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)

In the course of a previous study addressing autoantibody generation in murine models for generalized autoimmune disorders, we observed a nonfunctional immunoglobulin heavy chain transcript in a B cell hybridoma from lupus-prone MRL-Mp-lpr/lpr mice. This transcript, the cDNA sequence of which is presented here, is of general interest for murine immunoglobulin genetics as it cannot be ascribed to any known heavy chain variable region gene (Vh) family by nucleic acid sequence homology criteria and, hence, may represent a new Vh gene family. The sequence showed about equal nucleotide similarity (70-73%) to 3 other Vh gene families (S107, J606, 7183) and less than 65% similarity to members of the remaining 6 Vh gene families. Nucleic acid sequence comparisons with unpublished immunoglobulin sequences uncovered a highly homologous (greater than 95%) functional Vh transcript indicating that the suggested Vh gene family also encodes expressed antibody molecules.
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PMID:Evidence for a new murine immunoglobulin heavy chain variable region gene family. 288 12

The mRNA encoding heavy and light chains of a hybridoma-derived monoclonal IgM, kappa anti-immunoglobulin (rheumatoid factor) and an IgG3, kappa anti-histone autoantibody from systemic lupus erythematosus and arthritis-prone MRL/Mp-lpr/lpr mice have been molecularly cloned, and the nucleotide sequences corresponding to their variable regions have been determined. To investigate whether autoantibodies with specificities frequently observed in lupus disease might share common structural components, the sequences obtained in this study have been compared with those of a monoclonal MRL/Mp-lpr/lpr IgM, kappa anti-DNA autoantibody previously analyzed in our laboratory (J. Exp. Med. 1985. 161: 805). The 3 immunoglobulins employed different heavy chain variable region (VH) genes belonging to the large J588 VH gene family, kappa light chain variable region (V kappa) genes from 3 different V kappa groups, and different diversity and joining segments. Our findings suggest that murine lupus-associated autoantibodies of different specificities do not have genetic components in common to signal their self-reactive nature and are encoded by a large number of immunoglobulin gene elements.
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PMID:Molecular analysis of the murine lupus-associated anti-self response: involvement of a large number of heavy and light chain variable region genes. 310 55

The variable region of the heavy chain of a prototypic anti-DNA autoantibody from the lupus-prone mouse, MRL-lpr/lpr, was cloned and sequenced. The VH and JH genes expressed by this antoantibody were found to be identical to germ line genes from the nonautoimmune mouse strain, BALB/c. The D gene of this autoantibody differed by one nucleotide from several members of the germ line SP2 family, but has been found in expressed D genes from several strains of mice. These results show that a normal mouse strain contains all of the structural information necessary for the expression of the heavy chain variable region of a lupus autoantibody. A fragment that is present in both BALB/c and MRL mice is highly homologous in both coding and flanking sequences to the autoantibody VH gene (VH130) and is the same size as the BALB/c germ line gene. This suggests that these two strains may share the same allele of this VH gene, despite the fact that they are polymorphic for this VH gene family. Other mouse strains that are polymorphic for this locus contained one to three VH genes that were highly related to VH130 in both coding and flanking regions. Thus, VH genes that may be allelic to the antibody VH gene or that may have arisen by gene conversion, unequal crossing over or gene duplication, are conserved in many mouse strains.
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PMID:The heavy chain genes of a lupus anti-DNA autoantibody are encoded in the germ line of a nonautoimmune strain of mouse and conserved in strains of mice polymorphic for this gene locus. 311 87

