Immunodeficiency associated with defective expression of the T-cell receptor-CD3 complex.
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Antigens, Differentiation, T-Lymphocyte↗
Biomedical subjects
B Lisowska-Grospierre
Publications and source records attributed to B Lisowska-Grospierre.
Effects of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) on the expression of LFA-1 in the moderate phenotype of leukocyte adhesion deficiency (LAD).
Leukocyte adhesion deficiency (LAD) is a recessive autosomal disease characterized by life-threatening recurrent bacterial infections, associated with defective functions of leukocytes due to deficient membrane expression of leukocyte adhesion glycoproteins. These proteins, LFA-1, Mac-1 (CR3), and p150,95 are alpha 1 beta 1 heterodimers composed of different alpha chains noncovalently associated with a common beta chain. Patients with the severe phenotype of the disease completely lack the three glycoproteins on leukocyte surfaces, while patients with the moderate phenotype can express low levels of leukocyte adhesion proteins (1-10%). We have studied a patient with the moderate phenotype of LAD. Polymorphonuclear functions such as chemotaxis and adherence were altered, natural killer activity was low, and cytotoxic T-lymphocyte activity was abolished. Previous biochemical studies showed a conserved synthesis of both the LFA-1 alpha-chain precursor and the beta-chain precursor with, occasionally, some amount of alpha-beta complexes in the cytosol. beta chain-specific mRNA transcripts of normal size were detected at normal levels in patients' cells. Attempts to increase the transcription of the beta gene by in vitro treatment with TNF-alpha or IFN-gamma were successful but did not result in increased membrane expression of the alpha-beta complexes.
Antigens, Differentiation↗
Combined immunodeficiency with abnormal expression of MHC class II genes.
The MHC class II CID represents an example of immunodeficiency in which the defect in expression of membrane glycoproteins leads to abnormal cell to cell interactions and thus to abnormal immune responses. It represents an interesting model which confirms the importance of MHC molecules in all immune responses to foreign antigens. It also underlines the complexity of regulatory mechanism which control the expression of MHC class II genes. To elucidate these mechanisms, it is essential to identify and characterize the genes involved in control of MHC class II expression.
Agammaglobulinemia↗
Inherited immunodeficiency with a defect in a major histocompatibility complex class II promoter-binding protein differs in the chromatin structure of the HLA-DRA gene.
A defect in a trans-regulatory factor which controls major histocompatibility complex class II gene expression is responsible for an inherited form of immunodeficiency with a lack of expression of human leukocyte antigen (HLA) class II antigens. We have recently described and cloned an HLA class II promoter DNA-binding protein, RF-X, present in normal B cells and absent in these class II-deficient regulatory mutants. Here we report that these in vitro results correlate with a specific change in the chromatin structure of the class II promoter: two prominent DNase I-hypersensitive sites were identified in the promoter of the HLA-DRA gene in normal B lymphocytes and found to be absent in the class II-deficient mutant cells. The same two prominent DNase I-hypersensitive sites were observed in normal fibroblastic cells induced by gamma interferon to express class II genes. Interestingly, they were also observed in the uninduced class II-negative fibroblastic cells, which have also been shown to have a normal RF-X binding pattern. We conclude that the two DNase I-hypersensitive sites in the HLA-DRA promoter reflect features in chromatin structure which correlate with the binding of the trans-acting factor RF-X and which are necessary but not sufficient for the expression of class II genes.
B-Lymphocytes↗
Combined immunodeficiency with defective expression in MHC class II genes.
