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

We investigated the role of IL-7 receptor alpha (IL-7Ralpha) signal in the formation of Peyer's patch (PP) anlage. Although pan-lymphopenia is a common phenotype of rag2-/- and il7ralpha-/- mice, a close inspection revealed nodules corresponding to PP in the adult rag2-/- but not in the il7ralpha-/- mouse. In our previous study, three histologically distinct steps in the formation of PP were identified. The first is the appearance of VCAM-1 + spots in the intestine, which probably represents an initial stage of the formation of the PP anlage. Accumulation of cells bearing IL-7Ralpha, CD4 or Ia in this region then follows and eventually entry of mature lymphocytes expressing CD3 or B220 occurs just before birth. Based on this criterion, we next investigated which of these events is defective in mice with severe combined immunodeficiency. Formation of VCAM-1 + spots and cluster formation of IL-7Ralpha+ cells proceed normally in the rag2-/- mouse which completely lacks mature lymphocytes. In contrast, no VCAM-1+ spots were detected in the embryonic nor neonatal il7ralpha-/- mice, suggesting that IL-7Ralpha signal is involved in the early phase of PP anlage formation. The same defect was found in the jak3-/- mouse. In addition to the appearance of VCAM1+ spots, the clustering of IL-7Ralpha+ cells was absent in the jak3-/- mouse, though IL-7Ralpha+ cells are found to scatter over the intestine. These results indicate that IL-7Ralpha is an essential signal for an early step of PP anlage formation, without which the subsequent processes cannot be initiated.
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PMID:Essential role of IL-7 receptor alpha in the formation of Peyer's patch anlage. 948 50

Adenosine deaminase (ADA) deficiency causes lymphopenia and immunodeficiency due to toxic effects of its substrates. Most patients are infants with severe combined immunodeficiency disease (SCID), but others are diagnosed later in childhood (delayed onset) or as adults (late onset); healthy individuals with "partial" ADA deficiency have been identified. More than 50 ADA mutations are known; most patients are heteroallelic, and most alleles are rare. To analyze the relationship of genotype to phenotype, we quantitated the expression of 29 amino acid sequence-altering alleles in the ADA-deleted Escherichia coli strain SO3834. Expressed ADA activity of wild-type and mutant alleles ranged over five orders of magnitude. The 26 disease-associated alleles expressed 0.001%-0.6% of wild-type activity, versus 5%-28% for 3 alleles from "partials." We related these data to the clinical phenotypes and erythrocyte deoxyadenosine nucleotide (dAXP) levels of 52 patients (49 immunodeficient and 3 with partial deficiency) who had 43 genotypes derived from 42 different mutations, including 28 of the expressed alleles. We reduced this complexity to 13 "genotype categories," ranked according to the potential of their constituent alleles to provide ADA activity. Of 31 SCID patients, 28 fell into 3 genotype categories that could express <=0.05% of wild-type ADA activity. Only 2 of 21 patients with delayed, late-onset, or partial phenotypes had one of these "severe" genotypes. Among 37 patients for whom pretreatment metabolic data were available, we found a strong inverse correlation between red-cell dAXP level and total ADA activity expressed by each patient's alleles in SO3834. Our system provides a quantitative framework and ranking system for relating genotype to phenotype.
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PMID:Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. 975 12

HIV-1 disease is often associated with CD4+ T lymphopenia as well as quantitative reductions in naive CD8+ T cells and cytopenias involving nonlymphoid hemopoietic lineages. Studies in HIV-1-infected humans as well as in animal models of lenti-virus disease indicate that these effects may be secondary to infection and destruction of multilineage and lineage-restricted hemopoietic progenitor cells. To define the stages of T cell differentiation that might be susceptible to HIV-1, we performed flow cytometric analysis of the surface expression of CXCR4 and CCR5 on T cells and their progenitors from fetal tissue, cord blood, SCID-hu Thy/Liv mice, and adult peripheral blood. We found that CXCR4 is expressed at low levels on hemopoietic progenitors in the bone marrow, is highly expressed on immature (CD3-CD4+CD8-) T cell progenitors in the thymus, and then is down-regulated during thymocyte differentiation. As thymocytes leave the thymus and enter the peripheral circulation, the expression of CXCR4 is again up-regulated. In contrast, CCR5 is undetectable on most hemopoietic progenitors in the bone marrow and on intrathymic T progenitor cells. It is up-regulated when thymocytes coexpress CD4 and CD8, then down-regulated either in the thymus (CD4+ cells) or during exit from the thymus (CD8+ cells). These results indicate that discrete, lineage-related populations of T cell progenitors may vary widely in their potential to respond to chemokines and to be infected by HIV-1, and that T lymphoid differentiation is particularly vulnerable to CXCR4-using viruses.
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PMID:CXCR4 and CCR5 expression delineates targets for HIV-1 disruption of T cell differentiation. 975 95