The mRNAs encoding heavy and light chains of a hybridoma-derived monoclonal IgM kappa anti-DNA autoantibody from lupus-prone MRL/Mp-lpr/lpr mice (Ighj) have been transcribed into cDNA copies and molecularly cloned, and their complete nucleotide sequences have been determined. The mRNA for the heavy chain variable region, including leader peptide and 5' untranslated region, is transcribed from a heavy chain variable region (VH) gene closely related (and possibly allelic) to VH genes of the C57BL/6 (Ighb) nitrophenyl antibody family. The deduced amino acid sequence corresponding to the light chain variable region of this autoantibody shows extensive similarities with non-autoantibody molecules of the V kappa 1 group, suggesting a common variable gene origin. The joining segments, constant regions, and 3' untranslated regions of both the heavy and light chain mRNAs are nearly identical to corresponding sequences of non-autoantibodies from normal mice. Our findings suggest that this anti-DNA autoantibody originated from the same germline repertoire as antibodies to exogenous antigens.
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PMID:Genetic elements used for a murine lupus anti-DNA autoantibody are closely related to those for antibodies to exogenous antigens. 392 Mar 43

Previous studies have suggested that the CDR3 genetic element of the heavy chain variable region of autoantibodies is important in determining reactivity against self antigens, particularly against DNA. The lpr mutation was recently found to encode for a defective form of the fas protein, a molecule important for the transmission of the apoptotic signal into cells. Our aim was to determine whether CDR3 elements similar to those described for autoantibody-producing hybridomas derived from lupus-prone strains could be found in the preimmune repertoire of B cells in mice with the lpr mutation. The analysis of the junctions of the VH-C mu functional rearrangements derived by polymerase chain reaction (PCR) amplification of RNA obtained from splenic small, resting cells stimulated with lipopolysaccharide (LPS) from male lpr mice showed that a large proportion of them expressed D genes in the unusual reading frames 2 and 3. Two of the lpr joints were formed by D-D fusions. Similarly, nearly half of the lpr sequences had arginines, an amino acid which promotes binding to dsDNA and is seldom observed in normal junctions. Our results show that the preimmune repertoire of lpr animals has abnormal CDR3 elements which may result from a failure at different levels of selection. The antigen-dependent selection of such elements that leads to the expansion of specific, high-affinity anti-dsDNA antibody-producing clones might depend on other genetic factors not found in the C57B1/6-lpr strains but in the MRL-lpr.
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PMID:CDR3 regions in the preimmune VH B cell repertoire of lpr mice. 762 95

The stimulus for the production of anti-DNA autoantibodies in lupus remains unknown. Since double-stranded DNA (dsDNA) is a weak immunogen, other stimuli such as B cell superantigens or anti-idiotypic antibodies may provide an alternative mechanism for their production. The presence of regulatory determinants on autoantibodies might be revealed through their structural characterization, but they have eluded detection, perhaps because they may be three-dimensional and require closer analysis. In this report we cloned and sequenced the heavy chain variable region (VH) of a monoclonal anti-dsDNA antibody, mAb 3E10, derived from MRL/lpr mice with lupus nephritis previously shown to express an idiotype associated with nephritis in murine and human lupus. We now show that mAb 3E10 VH contains novel structural features unrelated to DNA binding which are shared only by a subset of autoantibodies expressed in murine lupus. These lupus autoantibodies can be distinguished from antibodies of non-autoimmune strains by the presence of a specific sequence at the junction of the diversity and joining genes combined with the use of variable region genes with conserved sequences in framework 1 (FR1) and FR3. The location of the novel sequences indicates the possibility of a three-dimensional solvent-exposed determinant located distant from the classical antigen binding site that could regulate their production, possibly through binding B cell superantigens or other infectious agents.
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PMID:Novel structural features of autoantibodies in murine lupus: a possible superantigen binding site? 769 22

In order to investigate the genetic origin of nephritogenic antibodies in MRL/Mp-lpr/lpr (MRL/lpr) lupus mice, we isolated the germ-line heavy chain variable region (VH) gene corresponding to the nephritogenic antibody, B1, derived from an unmanipulated MRL/lpr mouse. Injection of this antibody into C.B-17/Icr-scid/scid mice resulted in the generation of wire loop-like glomerular lesions resembling those of lupus nephritis. Nucleotide sequences of this germ-line VH gene showed no replacement mutation in the VH region of the B1 antibody. Furthermore, this gene was identical to that found in the C3H/HeJ-lpr/lpr strain of mice. Our results suggest that germ-line VH genes can encode nephritogenic antibodies without somatic mutation, even in a mouse strain not prone to lupus.
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PMID:Sequence analysis of the germ-line VH gene corresponding to a nephritogenic antibody in MRL/lpr lupus mice. 774 68