MHC class II deficiency is an inherited immunodeficiency disease characterized by the presence of a normal number of T and B lymphocytes and profound anomaly of cellular and humoral responses to foreign antigens. All bone-marrow-derived cells (including B lymphocytes, monocytes and activated T lymphocytes) and also enterocytes and endothelial cells do not express all HLA class II (DR, DQ and DP) molecules on their membrane. It is known that the proper recognition of foreign antigens depends on their presentation, together with HLA class II molecules, on the membrane of antigen-presenting cells. MHC class II deficient combined immunodeficiency confirms the important role of MHC gene products in immune-defence mechanisms. Patients suffer from repeated and severe infections that are frequently the cause of death. The defect in HLA class II expression is the consequence of a lack of synthesis of HLA class II alpha and beta chains in patients' cells. Studies performed at DNA and RNA levels showed that there was no gross abnormality of MHC class II genes and that mRNA for all HLA molecules was not detected in patients' cells. These results, together with segregation studies performed in several families, suggested that the defect in HLA class II gene expression involves a transacting regulatory factor. Direct transcription assays showed that the disease is characterized by an absence of HLA class II gene transcription. An analysis of the specific binding of nuclear proteins from patients' cell lines to HLA class II promotor showed that a specific protein, RF-X, which normally binds to a regulatory sequence common to HLA class II promotors, is affected in MHC class II combined immunodeficiency.
Gene Expression Regulation↗
Congenital immunodeficiency with a regulatory defect in MHC class II gene expression lacks a specific HLA-DR promoter binding protein, RF-X.
The expression of MHC class II genes is tightly regulated. One form of congenital severe combined immunodeficiency (SCID) is characterized by a regulatory defect that precludes expression of HLA class II genes. B lymphocyte cell lines from such SCID patients provide a tool for identifying putative regulatory proteins that bind to class II gene promoters. We have identified three proteins binding to specific segments of the HLA-DRA promoter, two of which interact to form the predominant DNA-protein complex observed. One of these proteins, defined as an X box binding protein (RF-X), is specifically missing in cells from class II deficient SCID patients. We propose that the molecular defect in this congenital HLA class II regulatory deficiency is a lack of RF-X and that this factor plays an important role in the normal regulation of MHC class II gene expression.
B-Lymphocytes↗
Heterogeneity in the molecular defect leading to the leukocyte adhesion deficiency.
Leukocyte adhesion deficiency (LAD) is a recessive autosomal disease characterized by life-threatening recurrent bacterial infections, by defective functions of leukocytes and by deficient membrane expression of leukocyte adhesion glycoproteins. These proteins, LFA-1, Mac-1 and p150,95, are alpha 1/beta 1 heterodimers composed of different alpha chains and of a common beta chain. Patients with the severe phenotype of the disease completely lack the three glycoproteins on cell surface. Previous studies showed a conserved synthesis of the LFA-1 alpha chain precursor in cytosol of patients' cells and an inconstant presence of the beta chain precursor. When present, precursors are in free form and not associated to alpha/beta complexes in the cells of patients with the severe phenotype. The availability of the beta chain cDNA probe allowed us to examine the beta chain gene expression in the lymphoblastoid cell lines of 4 patients. On the basis of the results obtained both at protein and RNA levels we can distinguish 3 types of mutations characterized by (a) barely detectable beta subunit messenger RNA and undetectable beta precursor, (b) decreased level of beta subunit mRNA and undetectable beta precursor and (c) normal beta subunit mRNA level and detectable beta precursor of normal size.
Antigens, Differentiation↗
Leukocyte adhesion deficiency: molecular basis and functional consequences.
Leukocyte adhesion deficiency disease is characterized by a mutation in the gene encoding the beta-subunit shared by three adhesive heterodimers, LFA-1, Mac-1 (CR3) and p150,95 expressed by leukocytes. An absent or abnormal beta-subunit leads to defective expression of the three heterodimers. Severe and moderate phenotypes of the disease are defined by absent and low surface expression of the adhesion molecules. The disease causes an inability of phagocytic cells to adhere to endothelial cells and thereafter to migrate to sites of infections. Severe widespread life-threatening bacterial and fungal infections are the consequences of this abnormality. Cure of the disease can be effected by allogeneic bone marrow transplantation. T-lymphocyte adhesion to various cells is also impaired; its consequences are, however, limited because of the existence of other T-cell-adhesive pathways. Nevertheless, haploidentical bone marrow graft rejection does not occur in the severe phenotype, an indication for possible immunotherapy with LFA-1 specific monoclonal antibodies.
Bone Marrow Transplantation↗
Monoclonal antibodies specific for intestinal lymphocytes.
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Animals↗
LFA-1 beta-chain synthesis and degradation in patients with leukocyte-adhesive proteins deficiency.
