Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human leukocyte antigens (HLA) are transmembrane bicatenar glycoproteins; their heavy chain is coded by chromosome 6 and carries allotypic determinants. These molecules are present in nearly every cell, tissue and biologic fluid. Their congenital absence from fibroblasts is associated with progeria, while their absence from lymphocytes is associated with immunodeficiency. HLA antigens are usually studied microlymphocytotoxicity tests. The numerous cross-reactions encountered make the interpretation of results quite difficult. To clearly understand these reactions a complex-complex model is mandatory. The antigen, the HLA molecule, is complex since it carries many antigenic determinants; some of them are private ("subtypic"), while others are public ("subtypic"). Anti-HLA antibodies are also complex since they are heterogeneous, reacting with variable affinity with different antigenic determinants. The in vitro cross-reactions represent a partial explanation for varying cross-immunogenicity in vivo.
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PMID:[Serologic properties of antigens HLA-A, B and C]. 700 27

Basophils and mast cells, as the main effector cells in IgE-mediated type I hypersensitivity, are involved in the elimination of parasites and, according to recent findings, may also play an important role in the defense against bacterial and viral infections. Using a genetic engineering approach we wanted to redirect this potent IgE-mediated defense system against intruding human immune deficiency virus. We constructed a recombinant CD4-IgE molecule, consisting of the two N-terminal domains of CD4 and the CH2-4 domains of the IgE heavy chain, thus providing the IgE with specificity for the gp120 of human immunodeficiency virus (HIV). The binding properties of hybrid CD4-IgE to the high-affinity receptor for IgE (Fc epsilon RI) on basophils as well as to the low-affinity receptor (Fc epsilon RII or CD23) for IgE on lymphoid cells were found to be similar to those of native IgE. At the same time, the CD4 domains of the recombinant molecule retained the gp120 binding specificity with an affinity similar to that of the native CD4. By functional tests, we demonstrated that CD4-IgE armed basophils can be triggered by free HIV and by HIV-infected cells to release their mediators. We further show that HIV-triggered basophils lead to a decreased replication of HIV in susceptible T cells. We, therefore, conclude that the type I hypersensitivity effector cells can be engaged in the elimination of HIV-infected cells, at least in vitro. Because of the strong binding of the CD4-IgE construct to the Fc epsilon RI, we assume that CD4-IgE has a short t1/2 in serum, but may similarly to IgE exhibit prolonged resident time on basophils and mast cells, which are located close to mucosal surfaces or in the connective tissue. Thus CD4-IgE could play an important role in the elimination of HIV also in vivo.
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PMID:Recombinant CD4-IgE, a novel hybrid molecule, inducing basophils to respond to human immunodeficiency virus (HIV) and HIV-infected target cells. 753 Nov 44

Recombinant CD4-immunoglobulin G (rCD4-IgG) is a 98-kDa human immunoglobulin-like protein that is produced by fusing the gp120 binding domain of CD4 to the Fc portion of the human IgG1 heavy chain. This hybrid molecule was given to human immunodeficiency virus (HIV)-infected pregnant women at the onset of labor by intravenous bolus at 1 mg/kg of body weight (group A; n = 3) and 1 week prior to and at the onset of labor by the same route and at the same dose (group B; n = 3). In addition to pharmacokinetic studies, safety in the mothers and infants was determined through routine chemistries, hematology, and urinalysis; immunologic and HIV infection statuses in the infants were assessed through lymphocyte cultures, p24 antigen level determination, culture of HIV from plasma, PCR, lymphocyte subset enumeration, quantitative immunoglobulin analysis, and lymphocyte proliferation. Thirty minutes after the rCD4-IgG injection, concentrations in maternal serum were 12 to 23 micrograms/ml. These concentrations declined slowly, with initial and terminal half-lives (mean +/- standard deviation) of 9.95 +/- 3.23 and 47.6 +/- 22.3 h, respectively. Infants were born 2.6 to 46.5 h after rCD4-IgG administration; concentrations of rCD4-IgG in cord blood ranged from 28 to 107 ng/ml. The half-life of rCD4-IgG in infants ranged from 5 to 29 h. These data demonstrate that the transfer of rCD4-IgG from the mother to the fetus is rapid and that newborns do not appear to have any difficulty eliminating rCD4-IgG. No safety concerns in mothers or infants were encountered. Although the study did not address the question of efficacy, none of the infants was HIV type 1 infected 36 months later. In summary, these findings document that bifunctional immune molecules can be transported across the placenta, and this general approach may be used in the future to block vertical transmission of HIV type 1.
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PMID:Transport of recombinant human CD4-immunoglobulin G across the human placenta: pharmacokinetics and safety in six mother-infant pairs in AIDS clinical trial group protocol 146. 766 72

