Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lymphoproliferative disease of granular lymphocytes (LDGL) is a recently recognized, relatively rare atypical lymphocytosis characterized by the presence of over 2000 lymphocytes with cytoplasmic azurophilic granules/mm3 in the peripheral blood. The clinical course is heterogeneous, varying from spontaneous regression to progressive, malignant disease. As a consequence, clinical intervention is not standardized. In a worldwide multicenter study, the authors observed 151 patients with LDGL for a mean follow-up time of 29 months. Forty-three patients were asymptomatic at the time of diagnosis. In the remaining cases, clinical symptoms included fever (41 cases), infections (58), neutropenia (47), anemia (17), and thrombocytopenia (12). In 69 cases, LDGL coexisted with an associated disease. Most patients had a nonprogressive clinical course despite the presence of severe symptoms. In 19 patients, death related to LDGL occurred within 48 months. The authors investigated which features at diagnosis were significantly associated with increased mortality. In the univariate analysis, lymph node and liver enlargement, fever at presentation, skin infiltration, a low (less than or equal to 5000/mm3) or high (greater than 20,000/mm3) peripheral leukocyte count, relatively low (less than or equal to 3000) or high (greater than 7000/mm3) absolute peripheral granular lymphocyte (GL) count, and a low (less than or equal to 15%) percentage of HNK-1-positive cells were found to be predictors of increased mortality. In the multivariate analysis, significant independent predictors were fever at diagnosis, a low (less than or equal to 15%) percentage of HNK-1-positive peripheral blood mononuclear cells (PBMC) and a relatively low (less than or equal to 3000) GL count. These results showed that about 25% of the patients with LDGL were diagnosed after a routine blood count and had no clinical symptoms. The remaining patients were symptomatic, with some experiencing a fatal clinical course. The author's analysis of the significant prognostic features of LDGL may help in understanding the heterogeneous nature of this syndrome.
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PMID:Clinical course and prognosis of the lymphoproliferative disease of granular lymphocytes. A multicenter study. 240 36

Repeated analysis of peripheral blood lymphocytes (PBLs) from a patient with large granular lymphocytosis, neutropenia, and rheumatoid arthritis revealed that approximately 45% of PBLs displayed the following phenotype: CD3+, CD4-, CD8-, CD16+, HNK-1-, WT31-. This population was purified for further analysis by depletion with anti-CD4 and anti-CD8 monoclonal antibodies (MoAbs). Southern blot analysis showed preferential rearrangements of the V gamma 9 genes. Northern blot demonstrated the presence of V gamma 9 mRNA transcripts. With MoAbs directed against either the V gamma 9 peptide (Ti gamma A) or the delta chain of the gamma delta T-cell receptor (TCR delta 1), we further demonstrated that those cell surfaces expressed both V gamma 9 and a delta gene product. In addition, analysis of the gamma gene rearrangements on six clones derived from this population demonstrated a unique rearrangement on a single chromosome, strongly suggesting the monoclonality of this T-cell population. Significant cytotoxic activity against K562, U937 was observed only after an in vitro culture period with interleukin-2 (IL-2), whereas no specific inhibitory effect on autologous bone marrow (BM) CFU-G was noted.
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PMID:Clonal expansion of lymphocytes bearing the gamma delta T-cell receptor in a patient with large granular lymphocyte disorder. 254 20

A 14-year-old Japanese female with neutropenia showed malignant proliferation of the large granular lymphocytes (LGLs). These LGLs were E rosette+ and Fc(IgG) receptor+ and therefore are referred to as T gamma lymphocytes. They were also Leu-11+ and OKT11+; however, they were clearly negative for Leu-7, OKT3, OKT8, OKM1, and HNK-1 antigens as well as for terminal deoxynucleotidyl transferase activity. Karyotype analysis revealed 47, XXX. The LGLs showed no rearrangement of T cell receptor C beta genes. The natural killer (NK) cell activity against K562 target cells was low, but was significantly augmented after stimulation by recombinant human interleukin 2 (IL 2) in contrast to minimal NK boosting by recombinant human gamma-interferon (gamma-IFN). Such a unique responsive ability to lymphokines was quite similar to that noted in fetal and cord blood cells. These LGLs also demonstrated a considerable increase in antibody-dependent cell-mediated cytotoxicity (ADCC) and lymphokine-activated killer (LAK) activity after a short incubation with IL 2. Although in a resting stage they showed no IL 2 receptor expression as examined by anti-Tac antibody, Tac antigen appeared after IL 2 treatment followed by a marked increase in 3H-thymidine incorporation and a remarkable production of gamma-IFN. To investigate the mechanism of neutropenia, in vitro IL 2-stimulated coculture studies of these cells with normal bone marrow cells were performed. Colony formation of myeloid progenitors (CFU-C) was significantly suppressed. In addition, the conditioned medium from IL 2-stimulated LGLs indicated a remarkable suppression of CFU-C. These results suggest that these LGLs with a Leu-11+, Leu-7- surface phenotype might belong to a unique subset of pre-NK cells that are functionally and phenotypically similar to those represented at any early stage of human ontogeny and that they strongly express Tac antigen under the influence of IL 2 administration, followed by remarkable cell proliferation and gamma-IFN production.
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PMID:Malignant clonal expansion of large granular lymphocytes with a Leu-11+, Leu-7- surface phenotype: in vitro responsiveness of malignant cells to recombinant human interleukin 2. 294 3

