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)

In a search for novel factors that interact with the octamer element, immunoglobulin kappa light chain (V kappa) and heavy chain VH) gene promoters were compared for binding to nuclear proteins from lymphoid cells. Both promoters showed a similar pattern of bound factors, which was entirely different from that seen with the human immunodeficiency virus, type I promoter. Besides OTF-1 (Oct-1) and OTF-2 (Oct-2), at least three additional complexes were observed. Two of these were functionally analyzed: C1, a slowly migrating complex, which was much more abundant in B cells than in non-lymphoid cells, and C4, which appeared to have ubiquitous distribution. As determined by several methods, the protein(s) forming the C1 complex bound on the V kappa gene to a site that partially covers the octamer element, whereas, surprisingly, in the VH gene a region spanning the TATA box up to the transcriptional initiation site was recognized. The ubiquitous C4 complex was analyzed for the light chain promoter. The protein specifically bound to a site immediately 5' to the octamer. By in vitro transcription analysis, we found that C4 augments the octamer-dependent transcription of the V kappa gene. The activation required binding of OTF-1/OTF-2, and C4 could not stimulate transcription by itself, implying a synergistic interaction. Due to the overlapping binding sites, the effect of C1 by itself could not be clearly separated from the C4 effect. However, the specific interaction of C1 with crucial control elements of light chain and heavy chain promoters strongly suggests a functional role in immunoglobulin gene transcription control.
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PMID:Identification of novel ubiquitous and cell type-specific factors that specifically recognize immunoglobulin heavy chain and kappa light chain promoters. 805 Oct 94

Using the process of "antibody antigenization," we engineered two antibody molecules carrying in the third complementarity-determining region of the heavy chain variable domain a 7-mer or a 15-mer peptide epitope of the first extracellular domain (D1) of human CD4 receptor--namely, Ser-Phe-Leu-Thr-Lys-Gly-Pro-Ser (SFLTKGPS; positions 42 through 49) and Gly-Ser-Phe-Leu-Thr-Lys-Gly-Pro-Ser-Lys-Leu-Asn-Asp-Arg-Ala (GSFLTKGPSKLNDRA; positions 41 through 55). These amino acid sequences are contained in the consensus binding site for the human immunodeficiency virus (HIV) on CD4 receptor. Both antigenized antibodies (AgAbs) bound recombinant gp120 and were recognized by a prototype monoclonal antibody to CD4 whose binding site is within amino acid residues 41-55. AgAbs were then used as immunogens in rabbits and mice to elicit a humoral response against CD4. Only the AgAb carrying the sequence 41GSFLTKGPSKLN-DRA55 induced a response against CD4. The induced antibodies showed specificity for the amino acid sequence of CD4 engineered in the AgAb molecule, were able to inhibit the formation of syncytia between human CD4+ T cells MOLT-3 and 8E5 (T cells that are constitutively infected with HIV), and stained human CD4+ CEM T cells. Four murine monoclonal antibodies were used to analyze the relationship between syncytia inhibition and CD4 binding at the single antibody level, and indicated that recognition of native CD4 is not an absolute requirement for inhibition of syncytia. This study demonstrates that antigenized antibodies can be used as immunogens to elicit site-specific and biologically active immunity to CD4. The importance of this approach as a general way to induce anti-receptor immunity and as a possible new measure to immunointervention in HIV infection is discussed.
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PMID:Active immunity against the CD4 receptor by using an antibody antigenized with residues 41-55 of the first extracellular domain. 826 9

Lymphoproliferations associated with Epstein-Barr virus (EBV) commonly arise in settings of immune dysfunction, including human immunodeficiency virus (HIV) infection. In this study, EBV was associated with 39 of 59 (66%) HIV-related systemic lymphomas. Unlike the lymphoproliferations that arise in the setting of transplantation, the HIV-related lymphomas were monoclonal, as evaluated by Ig heavy chain rearrangements and EBV termini analysis, and associated (40%) with c-MYC rearrangements. Furthermore, analysis of multiple lymphoma tissues from one autopsy showed evidence that a single lymphoma clone was responsible for dissemination. The latent EBV nuclear antigen (EBNA-1) transcripts detected in the HIV-related lymphomas were characteristic of the pattern found in Burkitt lymphoma (g1 EBNA1) and not in transplant-related lymphoproliferations. However, unlike Burkitt lymphoma, EBV latent membrane-associated protein (LMP) transcripts were also detected, thereby constituting an EBV expression pattern (g1 EBNA1+, LMP+) not previously observed in B-cell lymphomas. These findings demonstrate a high frequency of EBV-associated lymphomas in the setting of HIV infection that are distinct from the lymphoproliferations that arise during iatrogenic transplant-associated immuno-suppression or in the general population. However, it is also apparent that HIV-related lymphomas are biologically heterogeneous, which may reflect the multiple mechanisms or steps necessary for eventual malignant transformation.
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PMID:Epstein-Barr virus-associated non-Hodgkin's lymphoma in patients infected with the human immunodeficiency virus. 812 67

