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)

Human B-cell lines were derived by limiting dilutions of Epstein-Barr virus (EBV) transformed peripheral B cells from a patient with an autoantibody against glycoprotein (GP)Ia/IIa, and manifesting defective collagen-induced platelet aggregation and a bleeding problem. Antibody-producing clones were selected for their reactivity with whole platelets or with affinity-purified GPIa/IIa by enzyme-linked immunosorbent assay (ELISA). One of these cell lines, selected for further evaluation, produced an IgM (E3G6) that interfered with platelet aggregation responses. Polymerase chain reaction (PCR) amplifications with two different sets of primers specific for human kappa-chains resulted in the rescue of a unique and identical sequence. The same was true for the mu-chain, from which it was concluded that the cell line was monoclonal. Further analysis showed that the kappa variable domain sequence is similar to the germline gene A30, to 2E7, an anti-GPIIb human autoantibody, and to HF2-1/17, a systemic lupus erythematosus (SLE)-associated broad-specificity human autoantibody. Thus, the specificity of our antibody, E3G6, appears to be determined by the mu-chain, the sequence of which is encoded by a VHIII gene segment strongly homologous to the germline gene DP-77, by a D gene that is not homologous to any of the germline D genes reported to date, and by JH4 gene segment that is germline. All four mutations versus DP-77 are in CDRs, and result in amino acid substitutions, which implies that E3G6 may have been derived from an antigen-driven response.
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PMID:Production and nucleotide sequence of an inhibitory human IgM autoantibody directed against platelet glycoprotein Ia/IIa. 754 50

Alleles of the major histocompatibility complex (MHC) have been recognized as genetic factors for the development of SLE. The [HLA-B8; SC01; DR3] extended haplotype seems to be relevant in patients from white European descent, pertinent alleles, however, are difficult to select on haplotypes with linkage disequilibrium. Studies in non-Caucasian patients are therefore mandatory. Admixture estimates in Mexicans have shown a proportion of 56% of Indian genes, 40% of Caucasian genes and from 4 to 12% of Black genes. In order to determine the relevant MHC loci in the genetic susceptibility for SLE we studied Class I, II and III alleles in 102 Mexican SLE patients and 350 of their first degree relatives and compared these two groups to another one composed by 200 ethnically matched normal individuals. We found significantly increased frequencies of HLA-DR3 (pC = 0.03, RR = 2.56) and DR7 (pC = 0.004, RR = 3.08) in SLE patients as compared to controls. On the other hand, first degree relatives had a significantly increased frequency of HLA-DR7 (pC = 0.01, RR = 2.98). There were 21 out of 33 HLA-DR3 haplotypes with complotypes other than SC01 and 25 out 37 SC01 haplotypes with DR alleles other than DR3. Nevertheless, [SC01; DR3] haplotypes were also increased (pC = 0.01, RR = 12.4). After removing [HLA-B8; SC01; DR3] haplotypes, DR3 was the only allele that remained significantly increased (p = 0.04, RR = 2.1). We also found in SLE patients significantly decreased frequencies of the autochthonous Mexican alleles (A30, B39 and DR4) and no deviation from normality of any of the HLA-DQ alleles. These data suggest a fundamental role of the HLA-DR3 allele in the predisposition to SLE in Mexican patients which might be hightened by genes located around the class III MHC region. They also substantiate the pertinence of ethnic admixture estimates in modern human populations.
Lupus 1996 Jun
PMID:The role of HLA-DR alleles and complotypes through the ethnic barrier in systemic lupus erythematosus in Mexicans. 880 88

We found previously that cationic anti-DNA autoantibodies (autoAbs) have nephritogenic potential and usage of a specific germline Vk gene, A30, has major influences on cationic charge of the autoAb in human lupus nephritis. In the present study, we have characterized A30 germline Vk gene using cosmid cloning technique in patients with SLE. A30 gene locus locates in less than 250 kb from the Ck region, and the cationic anti-DNA mRNA used the upstream Jk2 gene, indicating that cationic anti-DNA mRNA is a product of primary gene rearrangement. By using PCR technique, we found that A30 gene locus in the genome was defective in eight out of nine SLE patients without nephritis. In contrast, all nine patients with lupus nephritis had intact A30 gene. The presence and absence of A30 gene was associated with the development of lupus nephritis or not (P < 0.01, by Fisher's exact test, two-sided). It was thus suggested that absence of functional A30 gene may rescue from developing lupus nephritis in the patients. A30 is reported to be a potentially functional but rarely expressed Vk gene in humans. It is possible that normal B cells edit primarily rearranged A30 gene with autoreactive potentials by receptor editing mechanism for changing the affinity of the B cell Ag receptor to avoid self-reactivity, whereas SLE B cells may have a defect in this mechanism. Indeed, we found that normal B cells edit A30-Jk2 gene in their genome possibly by inversion mechanism, whereas SLE B cells contain rearranged A30-Jk2-Ck gene in the genome and express A30-associated mRNA, suggesting that receptor editing mechanism is also defective in patients with SLE. Our study suggests that polymorphism of Ig Vk locus, and failure of receptor editing may contribute to the development of pathogenic anti-DNA responses in humans.
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PMID:Characterization of a germline Vk gene encoding cationic anti-DNA antibody and role of receptor editing for development of the autoantibody in patients with systemic lupus erythematosus. 887 36

