Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease marked by hyperglycemia and mononuclear cell infiltration of insulin-producing beta islet cells. Predisposition to IDDM in humans has been linked to the class II major histocompatibility complex (MHC), and islet cells often become aberrantly class II positive during the course of the disease. We have used two recently described transgenic lines to investigate the role of class II molecules and CD4+ T cells in the onset of autoimmune insulitis. Mice that are class II deficient secondary to a targeted disruption of the A beta b gene were bred to mice carrying a transgene for the lymphocytic choriomenigitis virus (LCMV) glycoprotein (GP) targeted to the endocrine pancreas. Our results indicate that class II-deficient animals with and without the GP transgene produce a normal cytotoxic T lymphocyte response to whole LCMV. After infection with LCMV, GP-transgenic class II-deficient animals develop hyperglycemia as rapidly as their class II-positive littermates. Histologic examination of tissue sections from GP-transgenic class II-deficient animals reveals lymphocytic infiltrates of the pancreatic islets that are distinguishable from those of their class II-positive littermates only by the absence of infiltrating CD4+ T cells. These results suggest that in this model of autoimmune diabetes, CD4+ T cells and MHC class II molecules are not required for the development of disease.
 ...
PMID:Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice. 810 62

Heymann nephritis in the rat is the most widely used model of human membranous glomerulonephritis. Glycoprotein (gp)330, a large (M(r) > 550,000) membrane-associated glycoprotein, has been identified as the main antigen in this autoimmune disease. Studies of gp330 and receptor-associated protein (RAP), its 44-kd subunit, have been restricted largely to rat kidney, as no stable cultured cell line has been available that expresses gp330. We have recently identified a rat yolk sac carcinoma cell line (L2) that expresses both gp330 and RAP. In this report, we have carried out detailed morphological, immunocytochemical, and biochemical studies characterizing the biosynthesis and localization of gp330 and RAP in the L2 rat yolk sac cell line. At the electron microscope level, the L2 cells are seen to be attached by cell junctions, and their predominant morphological features include extensive networks of rough endoplasmic reticulum (ER) and numerous clathrin-coated pits found on the cell membrane. By immunocytochemistry, gp330 was localized primarily to clathrin-coated pits at the cell surface, whereas RAP was localized predominantly to the lumen of the rough ER. Pulse-chase experiments indicated that gp330 spends a prolonged time maturing in the ER of L2 cells, as transport of gp330 to the Golgi complex (based on acquisition of endoglycosidase H resistance) is slow (t1/2 = 90 to 120 minutes). Gp330 reached the L2 cell surface beginning at 2 hours after synthesis, where it could be detected by cell surface immunoprecipitation. RAP was found to be an N-linked glycoprotein, and it remained endoglycosidase H-sensitive up to 4 hours after synthesis. Co-precipitation and co-sedimentation experiments demonstrated that gp330 and RAP form a large heterodimer (M(r) approximately 669,000) immediately after biosynthesis and are further assembled into a large hetero-oligomer in the ER. These findings demonstrate that the localization and the kinetics of assembly of gp330 and RAP into the Heymann nephritis antigenic complex are similar in both L2 cells and rat kidney. They also provide new information on the intracellular processing of these two molecules and their delivery to the cell surface. Thus, the L2 cell system should facilitate further characterization of the functions and interactions of gp330 and RAP, which may shed light on the cellular and molecular mechanisms of Heymann nephritis.
 ...
PMID:Immunocytochemical and biochemical characterization of the Heymann nephritis antigenic complex in rat L2 yolk sac cells. 823 58