Epstein-Barr virus (EBV) is generally held to infect B cells and epithelial cells, although there are now reports of EBV infection in normal T cells and neoplastic T-cell diseases. In patients with human immunodeficiency virus (HIV) infection, EBV is associated with the benign epithelial lesion, hairy leukoplakia, and has been reported in up to 80% of acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma. This study shows the presence of EBV in malignant oral T-cell lymphoma in three AIDS patients, two of whom had concurrent manifestation of hairy leukoplakia. The T-cell lineage of the tumor cells was determined by positive immunophenotyping for T-cell markers and lack of B-cell or nonhematopoietic (cytokeratin) determinants. All tumors contained monoclonal T-cell populations shown by polymerase chain reaction, which showed amplification of T-cell receptor gamma chain DNA without evidence of Ig heavy chain gene rearrangement. Furthermore, these lesions showed the presence of EBV DNA and expression of EBV latent gene products in the tumor cells. EBV involvement in AIDS-related T-cell lymphoma has not been widely reported and may represent a further manifestation of opportunistic EBV infection arising in the HIV-immunocompromised host.
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PMID:Epstein-Barr virus-related oral T-cell lymphoma associated with human immunodeficiency virus immunosuppression. 838 15

We describe a patient with angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), who subsequently developed large-cell immunoblastic lymphoma of B-cell immunophenotype. At the time of the initial diagnosis, histologic examination of an inguinal lymph node showed typical features of AILD, and there was no evidence of a monoclonal B-cell population by immunohistochemical analysis. In situ hybridization and Southern blot analysis for Epstein-Barr virus (EBV) were negative. At autopsy 2 years later, the patient had widespread lymph node and organ involvement by large-cell immunoblastic lymphoma of B-cell immunophenotype. Southern blot analysis performed on DNA extracted from lymph nodes, liver, and spleen showed two patterns of Ig heavy chain and kappa light chain gene rearrangements. The T-cell receptor beta chain gene was in the germline configuration. Analysis with an EBV terminal repeat region probe showed two clonal populations that paralleled the Ig gene rearrangement studies. Double-labeling immunohistochemistry and in situ hybridization confirmed the presence of EBV within the neoplastic B cells. The data support the hypothesis that EBV was not etiologically related to AILD in this case, and that EBV proliferation may occur after the onset of the disease. Further, the data suggest that some B-cell lymphomas that arise in the setting of AILD resemble EBV-associated B-cell lymphomas that arise in other immunodeficiency states.
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PMID:B-cell lymphoma after angioimmunoblastic lymphadenopathy: a case with oligoclonal gene rearrangements associated with Epstein-Barr virus. 839 75

Vitamin A deficiency severely compromises the magnitude of the primary and secondary antibody response to tetanus toxoid (TT) but does not impair the development of immunologic memory. To further characterize this immunodeficiency in antibody production, we have quantified the immunoglobulin G (IgG) subclasses (IgG1, IgG2a, IgG2b, and IgG2c) during the primary and secondary response to TT in normal, vitamin A-deficient, and retinol-repleted rats. In the primary response in normal rats, anti-TT IgG1 and IgG2b predominated. In vitamin A-deficient rats the production of anti-TT IgG2b was severely impaired, with little change in either IgG1 or IgG2a. In the secondary response vitamin A-deficient rats produced low levels of all anti-TT IgG subclasses. However, when vitamin A-deficient rats were repleted with retinol 2 days before reimmunization their secondary anti-TT IgG response was normal both in magnitude and IgG subclass distribution. This result implies that although vitamin A deficiency during the primary antibody response impaired anti-TT IgG2b production, it did not inhibit Ig heavy chain recombination or the differentiation of lymphocytes that formed memory B cells for each subclass; furthermore, these cells were activated in the secondary response after vitamin A status was improved. Thus, these experiments further support the concept that memory cell formation remains normal during vitamin A deficiency despite low levels of antibody production.
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PMID:Vitamin A status and immunoglobulin G subclasses in rats immunized with tetanus toxoid. 840 13

