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At least 811 records · Page 45Linked to original sources
PubMed1983

Evidence for HLA-linked susceptibility factors in childhood leukemia.

To test the hypothesis that susceptibility to leukemia can be governed by (a) recessive gene(s) associated with the major histocompatibility complex (MHC) in man, we performed an analysis of the inheritance of HLA antigens in 55 families in which one of the children developed ALL. We found among the parents of affected children a highly significant increased compatibility at the DR locus (p = 0.003). A similar increase was observed in sharing HLA antigens of the B locus (p = 0.02). The observed number of homozygotes among the patients was twice the expected value in families where the parents shared a B and a DR antigen. In segregation analysis, heterozygotes for the shared parental HLA antigen were significantly more prevalent among the healthy siblings. Our genetical analysis indicates that mating of certain shared alleles of the HLA system (especially of the DR locus) is associated with the risk for the offspring to develop ALL in childhood. This situation favors the expression of recessive genes associated with the MHC, and presumably those involved in the susceptibility to acute leukemia. Because familial leukemia is a rare event, the susceptibility to childhood ALL must also implicate genes outside the MHC and important environmental factors.

Child↗
PubMed1987

Presentation of soluble antigen to human T cells by products of multiple HLA-linked loci: analysis of antigen presentation by a panel of cloned, autologous, HLA-mutant Epstein-Barr virus-transformed lymphoblastoid cell lines.

Epstein-Barr virus-transformed human B lymphoblastoid cell lines (EBV-LCL) can present soluble antigens to antigen-primed T lymphocytes. In this study, we used HLA antigen-loss mutants of an EBV-LCL line (LCL 721) to demonstrate that the presentation of a soluble antigen from Candida albicans (CAN) by EBV-LCL to primed T cells can be restricted by multiple HLA determinants. Haplotype-deletion mutants that contained only the maternal or only the paternal HLA-haplotype were used to demonstrate the preferential role of autologous HLA antigens in presenting soluble antigens to Candida-primed T cells from the donor of LCL-721, and to T cells from her mother and father. Immunoselected mutants of LCL-721 showing a variety of distinct phenotypes that are deficient in HLA-DR, DQ, or DP antigen expression were tested as antigen-presenting cells. The antigen-presenting ability of these class II deficient EBV-LCL variants weakened with progressive loss of class II HLA determinants expressed on the cell surface. Our study, therefore, provides evidence for multiple HLA restriction determinants, including HLA-DR, DQ, and DP. Furthermore, LCL lacking all HLA-DR, DQ, and DP expression because of homozygous deletion of these MHC class II genes still presented CAN and Tetanus toxid (TET), although to a much lesser degree than presented by LCL-721. This suggests that determinants other than DR, DQ, and DP which are expressed on these EBV-LCL may also function as restriction elements for the proliferative T-cell response to soluble antigens.

Antigen-Presenting Cells↗
PubMed1982

The rex region of bacteriophage lambda: two genes under three-way control.

The nucleotide sequence of the phage lambda rex region consists of 1428 bp and codes for two genes, rexA and rexB. Hence the complete lambda immunity region codes for four genes and covers 2664 bp of sequence unique to lambda, as defined by the left and right boundaries of the imm434 region. Coordinate expression of both rexA and rexB, which are co-regulated with the cI repressor gene from promoters p rm and p re is responsible for the Rex phenotype, i.e. exclusion of a wide variety of superinfecting phage such as T4rII. The position of a third promoter, p lit, which overlaps the carboxy-terminal end of the rexA coding region, permits expression of rexB without rexA, from the resulting 470 nucleotide lit RNA. The lit transcript, therefore, must act as messenger for rexB in the noncoordinate expression of the rex genes that occurs late in lambda lytic infection. The coordinate and noncoordinate expression of rexB and rexA suggests a dual role for the very hydrophobic rexB protein. Studies of lambda early and late DNA replication implicate rexB as having auxiliary functions in both lysogenisation and lytic infection.