We have recently characterized the heavy chain variable region (VH) genes expressed by a panel of human anti-DNA antibodies derived from four patients with systemic lupus erythematosus and expressing an idiotypic marker representative of a subset of pathogenic autoantibodies. Here, we have cloned and sequenced the kappa chain variable region genes (V kappa) of the clones whose VH genes had been previously analysed. All the V kappa genes utilized map to the 280 kb portion of the 3' end of the locus, suggesting that they represent essentially the products of primary rearrangements. This proximal clustering of the V kappa genes used contrasts with the broad distribution of immunization-induced human antibody V kappa genes over 1400 kb of the locus. In addition, lupus autoantibodies show no tendency to express the downstream junctional (J kappa) exons--another indication of infrequent secondary variable gene assembly. Since successive rearrangements may extinguish high-affinity recognition of self antigens, we propose that this bias in V kappa and J kappa expression reflects a low rate of secondary light chain rearrangements among lupus autoantibodies. We also postulate that the corrective mechanism capable of editing potentially aggressive, self-reactive antibodies in these patients may be deficient--a deficit that could be genetically determined and/or somatically acquired.
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PMID:Human lupus anti-DNA autoantibodies undergo essentially primary V kappa gene rearrangements. 803 91

Naturally occurring polyreactive anti-DNA mAbs derived from a nonimmunized (NZB x NZW)F1 mouse with spontaneous lupus erythematosus penetrated and accumulated in the nuclei of a variety of cultured cells. These mAbs and their F(ab')2 and Fab' fragments, covalently coupled to fluorescein, peroxidase, or a 15-mer polynucleotide, also translocated to the cell nuclei. A 30-amino acid peptide corresponding to the combined sequences of the complementary-determining regions 2 and 3 of the heavy chain variable region of one mAb was able to penetrate into the cytoplasm and nucleus of cells of several lines. This peptide recognized DNA and was strongly polyreactive. Streptavidin-peroxidase conjugates complexed with the N-biotinylated peptide were rapidly translocated into cells. Similarly, peroxidase or anti-peroxidase polyclonal antibodies covalently coupled to the N-cysteinylated peptide through an heterobifunctional maleimide cross-linker were also rapidly internalized and frequently accumulated in nuclei. The peptide carrying 19 lysine residues at its N-terminal was highly effective in transfecting 3T3 cells with a plasmid containing the luciferase gene. Thus, penetrating mAbs and derived peptides are versatile vectors for the intracellular delivery of proteins and genes.
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PMID:Polyreactive anti-DNA monoclonal antibodies and a derived peptide as vectors for the intracytoplasmic and intranuclear translocation of macromolecules. 957 29

Current treatments for autoantibody-mediated diseases, such as lupus, can cause nonspecific immune suppression. In this paper, we used a bioinformatic approach to identify major histocompatibility complex class I-binding epitopes in the heavy chain variable region of anti-DNA antibodies from lupus-prone (NZB/NZW F1) mice. Vaccination of such mice with plasmid DNA vectors encoding these epitopes induced CD8(+) T cells that killed anti-DNA antibody-producing B cells, reduced serum anti-DNA antibody levels, retarded the development of nephritis, and improved survival. Vaccine-mediated induction of anti-V(H) cytotoxic T lymphocytes that ablate autoreactive B cells represents a novel approach to treat autoantibody-mediated diseases.
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PMID:Vaccination with minigenes encoding V(H)-derived major histocompatibility complex class I-binding epitopes activates cytotoxic T cells that ablate autoantibody-producing B cells and inhibit lupus. 1223 7


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