Severe combined immunodeficiency (SCID) is a rare pediatric medical emergency in Taiwan. The early diagnosis of infants with SCID is very important because it can save the life of these critical infants. The essential clues important for early diagnosis of SCID patients include positive family history of early infant death, paucity of tonsil and lymphoid tissue, cutaneous fungal infection and lymphopenia. Severe combined immunodeficiency is a heterogeneous group of inherited disorders characterized by the failure of both cellular and humoral immunity. It can be categorized into SCID with B-lymphocytes predominant (T-B+SCID) and SCID with paucity of B-lymphocytes (T-B-SCID), according to the number of B-lymphocytes in the patient's peripheral circulation. We report two male infants with T-B+SCID who had been suffering from severe pulmonary distress with persistent O2 desaturation when they were transferred to our pediatric intensive care unit. Tracing back these infant's family histories, it was discovered that both of them had an elder brother who had died to overwhelming infection within the first year of life, and Pneumocystis carinii pneumonitis (PCP) was confirmed in the elder brother of case 2. After hospitalization, the immune condition of these two infants were evaluated which showed a decrease in T-cell and NK cell number, an increase in B-cell number, and decreased serum levels of all the Igs except IgM, which was elevated in case 1. These were the diagnostic immunological findings for T-B+SCID, which included X-linked SCID and Jak-3-deficient SCID. During hospitalization, severe mucocutaneous candidiasis and PCP were noted and confirmed in case 1 and PCP was highly suspected in case 2. Bone marrow transplantation, the only curable treatment for T-B+SCID at present, could not be performed in these two patients because of their grave clinical condition. Both of them expired due to their progressively downhill pulmonary conditions.
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PMID:Severe combined immunodeficiency with B-lymphocytes (T-B+SCID): report of two cases. 992 17

A 2-month-old girl with severe combined immunodeficiency (SCID), presented with mild staphylococcal skin infection, lymphopenia, low T cell number, absence of B cells, high number of NK cells, and a negligible response to mitogens. Since her older brother died as a result of SCID 2 years earlier, cord blood was harvested from a sister born 2 1/2 years earlier, who was normal and fully matched both by serology and molecular typing. In view of her clinical condition and in spite of a high number of NK cells with normal activity, HUCBT without preparative conditioning was performed. No G-CSF was administered. Engraftment with mixed chimerism was evident 3 weeks post transplantation. There were no peritransplantation complications. Eighteen months post transplantation, the girl is in excellent condition, blood counts are normal, T cell engraftment is complete, B cell engraftment is proceeding gradually, and the mitogen stimulation tests are normal. Due to the unique nature of HUCB hematopoietic cells, engraftment without conditioning may be possible in patients with SCID with fully matched donors. This is the first HUCBT performed without conditioning.
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PMID:Successful human umbilical cord blood stem cell transplantation without conditioning in severe combined immune deficiency. 1010 May 87

Common variable immunodeficiency (CVID) is a congenital immunological disorder characterized by defective antibody production with normal count of peripheral B lymphocytes. The basic immunologic defects that leads to CVID are still unknown, however, a proportion of CVID is suggested to be caused by decreased CD4+ helper T cell activity. In addition, recent reports indicate that a defect of T cell receptor (TCR)-associated signaling molecules results in congenital immune deficiency in human. In the present study, we investigated lck, a signaling molecule downstream of TCR, in a patient with CVID plus CD4 lymphopenia, and found an aberrantly spliced lck transcript lacking the entire exon 7 associated with the decrease in the expression of lck protein. An identical splicing abnormality has been previously demonstrated in a case of severe combined immunodeficiency with selective CD4 lymphopenia, although the case showed almost complete loss of the expression of lck protein. Considering these findings, the aberrant splicing of lck gene is suggested to be correlated, at least with a subset of congenital immunodeficiency plus CD4 lymphopenia.
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PMID:Defect of lck in a patient with common variable immunodeficiency. 1135 Dec 73