Bacteriophage lambda↗
PubMed2005

The role of viral and host genes in corneal infection with herpes simplex virus type 1.

Herpes simplex virus infection of the eye is the leading cause of blindness due to infection in the US despite the availability of several antiviral drugs. Studies with animal models have shown that three factors, innate host resistance, the host adaptive immune response, and the strain of virus interact to determine whether an infection is asymptomatic or proceeds to the development of blinding keratitis (HSK). Of these, the role of adaptive immunity has received the most attention. This work has clearly shown that stromal keratitis is an immunopathological disease, most likely due to the induction of a delayed type hypersensitivity response. Substantially less is known about the role of specific host genes in resistance to HSK. The fact that different strains of virus display different disease phenotypes indicates that viral 'virulence' genes are critical. Of the 80 plus HSV genes, few have been formally tested for their role in HSV keratitis. Most studies of virulence genes to date have focused on a single gene or protein and large changes in disease phenotypes are usually measured. Large changes in the ability to cause disease are likely to reduce the fitness of the virus, thus such studies, although useful, do not mimic the natural situation. Viral gene products are known to interact with each other, and with host proteins and these interactions are critical in determining the outcome of infection. In reality, the 'constellation' of genes encoded by each particular strain is critical, and how this constellation of genes works together and with host proteins determines the outcome of an infection. The goal of this review is to discuss the current state of knowledge regarding the role of host and viral genes in HSV keratitis. The roles of specific genes that have been shown to influence keratitis are discussed. Recent data showing that different viral genes cooperate to influence disease severity and confirming that the constellation of genes within a particular strain determines the disease phenotype are also discussed, as are the methods used to test the role of viral genes in virulence. It will become apparent that there is a paucity of information regarding the function of many viral genes in keratitis. Improving our knowledge of the role of viral genes is critical for devising more effective treatments for this disease.

Animals↗
PubMed2006

HLA-associated production of anti-DFS70/LEDGF autoantibodies and systemic autoimmune disease.

Autoantibodies against DFS70/LEDGF, which is also known as an important partner of HIV-1 integrase, are found in 10% of healthy Japanese people, but in only approximately 2% of patients with systemic autoimmune disease (SAD). We wished to characterize the association of HLA class II alleles with the presence of autoantibodies against this molecule. MHC class II genes (DR, DQ, and DP alleles) were analyzed by the polymerase chain reaction-sequence specific primer method in 24 individuals with anti-DFS70 antibodies. The frequencies of HLA-DRB1*0410, -DQB1*0402, and -DPB1*0301 were increased in anti-DFS70 Ab-positive patients, while HLA-DQB1*0302 was decreased compared to Japanese controls. All anti-DFS70 Ab-positive individuals expressed at least one HLA-DQB1 allele with an aspartic acid at residue 57. The immunogenetic background of Japanese individuals with anti-DFS70 antibodies differs from that of patients with SAD. HLA class II genes influence the production of anti-DFS70 antibodies among individuals with various clinical manifestations.

Adaptor Proteins, Signal Transducing↗
PubMed1978

HLA antigens in severe pre-eclampsia.

When the HLA types of 80 pre-eclamptic women and their husbands and 83 control couples were compared significantly more pre-eclamptic women had only one identifiable HLA B antigen, and were presumed to be homozygous at this locus. Those who were homozygous for HLA B were more likely to be homozygous for HLA A as well, and more likely to be homozygous for HLA A as well, and to have more severe pre-eclampsia. There was neither increased HLA incompatibility nor greater antigen-sharing between pre-eclamptic women and their husbands, but maternal HLA A and B homozygosity reduced the number of antigenic disparities between pre-eclamptic women and their husbands. The data are consistent with the hypothesis that maternal recessive immune-response genes may contribute to the development of pre-eclampsia. Alternatively maternal HLA homozygosity may predispose to fetal changes comparable to runting.