Active Heymann nephritis is an organ-specific autoimmune disease of the rat kidney, characterized by the formation of immune complexes located subepithelially in the glomerulus. The T cell-mediated humoral immune response is directed to gp330, a large renal epithelial glycoprotein which is expressed both in the proximal tubule and on glomerular podocytes. In this study polyclonal rabbit antibodies raised against affinity-purified rat gp330 were used to screen a lambda-gt11 expression library of the rat kidney. One cDNA clone that was recognized by the antibodies coded for a 2.7-kb protein that is not described in the sequence database of GenBank/EMBL. Two other groups of cDNA clones were identified that displayed similarity with several members of the low-density lipoprotein (LDL)-receptor gene family to which gp330 belongs. By comparison with the gp330-cDNA sequence, these two clones could be mapped to two remote areas on the extracellular domain of gp330. The antigenicity of these two areas is in accordance with their location in highly hydrophilic regions on the extracellular domain of gp330. The cDNA clones described in this study may represent two main immunodominant regions on rat gp330.
 ...
PMID:Isolation of cDNAs encoding immunogenic regions of gp330, the autoantigen involved in Heymann nephritis. 862 26

The zona pellucida (ZP), an ovarian extracellular structure, contains three major glycoproteins: ZP1, ZP2, and ZP3. A ZP3 peptide contains both an autoimmune oophoritis-inducing T cell epitope and a B cell epitope that induces autoantibody to ZP. This study investigates two major T cell costimulation pathways in this disease model. Herein we show that blockage of glycoprotein (gp)39 and CD40 interaction with gp39 monoclonal antibody (mAb) results in the failure to induce both autoimmune oophoritis and autoantibody production. Inhibition of ligand binding to the CD28 receptor with the fusion protein, murine CTLA4-immunoglobulin (Ig), also results in failure to generate antibody to ZP and significantly reduces disease severity and prevalence. Surprisingly, the frequencies of antigen-specific T cells in anti-gp39 mAb-treated mice, CTLA4-Ig treated mice, and in mice given control hamster IgG or control fusion protein L6, were equivalent as determined by limiting dilution analysis (approximately equals 1:5,000). These T cells, which produced comparable amounts of interleukin 4 and interferon gamma in vitro, were able to transfer oophoritis to normal recipients. When anti-gp39 mAb and CTLA4-Ig were given together, the effect was additive, leading to inhibition of T cell activation as determined by in vitro proliferation and limiting dilution analysis (approximately equals 1:190,000); disease and antibody responses were absent in these mice. By studying these two costimulatory pathways in parallel, we have shown that autoimmune disease and autoantibody production are inhibitable by blocking either the gp39 or the CD28 pathway, whereas inhibition of clonal expansion of the effector T cell population occurs only when both pathways are blocked.
 ...
PMID:The relative contribution of the CD28 and gp39 costimulatory pathways in the clonal expansion and pathogenic acquisition of self-reactive T cells. 864 84

Two MAIPA (monoclonal antibody [MAb] immobilization of platelet antigen) assays were performed to determine (a) autoantibodies to platelet glycoproteins (GP) and (b) serum antibodies recognizing mouse MAbs used in the assay. In MAIPA I, control platelets were incubated simultaneously with human serum and a mouse MAb to a platelet glycoprotein (GP IIb-IIIa, Ib-IX, Ia-IIa, IV and p24). In MAIPA II, the control platelets were incubated first with the human serum and then, after washing, with the selected mouse MAb. A series of 25 patients with autoimmune thrombocytopenic purpura (ATP) associated or not with other autoimmune states were examined. Autoantibodies (both MAIPA I and MAIPA II positive) or anti-mouse Abs (MAIPA I positive and MAIPA II negative) were frequent in both groups of patients. Statistically significant differences existed in the incidence of anti-mouse Abs between patients (56.5%) and healthy donors (10%). This suggests that their production may be related to thrombocytopenias associated with autoimmune disease. We speculate that the presence of anti-mouse antibodies could reflect an abnormality in the immunological modulation of the idiotypic network.
 ...
PMID:Autoantibodies and anti-mouse antibodies in thrombocytopenic patients as assessed by different MAIPA assays. 885 54

