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Biomedical subjects

M E Elder

Publications and source records attributed to M E Elder.

15 recordsLinked to original sources
PubMed2005

Association between beta2-glycoprotein I gene polymorphisms and pediatric SLE and antiphospholipid antibodies.

Antibodies against phospholipids (PL) and PL-binding proteins have been causally implicated in antiphospholipid syndrome (APS). Mutations in the fifth domain of the beta2-glycoprotein I (beta2GPI) protein, a putative PL-binding site, may play a critical role in APS pathogenesis. The purpose of this study was to identify associations between beta2GPI mutations and both antiphospholipid antibodies (aPL) and their associated clinical manifestations in a pediatric and adolescent cohort and to search for novel mutations. Genetic analysis of beta2GPI was performed in 58 youths with systemic lupus erythematosus (SLE) and/or aPL, to identify known polymorphisms at amino acids 247 and 306 as well as novel mutations in exon 7 of the beta2GPI gene, and their association with aPL-associated clinical manifestations. Our results demonstrate an association between substitution of Val for Leu at AA247 (L247V) of beta2GPI and both the development of aPL (P = 0.05) and aPL-associated clinical manifestations (P = 0.03) among pediatric patients. The odds ratio associated with risk of aPL-associated clinical manifestations for the homozygous VV polymorphism was 5.5 (CI 1.3-23, P = 0.03) for the overall cohort, and 4.75 (CI 0.66-55.49, P = 0.06) after adjusting for ethnicity. The association was not significant after stratifying for SLE versus non-SLE. Association between the VV genotype at amino acid 247 of beta2GPI and clinical disease supports a genetic cause for APS among children and adolescents. Neither novel exon 7 beta2GPI mutations or the previously described C306G polymorphism was identified in this pediatric cohort.

Adolescent↗
PubMed2001

Distinct T cell developmental consequences in humans and mice expressing identical mutations in the DLAARN motif of ZAP-70.

The protein tyrosine kinase, ZAP-70, is pivotally involved in transduction of Ag-binding signals from the TCR required for T cell activation and development. Defects in ZAP-70 result in SCID in humans and mice. We describe an infant with SCID due to a novel ZAP-70 mutation, comparable with that which arose spontaneously in an inbred mouse colony. The patient inherited a homozygous missense mutation within the highly conserved DLAARN motif in the ZAP-70 kinase domain. Although the mutation only modestly affected protein stability, catalytic function was absent. Despite identical changes in the amino acid sequence of ZAP-70, the peripheral T cell phenotypes of our patient and affected mice are distinct. ZAP-70 deficiency in this patient, as in other humans, is characterized by abundant nonfunctional CD4(+) T cells and absent CD8(+) T cells. In contrast, ZAP-70-deficient mice lack both major T cell subsets. Although levels of the ZAP-70-related protein tyrosine kinase, Syk, may be sufficiently increased in human thymocytes to rescue CD4 development, survival of ZAP-70-deficient T cells in the periphery does not appear to be dependent on persistent up-regulation of Syk expression.

Amino Acid Motifs↗
PubMed2000

A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO).

Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and recessive forms exist. We have studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections. Recently, mutations in IKK-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (IP). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. IKK-gamma is required for the activation of the transcription factor known as "nuclear factor kappa B" and plays an important role in T and B cell function. We hypothesize that "milder" mutations at this locus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor-like signaling pathway, with the IKK signalsome complex playing a significant role.

Adolescent↗
PubMed2000

T-cell immunodeficiencies.

T-cell immune defects include most inherited immunodeficiencies diagnosed in childhood. Most cellular immunodeficiencies have associated humoral defects with variable clinical and laboratory features. The underlying gene defects are now known for most inherited T-cell immune defects, and mutation analysis is quickly becoming an integral part of evaluation and diagnosis. Detailed discussion of disease genotype-phenotype correlation with families is critical to medical management and long-term prognosis.

Antibody Formation↗
PubMed1999

Cytokine profile of a long-term pediatric HIV survivor with hyper-IgE syndrome and a normal CD4 T-cell count.

