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 relatively large number of variable region genes (V) contribute, via gene rearrangements with smaller numbers of additional gene elements (D and J), to generate diversity in the immune response. While some VH gene families are thought to contain 100- 1000 members, the VH10 family has only two known functioning members with 99% sequence homology. Both members (monoclonal antibodies) are capable of binding DNA, and since they were derived from inbred mice afflicted with the lupus syndrome they are considered autoimmune antibodies. Relative uniqueness of the VH10 primary nucleotide sequence presents a model system with which to examine unrearranged VH genes and attempt to identify germline genes eventually expressed as autoantibodies. PCR amplified germline sequences of the VH10 family are highly conserved, with few base substitutions evenly distributed between both framework and CDR regions. It was determined that the PCR amplified germline sequences are highly similar to the DNA sequences of the two monoclonal VH10 antibodies, and a non-functional psuedo-germline gene was found that is identical to a non-functional cDNA derived from a hybridoma cell line. These findings indicate that the use of unique CDR DNA sequences for the identification and amplification of specific germline V genes via PCR can yield vital information that may answer fundamental questions about the origins of autoimmune anti-DNA antibodies in afflicted individuals. The nature of the germline gene populations and the possible microheterogeniety of these genes may prove to be important in understanding the role of autoimmune antibodies in normal and diseased individuals.
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PMID:Autoimmune VH gene family: PCR-generated murine germline VH10 genes. 155 50

Id-16/6 is an idiotypic marker found in both IgM and IgG antibodies, as well as in the tissue lesions of patients with SLE. The prototypic Id-16/6+ mAb is 18/2, whose VH3-derived H chain is encoded by an unmutated germ-line gene. We found that the H chains of VH3-derived Id-16/6+ antibodies contain the major determinants of Id-16/6. Moreover, B cell clones from which those antibodies were harvested produce RNA that hybridized under conditions of high stringency to oligonucleotide probes corresponding to the CDR of the VH segment of 18/2. Western blots of Id-16/6+ mAbs with anti-Id confirmed the association of the Id with H chains. Id-16/6 can identify a subgroup of VH3-derived antibodies we have termed the 18/2 CDR family. However, Id-16/6 can also be expressed in some antibodies unrelated to the 18/2 CDR family. No characteristic Ag-binding specificity was found among the members of the 18/2 CDR family. The principal phenotypic feature shared by all known members of the family is Id-16/6.
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PMID:Molecular analysis of a germ line-encoded idiotypic marker of pathogenic human lupus autoantibodies. 212 Mar 34

The V region sequences of two anti-DNA (A52, D42) and two anti-RNA (D44, D444) autoantibodies, derived from lupus prone NZB/NZW F1 female mice, were determined by mRNA sequencing. The sequences had the following features: 1) there was no clear sequence relationship between anti-DNA and anti-RNA antibodies; 2) there were no major similarities between any of the L chain sequences and each VL gene segment belonged to a different mouse VK subgroup; 3) the H chains of the two anti-RNA antibodies showed closely related sequences of VH gene segments and very similar third complementarity determining regions (CDR3); 4) the H chains of the two anti-DNA antibodies had VH segments belonging to different VH gene families but had a unique and similar combination of D segments and junctional sequences, suggesting a common recognition element for Ag and/or for idiotypic regulation in the H chain CDR3; and 5) the VH gene segment of one anti-DNA antibody (D42) was found to be very similar to the VH gene segment of a CBA mouse hybridoma antibody (6G6) which binds to the environmental Ag phosphocholine. The three-dimensional structure of the Fv-region of the anti-DNA antibody (D42) was modeled by computer and a stretch of poly(dT), ssDNA was docked to a cleft in the antibody combining site, formed by the three H chain CDR and by CDR1 and CDR3 of the L chain. The cleft is characterized by a preponderance of arginine and tyrosine residues, lining both the walls and base of the cleft.
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PMID:V region sequences of anti-DNA and anti-RNA autoantibodies from NZB/NZW F1 mice. 245 27