Epitopes↗
PubMed2003

The IRF-2 DNA binding domain facilitates the activation of the class II transactivator (CIITA) type IV promoter by IRF-1.

IFN-gamma induced transcription of class II transactivator (CIITA), a major regulator of MHC class II gene expression, is directed by the CIITA type IV promoter. The IFN-gamma activation of the CIITA type IV promoter is mediated by STAT1 and IRF-1, which bind to the GAS and IRF-E of the promoter, respectively. We and others have determined that IRF-2, another member of the IRF family, also activates the CIITA type IV promoter, by binding to the IRF-E. Also, IRF-2 cooperates with IRF-1 to activate the promoter. DNA binding analyses determined that IRF-1 and IRF-2 can co-occupy the IRF-E of the CIITA type IV promoter. To further understand the mechanism of IRF-1 and IRF-2 cooperativity in the activation of CIITA type IV promoter, we characterized the binding of IRF-1 and IRF-2 to the CIITA IRF-E and mapped the domains of IRF-2 required for the cooperative transactivation. Off-rate experiments revealed that the IRF-2/IRF-E complex was more stable than the IRF-1/IRF-E complex and that the affinity of IRF-1 for the IRF-E was increased when IRF-1 co-occupied the IRF-E with IRF-2. Deletion analysis of functional domains of IRF-2 revealed that a previously described latent activation domain of IRF-2 was essential for IRF-2 transactivation and participated in cooperative activation of the CIITA promoter by IRF-1 and IRF-2. However, the DNA binding domain of IRF-2 was sufficient for cooperativity with IRF-1 in the activation of the CIITA type IV promoter. DNA binding assay demonstrated that, like the full-length IRF-2, the IRF-2 DNA binding domain could co-occupy the CIITA IRF-E with IRF-1.

Animals↗
PubMed1998

Down modulation of MHC surface molecules on B cells by suppressive immune complexes obtained from chronic intestinal schistosomiasis patients.

Granulomatous inflammation around parasite eggs is the prominent lesion in human schistosomiasis. Studies have suggested the involvement of a series of suppressive mechanisms in the control of this reaction, such as macrophages, cytokines, idiotypic interactions and immune complexes (IC). The studies examine the role of IC obtained from chronic intestinal schistosomiasis patients (ISP) in the reactivity of peripheral blood mononuclear cells (PBMC). The results have shown that these immune complexes are able to suppress cell reactivity by inducing an increase in the production of soluble mediators such as prostaglandins and IL-10. To gain a better understanding of how this suppression occurs the present study examines the phenotypic pattern of PBMC after immune complex treatment in cell proliferation assays. These data show that cultures including immune complex present a higher percentage of B lymphocytes in which a lower expression of a MHC-class II gene product, HLA-DR was detected. This altered expression of the HLA-DR molecule on B lymphocytes after IC treatment suggests a novel mechanism for the suppression observed, that is, IC might decrease the antigen-presenting function of B lymphocytes.

Antigen-Antibody Complex↗
PubMed2000

Impaired NFAT regulation and its role in a severe combined immunodeficiency.

Severe Combined Immunodeficiency (SCID) is a primary immunodeficiency affecting T cells, B cells, or both. Whereas the clinical symptoms are uniformly dominated by recurrent infections, the molecular causes for SCID are very heterogeneous. Mutations in cell surface receptors, signal transduction molecules and transcription factors have been described, including the common gamma chain of the IL-2 (and IL-4, IL-7, IL-9 and IL-15) receptors, the kinase JAK-3, the epsilon and gamma chains of CD3, the protein tyrosine kinase ZAP-70, as well as CIITA and RFX5 involved in MHC class II gene expression. In this work we describe two infants with SCID whose T cells display a severe defect in T cell activation and cytokine transcription due to impaired activation of the transcription factor NFAT. We show that this defect in activation is not due to mutations in the NFAT proteins expressed in T cells or the phosphatase calcineurin which regulates the activation of NFAT. However, nuclear import of NFAT in response to T cell activation was severely compromised in the patients' T cells. A modest degree of nuclear translocation of NFAT was achieved in the patients' T cells when nuclear export was inhibited using lithium chloride. This low level of nuclear NFAT in the nucleus was not sufficient to compensate for the defect in cytokine production in the patients' T cells. However, elevated levels of extracellular calcium led to an increase in cytokine gene transcription by the SCID T cells, suggesting that the underlying genetic defect in the patients involved calcium influx or the initiation of calcium signalling.

