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)

Expression of monoclonal anti-DNA antibodies in vitro can be used to study the relationships between molecular structure, binding properties and pathogenicity. Bacterial and yeast systems can be used to produce antibody fragments such as Fab. The yields are potentially sufficient to allow structural studies such as crystallization, but purification of the anti-DNA Fab from the bacterial periplasm may be challenging. Mammalian cell expression systems produce lower yields, but the products are whole antibodies, which can be used in assays of pathogenicity. This article describes some recent experiments in which bacterial and mammalian systems were used to study human monoclonal anti-DNA antibodies. Light chain sequence motifs were found to be important both in binding to antigens and in determining pathogenicity of the antibodies in severe combined immunodeficiency mice. The distribution of B cell subpopulations is disturbed in patients with systemic lupus erythematosus (SLE). These patients, like those with infectious mononucleosis, have an overall B cell lymphopenia but an increased frequency of plasmablasts/early plasma cells in their blood. Some of these early plasma cells belong to clones that have rearranged the V(H) gene V4-34. There is a selective rise in immunoglobulins encoded by this gene in both infectious mononucleosis and SLE.
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PMID:Anti-DNA antibodies--structure and function. 1252 38

IL-7 is a critical component of thymopoiesis in animals and has recently been shown to play an important role in T cell homeostasis. Although there is increasing interest in the use of IL-7 for the treatment of lymphopenia caused by the HIV type 1, evidence that IL-7 may accelerate HIV replication has raised concerns regarding its use in this setting. We sought to identify the effects of IL-7 on human thymocyte survival and to determine the impact of IL-7 administration on in vivo HIV infection of the human thymus. Using in vitro analysis, we show that IL-7 provides potent anti-apoptotic and proliferative signals to early thymocyte progenitors. Analysis of CD34(+) subpopulations demonstrates that surface IL-7 receptor is expressed on most CD34(high)CD5(+)CD1a(-) thymocytes and that this subpopulation appears to be one of the earliest maturation stages responsive to the effects of IL-7. Thus, IL-7 provides survival signals to human thymocytes before surface expression of CD1a. CD4(+)CD8(+) thymocytes are relatively unresponsive to IL-7, although IL-7 protects these cells from dexamethasone-induced apoptosis. IL-7 has a predominantly proliferative effect on mature CD4(+)CD3(+)CD8(-) and CD8(+)CD3(+)CD4(-) thymocytes. In contrast to the in vitro findings, we observe that in vivo administration of IL-7 to SCID-hu Thy/Liv mice does not appear to enhance thymocyte survival nor does it appear to accelerate HIV infection. Given the growing interest in the use of IL-7 for the treatment of human immunodeficiency, these findings support additional investigation into its in vivo effects on thymopoiesis and HIV infection.
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PMID:Effects of IL-7 on early human thymocyte progenitor cells in vitro and in SCID-hu Thy/Liv mice. 1284 29

Severe combined immunodeficiency (SCID) is an inherited immune disorder characterized by T-cell lymphopenia (TCLP), a profound lack of cellular (T-cell) and humoral (B-cell) immunity and, in some cases, decreased NK-cell number and function. Affected children develop severe bacterial and viral infections within the first 6 months of life and die before 1 year of age without treatment. Mutations in any of eight known genes: IL2RG, ARTEMIS, RAG1, RAG2, ADA, CD45, JAK3, and IL7R cause SCID. Mutations in unidentified genes may also cause SCID. Population-based genotype and allelic frequencies of these gene defects have not been measured. Some minimal estimates of SCID prevalence are presented. Currently, hematopoietic stem cell transplants are the standard treatment. In clinical trials, gene therapy has been used to reconstitute immune function in patients with IL2RG and ADA defects. The availability of effective therapies, plus the short asymptomatic period after birth, (when stem-cell transplantation is most effective), make SCID a potentially good candidate for newborn screening. Dried blood spots are currently collected from all infants at birth for newborn metabolic screening. Tests for TCLP on dried blood spots could be developed as a screen for SCID. Because SCID may be unrecognized, with infant deaths from infection attributed to other causes, newborn screening is the only way to ascertain true birth prevalence. Validated tests and pilot population studies are necessary to determine newborn screening's potential for identifying infants with SCID.
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PMID:Mutations in genes required for T-cell development: IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HuGE review. 1472 5

We describe the case of a 14-month-old boy with delayed-onset SCID due to ADA-deficiency which was masqueraded only by failure to thrive. Remarkably, the child had no serious infections and an adequate immune response. However, absolute lymphopenia, eosinophilia and absent thymus on chest x-ray were indicative for immunodeficiency.
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PMID:Failure to thrive in a 14-month-old boy with lymphopenia and eosinophilia. 1474 67

