Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monoclonal antibody (mAb) BEG-2 is a dsDNA binding IgM lambda derived from a 12-week human fetus. Two binding site idiotypes (BEG-2 Id alpha and BEG-2 Id beta) have been defined with the use of polyclonal rabbit anti-idiotypic anti-serum. BEG-2 Id alpha is located on the lambda light chain and has been described previously. The BEG-2 Id beta is present on the mu heavy chain. By means of a direct binding ELISA, BEG-2 Id beta has been identified on EBV-derived mAbs from human fetal liver or spleen (5%), human cord blood (2.7%) and adult peripheral blood (1%). In addition, the Id is present on 8.5% of adult spleen-derived hybridoma antibodies and 6% of RA synovium-derived hybridoma antibodies. In all populations the presence of the Id is strongly associated with binding to DNA and other polyanions. Competition assays indicated that the Id was located at or near the antigen-binding site on these molecules. To explore the structural basis of this binding, a major part of the BEG-2 heavy chain was sequenced and found to be encoded by a member of the VH4 family joined to a variant of JH5 by a very short Diversity or N region. Of the BEG-2 Id beta positive mAbs for which the VH family has been determined, five are encoded by VH4 and two are encoded by VH6, but none is encoded by other families. Thus, the BEG-2 Id beta identifies a set of polyreactive antibodies that are common in fetal life, persist into adulthood and are encoded by VH6 and, a subset of VH4 genes.
Lupus 1991 Nov
PMID:Sequence analysis and idiotypic relationships of BEG-2, a human fetal antibody reactive with DNA. 184 65

The GM 4672 lymphoblastoid cell line has been used in cell hybridization experiments with peripheral blood lymphocytes (PBLs) in order to generate human-human hybridomas that secrete immunoglobulins directed against a number of different autoantigens. The GM 4672 cells were fused with PBLs isolated from patients with rheumatoid arthritis or systemic lupus erythematosus, or from normal individuals, and the resulting hybridomas were screened for reactivity to platelets, erythrocytes, DNA, cardiolipin, human IgG-Fc, phosphatidylethanolamine, and for lupus anticoagulant activity. This report analyzes the results from 149 fusion experiments completed over a period of nine years. Fifty to sixty-six percent of the fusion experiments resulted in immunoglobulin-secreting clones, with an average of 15 clones/fusion. The hybridoma antibodies were predominantly of the IgM heavy chain isotype, and 67% expressed kappa light chains. Although most hybridoma antibodies (78%) recognized a single autoantigen, 22% recognized more than one autoantigen and were considered polyreactive. In addition, the light and heavy chain variable regions of the antibody secreted by the GM 4672 cell line were amplified by the polymerase chain reaction technique and sequenced. The GM 4672 light chain was encoded by a VkI gene and used a Jk4 minigene. The GM 4672 heavy chain was derived for the rearrangement of a gene from the VH4 subgroup and used a JH4 minigene. The 8 amino acid long diversity region was generated by the fusion of the DK1 and DLR2 genes. The hybridomas generated in fusion experiments, when examined, did not appear to secrete antibodies using the immunoglobulin variable regions derived from the GM 4672 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular characterization of the GM 4672 human lymphoblastoid cell line and analysis of its use as a fusion partner in the generation of human-human hybridoma autoantibodies. 768 47

An idiotope designated 9G4 (9G4Id) is known to be a marker for immunoglobulins which utilize a particular VH gene, VH4-21. The idiotope has been found to be present on anti-DNA antibodies, and have been identified in 45% of sera from patients with SLE. This idiotope is strongly associated with lupus being very uncommon amongst the other autoimmune rheumatic diseases tested. This distinction is unlike virtually any of the other DNA antibody idiotypes described which are much more widely distributed. 9G4Id levels were found to fluctuate with disease activity in some lupus patients and this idiotope was detected in 3/11 SLE renal biopsies tested. Its presence is associated with the HLA markers A1 and B8 and raised 9G4Id levels are not simply a reflection of hypergammaglobulinaemia. Thus a new DNA antibody associated idiotope has been identified. Expression of the idiotope indicates that a notable proportion of anti-DNA antibodies have VH segments encoded by the same, or closely related genes, and that these restricted immunoglobulins are involved in the renal pathology found in SLE.
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PMID:Identification of the 9G4 idiotope in systemic lupus erythematosus. 769 67

In many autoimmune diseases autoantibodies are intimately involved in disease manifestations. Molecular characterization of these autoantibodies should provide insights into the pathogenesis of these diseases, as well as suggest novel avenues for development of therapeutics. While some prior studies suggest that DNA binding may be a characteristic of individual heavy chain variable regions, the ability of these V regions to bind DNA in isolation has not been investigated. We have utilized a bacterial vector for cloning and expressing isolated antibody heavy chain variable regions. RNA was extracted from peripheral blood mononuclear cells of patients with active SLE, cDNA synthesized and heavy chain V regions amplified with VH specific oligonucleotide primers. The VH fragments were cloned into a bacterial expression plasmid including the pelB leader peptide to direct appropriate expression. Recombinant antibodies were screened for binding to 32P-labeled double-stranded plasmid DNA and later also characterized for binding to single-stranded DNA. Binding was confirmed by standard ELISA methodology. Sequence analysis of seven DNA binding VH fragments revealed that they utilized the VH gene family previously described to be associated with autoimmune responses, with a JH6 segment. On VH sequence analysis only one residue substitution in the consensus sequence is needed to form a VH4 germline gene. Potential contact residues with DNA were delineated by three-dimensional structure analysis. We concluded that the DNA binding characteristics of VH regions can be examined in the absence of light chain. DNA binding specificity appears to be a property of the germline VH4 gene. Analysis of such V regions can aid in the identification of hypervariable region contact residues important for DNA binding.
Lupus 1994 Oct
PMID:Isolated VH4 heavy chain variable regions bind DNA characterization of a recombinant antibody heavy chain library derived from patient(s) with active SLE. 784 91

