Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A monoclonal antibody (9G4) which detects an idiotope (Id) rising from heavy chains encoded by the VH4-21 gene segment has been utilized to investigate the role of this gene in encoding anti-DNA antibodies in SLE. Two hybridomas secreting Id-positive anti-DNA antibodies were established from two patients with SLE, with one (RT-79) an IgM kappa and the other (D-5) IgG kappa. Nucleotide sequence analysis of the heavy chain variable regions revealed involvement of the VH4-21 gene; the IgM antibody used the gene in germ line configuration, whereas the IgG antibody had 18 nucleotide changes. The CDR3 sequences for both the antibodies had a predominance of basic amino acids, with RT-79 having five and D-5 two arginine residues respectively. The VH4-21 gene segment, often in germ line configuration, is also used by IgM autoantibodies against red cell Ii antigens. However, IgM from a panel of six hybridomas secreting antibodies of Ii specificity, had no detectable activity against DNA. Conversely, RT-79 had only a weak ability to agglutinate red cells. Comparisons of Ig variable regions indicate that the amino acids in the CDR3 region of the mu chain influence the ability of IgM encoded by the VH4-21 gene segment to discriminate between a carbohydrate Ii antigen and DNA, and strongly support the suggested role of arginine in interaction with DNA. Sera from patients with SLE were found to have significantly raised levels of Id which was expressed by anti-DNA antibodies against both ss and dsDNA.
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PMID:Utilization of the VH4-21 gene segment by anti-DNA antibodies from patients with systemic lupus erythematosus. 815 58

Polyreactive (natural) antibodies are primarily IgM and account for a major proportion of circulating Ig in humans. They use various V gene segments, in general, in germ line (unmutated) configuration. To analyze the VH regions of polyreactive antibodies, with particular attention at their somatically mutated status, we generated five IgG (three IgG1 and two IgG3) mAb (using B cells from a healthy subject, a patient with insulin-dependent diabetes mellitus and a patient with SLE), which bound with various efficiencies a number of different self and foreign Ag. Gene cloning experiments showed that the VH region sequences were unique to each IgG mAb. The H chain complementary determining region (CDR3) of two IgG (mAb10 and mAb426.4.2F20) displayed an identical stretch of five amino acids (RFLEW), but the other three IgG mAb CDR3 were divergent in both length and composition. The VH gene sequences of two IgG, mAb426.4.2F20 and mAb410.7.F91, were 99% identical to those of the germ line VH4.11 and VH4.21 genes, respectively. Those of the remaining three IgG mAb displayed a number of differences (93.6 to 95.9% identity) when compared with the germ line VH4.18, VH4.11, and hv1263 gene sequences. These and the VH4.21 gene have been found to encode polyreactive IgM and IgA and, in mutated configuration, monoreactive high affinity autoantibodies and antibodies induced by foreign Ag. When compared with the respective framework region, the CDR of three IgG mAb VH segment sequences displayed a significantly higher: 1) frequency of total nucleotide differences (6.1 x 10(-2) vs 4.5 x 10(-2) difference/base); 2) frequency of putative nucleotide changes yielding amino acid replacements (5.6 x 10(-2) vs 1.4 x 10(-2) replacement change/base); and 3) ratio of overall putative replacement to silent (R:S) mutations (11.0 vs 0.4). Thus, the distribution and nature of the nucleotide differences were consistent with a process of somatic mutation and Ag-dependent clonal selection. This was formally proved in IgG mAb426.12.3F1.4 and IgG mAb10 by differentially targeted polymerase chain reaction amplification and cloning and sequencing of the germ line genes that gave rise to the expressed VH segments, using DNA from polymorphonuclear cells of the same subjects whose B cells were used for the generation of these IgG mAb. Somatic mutations might have been responsible for bringing about polyreactivity in originally monoreactive antibodies or, more likely, they accumulated in originally polyreactive antibodies, which after undergoing a process of Ag selection, retained polyreactivity and may have or may have not acquired a higher affinity for the selecting Ag.
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PMID:Structural analysis of the VH-D-JH segments of human polyreactive IgG mAb. Evidence for somatic selection. 837 96

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 analysed the heavy and light chain variable region genes of two monoclonal antibodies, specific for the Sm antigen (RSP1; IgG kappa) and for cardiolipin (RSP4; IgM lambda), derived from a patient with active systemic lupus erythematosus (SLE). We have established that the variable region genes of the RSP1 autoantibody are somatic mutants of two germ line genes from the VH4 and V kappa 1 gene families. RSP4 antibody uses gene segments closely related to a VH3 gene member and to a V lambda 1 gene. The presence and distribution of the somatic mutations on both monoclonal autoantibodies are compatible with an antigen-driven immune process. These data suggest that in SLE a common antigenic stimulus may govern the autoantibody response against a wide spectrum of unrelated antigens, including native DNA, cardiolipin or Sm antigens, and provide further evidence that disease-associated autoantibodies are generated through antigen-selected somatic mutations.
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PMID:Analysis of variable region genes encoding anti-Sm and anti-cardiolipin antibodies from a systemic lupus erythematosus patient. 855 90