The anti-DNA response is a hallmark of systemic lupus erythematosus (SLE). The precise mechanisms leading to anti-DNA antibody (Ab) production remain to be studied. Nonetheless, it is becoming clear that anti-DNA Abs cause inflammatory lesions not only via deposition of circulating immune complexes (IC) consisting of anti-DNA Ab and antigens (Ags), but also via in situ IC formation by cationic anti-DNA Abs. It is intriguing that cationic anti-DNA Abs are encoded by a unique germline Vkappa gene, A30, which encodes an extraordinary cationic light chain, whereas somatic mutations did not induce a cationic shift of electrical charge in human lupus nephritis, suggesting that the usage of a specific germline gene may confer the cationic charge (or pathogenicity) on anti-DNA Abs and that somatic mutations induce the affinity maturation of Abs. Whether cationic anti-DNA Abs will develop depends at least partly on the presence or absence of the germline A30 gene, since patients who lack this gene in the germline Vkappa repertoire did not develop severe lupus nephritis. Receptor editing, a mechanism for changing the affinity of the B cell Ag receptor [surface immunoglobulin (Ig) receptor] to avoid self-reactivity actually seems defective in patients with SLE because normal B cells edited the A30 gene, whereas SLE B cells express A30 mRNA. Thus, along with the importance of somatic mutations, polymorphisms of Ig Vkappa locus, and genetic predisposition, the failure of receptor editing may contribute to the development of pathogenic anti-DNA responses in humans.
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PMID:Development of pathogenic anti-DNA antibodies in patients with systemic lupus erythematosus. 933 56

Although contribution of light chain to DNA reactivity of some murine anti-DNA antibodies (Abs) has been demonstrated, similar studies on human anti-DNA Abs are limited. To investigate this contribution, we reproduced Fab molecules on the surface of phages from a human B cell line producing IgM anti-DNA monoclonal Ab (NE-1) by an Ab-phage display technique. Expressed Fab molecules (p4-1 clone) were similar to the parental mAb in their binding activities and idiotypic expression. We constructed a light chain shuffled library containing Vkappa genes derived from peripheral blood lymphocytes of a patient with systemic lupus erythematosus (SLE) in combination with the NE-1 heavy chain gene. After panning to ss- or dsDNA, 7 Fab-phage clones which showed significant bindings to ss- or dsDNA were isolated. Many other Fab-phage clones from the library did not bind to ss- nor dsDNA. Sequence analysis revealed that light chains of the 7 clones are derived from diverse Vkappa germline genes including rarely used ones such as the L5 and A30. Most of the Vk germline genes have been used for previously reported anti-DNA antibodies. These findings suggest that diverse Vkappa genes can pair with the NE-1 heavy chain for anti-DNA Ab activity. In addition, kappa light chains seem to modulate DNA binding activities in various ways.
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PMID:Analysis of kappa light chain contribution to anti-DNA antibody activity of a human VH4-21-encoded monoclonal antibody (NE-1) by antibody-phage display technique. 985 8

Although a heterozygous deficiency of either complement component C4A or C4B is common, and each has a frequency of approximately 20% in a Caucasian population, complete deficiencies of both C4A and C4B proteins are extremely rare. In this paper the clinical courses for seven complete C4 deficiency patients are described in detail, and the molecular defects for complete C4 deficiencies are elucidated. Three patients with homozygous HLA A24 Cw7 B38 DR13 had systemic lupus erythematosus, mesangial glomerulonephritis, and severe skin lesions or membranous nephropathy. Immunofixation, genomic restriction fragment length polymorphisms, and pulsed field gel electrophoresis experiments revealed the presence of monomodular RP-C4-CYP21-TNX (RCCX) modules, each containing a solitary, long C4A mutant gene. Sequencing of the mutant C4A genes revealed a 2-bp, GT deletion in exon 13 that leads to protein truncation. The other four patients with homozygous HLA A30 B18 DR7 had SLE, severe kidney disorders including mesangial or membranoproliferative glomerulonephritis, and/or Henoch Schoenlein purpura. Molecular genetic analyses revealed an unusual RCCX structure with two short C4B mutant genes, each followed by an intact gene for steroid 21-hydroxylase. Nine identical, intronic mutations were found in each mutant C4B. In particular, the 8127 g-->a mutation present at the donor site of intron 28 may cause an RNA splice defect. Analyses of 12 complete C4 deficiency patients revealed two hot spots of deleterious mutations: one is located at exon 13, the others within a 2.6-kb genomic region spanning exons 20-29. Screening of these mutations may facilitate epidemiologic studies of C4 in infectious, autoimmune, and kidney diseases.
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PMID:Complete complement components C4A and C4B deficiencies in human kidney diseases and systemic lupus erythematosus. 1529 99