Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BACKGROUND AND DESIGN--The pathophysiology of toxic epidermal necrolysis (TEN) remains largely unknown. Toxic epidermal necrolysis is considered a hypersensitivity reaction to drugs, but direct evidence of an immunologic mechanism is still lacking. Lymphopenia and a decrease in the numbers of circulating CD3- and CD4-positive lymphocytes have been reported in acute phase, but, to our knowledge, no study of cellular immune functions of patients with TEN has been reported so far. Herein, we investigated several T-cell functions in a series of 11 patients with TEN. Peripheral blood mononuclear cells (PBMC) obtained in the acute phase were tested together with PBMC obtained after the patient's recovery and compared with those of age- and sex-matched healthy control subjects. RESULTS--Phytohemagglutinin-induced proliferations and lymphocyte responses in allogeneic mixed lymphocyte reactions were not impaired in the acute phase compared with those after recovery in the same patients and with those in control subjects. In contrast, natural killer cytotoxicity and allogeneic cytotoxic responses were significantly decreased in early TEN. The most striking feature was the significantly impaired ability of acute-phase lymphoid cells to activate allogeneic T cells. Patient PBMC in acute-phase TEN did not inhibit the proliferation induced by patient PBMC after recovery, suggesting that their defect was not related to the presence of radioresistant suppressor cells. The phenotypic expression of HLA-DR, -DQ, and -DP antigens on circulating peripheral blood lymphocytes was then assessed by immunoalkaline phosphatase staining and flow cytometry. Results showed decreased percentages of HLA-DR-positive mononuclear cells and a decreased density of HLA-DR antigens, mainly on monocytes, in acute-phase TEN. CONCLUSIONS--These results demonstrate that peripheral blood lymphocytes of patients with TEN have an impaired ability to activate allogeneic T cells. This defective antigen presentation is not secondary to the presence of suppressor lymphocytes, but it is probably related to a decreased expression of HLA-DR antigens on circulating mononuclear cells in acute-phase TEN.
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PMID:Impaired antigen presentation in toxic epidermal necrolysis. 850 74

Animals lacking Src homology 2 domain-containing inositol 5-phosphatase (SHIP) display a reduction in lymphopoiesis and a corresponding enhancement of myelopoiesis. These effects are mediated at least in part by elevated levels of interleukin 6 (IL-6). Here, we show the lymphopoiesis block in SHIP-/- mice is due to suppression of the lymphoid lineage choice by uncommitted progenitors. The suppression can be reproduced in vitro with recombinant IL-6, and IL-6 acts directly on hematopoietic progenitors. The block is partially overcome in SHIP-/- IL-6-/- double-deficient animals. IL-6 does not suppress but actually enhances proliferation of lymphoid-committed progenitors, indicating the IL-6 target cells are hematopoietic stem cells or multipotent progenitors. The findings suggest a mechanism for the lymphopenia that accompanies proinflammatory diseases.
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PMID:IL-6 blocks a discrete early step in lymphopoiesis. 1583 1

A boy with lifelong recurrent bacterial infection at cutaneous and mucosal sites was investigated. PMN oxidative burst to phorbol myristate acetate (PMA) and zymosan was normal but was increased 20- to 50-fold upon C5a or formyl-met-leu-phe (fMLP) chemoattractant stimulation, accompanied by accelerated PMN apoptosis. His PMNs showed increased constitutive tyrosine phosphorylation of 21-, 25-, and 44-kDa proteins, and of src-family kinases (p59(hck), p58(fgr), and p53/56(lyn)). Phosphorylation was abnormally enhanced following fMLP stimulation. Expression and activity of the major PMN tyrosine phosphatases, i.e., CD45, CD148, and SHP-1 and -2, was normal. However, dephosphorylation of phospho-p58(fgr) and phospho-p53/56(lyn) by lysates of patient's PMNs was enhanced. Thus, another phosphatase may be overactive, perhaps dephosphorylating a regulatory (inhibitory) site on a protein tyrosine kinase, accounting for the abnormal PMN tyrosine phosphorylation and function. With age (now 13 years), T-cell lymphopenia and loss of T-cell responses developed. This appears to be a unique primary immunodeficiency with abnormal PMN oxidative and apoptotic responses to chemoattractants, dysregulated protein tyrosine phosphorylation, serious bacterial infection, and T-lymphocyte attrition.
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PMID:Increased chemoattractant induced neutrophil oxidative burst, accelerated apoptosis, and dysregulated tyrosine phosphorylation associated with lifelong bacterial infections. 1601 63

Idiopathic CD4 lymphopenia (ICL) is a rare heterogeneous immunological syndrome of unclear etiology. ICL predisposes patients to severe opportunistic infections and frequently leads to poor vaccination effectiveness. Chronic immune activation, expansion of memory T cells, and impaired T-cell receptor (TCR) signaling have been reported in ICL, but the mechanistic and causative links remain unclear. We show that late-differentiated T cells in 20 patients with ICL displayed defective TCR responses and aging markers similar to those found in T cells from elderly subjects. Intrinsic T-cell defects were caused by increased expression of dual-specific phosphatase 4 (DUSP4). Normalization of DUSP4 expression using a specific siRNA improved CD4(+) T-cell activity in ICL, as this restored TCR-induced extracellular signal-regulated kinase activation and increased the expression of the costimulatory molecules CD27 and CD40L. Conversely, repeated TCR stimulation led to defective signaling and DUSP4 overexpression in control CD4(+) T cells. This was associated with gradual acquisition of a memory phenotype and was curtailed by DUSP4 silencing. These findings identify a premature T-cell senescence in ICL that might be caused by chronic T-cell activation and a consequential DUSP4-dependent dampening of TCR signaling.
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PMID:DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia. 2573 83

Objectives Severe congenital neutropenia (SCN) is a primary immunodeficiency (PID) characterized by persistent severe neutropenia, recurrent infections, and oral aphthous lesions. Severe congenital neutropenia is caused by various genetic defects such as ELANE, GFI, HAX-1, JAGN1, SRP54, and glucose-6 phosphatase catalytic subunit 3 (G6PC3) deficiency. Clinical features of the patients with G6PC3 deficiency vary from neutropenia to several systemic features in addition to developmental delay. Case presentation In this report, we presented three unrelated patients diagnosed with G6PC3 deficiency. All these patients had short stature, prominent and superficial vascular tissue, cardiac abnormalities (Atrial septal defect (secondary), mitral valve prolapse with mitral insufficiency, pulmonary hypertension) and lymphopenia. Patient 1 (P1) and 2 (P2) had urogenital abnormalities, P2 and P3 had thrombocytopenia. Conclusions We have shown that lymphopenia and CD4 lymphopenia do not rarely accompany to G6PC3 deficiency. Characteristic facial appearance, systemic manifestions, neutropenia could be the clues for the diagnosis of G6PC3 deficiency.
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PMID:Three patients with glucose-6 phosphatase catalytic subunit 3 deficiency. 3262 77