Most patients with common variable immunodeficiency (CVI) have normal numbers of circulating B cells but low concentrations of serum Ig. To determine if the hypogammaglobulinemia is caused by an intrinsic B cell defect, we studied B cell function of 22 CVI patients. Cultured B cells from all CVI patients underwent normal proliferation and synthesized normal quantities of IgE in the presence of anti-CD40 and IL-4. If cultured with anti-CD40 and IL-10, four patterns of Ig isotype synthesis were observed. Six CVI patients produced normal amounts of IgM, IgG, and IgA. Four patients produced normal quantities of IgM and IgG. Of the remaining 12 patients who failed to synthesize IgG and IgA, 8 produced normal and 4 synthesized decreased amounts of IgM. Analysis of the IgG subclasses produced by 10 patients with IgG-secreting B cells revealed that IgG4 was the most affected subclass, followed by IgG2; synthesis of IgG3 and IgG1 remained normal. Similarly, in the six IgA producing patients, IgA2 was more often affected than IgA1. The hierarchy of Ig isotype and subclass synthesis corresponds to Ig heavy chain constant region gene location on chromosome 14. Thus, circulating B cells of CVI patients are committed to synthesize one or more Ig isotypes or subclasses, and under proper conditions can proliferate, mature into Ig-secreting cells, and undergo class switch to IgE.
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PMID:Activated B cells from patients with common variable immunodeficiency proliferate and synthesize immunoglobulin. 769 Jul 75

Complexity in the activation/regulatory apparatus and the variable nature of the antigen-binding site dictate that B and T cells establish and select, during their development, appropriate activation and control mechanisms beyond simple antigen-binding specificity. These mechanisms are established partly by fixed interactions dictated by genetically defined structures, but they are also attained by calibration during ontogeny. This calibration depends on the ordered expression of early components (each of which is invariant), on their interaction with specific ligands, and on the receipt of invariant signals for calibration. Lymphocytes calibrate themselves by expressing various cell surface components, such as restricted heavy chain D-regions and pseudo-light chains. These are expressed in association with elements that will make up the antigen-receptor complex of mature lymphocytes. Calibration by invariant signals results in the establishment, selection and active maintenance of cellular activities which serve to control lymphocyte function. Since these cellular activities are one of a number of possible conditions, they are referred to as variant controls. Effectively calibrated basic cellular functions, specialized responses and cellular interactions allow lymphocytes to attain self-nonself discrimination. If calibration fails, lymphocytes will develop abnormalities, such as immunodeficiency and autoimmunity.
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PMID:Do lymphocytes require calibration? 769 21

Inactivated simian immunodeficiency virus (SIV) grown in a human T-cell line induces protection from infection by the virus in macaques. However, observations that immunization with uninfected human T cells or with SIV-1 prepared in human T cells can also induce protection, has raised the possibility that protective antigens could be of human cellular origin. Sera from animals immunized with fixed infected and uninfected human T cells, as well as from animals immunized with partially purified cell-free SIV have been examined for their ability to bind to human and macaque peripheral blood mononuclear cells (PBMC) and to-components present in fetal calf serum (FCS) in which the cells were grown. Analysis by flow cytometry suggests that antibodies to human cell surface antigens can be elicited with both inactivated SIV grown in human T cells and by uninfected T cells. There was a significant association between the presence of anti-cell antibodies and protection from infection. However, anti-cell surface antibodies were not detected with macaque mononuclear cells by flow cytometry or by immunoprecipitation, unless these cells were first treated with FCS or activated by a mitogen. Immunoprecipitation of resting human PBMC with sera from immunized animals suggests the presence of antibodies to class I heavy and light chains [beta 2-microglobulin (beta 2 m)] and to bovine beta 2m, which may originate in FCS used to grow the cell line. Antibodies to CD4 were also found in sera from animals immunized with SIV grown in human T cells. We suggest that human cellular components augmented by FCS elicit anti-class I heavy chain, beta 2m, CD4 and FCS antibodies which may be responsible for protection against SIV infection in macaques.
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PMID:Antibodies to human and non-human primate cellular and culture medium components in macaques vaccinated with the simian immunodeficiency virus. 783 37

Patients undergoing bone marrow transplantation are humorally immunodeficient for one or more years post-transplant. This immunodeficiency could be partially caused by B cell repertoire restriction similar to that observed in ontogeny. To test this idea, the abundance of rearranged genomic segments bearing five variable heavy chain (VH) genes was compared in patients at several timepoints post-transplant and in immunologically normal neonates, infants and adults. The genes evaluated in the study (VH6, VH4-58p2, VH3-56p1, VH3-20p1 and VH3-13-2) were selected from those commonly utilized by fetal B cells. The assay employed quantitative PCR and oligonucleotide hybridization detection under conditions designed to detect relatively unmutated forms of these genes. In blood B cells from early post-transplant (2-5 months) patients, these VH genes were markedly overutilized compared with normal adults. B cells from late post-transplant (6-21 months) patients and from normal neonates and infants also overutilized these genes; however, to a lesser degree than early post-transplant B cells. The data suggest that, as in ontogeny, the B cell repertoire is strikingly restricted to fetal-type VH genes early post-transplant, and may become normal only very late (years) post-transplant.
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PMID:Abundance of a restricted fetal B cell repertoire in marrow transplant recipients. 788 12