In 1990, three groups simultaneously reported that putative IgG antibodies to anionic phospholipids were either not directed to phospholipids or at least required beta 2-glycoprotein-I (beta 2-GP-I) for reactivity in vitro. During the same year, our group described a patient with "idiopathic' hemolytic anemia with serum and erythrocyte-bound IgM antibodies to phosphatidylcholine later found to be independent of beta 2-GP-I for antigen recognition. Lately, the field has been expanded considerably with: (1) the description of other potential antigens such as prothrombin for some lupus anticoagulants, (2) the finding of crossreactivity between some antiphospholipid antibodies (aPL) with thrombomodulin, (3) the presence of serum antibodies to beta 2-GP-I (anti-beta 2-GP-I) in patients with SLE and thromboses, (4) the findings that the clinical manifestations of APS in SLE patients associate more strongly with anti-beta 2-GP-I than with aPL, (5) our finding of a group of SLE patients with the clinical manifestations of APS, with negative serum aPL, but with positive anti-beta 2-GP-I, (6) the description of a group of patients with the clinical manifestations of APS, without serum aPL, without serological nor clinical evidence of any autoimmune disease, but with IgG anti-beta 2-GP-I, and (7) the observation that serum anti-phosphatidylethanolamine antibodies detected in some patients with APS require kininogen (alone or complexed with the kininogen-binding protein), prekallikrein and/or factor XI for in vitro reactivity. Thus, there are antibodies that may be considered true aPL; other "aPL' require a protein cofactor for their detection in vitro, at least in the case of beta 2-GP-I it would appear that their epitope is present on the protein proper not on the phospholipid, hence these are pseudo aPL, and a third group of related anti-cofactor autoantibodies that are directed to the protein in the absence of phospholipid. Clearly, the term "antiphospholipid syndrome' has become obsolete. We propose the term "Antiphospholipid/Cofactor Syndromes' to cull the various syndromes.
 ...
PMID:The concept and classification of antiphospholipid/cofactor syndromes. 890 61

Ricin toxin, the heterodimeric 65 kDa glycoprotein synthesized in castor bean seeds, contains a cell binding lectin subunit (RTB) disulfide linked to an RNA N-glycosidase protein synthesis-inactivating subunit (RTA). Investigations of the molecular nature of the lectin sites in RTB by X-ray crystallography, equilibrium dialysis, chemical modification, and mutational analysis have yielded conflicting results as to the number, location, and affinity of sugar-combining sites. An accurate assessment of the amino acid residues of RTB involved in galactose binding is needed both for correlating structure-function of a number of plant lectins and for the design and synthesis of targeted toxins for cancer and autoimmune disease therapy. We have performed oligonucleotide-directed mutagenesis on cDNA encoding RTB and expressed the mutant RTBs in insect cells. Partially purified recombinant proteins obtained from infected cell supernatants and cell extracts were characterized as to yields, immunoreactivities, asialofetuin binding, cell binding, ability to reassociate with RTA, and recombinant heterodimer cell cytotoxicity. Two single-site mutants (subdomain 1 alpha or 2 gamma) and two double-site mutants (subdomains 1 alpha 2 gamma) were produced and studied. Yields varied by two logs with lower recoveries of double-site mutants. All the mutants showed immunoreactivity with a panel of anti-RTB monoclonal and polyclonal antibodies. Single-lectin site mutants displayed up to a 1 log decrease in asialofetuin binding avidity, while the double-site mutants showed close to a 2 log decrease in sugar binding. However, for each of the double-site mutants, residual sugar binding was demonstrated to both immobilized asialofetuin and cells, and this binding was specifically inhibitable with alpha-lactose. All mutants reassociated with RTA, and the mutant heterodimers were cytotoxic to mammalian cells with potencies 1000-fold or more times that of unreassociated wild-type RTA or RTB. These data support a model for three or more lectin binding subdomains in RTB.
 ...
PMID:Double-lectin site ricin B chain mutants expressed in insect cells have residual galactose binding: evidence for more than two lectin sites on the ricin toxin B chain. 895 Apr 84