The present study set out to investigate whether phage display could be used to improve the properties of a high-affinity human monoclonal antibody directed against the third hypervariable loop (V3 loop) of human immunodeficiency virus (HIV). The aim was to increase affinity through slowing the dissociation rate (off-rate constant of koff), whilst retaining the ability of this antibody to bind diverse V3 loop sequences. When reformatted as a scFv, the antibody fragment retained the properties of the parental IgG, including the ability to neutralise virus. Heavy and light chains were sequentially replaced with repertoires of variable domains from non-immunised human donors followed by selection on biotinylated synthetic peptide. All selected variants derived from the same germline as the parental antibody. Variants of the light chain provided little if any improvement, whereas two residue changes in VHCDR2 and one in VHFR3 resulted in a reduced koff from gp120 protein of the MN strain (MNgp120) and synthetic V3 loop peptides as measured by surface plasmon resonance using the BIAcore instrument (Pharmacia Biosensor). VHCDR3 was modified using synthetic oligonucleotides and several clones with reduced koff identified, a number of different substitutions occurring at a single residue position. The residues in the heavy chain identified as reducing koff were simultaneously randomised by site-directed mutagenesis, resulting in scFv variants with koff slowed up to sevenfold. Far from compromising recognition of variant loops, binding to these sequences was improved; the koff from synthetic peptides modelled on V3 loop variants being slowed to a degree similar to that observed with MNgp120. All four changes were located towards either extremes of CDRs 2 and 3, suggesting that the mechanism of improvement may be one of alternation of loop conformation. This work illustrates that phage display can be used to tailor the properties of a therapeutic monoclonal antibody in a predefined fashion.
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PMID:Affinity maturation of a high-affinity human monoclonal antibody against the third hypervariable loop of human immunodeficiency virus: use of phage display to improve affinity and broaden strain reactivity. 860 15

We studied a patient who had a typical seronegative rheumatoid arthritis (RA) and an immunodeficiency with hyper-IgM (HIM syndrome). CD40L was normally expressed by activated T cells, but CD40-mediated signal transduction was defective in B cells, preventing heavy chain switching (CD40L+ type of the HIM syndrome). These data suggest that a typical RA can develop in at least some patients with dysfunction of the CD40 pathway, i.e. in the absence of a normal co-operation between T and B cells. Accordingly, the blockade of CD40L-CD40 interactions, which has been proposed as a treatment of RA, might not be adapted to all patients.
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PMID:Hyper-IgM syndrome associated with rheumatoid arthritis: report of RA in a patient with primary impaired CD40 pathway. 862 Mar 5

A human Fab phage display library has been produced from peripheral blood lymphocytes of an individual who was asymptomatic after 10 years of infection with human immunodeficiency virus type-1 (HIV-1). The library was panned against the HIV-1 Rev and Tat regulatory proteins and several clones, producing Fab binding to these proteins, were isolated (3 to Rev and 4 to Tat) with binding constants varying from 10(-6)M to 10(-8)M. DNA sequencing demonstrated two unique anti-Rev Fab clones, but the four anti-Tat Fab comprised only two unique IgG1 heavy chain Fd fragments, illustrating redundancy of light chains. Peptide mapping of the epitopes recognized by these Fab indicated that three of the anti-Tat Fab were directed to the functional domain between amino acid residues 22-33 of the Tat molecule, and that binding was inhibited by reduction of this cysteine-rich region with dithiothreitol. The anti-Rev Fab were directed to sites adjacent to the Rev basic nucleolar localization sequence (residues 52-64) and to the Rev activation domain (residues 75-88). Binding constants were of a similar order to that of an anti-Rev single-chain Fv fragment (SFv) used successfully for intracellular immunization, and as such intracellular effects with the human anti-Tat and anti-Rev Fab are not precluded. These newly described human antibody fragments to HIV-1 regulatory proteins may be critical moieties for gene therapeutic protocols, to control HIV-1 replication in human cells.
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PMID:Recombinant human Fab antibody fragments to HIV-1 Rev and Tat regulatory proteins: direct selection from a combinatorial phage display library. 867 95

A case report of a 16 year old boy in whom selective IgA deficiency progressed to typical common variable immunodeficiency (CVID) is described. This boy with a history of frequent but not severe respiratory tract infections was referred to hospital because of severe pleuropneumonia and decreased levels of IgA (0.23 g/L), but normal IgG and IgM levels. Lymphocyte subpopulation determination revealed a decreased proportion of CD4+ lymphocytes (30%) and an increased proportion of CD8+ lymphocytes (32%), while CD3+, CD19+ and CD16+/56+ subpopulations were normal. During the subsequent 17 months a gradual decrease in IgG (ultimate level 2.23 g/L), IgA (< 0.05 g/L) and IgM (< 0.05 g/L) levels was observed, the decrease in IgM being the slowest reflecting a constant heavy chain gene order on chromosome 14. The observation supports the thesis of a close relation of selective IgA deficiency and common variable immunodeficiency.
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PMID:Progression of selective IgA deficiency to common variable immunodeficiency in a 16 year old boy. 893 74


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