/NEP cDNA predicts a 750-amino acid (aa) type II integral membrane protein with 90% identity to the human CD10 sequence and 100% conservation of critical aa and functional motifs. The latter include the pentapeptide consensus sequence required for zinc binding and catalytic activity, additional aa associated with substrate binding, and the extracellular cysteines that participate in disulfide bonds required for enzymatic activity. Like its human homologue, murine CD10/NEP has multiple alternative 5'-untranslated region sequences. The gene is localized on the proximal half of murine chromosome 3. In Northern analysis, murine CD10/NEP transcripts are abundant in bone marrow stromal cells that support pre-B cell differentiation but are undetectable in representative Abelson transformed pre-B cell lines. The murine CD10/NEP active site was modeled by aligning critical conserved CD10/NEP residues with comparable residues in the active site of thermolysin, a bacterial metalloprotease with similar substrate specificity. The model predicts that the two enzymes have similar clefts that comprise the active site and permit zinc-dependent substrate interactions.

Amino Acid Sequence↗

Receptor-mediated down-regulation of neutral endopeptidase (NEP; EC 3.4.24.11; CD10) on immature B lymphocytes by dexamethasone.

Neutral endopeptidase is a membrane bound enzyme with various functions depending on cell type or tissue origin. Normal development and differentiation of immature B lymphocytes depends on expression of CD10/NEP on B cell progenitors and bone marrow stromal cells. Synthetic glucocorticoid dexamethasone (dex), an immunosuppressive and anti-inflammatory drug, was shown to be a potent modulator of CD10/NEP expressed on cells of non-hematopoietic origin. We investigated the effect of dex on expression of differentiation marker CD10/NEP on immature B cells. The drug was applied in concentrations corresponding to the physiological range. CD10/NEP was measured at three levels of expression: mRNA (by means of duplex PCR), membrane protein marker (FACS analysis) and enzyme activity (hydrolysis of a selective chromogenic substrate). Dex down-regulated CD10/NEP expression on immature B cell line NALM-6 in a concentration- and time-dependent fashion. The effect was detected at all three levels. Dex-induced CD10/NEP down-regulation was mediated via glucocorticoid receptors (GR), as it was fully abrogated by a GR antagonist, RU 38486. That occurred at all three levels. The mechanism of dex-induced CD10/NEP down-regulation is not likely to include selection of cells that are CD10low since the effect was partly reversible after the removal of dex. However, dex-induced CD10/NEP down-regulation did include decreased transcription of the CD10 mRNA. Transcriptional inhibitor actinomycin D completely abolished dex-induced CD10/NEP down-regulation. Since differentiation of normal B lymphocytes is associated with down-regulation of CD10/NEP, the data presented suggest that low, physiologically relevant concentrations of glucocorticoids (such as observed in acute stress) may play a regulatory role in normal development and maturation of B lymphocytes.

Anti-Inflammatory Agents↗

Proteomic profiling of mature CD10+ B-cell lymphomas.

Proteomic profiling with protein-chip technology has been used successfully to discover biomarkers with potential clinical usefulness in several cancer types. Little proteomic study has been done in B-cell lymphomas. We determined whether the expression of a set of proteins by protein-chip technology coupled with new informatics tools could be used to build a model to molecularly classify B-cell lymphoma subgroups. We used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to analyze 18 CD10+ B-cell lymphomas, including 6 grade 1 (G1) follicular lymphomas (FLs), 7 grade 3 (G3) FLs, and 5 Burkitt lymphomas. We used 7 reactive follicular hyperplasia cases as a control group. By using SAX2 ProteinChip arrays (Ciphergen Biosystems, Fremont, CA), we found a unique protein expression profile for each type of lesion. Two-way hierarchical clustering analysis of these protein expression profiles differentiated reactive follicular hyperplasia, FL, and Burkitt lymphoma, with 5 major clusters of differentially expressed protein peaks. In addition, we identified histone H4 as a potential differentially expressed protein marker that seems to distinguish G1 from G3 FL. To our knowledge, this is the first proteomic study using protein-chip technology for molecular classification of B-cell lymphoma subtypes with clinical samples.

Biomarkers, Tumor↗