All genetic types of severe combined immunodeficiency (SCID) can be cured by stem cell transplantation from related donors. The survival rate approaches 80%, and most deaths result from opportunistic infections acquired before transplantation. It was hypothesized that the survival rate and kinetics of immune reconstitution would be improved for infants receiving transplants in the neonatal period (first 28 days of life), prior to the development of infections. A 19.2-year retrospective/prospective analysis compared immune function in 21 SCID infants receiving transplants in the neonatal period with that in 70 SCID infants receiving transplants later. Lymphocyte phenotypes, proliferative responses to mitogens, immunoglobulin levels, and T-cell antigen receptor excision circles (TRECs) were measured before transplantation and sequentially after transplantation. Of 21 SCID infants with transplantations in the neonatal period, 20 (95%) survive. Neonates were lymphopenic at birth (1118 +/- 128 lymphocytes per cubic millimeter). Infants receiving transplants early developed higher lymphocyte responses to phytohemagglutinin and higher numbers of CD3(+) and CD45RA(+) T cells in the first 3 years of life than those receiving transplants late (P <.05). TRECs peaked earlier and with higher values (P <.01) in the neonatal transplantations (181 days to 1 year) than in the late transplantations (1 to 3 years). SCID recipients of allogeneic, related hematopoietic stem cells in the neonatal period had higher levels of T-cell reconstitution and thymic output and a higher survival rate than those receiving transplants after 28 days of life. An improved outcome for this otherwise fatal syndrome could be achieved with newborn screening for lymphopenia so that transplantation could be performed under favorable thymopoietic conditions.
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PMID:Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival. 1180 89

Genetic defects in T-cell function lead to susceptibility to infections or to other clinical problems that are more grave than those seen in disorders resulting in antibody deficiency alone. Those affected usually present during infancy with either common or opportunistic infections and rarely survive beyond infancy or childhood. The spectrum of T-cell defects ranges from the syndrome of severe combined immunodeficiency, in which T-cell function is absent, to combined immunodeficiency disorders in which there is some, but not adequate, T-cell function for a normal life span. Recent discoveries of the molecular causes of many of these defects have led to a new understanding of the flawed biology underlying the ever-growing number of defects. Most of these conditions could be diagnosed by means of screening for lymphopenia or for T-cell deficiency in cord blood at birth. Early recognition of those so afflicted is essential to the application of the most appropriate treatments for these conditions at a very early age. The latter treatments include both transplantation and gene therapy in addition to immunoglobulin replacement. Fully defining the molecular defects of such patients is also essential for genetic counseling of family members and prenatal diagnosis.
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PMID:Primary cellular immunodeficiencies. 1199 95

Because of unexplained mortality among 33 sibling offspring of a single pair of dogs, a family of Jack Russell Terriers was investigated. Twelve pups, 5 male and 7 female, died between 8 and 14 weeks of age. Six of those animals died in the field within 50 hours following vaccination with modified live vaccines. Subsequent histopathologic examination revealed the absence of splenic white pulp in 4 dogs and hepatic inclusions diagnostic for adenoviral infection in 2 dogs. Two additional litters yielded 2 pups with the same splenic and hepatic lesions. These observations led to a detailed study of 7 siblings whelped specifically for this investigation. Four of these 7 siblings had a profound lymphopenia and a decrease in serum immunoglobulins. Six of these dogs were necropsied at 7 weeks of age, and 4 of them had marked hypoplasia of all lymphoid tissue. The affected pups had an 86% decrease in mean thymic weight, with poor corticomedullary differentiation, and very few CD3-positive (T cell) thymocytes were detected immunohistochemically. However, the affected thymic tissue stained intensely with a immunochemical stain for cytokeratin. The other affected lymphoid tissues were identified histologically only by stromal architectural characteristics. Lymph nodes lacked both CD3 and CD79a (B cell) positive cells. The analyzed breeding data were consistent with an autosomal recessive mode of inheritance. This canine severe combined immunodeficiency has immunologic and pathologic features similar to those observed in immunodeficient C.B-17 mice and Arabian horses.
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PMID:Autosomal recessive severe combined immunodeficiency of Jack Russell terriers. 1203 74

Recognition of immunodeficiency allows steps to be taken to minimize morbidity and mortality. Immunodeficiency can be secondary to viral infection, most importantly secondary to HIV-1 worldwide, medications, disruption of the usual infection clearance mechanisms, or secondary to a myriad of systemic disorders. Immunodeficiency may also be due to one of the growing list of primary immunodeficiency disorders. In infancy, lymphopenia should trigger an evaluation investigating the possibility of severe combined immunodeficiency. Evaluations of children should be done keeping in mind that normal numbers of lymphocytes are higher in children than in adults, immunoglobulin levels in children are lower than in adults in younger age groups, and antibody production in response to polysaccharide antigens is not usually fully developed in the less-than 2-year-old child.
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PMID:Diagnosis of immunodeficiency: clinical clues and diagnostic tests. 1216 99


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