Autoantibodies to ZP3, a major glycoprotein of the zona pellucida (ZP) with sperm receptor function, can block sperm/oocyte interaction. However, only mice of certain major histocompatibility complex (MHC) haplotype respond to the ZP3 peptide. Moreover, ZP3-specific T cells can mediate ovarian autoimmune disease. A chimeric peptide has been designed that induces antibody to native ZP3 regardless of the MHC haplotype of the inbred mice tested. This results in reduction in fertility that is reversible. Infertility correlates well with ZP antibody titer, and the mice do not develop concomitant autoimmune oophoritis. The vaccine contains (1) a promiscuous foreign T-cell peptide capable of eliciting a T-cell response regardless of the animals' MHC haplotype, and (2) a modified native B-cell peptide of ZP3.
 ...
PMID:ZP3 peptide vaccine that induces antibody and reversible infertility without autoimmune oophoritis. 896 44

One hypothesis for the etiology of central nervous system (CNS) autoimmune disease is that infection by a virus sharing antigenic epitopes with CNS antigens (molecular mimicry) elicits a virus-specific immune response that also recognizes self-epitopes. To address this hypothesis, transgenic mice were generated that express the nucleoprotein or glycoprotein of lymphocytic choriomeningitis virus (LCMV) as self in oligodendrocytes. Intraperitoneal infection with LCMV strain Armstrong led to infection of tissues in the periphery but not the CNS, and the virus was cleared within 7-14 d. After clearance, a chronic inflammation of the CNS resulted, accompanied by upregulation of CNS expression of MHC class I and II molecules. A second LCMV infection led to enhanced CNS pathology, characterized by loss of myelin and clinical motor dysfunction. Disease enhancement also occurred after a second infection with unrelated viruses that cross-activated LCMV-specific memory T cells. These findings indicate that chronic CNS autoimmune disease may be induced by infection with a virus sharing epitopes with a protein expressed in oligodendrocytes and this disease may be enhanced by a second infection with the same or an unrelated virus. These results may explain the association of several different viruses with some human autoimmune diseases.
 ...
PMID:Viral infection of transgenic mice expressing a viral protein in oligodendrocytes leads to chronic central nervous system autoimmune disease. 897 91

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by the synthesis of antinuclear antibodies. Nucleosomes-the disc-like-structural unit of chromatin being composed of histones and DNA-are the primary antigenic structure that induces the formation of complement-activating antigen-antibody complexes in basement membranes. The autoreactivity in SLE has been elucidated in drug-induced SLE: Hypomethylation of DNA leads to overexpression of integrin CD 11a/CD 18, increased binding of T-cells to macrophages and B-cells, a higher rate of apoptosis of macrophages and elevated B-cell activity with consecutive production of autoantibodies. Disturbances of apoptosis (e.g. mutation of Fas gene) are relevant also in non drug-induced SLE. The morphologic diagnosis-by light microscopy, immunohistology and electron microscopy-of skin and renal biopsies can confirm the diagnosis and help in prognostic assessment as well as therapeutic decisions in SLE. The value of the morphologic diagnosis in SLE is enhanced by reporting semiquantitative scores of disease activity and chronicity. The antiphospholipid syndrome (APS) is characterized by thrombosis, thrombocytopenia, recurrent fetal loss and antiphospholipid antibodies. APS associated with SLE or other systemic autoimmune diseases has been termed secondary APS. Antibodies in APS are directed against phospholipids and phospholipid-protein complexes. One of these proteins is beta 2-glycoprotein 1. An important mechanism of the increased rate of thrombosis in APS is probably the inhibition of the protein C catalyzed inactivation of clotting factors V and VIII. Venous thrombosis with recurrent pulmonary emboli and arterial thrombi in brain, heart and kidney (thrombotic microangiopathy) can lead to divergent clinical manifestations in APS.
 ...
PMID:[Systemic lupus erythematosus and antiphospholipid syndrome]. 906 4


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>