A female patient with an unusual lymphoproliferative disease associated with marked neutropenia has been observed for 36 months. The expanded cell population consists of large lymphocytes, many of which contain large azurophilic granules with acid phosphatase activity. These cells were T3, T8, T11 and Leu 11 positive but lacked the M1, T10, IL-2 receptor and HLA.DR antigens. The majority of these cells (60-70%) were also Leu 7 (HNK-1) positive. Strong natural killer (NK) activity was found in both the Leu 7 positive and negative cell populations. This cytotoxic activity was inhibited by monoclonal antibodies known to inhibit NK activity but was unaffected by antibodies which block T cell and T/NK cell cytotoxicity. Further functional analysis indicated that these cells suppressed normal T cell responses to mitogens, MLC responses and PWM induced B cell immunoglobulin synthesis. No effect on bone marrow progenitor cell growth was demonstrated. Antibody dependent cellular cytotoxic (ADCC) activity was barely detectable despite the presence of the Leu 11 antigen. Southern blot DNA analysis demonstrated clonal rearrangement of the T cell receptor beta gene thereby confirming that this variant of T gamma lymphoproliferative disease was a neoplastic condition.
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PMID:Functional analysis of a clonal expansion of Leu 11 positive NK active lymphoid cells. 295 59

Large granular lymphocyte (LGL) leukemia is a rare disease characterized by clonal expansion of LGL associated with chronic neutropenia, multiple auto-antibodies, and occasionally polyarthritis. We studied cell surface antigen expression and functional activity of leukemic LGL from ten such patients. Using two-color flow cytometric analysis, we found that leukemic LGL from all ten patients expressed the CD3 and HNK-1 markers, while cells from only four patients expressed IgG Fc receptors (FcR). The LGL leukemic cells had little or no NK activity (defined as MHC-nonrestricted cytotoxicity against K562 target cells); however, NK activity could be induced in leukemic LGL by in vitro treatment with as little as 0.05 microgram/mL of anti-CD3 monoclonal antibody. Cell sorting experiments demonstrated that NK activity was induced in CD3+ leukemic LGL (either CD3+, HNK-1+ or CD3+, FcR+) with anti-CD3 monoclonal antibody but not in normal CD3+, FcR- T cells. Treatment with purified interleukin 2 (IL 2) also caused direct activation of some CD3+ leukemic LGL. Despite induction with anti-CD3 MAb or IL 2, activated leukemic LGL did not proliferate or express high density IL 2 receptors detectable by cell sorter analysis. Treatment with alpha interferon had minimal effect on NK activity of LGL leukemic cells. These results suggest that leukemic LGL may provide a useful model for examining the signals required for LGL maturation and activation.
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PMID:Induction of NK activity in large granular lymphocyte leukemia: activation with anti-CD3 monoclonal antibody and interleukin 2. 309 27

Lymphocytosis of large granular lymphocytes (LGL) has been observed in 6 patients splenectomized for various pathological conditions. In all of them the LGL count was higher than 3.5 x 10(9)/l. No patient showed neutropenia nor suffered from rheumatoid arthritis. A surface markers heterogeneity was observed by immunophenotypic studies. A reversal of the CD4/CD8 ratio was observed in all patients, indicating that LGL are in the majority CD8+. Three patients showed the phenotype CD2+ CD3+ CD4- CD8+ indicating the T-lineage derivation of LGL; patient 6 showed a non-T non-B phenotype (CD2- CD3- CD4- CD8+/-). The percentage of lymphocytes presenting LGL-related markers (HNK-1, CD16, CD11b) was higher than that observed in normal subjects in 4 out of 5 examined patients. However, the percentage of cells bearing these markers was inferior to the LGL counts indicating that not all LGL express them. NK cytotoxic activity was similar to that of normal subjects in the three examined patients. Our data suggest that lymphocytosis of LGL in splenectomized subjects is a reactive process favoured by the asplenic state.
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PMID:Lymphocytosis of large granular lymphocytes in splenectomized subjects. 327 71