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

We have previously described complement-independent killing of human B lymphocytes by two IgM MoAbs derived from the VH4-34 (VH4.21) gene. Analysis of 17 independently derived VH4-34-encoded MoAbs shows that B cell toxicity is not limited to the two described MoAbs, but is a general property shared by a subset of MoAbs derived from the VH4-34 gene. As observed by two independent microscopy techniques, giant membrane pores were formed on target B cells within 10-15 min of exposure to cytotoxic VH4-34-derived MoAbs. Toxicity by individual MoAb correlated directly to its B cell binding intensity measured by FACS, i.e. stronger the binding greater the killing. Sequence analysis showed that V(H) region in germ-line or in near germ-line configuration was necessary but not sufficient for B cell binding. In addition, a particular sequence motif enriched in basic amino acids in the CDR3 may be required to supplement the reactivity mediated by the V(H) region of the MoAb molecule. VH4-34-encoded antibodies that fulfil the above sequence requirements have cold agglutinin activity towards the i antigen of cord erythrocytes. In vivo, such anti-i/anti-B cell antibodies are rarely detected in healthy adults, but serum levels are dramatically elevated in selective pathological conditions, such as systemic lupus erythematosus and infectious mononucleosis. This strict regulation may be related to the novel and rapid mechanism of human B cell toxicity demonstrated by antibodies encoded by a single human V(H) gene.
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PMID:Rapid cytotoxicity of human B lymphocytes induced by VH4-34 (VH4.21) gene-encoded monoclonal antibodies, II. 909 24

The studies for autoantibody-associated V genes have failed to find any V gene which might be specific for pathogenic autoantibodies in humans; Namely, both normal subjects and patients have immunoglobulin V genes which can encode autoantibodies. Also single V gene can encode antibodies for both foreign antigens and autoantigens. However, some germline V genes such as V3-7 and VH4-21 are preferentially used for autoantibodies and may be regarded as prototype V genes for autoantibodies. Although somatic mutation in V genes is characteristic in IgG autoantibodies, 0-81 idiotype-positive IgM antibodies, which may be precursor B cells for pathogenic anti-DNA antibody also included many somatic mutations in VH genes, indicating an intrinsic abnormality in B cell development in SLE. Some studies also indicated an abnormal V gene repertoire in autoimmune states. These results may be attributed to dysregulation of autoantibody-associated B cell development.
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PMID:[V gene repertoire and pathogenic autoantibodies]. 920 Sep 32

Anti-double stranded(ds) DNA antibody is one of markers of systemic lupus erythematosus (SLE). Two human monoclonal anti-DNA antibody-producing cell lines were established from two SLE patients. One cell line secreted IgG isotype antibody (KSUG) and the other secreted IgM isotype antibody (KSUN). The light chains of the two immunoglobulins were lambda chains. The nucleotide sequences for the immunoglobulin variable region genes of the two antibodies were determined and compared to germline sequences. The heavy and lambda light chains of KSUG were VH3 family and V lambda IIIb, respectively. The heavy and lambda light chains of KSUN were VH4 family and V lambda IX, respectively. Antibody KSUG, IgG isotype, showed somatic mutations, whereas KSUN, IgM isotype, used the germline gene without mutation. These findings reconfirm the current paradigms that IgM anti-DNA antibodies are produced by utilizing germline genes whereas IgG anti-DNA antibodies are produced by somatic mutations.
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PMID:Molecular and genetic characterization of two anti-DNA antibodies derived from patients with systemic lupus erythematosus. 959 61

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

An antibody phage library obtained from peripheral blood lymphocytes of a systemic lupus erythematosus (SLE) patient was used to isolate four monoclonal autoantibodies against histones H2A and H2B. Analysis of the variable region sequences revealed that the anti-histone monoclonal antibodies were not clonally related; they used VH genes from three different VH gene families (VH3, VH4, and VH5) and distant members of the Vkappa group (L25, L6, A27, and O8) in conjunction with different D and J gene segments. These observations suggest that certain gene families or segments are not critical in producing anti-histone autoantibodies in SLE. Most of the utilized VH and Vkappa sequences were highly mutated and the complementarity-determining regions (CDRs) varied greatly in length. The VH region of the antibody SLEhis18 had an isoelectric point of 6.1, and 29% of the mutations were changes to acidic amino acid residues. The second CDR (CDR2) of SLEhis18 VH contained one basic and three acidic residues. Acidic residues were observed in the CDR3 regions of VH, but not VL, in all isolated clones; this is unusual, as most autoantibodies are comprised predominantly of non-acidic residues. This is the first report of a systematic sequence analysis of human anti-histone monoclonal antibodies. Our results suggest that certain V genes are not important for autoreactive specificity to histones in SLE; instead, other mechanisms such as an existence of acidic residues and somatic mutations in CDRs are required for specific binding to histones, which might play a role as a stimulatory autoantigen for the activation of autoantibody-producing B-cells and the selection of high affinity antibody.
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PMID:Variable region genes of human monoclonal autoantibodies to histones H2A and H2B from a systemic lupus erythematosus patient. 1558 19


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