The defective membrane expression of the adhesive protein family (LFA-1, Mo1 and p150,93) on leukocytes from certain patients with recurrent bacterial infections was shown to be secondary to the absence of synthesis of mature beta chain that is common to all three antigens (Springer et al., 1984, Lisowska-Grospierre et al., 1986). In all patients, studies of beta-chain biosynthesis that lead to this conclusion were performed using the monoclonal anti-beta chain antibody to isolate the beta subunit. Since this antibody detects the mature form of beta chain only, the potential presence of a precursor or of an abnormal beta chain in the patient's cells could not be tested. The availability of the polyclonal antibody to the purified beta subunit allowed us to re-examine the biosynthesis of the LFA-1 subunits in 3 affected children. In all 3 patients, the absence of membrane expression of the LFA-1, CR3 and p150,95 proteins was confirmed. The LFA-1 alpha-chain precursor of 170 kDa was detected in the lysates of PHA blasts of two children, but was not detected in the third. The beta-chain precursor of 85 kDa was isolated by the polyclonal anti-beta chain antiserum from the cytoplasm of phytohemagglutinin and Epstein-Barr virus-induced blasts of one patient. The same antibody precipitated some peptides of smaller mol. wt. from the cell lysates of 2 other patients. These results suggest that in this disorder the membrane nonexpression of the adhesive proteins is probably due to the structural abnormality of beta chain which, although synthesized, is rapidly degradated.
Antibodies, Monoclonal↗
A monoclonal antibody (HML-1) defining a novel membrane molecule present on human intestinal lymphocytes.
A monoclonal antibody, HML-1, was produced by fusion of NSI myeloma cells with spleen cells of a mouse immunized with isolated human intestinal intraepithelial lymphocytes (IEL). Immunofluorescence studies of isolated cells, as well as immunoperoxidase staining of tissue sections, indicated that HML-1 labeled all the various subsets of human intestinal IEL, approximately 40% of lamina propria T cells, 30% mesenteric lymphoblasts and some lymphocytes in other mucosae, particularly IEL. Conversely, it revealed only rare cells in all other lymphoid compartments. Analysis by polyacrylamide gel gradient electrophoresis showed that HML-1 precipitated two major noncovalently bound components of approximate mol. masses of 105 and 150 kDa from human IEL. HML-1 thus defines a novel human membrane antigen present on a subpopulation of lymphocytes preferentially associated with epithelia, and particularly with the intestinal epithelium. The characteristics of this human antigen are very similar to those of an antigen we had previously described in the rat. The possible functional role of this novel class of lymphocyte membrane antigens as well as the nature of the mechanism that triggers their expression remain to be elucidated.
Adult↗
Monoclonal antibodies specific for human and rat intestinal lymphocytes.
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Animals↗
Defective membrane expression of the LFA-1 complex may be secondary to the absence of the beta chain in a child with recurrent bacterial infection.
Membrane and intracellular processing of the LFA-1 macromolecular complex, known to be involved in cytolytic function of T lymphocytes, was investigated in a child with recurrent bacterial infections, impaired natural killer activity, T cell-mediated lymphocytolysis and absent adhesion and migration of phagocytic cells. Monoclonal antibodies to the LFA-1 alpha and beta subunits, able to precipitate the LFA-1 alpha, 180-kDa chain, the p151 chain and beta 94-kDa chain (shared by both alpha chains), were used in immunoprecipitation studies of patient and control phytohemagglutinin-blasts. Neither of the alpha chains nor the beta chain were found in precipitates obtained from 125I-surface-labeled patient cells in contrast to controls. However, the precursor of the LFA-1 alpha chain, a 170-kDa polypeptide, was identified in lysates of biosynthetically labeled patients' cells. These results suggest that the defective membrane expression of the LFA-1 complex may be secondary to the absence of the mature beta chain.
Antigens, Surface↗
A monoclonal antibody specific for rat intestinal lymphocytes.