To address the role of cellular immunity during ehrlichia infection, we have used a newly described model of monocytic ehrlichiosis that results from infection of mice by an ehrlichia that was isolated from an Ixodes ovatus tick (Ixodes ovatus ehrlichia, IOE). Immunocompetent C57BL/6 and BALB/c mice exhibited a dose-dependent susceptibility to IOE infection. Mice infected with a high dose inoculum ( approximately 1000 organisms) exhibited pronounced thrombocytopenia, lymphopenia, anemia, and morbidity within 12 days postinfection. Infection was associated with bacterial colonization of a number of tissues. In contrast, mice infected with a low dose inoculum ( approximately 100 organisms) exhibited only transient disease and were able to resolve the infection. SCID mice were highly susceptible to low-dose infection, indicating that adaptive immunity was required. Resistance to sublethal challenge in both C57BL/6 and BALB/c mice was CD4-, but not CD8-, dependent and required IL-12p40-dependent cytokines, IFN-gamma, and TNF-alpha, but not IL-4. CD4 T cells purified from infected mice proliferated in vitro in response to IOE Ags. T cell proliferation was associated with production of IFN-gamma, and the production of this cytokine by CD4 T cells rescued IFN-gamma-deficient mice from fatal infection. Exogenous IFN-gamma was capable of inducing microbiocidal activity in infected macrophages. The data suggest that classical immune mechanisms involving CD4 cells and type 1 cytokines are responsible for macrophage activation and for elimination of this intracellular bacterial pathogen.
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PMID:Production of IFN-gamma by CD4 T cells is essential for resolving ehrlichia infection. 1515 8

The discovery that Jak3 mutations are a significant cause of severe combined immunodeficiency (SCID), a rare inherited defect characterized by lymphopenia, has provided valuable insights into the functions of Jak3 in lymphoid development and function. The current therapy for patients suffering from Jak3 SCID is hematopoetic stem cell transplantation, although gene therapy trials have also been performed. In lieu of crystal structure data, these patient-derived mutations have aided in the elucidation of the functions of various structural components of Jak3. By virtue of its requirement for lymphoid functions, Jak3 makes a tantalizing target for immunosuppression and anti-cancer therapy. Herein, we discuss the normal actions of the gammac cytokines, the pathogenesis and treatment protocols for SCID, and finally, the production of a new, selective Jak3 inhibitor capable of preventing transplant rejection in two animal models. Further study of Jak3 will hopefully provide insights into the clinical treatment of patients suffering from immune-mediated diseases.
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PMID:Jak3 and the pathogenesis of severe combined immunodeficiency. 1522 7

Interleukin-7 (IL-7) is a stromal factor that is crucial for the development of T lymphocytes in humans and mice, and also B lymphocytes in mice. IL-7 can act as a T cell growth factor as well as a critical anti-apoptotic survival factor. The essential non-redundant role of this cytokine for T cell development in vivo is indicated by the phenotype of murine knockout models as well as by humans with a T-B+NK+ form of severe combined immunodeficiency (SCID) resulting from mutations in IL-7 receptor alpha chain. IL-7 deficiency has now been found in patients with rheumatoid arthritis, a finding that relates not only to the T-lymphocyte status in this disease but also to the ability of patients with rheumatoid arthritis to recover from therapy-induced lymphopenia.
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PMID:Interleukin-7 deficiency in rheumatoid arthritis. 1564 46

Because prompt intervention may prevent complications, early diagnosis is important in many inherited metabolic diseases. Early diagnosis of Severe Combined Immunodeficiency (SCID) is critical - because chances for successful treatment are highest for infants who have not yet experienced severe opportunistic infections. SCID is a rare disease that can be detected in newborn infants (i.e., those more or equal 1 month of age) by automated blood count and manual differential. Early diagnosis of SCID is rare since, because estimates of the incidence rate range from one in 50,000 to 100,000 births, most pediatricians do not routinely count white blood cells in newborns. Tests for T-cell lymphopenia (TCLP) using dried blood spots (DBS) could be used to identify children with SCID - as well as for other immunodeficiencies that would not be apparent until after the child developed an infection. Screening newborns for SCID would allow early diagnosis and treatment -- as well as genetic counseling for the family.
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PMID:Newborn screening for severe combined immunodeficiency (SCID): a review. 1576 2

Outcomes for infants with severe combined immunodeficiency (SCID) would be improved by universal newborn screening, but there are not yet screening tests of sufficient accuracy for the disorder. In a pilot study, we assessed the ability of a two-tiered strategy to improve accuracy. Dried blood samples from patients were assessed with two tests for lymphopenia: interleukin-7, a T-cell growth cytokine, and TRECs, a byproduct of T-cell receptor recombination. IL-7 screening has a specificity of 96.1% and TRECs have a specificity of 92.3%. Combining these tests in a two-tiered strategy increases specificity to 100% (97-100% CI). Sensitivity was 85% for IL-7 screening and 100% for TREC screening. A two-tiered strategy may be of sufficient accuracy to enable universal SCID screening, and should be assessed in a prospective trial.
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PMID:Two-tiered universal newborn screening strategy for severe combined immunodeficiency. 1626 Jan 63

Amorphic mutations in the recombination activating genes RAG1 and RAG2 have been reported to cause T- B- SCID, whereas hypomorphic mutations led to the expansion of a few autoimmune T cell clones responsible for the Omenn syndrome phenotype. We report here a novel clinical and immunological phenotype associated with recessive RAG1 hypomorphic mutations in 4 patients from 4 different families. The immunological phenotype consists of the oligoclonal expansion of TCR gammadelta T cells combined with TCR alphabeta T cell lymphopenia. The clinical phenotype consists of severe, disseminated CMV infection and autoimmune blood cell manifestations. Repertoire studies suggest that CMV infection, in the setting of this particular T cell immunodeficiency, may have driven the TCR gammadelta T cell clonal expansion. This observation extends the range of clinical and immunological phenotypes associated with RAG mutations, emphasizing the role of the genetic background and microbial environment in determining disease phenotype.
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PMID:A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. 1627 11


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