BACKGROUND: An elevated IgE level and increased production of T(H2) cytokines are factors associated with poor prognosis in HIV infection. We report a pediatric long-term survivor of vertically acquired HIV infection with a normal CD4 count and a low viral burden despite the lack of antiretroviral therapy and a phenotype resembling hyper-IgE syndrome. OBJECTIVE: We sought to characterize the patient's T(H1) versus T(H2) cytokine profile and anti-HIV-specific immune responses. METHODS: Supernatants collected from cultures of peripheral blood T cells stimulated with phorbol myristate acetate plus ionomycin were assayed for T(H1) and T(H2) cytokines by means of ELISA. Specific IgE antibodies were determined by immunoblot. HIV-specific cytotoxic T-lymphocyte responses were measured from cell lysis by fresh T cells of autologous B-lymphoblastoid cells expressing recombinant HIV proteins. RESULTS: Patient CD4(+) T cells secreted significantly more T(H2) cytokines, IL-4 (P <.003) and IL-5 (P <.03), than HIV-infected and seronegative control cells. No difference was noted in T(H1) cytokine production. IgE specific for HIV gp160, p24, p17, and p66 proteins and Aspergillus fumigatus was detected in patient sera. Despite predominance of T(H2) cytokines, HIV-specific cytotoxic T-lymphocyte activity was vigorous. CONCLUSIONS: The patient demonstrated predominantly T(H2) cytokine production in vitro. Unlike other patients with HIV who have hyper-IgE and increased T(H2) cytokine production, our patient has maintained HIV-specific immune responses, a low viral load, and a normal CD4 count without antiretroviral therapy. These findings support a diagnosis of primary hyper-IgE syndrome. Presence of anti-HIV-specific IgE may represent a protective mechanism against HIV replication in our patient.

CD4 Lymphocyte Count↗
PubMed1998

ZAP-70 and defects of T-cell receptor signaling.

The activation, function, and development of peripheral T lymphocytes are dependent on the ability to signal properly through the surface T-cell antigen receptor (TCR)-CD3 complex. Transmission of such signals requires the activation of specific cytoplasmic protein tyrosine kinases (PTK) associated with the TCR. Recently, mutations in one such PTK, called ZAP-70, have been shown to be responsible for a rare, autosomal recessive form of severe combined immunodeficiency syndrome (SCID) in humans. This distinctive SCID syndrome is characterized by the selective absence of peripheral CD8+ T cells and by the presence of circulating CD4+ T cells that do not respond to TCR-mediated stimuli in vitro. T-cell immunodeficiency syndromes that arise as a consequence of inherited mutations in either the CD3epsilon or CD3gamma subunit proteins have also been described in rare patients. Absence of these TCR components results in severely decreased expression of the surface TCR-CD3 complex and defective signal transduction through the TCR. In this report, the clinical, laboratory, and molecular findings of these immunodeficiency disorders are described, insights are provided by these inherited defects into the pathways of TCR signal transduction, and T-cell development is discussed.

Humans↗
PubMed1995

Severe combined immunodeficiency with absence of peripheral blood CD8+ T cells due to ZAP-70 deficiency.

During ontogeny, T lymphocytes are selected for CD4 or CD8 expression in part by their ability to signal properly through the TCR. Transmission of such signals requires the activation of specific cytoplasmic protein tyrosine kinases (PTKs) which lead to T-cell activation through poorly understood mechanisms. Recently, mutations in one such PTK, called ZAP-70, have been shown to be responsible for a rare, autosomal recessive form of severe combined immunodeficiency (SCID) in humans. This distinctive SCID syndrome is characterized by the selective absence of peripheral CD8+ T cells and by abundant circulating CD4+ T cells that fail to respond to TCR-mediated stimuli in vitro. In this report, we describe in detail the clinical and laboratory findings in one patient with ZAP-70 deficiency and discuss the insights provided by this disorder into the pathways of TCR signal transduction and T-cell development.

B-Lymphocytes↗
PubMed1994

Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase.

A homozygous mutation in the kinase domain of ZAP-70, a T cell receptor-associated protein tyrosine kinase, produced a distinctive form of human severe combined immunodeficiency. Manifestations of this disorder included profound immunodeficiency, absence of peripheral CD8+ T cells, and abundant peripheral CD4+ T cells that were refractory to T cell receptor-mediated activation. These findings demonstrate that ZAP-70 is essential for human T cell function and suggest that CD4+ and CD8+ T cells depend on different intracellular signaling pathways to support their development or survival.

Alleles↗
PubMed1994

ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency.

Protein tyrosine kinases (PTKs) play an integral role in T cell activation and differentiation. Defects in the Src-family PTKs in mice and in T cell lines have resulted in variable defects in thymic development and in T cell antigen receptor (TCR) signal transduction. Here, three siblings are described with an autosomal recessive form of severe combined immunodeficiency disease (SCID) in which ZAP-70, a non-Src PTK, is absent as a result of mutations in the ZAP-70 gene. This absence is associated with defects in TCR signal transduction, suggesting an important functional role for ZAP-70.