Peripheral blood mononuclear cells (PBMC) from human immunodeficiency virus (HIV)-infected patients, asymptomatic or with acquired immunodeficiency virus, produced 10-fold less interleukin 12 (IL-12) free heavy chain and fivefold less biologically active IL-12 heterodimer than PBMC from uninfected healthy donors when challenged in vitro with the common human pathogen Staphylococcus aureus. In contrast, PBMC from HIV-infected individuals and uninfected control donors produced similar levels of tumor necrosis factor alpha, IL-1 beta, and IL-10, and PBMC from HIV-infected individuals produced three- to fourfold more IL-6 compared with PBMC from uninfected control donors. The defect in IL-12 production is not due to hyperproduction of IL-10, a cytokine exerting an autocrine-negative feedback on IL-12 production, but was directly related to HIV infection, as suggested by the reduced ability of monocytes infected in vitro with HIV to produce IL-12. IL-12 deficiency may be an important component of the immunodeficiency associated with HIV infection.
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PMID:Impaired interleukin 12 production in human immunodeficiency virus-infected patients. 790 24

Hyper-IgM syndrome is a rare immunodeficiency characterized by low or absent IgG, IgA, and IgE with normal or elevated levels of IgM. It can occur as an acquired or familial disorder with either X-linked or autosomal modes of inheritance. The X-linked form (HIGM1) is a result of mutations in the CD40 ligand (CD40L) gene, but the defect in non-X-linked forms of the disease (HIM) has not been determined. We show here that CD40L expression on activated T cells from non-X-linked patients can be detected by CD40Fc, 5c8 Mab, and anti-TRAP, whereas activated T cells from HIGM1 patients either had no detectable CD40L (Type I), or stained with anti-TRAP but not CD40Fc or 5c8 (Type II). Activated T cells from obligate carriers varied from low to normal expression of CD40L. B cells from HIGM1 and non-X-linked HIM patients proliferated in response to CD40L. Costimulation of B cells from HIGM1, from sporadic HIM, or from non-X-linked HIM patients with CD40L plus IL-2 resulted in some IgM production, but no significant IgG or IgA. Costimulation with CD40L plus IL-10 resulted in significant IgG and/or IgA secretion by B cells from some HIGM1 patients, but consistently failed to stimulate IgG or IgA secretion by B cells from non-X-linked patients. In addition, costimulation with CD40L and IL-4 failed to induce IgE secretion by B cells from one non-X-linked HIM patient, and induced a weak response in another. These results suggest that patients with non-X-linked forms of HIM may have an intrinsic B cell defect preventing heavy chain switching, which is not related to expression of CD40L.
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PMID:CD40 ligand (CD40L) expression and B cell function in agammaglobulinemia with normal or elevated levels of IgM (HIM). Comparison of X-linked, autosomal recessive, and non-X-linked forms of the disease, and obligate carriers. 791 70

The rapid whole blood test, developed for the detection of circulating antibodies to human immunodeficiency virus type 1 (HIV-1), is based on agglutination of autologous red blood cells using an anti-human glycophorin antibody conjugated to the HIV-1 immunodominant epitope of gp41 (579-613). A simplified procedure for preparing antibody-peptide conjugates for use in the autologous red cell agglutination test is described. F(ab')2 fragments of the anti-glycophorin antibody were prepared by pepsin digestion and reduced to F(ab') fragments with the use of tri-n-butylphosphine (TBP). This permitted the simultaneous reduction of the F(ab') fragments and coupling of a bromoacetyl derivative of the synthetic immunodominant peptide gp41 (579-613) [Cys-Acm 598, Lys-BrAc 604] containing epsilon-bromoacetyl-lysine at residue 604 to the resultant F(ab') fragment. Conjugation to the F(ab') fragment resulted in a stable thio-ether linkage between the peptide Lys-604 and the inter heavy chain cysteines of the F(ab'). The resultant F(ab')-peptide conjugate was comparable to the previously described disulfide coupled conjugate when used in the autologous red cell agglutination test. This simplified conjugation chemistry may also be useful for the development of reagents for FACS analysis as well as targetted vaccines.
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PMID:Simplified conjugation chemistry for coupling peptides to F(ab') fragments: autologous red cell agglutination assay for HIV-1 antibodies. 793 Jun 54


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