A monoclonal antibody, RGL-1, was produced by fusion of NSI myeloma cells with spleen cells of a mouse immunized with isolated rat intraepithelial lymphocytes (IEL). SDS-PAGE analysis revealed that RGL-1 precipitated two major noncovalently bound chains of about m.w. 100,000 and 125,000, and a minor component of m.w. 200,000. Examination of both tissue sections and isolated cells indicated that RGL-1 stained the majority of the lamina propria lymphocytes and IEL but only very few cells (less than 2%) in the lymphoid organs and small numbers of lymphocytes in other mucosae. In the small intestine, RGL-1 stained lymphocytes with the helper (W3/25) as well as the cytotoxic/suppressor (OX8) phenotype. The antibody reacted with 95% of the granular IEL but with less than 0.1% of the blood large granular lymphocytes. Although mature IgA plasma cells in the lamina propria were RGL-1-, some large IgA-containing cells were weakly positive. In the gut-associated lymphoid tissues (GALT), studies combining immunofluorescence and autoradiography indicated that 56 and 73% of rapidly dividing cells of mesenteric lymph nodes and of thoracic duct lymph (TDL) stained with RGL-1, respectively. In addition, 90 to 100% of the IgA-containing blasts of MLN and 75% of those of TDL were labeled by RGL-1. In contrast, rapidly dividing cells of spleen and of peripheral lymph nodes did not stain with RGL-1. Because RGL-1 can be demonstrated on both intestinal lymphocytes and their immediate precursors in the GALT, its expression may be related to the homing of lymphocytes into the gut mucosa.
Animals↗
A defect in the regulation of major histocompatibility complex class II gene expression in human HLA-DR negative lymphocytes from patients with combined immunodeficiency syndrome.
Patients with an autosomal recessive combined immunodeficiency are characterized by an HLA negative phenotype of activated T and B lymphocytes. To determine the molecular basis of this syndrome we have studied the biosynthesis of class I and II antigens and the expression of relevant genes in these patients. The synthesis of the HLA A, B, and C heavy chain is markedly decreased, while beta 2 microglobulin is made in normal amounts. Biosynthesis of HLA-DR alpha-chain and beta-chain is abolished in the lymphocytes of these patients and there is a total absence of mRNA for either alpha-chains or beta-chains of HLA-DR. This indicates that the lack of class II antigen on these lymphocytes results from a block in the expression of HLA-DR genes. The Ii-chain, the invariant polypeptide associated intracellularly with HLA-DR, and its mRNA are made in normal amounts. Since the structural genes coding for class II polypeptides do not seem to be affected, the reported genetic defect in the patients concerns the regulation of the expression of HLA-DR genes.
Antigens, Surface↗
Diagnostic significance of the human antibody response to a major cytoplasmic antigen of C. albicans.
In contrast to the ubiquitous presence of IgG antibodies to mannan or to crude antigen preparations of C. albicans (CA), antibodies to a purified cytoplasmic antigen (SSF) of CA were detected by ELISA only in patients with candidiasis. The differences of mean absorbancy values found in different groups of sera can allow the distinction of normal sensitized controls from patients with candidiasis and can also distinguish between patients with different degrees of C. albicans invasion.
Antibodies, Fungal↗
Bone-marrow transplantation for inborn error of phagocytic cells associated with defective adherence, chemotaxis, and oxidative response during opsonised particle phagocytosis.
Two girls had delayed umbilical cord detachment, recurrent bacterial infection, inability to form pus, and marked leucocytosis. Their phagocytes were defective in tests of adherence, random migration, chemotaxis, and oxidative burst. NK activity was virtually absent. This rare disorder, due to an inherited absence of a 180 kilodalton membrane glycoprotein on polymorphonuclear cells, is usually lethal within 2 years. Allogeneic HLA-matched bone-marrow transplantation done at ages 4 months in one patient and 2 years in the other after intensive conditioning was successful and resulted in nearly complete correction of phagocytic cell function and NK activity within two months. One patient died 9 months after transplantation from severe chronic graft-versus-host disease with obstructive bronchopneumopathy. The other is doing well 1 year after transplantation and showing stable chimerism and normal phagocytic function.
Bone Marrow Transplantation↗
Combined immunodeficiency with defective expression of HLA: modulation of an abnormal HLA synthesis and functional studies.
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Antibodies, Fungal↗