Autoimmune thrombocytopenia has been attributed to the presence of antiplatelet autoantibodies which mediate platelet destruction. The derivation of these autoantibodies is presently unknown. While normal B cells do not produce these autoantibodies in vivo, it has been demonstrated in vitro by somatic cell hybridization that the B lymphocytes of nonthrombocytopenic individuals have the potential to produce antiplatelet autoantibodies. Antigen specificities of these antibodies are similar to those seen in autoimmune thrombocytopenic purpura and the lupus anticoagulant syndrome. The immunoglobulin V region genes encoding two such human monoclonal antiplatelet antibodies, an anti-GP IIb (STO 171) and an anti-phospholipid antibody (STO 103) derived from tonsillar lymphocytes of a non-thrombocytopenic male, have now been sequenced. These antiplatelet antibodies were found to be encoded by unmutated germline VH and VK genes. The third complementarity determining region (CDR3) of the genes encoding both of these antibodies have unique D regions with evidence of N-nucleotide additions, and the light chain genes show VK-JK junctional diversity. STO 103 is encoded by the VH4 V71-2 germline gene and a truncated JH4 gene. The light chain gene showed closest homology with the VK4 Humk18 gene and JK2 gene. STO 171 showed closest homology with the VH4.18 germline gene and had a complete germline JH6 gene. The light chain of STO 171 is encoded by the VK3 Humkv325 germline gene, which is also used by some rheumatoid factors and cold agglutinins, and a JK4 gene. Although these antibodies were not derived from circulating B cells or found to be actively producing antibody at the time they were harvested, it is possible that naturally occurring antibody producing B cells, similar to those represented here, are recruited for the development of pathogenic autoantibodies in immune thrombocytopenia.
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PMID:Immunoglobulin V region sequences of two human antiplatelet monoclonal autoantibodies derived from B cells of normal origin. 798 Aug 53

Human monoclonal anti-single/double-stranded (ss/ds) DNA antibodies (NE-1 and NE-13) expressed cross-reactive idiotypes (Id), NE-1 Id, which have been detected on the lupus glomeruli-deposited anti-DNA antibodies. The nucleotide sequences of the variable regions of NE-1 and NE-13 clones were analogous except for one nucleotide difference in the Vk region. The VH and Vk gene segments of NE-13 clone were identical with germline genes VH4.21 and Vb (or Vb'), respectively. CDR3s of NE-1 and NE-13 heavy chains were arginine rich and CDR1s contained an amino acid stretch, SGYY, the inverted sequence of YYGS, which was shared among CDR3s of several anti-DNA antibodies. Clonal frequency analysis using a limiting dilution method revealed that NE-1 Id-positive clones at precursor cell level increased in lupus patients. These findings suggest that some IgM anti-DNA clones which express NE-1 Id associated with lupus nephritis use germline genes without mutation and they may be preferentially expanded at the precursor cell levels as well as at the mature cell level.
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PMID:Human B-cell clones expressing lupus nephritis-associated anti-DNA idiotypes are preferentially expanded without somatic mutation. 838 26

We have identified and characterised three new idiotypes on human IgM McAbs generated from the splenocytes of a SLE patient with active disease. RT-6, which binds H1 and Sm/RNP, expresses essentially a private Id. Its expression is limited to a small number of human McAbs and the sera from patients with infectious diseases. In contrast RT-72Id and RT-84Id, expressed on McAbs which are polyreactive for two or more antigens, have a public distribution. RT-72Id and RT-84Id are found on McAbs from murine and human adult, and foetal tissues. In sera, significant numbers of SLE, RA and patients with other autoimmune diseases are positive for both Ids. RT-84Id is also elevated in SLE relatives and spouses, and in patients with Klebsiella infection. No correlation with disease activity, IgM or IgG levels was observed with either Id. However, RT-72Id was significantly associated with anti-ssDNA antibodies and RhF. RT-6Id and RT-72Id are located on the framework regions of the mu heavy chain, whereas RT-84Id is present on the kappa light chain, within the binding site. The McAbs are encoded by mainly germline genes: heavy chains of RT-6, RT-72 and RT-84 are encoded by the genes VH26, VH4.22 and VH4.21, respectively, and the light chain sequences of RT-6 and RT-72 are derived from DPL11 and HK102. Immunofluorescent staining revealed the presence of RT-72Id and RT-84Id positive immunoglobulin deposits in 18% and 45%, respectively, of the lupus renal sections compared with none in the disease control group, suggesting that these Ids may contribute to the pathology of the disease.
Lupus 1995 Oct
PMID:Analysis of three new idiotypes on human monoclonal autoantibodies. 856 32

The use of the NOD/SCID mouse as a transplant recipient for human cord blood B cell progenitors as a tool for investigations into the development of human B cells has become an exciting reality. The characteristics of the immunoglobulin repertoire in such a model is important to investigate, as it is possible that normal or skewed representations could be produced. Here we review our current work in which we describe a normal VH4 repertoire produced in this chimeric mouse model and describe the differences in combinatorial diversity between the human cells that were isolated from the bone marrow and spleen. The implications of this model for studies of systemic lupus erythematosus are also discussed.
Lupus 2003
PMID:The NOD/SCID chimeric mouse model of human B cell development: studies on the VH4 family immunoglobulin repertoire and implications for SLE. 1270 73