Calcium↗
PubMedDate not supplied

Polygenic control of the expression of biological activities of an antitumor polysaccharide, lentinan.

Genetic studies were carried out on two in vivo responses of lentinan, delayed type-acute phase responses (DT-APR) and vascular dilation and hemorrhage (VDH). Linkage analyses showed that DT-APR was controlled by two recessive genes, ltnr1 and ltnr2, which were mapped on chromosome 3 and 11, respectively. VDH was also found to be controlled by polygenes. One dominant major gene, Ltnr3, and three dominant minor genes, Ltnr4, Ltnr5, and Ltnr6, were mapped on chromosomes 6, 9, 15 and 16, respectively.

Acute-Phase Reaction↗
PubMed2001

The role of the class II transactivator (CIITA) in MHC class I and II regulation and graft rejection in kidney.

Class II transactivator (CIITA) induces transcription of MHC class II genes, and induces class I in some cell lines. We examined the effect of CIITA deficiency on class I and II expression in mouse kidney. In CIITA knockout (CIITAKO) mice, basal class II was absent, but class I levels were mildly but significantly increased. Allogeneic stimulation or ischemic injury increased class I and II expression in kidneys of control (wild-type, WT) mice but induced only class I in CIITAKO mice. Thus, in kidney, all basal and induced class II expression was CIITA-dependent, but neither basal nor induced class I was CIITA-dependent. Rejecting kidney allografts from CIITAKO mice in CBA hosts manifested intense induction of donor class I but no donor class II expression. Rejecting kidneys from both WT and CIITAKO donors showed predominantly CD8 T-cell infiltration at days 7 and 21, with increasing tubulitis and arteritis at day 21. CIITAKO kidneys showed fewer infiltrating cells than WT kidneys at day 21. Thus CIITA-deficient kidneys have no basal and induced class II expression but display intense induction of class I expression, and evoke typical rejection lesions, although some indices of infiltration are reduced at day 21.

Animals↗
PubMed2002

T-cell engagement of dendritic cells rapidly rearranges MHC class II transport.

Assembly of major histocompatibility complex (MHC) molecules, which present antigen in the form of short peptides to T lymphocytes, occurs in the endoplasmic reticulum; once assembled, these molecules travel from the endoplasmic reticulum to their final destination. MHC class II molecules follow a route that takes them by means of the endocytic pathway, where they acquire peptide, to the cell surface. The transport of MHC class II molecules in 'professional' antigen-presenting cells (APCs) is subject to tight control and responds to inflammatory stimuli such as lipopolysaccharide. To study class II transport in live APCs, we replaced the mouse MHC class II gene with a version that codes for a class II molecule tagged with enhanced green fluorescent protein (EGFP). The resulting mice are immunologically indistinguishable from wild type. In bone-marrow-derived dendritic cells, we observed class II molecules in late endocytic structures with transport patterns similar to those in Langerhans cells observed in situ. We show that tubular endosomes extend intracellularly and polarize towards the interacting T cell, but only when antigen-laden dendritic cells encounter T cells of the appropriate specificity. We propose that such tubulation serves to facilitate the ensuing T-cell response.

Animals↗
PubMed1999

In utero sensitization in Chagas' disease leads to altered lymphocyte phenotypic patterns in the newborn cord blood mononuclear cells.