Some patients with chronically elevated large granular lymphocyte (LGL) numbers have rheumatoid arthritis (RA). Since these patients also may have neutropenia and splenomegaly, their symptoms resemble those of patients diagnosed as having Felty's syndrome (FS). We studied the immunophenotypic and genotypic characteristics of mononuclear cells from patients with RA and neutropenia to better determine the extent of heterogeneity in this condition. Four patients had markedly increased numbers of LGLs, which expressed HNK-1 antigen and IgG Fc receptors. In contrast, the remaining 8 patients, who had FS, had normal LGL counts, and surface marker studies showed normal numbers of HNK-1 and IgG Fc receptor positive cells. Clonal rearrangement of the T cell receptor beta chain gene was demonstrated in all 4 patients with excess LGLs, whereas a germline configuration of this gene was present in all 6 FS patients in whom this was studied. These results suggest that there are diverse groups among patients with RA and neutropenia. Since prognosis may differ, it is important to recognize that some patients who are considered to have Felty's syndrome may have a clonal proliferation of LGLs.
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PMID:Clonal proliferation of large granular lymphocytes in rheumatoid arthritis. 334 30

An immunoperoxidase technique was used to examine the distribution of lymphocyte subsets in bone marrow biopsies of 15 patients with neutropenia and seven non-neutropenic controls. The bone marrow of most patients and controls had similar distributions of immune effector cells characterized by a diffuse array of predominantly cytotoxic/suppressor T-cells and occasional nodular aggregates of helper T-cells. Cells displaying the natural killer cell marker HNK-1 were sparse in controls and most neutropenic patients. However, marked increases in marrow HNK-1 + cells were identified in four of the 15 patients. Three of these patients had diffuse HNK-1 + infiltrates associated with increased Leu 4+ (OKT-3+) T-cells while one had a nodular HNK-1+ infiltrate associated with small B-cell follicles. Each of these patients had clinical features similar to those described in the large granular lymphocyte (LGL) lymphocytosis (leukemia) syndrome, but only one of four demonstrated persistently increased numbers of LGLs in the peripheral blood. Thus, this study extends the association of neutropenia and increased numbers of cells with a T/NK phenotype to include patients whose bone marrow is the only demonstrable site of involvement. Since morphologic examination of the bone marrow could not identify the bone marrows with increased HNK-1+ cells, immunologic techniques are required to detect these cases.
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PMID:Immunoarchitecture of the bone marrow in neutropenia: increased HNK-1 + cells define a subset of neutropenic patients. 357 62

Human cyclic neutropenia occurs in adults as well as children. Clinical illness is similar in the childhood and adult diseases, but distinctly different modes of onset suggest heterogeneity in its pathophysiology. We studied seven patients with cyclic neutropenia, three with disease acquired in adulthood, and four with the childhood-onset disorder. All three patients with adult-onset cyclic neutropenia had increased numbers of circulating large granular lymphocytes (LGL), whereas the four children with cyclic neutropenia had normal LGL counts. LGL from patients with adult-onset cyclic neutropenia expressed cell surface antigens HNK-1 (three of three patients) and IgG Fc receptors (two of three patients), although natural killer activity was low. Two of these patients were treated with alternate-day steroids, resulting in decreased LGL counts and abrogation of neutrophil cycling. We suggest that adult-onset cyclic neutropenia may be distinguished from the childhood-onset form of the disease by increased numbers of LGL. Furthermore, increased LGL may identify a subset of patients with cyclic neutropenia who respond to steroid therapy.
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PMID:Adult-onset cyclic neutropenia is associated with increased large granular lymphocytes. 376 31

Three patients had leukocytosis of large granular lymphocytes and chronic neutropenia. Clonal chromosomal abnormalities (trisomy 8 and trisomy 14) and lymphocytic infiltration of splenic red pulp, hepatic sinusoids, and bone marrow indicated the neoplastic nature of the large granular lymphocytes. Demonstration of a T3+, T8+, HNK-1 + phenotype and low natural killer cell activity that was augmented by interferon treatment showed the leukemic cells to be immature natural killer cells. Multiple autoantibodies were present and included rheumatoid factor and antinuclear, antineutrophil, antiplatelet, and antierythrocyte antibodies, suggesting a defect of B-cell immunoregulation. In addition, in-vitro studies showed impaired suppression of immunoglobulin biosynthesis by abnormal cells from one patient. Antineutrophil antibodies and absence of direct cell-mediated inhibition of granulocyte-macrophage colony formation supported a humoral immune mechanism for the neutropenia. In these patients the syndrome of splenomegaly, multiple autoantibodies with neutropenia, and lymphocytosis of large granular lymphocytes is due to a neoplastic proliferation of immature natural killer cells.
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PMID:Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia. 396 54


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