We investigated idiotypic markers of monoclonal antibodies derived from patients with polyclonal B-cell activation. Four monoclonal antibodies with different ligand binding specificities derived from a patient with lepromatous leprosy and three monoclonal anti-DNA antibodies from two patients with SLE were studied. Three new public idiotopes, which were common to monoclonal antibodies from all three patients, were defined by five polyclonal rabbit antiidiotypes, two monoclonal mouse antiidiotopes, and a monoclonal mouse antibody against a synthetic peptide that contains residues of the heavy chain CDR-1 of a monoclonal lupus anti-DNA antibody. The antibody against the synthetic idiotype was found to react with native immunoglobulins in solution. One idiotope was found to be consistently immunogenic in all animals tested. Since the three patients are of different ethnic origins, these shared idiotypes are probably encoded by germline V genes. These genes may be recurrently expressed in states of polyclonal B-cell activation, regardless of etiology. The results suggest that some autoantibodies arise by expansion of a pool of precursors in the normal antibody repertoire.
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PMID:Idiotypic markers of polyclonal B cell activation. Public idiotypes shared by monoclonal antibodies derived from patients with systemic lupus erythematosus or leprosy. 349 14

Identification of the immunochemical and structural properties of pathogenic anti-DNA antibodies is a major goal for understanding their origins and the mechanisms whereby they induce tissue lesions. Herein, we report on the production of an IgG2a,k anti-DNA monoclonal antibody (4B1), derived from a 12-month-old (NZB x NZW)F1 lupus mouse, able to form glomerular immune deposits. mAb 4B1 is a polyspecific antibody able to bind to ssDNA, actin, tubulin, cardiolipin and to laminin as shown by solid phase ELISAs. Indirect immunofluorescence labeling of HEp-2 cells gave a cytoplasmic staining pattern similar to that obtained with anti-cytoskeleton antibodies. Western blot analysis demonstrated that mAb 4B1 bore idiotype D23, previously shown to be characteristic of natural antibodies derived from normal mice. After injecting the 4B1-secreting hybridoma intraperitoneally into normal (NZW x BALB/c)F1 mice, glomerular immune deposits were observed along the capillary wall. These deposits contained mainly IgM, IgG2a and mAb 4B1, as demonstrated by direct immunofluorescence using a biotinylated-rat anti-4B1 idiotype mAb and kidney eluate analysis. Nucleotide sequence analysis of the VH and VL genes showed that mAb 4B1 is encoded by VH Q52, DSP2.9 and JH2 genes with minimal mutations and by VK8 very similar to the canonic D23 light chain, and JK1 germline genes. No arginine residues were observed in the VH CDR and both chains lacked N-segment addition. Thus, no structural characteristics deduced from the primary structure of mAb 4B1 could explain its pathogenic potential. However, the immunochemical and structural properties suggest that autoantibodies closely related to natural autoantibodies may be pathogenic.
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PMID:An idiotype D23-bearing polyspecific, murine anti-DNA monoclonal antibody forms glomerular immune deposits. Pathogenic role of natural autoantibodies? 754 Feb 57

It has been shown that cationic anti-DNA autoantibodies have nephritogenic potential in murine models of lupus nephritis. We have recently reported the close relationship between the presence of cationic anti-DNA Abs and the development of lupus nephritis in humans. To investigate underlining mechanisms responsible for the production of pathogenic autoantibodies, we have isolated a cDNA clone (SC17) encoding cationic anti-DNA Ab of human systemic lupus erythematosus with severe nephritis that was present at the onset of disease but disappeared after disease remission with corticosteroids. We have also cloned a counterpart Ig VL germ-line gene (SG3) from purified neutrophils of the patient and found the presence of replacement mutations only in the CDR of SC17. Surprisingly, predicted isoelectric point (pI) of deduced protein encoded by SG3 was the most cationic one among those encoded by previously reported human V kappa germ-line genes in the DNA database. These results raise the possibility that the use of specific germ-line genes may confer a cationic charge on the anti-DNA Ab, whereas somatic mutations induce affinity maturation of anti-DNA Ab in human lupus nephritis. Anti-DNA Ab-secreting B cells, but not DNA nonbinding B cells of the same patient, constitutively expressed SC17 mRNA. This mRNA is also expressed by B cells from a vast majority of patients at the onset of disease or exacerbation of lupus nephritis. However, the mRNA is absent in B cells from patients with lupus nephritis during disease remission, systemic lupus erythematosus patients without renal involvements, and normal individuals. It is suggested that the SC17 mRNA expression of B cells is rather restricted to systemic lupus erythematosus patients with active renal involvements.
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PMID:Usage of a novel class of germ-line Ig variable region gene for cationic anti-DNA autoantibodies in human lupus nephritis and its role for the development of the disease. 796 46