Neonates are sensitized in utero to maternal circulating antigens and idiotypes that eventually cross the placental barrier. We believe that children born of mothers under long lasting antigenic stimulation, as in a chronic infection, would be affected by these maternal influences and show differences in the phenotypic repertoire of lymphocytes. To test this hypothesis, we evaluated flow cytometry studies in cord blood mononuclear cells (CBMC) from children born of chagasic mothers without congenital disease, with special attention to T and B cells and expression of activation markers. We have also evaluated the peripheral blood mononuclear cells (PBMC) of these children 6 months after delivery. We show that CBMC of children born of infected mothers have high proliferative responses to antigenic stimulation, significantly lower mean percentages of CD3+ T cells, CD4+ T cells and diminished expression of the costimulatory molecule CD28 in the CD8+ T cell subset. Interestingly, this subpopulation has an increased expression of the MHC class II gene product as evidenced by the expression of HLADR. It is noteworthy that the patterns observed in CBMC T lymphocyte populations of these children closely resemble earlier findings on lymphocytic profiles of chronic chagasic adult patients and those of their mothers. We also show that, 6 months after delivery, some alterations observed at birth are reversed to levels observed in noninfected individuals.

Adult↗
PubMed1999

Intravenous or intranasal administration of gliadin is able to down-regulate the specific immune response in mice.

The mucosal lesion in coeliac disease (CD) represents an immunologically mediated injury triggered by gliadin and is restricted by a particular assortment of major histocompatibility complex (MHC) class II genes. Therefore, immunomodulatory strategies to tolerize gliadin-specific, class II-restricted T-cell responses could represent an alternative to current treatments of CD, which are based on a gluten-free diet. In this study, BALB/c mice derived from a gluten-free diet colony were tolerized by either intranasal (i.n.) or intravenous (i.v.) administration of single or multiple doses of gliadin. While a single dose failed to induce tolerance, a significant decrease in gliadin-specific T-cell proliferation was detected (P < 0.001) after multiple i.n. or i.v. administrations. No significant difference in antibody titre was detected for antigen-specific immunoglobulin G (IgG) or the IgG1 subclass, but a lower IgG2a-specific titre was observed. Both interferon-gamma (IFN-gamma) and interleukin (IL)-2 expression, measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR), were reduced on antigen administration, both i.v. and i.n. Neither regimen showed a regulatory effect on IL-4 production. As T helper 1 (Th1) cytokines seem to be important in the pathogenesis of CD, our data therefore highlight the potential of i.n. and i.v. routes for the design of useful immunomodulatory strategies for CD.

Administration, Intranasal↗
PubMed1998

RFX1, a single DNA-binding protein with a split dimerization domain, generates alternative complexes.

The transcription of various viral and cellular genes is regulated by palindromic and nonpalindromic DNA sites resembling the EP element of the hepatitis B virus enhancer, which generate similar DNA-protein complexes. The upper EP complex contains homodimers of the transcription regulator RFX1. We show that RFX1 possesses a split, extended dimerization domain composed of several evolutionarily conserved boxes, one of which was previously shown to mediate dimerization. Such an unusually long and complex dimerization domain could potentially serve for generating multiple complexes. In addition to the previously characterized complex, RFX1 generated a novel DNA-protein complex of extremely low mobility, formed only with palindromic DNA sites. Different deletions within the dimerization domain altered the relative abundance of the two complexes, suggesting an interplay between them. Formation of the low mobility complex correlated with transcriptional repression, in that both activities were mediated by several portions of the conserved region. Our results propose a mechanism by which the extended dimerization domain mediates the formation of alternative homodimeric complexes, which differ in the nature of the intersubunit interaction. By participating in different types of interactions, this domain may regulate the relative abundance of the different complexes, thus affecting transcriptional activity.

Alternative Splicing↗