Amino Acid Sequence↗
PubMed1992

trans-dominant inhibition of human immunodeficiency virus type 1 Rev occurs through formation of inactive protein complexes.

The human immunodeficiency virus type 1 Rev protein controls expression of certain viral RNAs by binding to these RNAs in the nucleus. To investigate how dominant negative Rev mutants inhibit Rev function, we fused such mutants to hormone-dependent localization signals from the glucocorticoid receptor. Each was found to have fully potent inhibitory activity whether expressed in the nucleus or in the cytoplasm. Wild-type Rev colocalized with an inhibitory fusion protein, implying that the two proteins interact. The resulting complexes accumulated within nuclei in response to steroids but had no effect on expression of Rev-responsive mRNAs. A mutation known to block in vitro oligomerization of Rev abolished both complex formation and inhibitory activity of the mutant fusion proteins. Thus, trans-dominant inhibition of Rev does not require competition for nuclear substrates but may instead reflect the ability of a mutant to form nonfunctional complexes with the wild-type protein in vivo.

Binding, Competitive↗
PubMed1983

Autoimmune diatheses and T lymphocyte immunoincompetences in BB rats.

BB rats were found to have autoantibodies to gastric parietal cells, thyroid colloid antigens, smooth muscle, and thymocytes. No autoantibodies reactive with pancreatic islet cells (cytoplasmic), thyroid epithelial cells, adrenal cortex, testes, or anterior pituitary sections were identified. BB rats with gastric parietal autoantibodies had modest degrees of lymphocytic gastritis, but none developed iron or vitamin B12 deficiencies. These results suggest that BB rats have an underlying autoimmune diathesis. In addition, reports of peripheral T lymphopenia in such rats were confirmed, and markedly reduced helper T cell and cytotoxic-suppressor T cell subsets were demonstrated. Histological studies also revealed depletions of the T cell areas of spleen and lymph nodes. Furthermore, BB rats exhibited a profound inability to reject skin grafts across major and minor histocompatibility barriers. This was confirmed by mixed lymphocyte culture studies in vitro. BB-rat lymphocytes from either spleen or peripheral blood also showed profoundly reduced responses to T cell mitogens. Although BB-rat lymphocytes could produce normal levels of interleukin-2, they were unable to respond to this T cell growth factor. However, examination of thymuses from BB rats showed largely normal histologies, normal numbers of thymocyte subsets, and good mitogenic responses to con A. Thus, it appears that BB rats may have a thymic or post thymic defect in T lymphocyte maturation. The relevance of the immunologic lesion to the etiology of IDD in BB rats remains to be shown.

Animals↗
PubMed1983

Identification of profound peripheral T lymphocyte immunodeficiencies in the spontaneously diabetic BB rat.

The BB rat is presently the best available animal model for human insulin dependent diabetes (IDD). Because of the extreme susceptibility of the strain to opportunistic infections and because current studies suggest that they have an autoimmune diathesis, of which IDD is but one result, aspects of the immune system of the BB rat were studied. Severe T lymphopenia was observed in all BB rats, irrespective of sex or the presence of IDD, while numbers of B cells and serum immunoglobulin levels were normal. Both the helper T lymphocyte and cytotoxic/suppressor T lymphocyte subsets, defined by reactions with monoclonal antibodies, were depressed, and an inversion of the helper T cell subset to cytotoxic/suppressor T lymphocyte subset ratio occurred in all BB rats with increasing maturity. Concomitantly, severe impairments of T cell-mediated immune responses were noted. BB rats poorly rejected allografts across both major and minor histocompatibility barriers, and BB splenic or peripheral blood lymphocytes had markedly defective proliferative responses to mitogens and to allogeneic cells in MLC. Irradiated and nonirradiated BB spleen cells did not inhibit WF mitogenic or MLC responses, which suggests that the T cell defect in BB rats is not solely due to increased suppressor activity. Because irradiated WF cells and Con A supernatants did not restore BB proliferative responses, and BB lymphocytes were able to produce IL-2 normally, a reduced ability of BB lymphocytes to respond to helper factors such as IL-2 is suggested. In contrast to T lymphocytes from spleen or peripheral blood, BB thymocytes responded as well as did WF thymocytes to Con A or Con A supernatants. Percentages of T lymphocyte subsets and histology of BB thymuses were also normal when compared to WF thymuses. However, spleens and lymph nodes from BB rats were severely depleted of T lymphocytes, and thymocytotoxic autoantibodies were detected in many BB rat sera. The above findings indicate that BB rats have T lymphocyte immunoincompetence, which appears to be a post-thymic or peripherally acquired maturational defect.

Animals↗