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

The origin and structure of two clonally unrelated IgG anti-DNA autoantibodies from lupus-prone MRL/Ipr mice were examined. One of these antibodies, H241, binds dsDNA and glomeruli and deposits in the kidneys of normal mice, whereas the other, H102, binds only ssDNA and does not deposit in kidneys. The VH genes of these two antibodies were almost identical to each other and were frequently expressed in anti-DNA antibodies derived from lupus-prone mice. Six other clonally unrelated anti-DNA antibodies from the literature or from data banks expressed nearly identical VH genes (< or = 4 nucleotide differences) and eight others had nearly identical protein sequences (< or = 3 amino acid differences). Analysis of the germ line with oligonucleotide probes from the CDR regions suggests that all 10 autoantibodies are derived from a single member of the J558 gene family, which is present only in mice with the j haplotype for the J558 gene family. The amount of somatic mutation in these VH genes appears to be low, suggesting that some V, N, and D gene combinations can generate high affinity IgG anti-DNA auto-antibodies with little or no somatic mutation. Unusual reading frames, D-D fusions, and inversions were common in the IgG antibodies and may have been co-selected. Although the N and D regions of one IgM and all five IgG autoantibodies contained Arg residues, the presence of Arg residues was not correlated with binding to dsDNA or with pathogenicity. These results suggest that differences in the Ag-binding properties and the pathogenicity of these antibodies are determined by the CDR3 region and the L chain.
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PMID:Independently derived IgG anti-DNA autoantibodies from two lupus-prone mouse strains express a VH gene that is not present in most murine strains. 840 27

Antiphospholid antibodies (APL) have a notable association with recurrent miscarriages, arterial and venous thrombosis and thrombocytopenia. Analysis of the potential pathogenic effects of such human antibodies has been hampered by the considerable difficulty in producing IgG as opposed to IgM monoclonal immunoglobulins. We have developed four human monoclonal IgG APL (LJ1, AH2, DA3 and UK4) by fusing the peripheral blood lymphocytes of three patients with SLE with a mouse human heteromyeloma cell line, CB-F7. These antibodies bind to a variety of anionic phospholipids, two (LJ1 and AH2) bind total histones but none binds to ssDNA or dsDNA. Binding to beta 2 GPI is non-specific. UK4 alone demonstrates lupus anticoagulant activity. All four have lambda light chains, two are IgG1 (AH2 and UK4) and two are IgG3 (LJ1 and DA3). These APL utilize VH genes present in the fetally restricted repertoire and multiple somatic mutations in the CDR suggest an antigen-driven process. In contrast, there is no restriction in V lambda gene usage and only one lambda chain is extensively mutated. Two clonally related hybridomas were isolated from a single patients. This supports the theory that clonal expansion is the mechanism whereby antigen selects high affinity mutations.
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PMID:The production, binding characteristics and sequence analysis of four human IgG monoclonal antiphospholipid antibodies. 908 Feb 99

IgA antibodies in the mucosal immune system are produced specifically to environmental antigens such as virus and bacteria, and possibly to some food components, which will provide a potential luminal antigen, DNA. To study the immune response to DNA in the gut, we established B-cell hybridomas producing IgA monoclonal antibodies (mAb) from Peyer's patches (PP) of non-immunized, non-autoimmune, specific pathogen-free BALB/c mice, and examined their specificity by enzyme-linked immunosorbent assay (ELISA). Three mAb out of 18 bound strongly to self, bacterial and synthetic DNA, with Kd of about 10-7 m. One of the three mAb also reacted with the histone component and another reacted with some mouse food component. The VH genes of these three mAb have not previously been reported to have anti-DNA specificity, and carry putative somatically mutated sites favouring DNA binding in CDR. The features resemble those of anti-DNA antibodies found in human and murine models of systemic lupus erythmatosus (SLE), and are indicative of an antigen-driven selection process. Our findings suggest that even in normal healthy animals, anti-DNA antibodies of IgA isotype can be produced in certain peripheral environments such as in PP by spontaneous antigenic stimulation.
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PMID:Anti-DNA IgA autoantibodies are spontaneously generated in mouse Peyer's patches. 982 76


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