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

The heavy and light chain nucleotide sequences of 17 monoreactive and polyreactive rheumatoid factors largely derived from the inflamed synovial tissue of two patients with rheumatoid arthritis are described. Some of these sequences have been the subject of a previous report from our laboratories. Additionally, a few rheumatoid factors from the peripheral blood of patients with systemic lupus erythematosus and Sjogren's syndrome as well as a normal individual are included. A review of our previous results as well as the new data provided within this paper lead to the following major conclusions: (1) Rheumatoid factors and polyreactive antibodies derive from a diverse array of VH and VL gene segments; (2) While many rheumatoid factors and polyreactive antibodies are direct or nearly direct copies of germline genes, some show clear evidence of somatic mutation; (3) The CDR3 of all of these antibodies is extraordinarily diverse in length and composition. Certain 'restrictions' do appear in this very large sample: (a) the polyreactive antibodies are exclusively lambda, and (b) there seems to be a preponderance of a particular subset of VH3 genes beyond that one would expect based on random utilization.
 ...
PMID:Nucleotide sequence analysis of rheumatoid factors and polyreactive antibodies derived from patients with rheumatoid arthritis reveals diverse use of VH and VL gene segments and extensive variability in CDR-3. 802 38

Rheumatoid factors (RF) are present in the plasma of patients with rheumatoid arthritis (RA) although the site of synthesis of most of these antibodies is within the synovium. This report primary concerns RF of the IgM isotype. While a few of the RF derive from patients with systemic lupus erythematosus or from normal individuals, the remaining derive from the inflamed synovial tissue of patients with RA. Two RF are encoded by members of the VH1 gene family, 8 from the VH3 family and 2 from the VH4 family. Two polyreactive antibodies derive from the VH3 family and 2 come from the VH4 family. This distribution is not fundamentally different from the distributions seen in a large array of autoantibodies and antibodies to external antigens. Similarly, the light chains derive from most of the known kappa and lambda VL families. It is hard to escape the preliminary conclusion that gene segments from virtually any light chain variable region can contribute to RF or polyreactive antibody structures. Most IgM RF and polyreactive antibodies are direct copies of germline genes in one of their polypeptide chains or at most are 2 nucleotides away in one of their chains from a known germline gene.
 ...
PMID:IgM rheumatoid factors in patients with rheumatoid arthritis derive from a diverse array of germline immunoglobulin genes and display little evidence of somatic variation. 161 33

The platelet glycoprotein (GP) IIb-IIIa complex figures prominently as an immunogen in autoimmune (idiopathic) thrombocytopenic purpura (ITP). 2E7 is a human monoclonal IgM autoantibody, derived from splenocytes of a patient with ITP, that recognizes a specific octapeptide amino acid sequence, Phe-Asp-Gly-Tyr-Trp-Gly-Tyr-Ser, on the heavy chain of GPIIb. This represents the first precise identification of an epitope on GPIIb-IIIa recognized by a human antibody. In this study, we have isolated total mRNA from 2E7, synthesized the corresponding cDNA using reverse transcriptase, and amplified the immunoglobulin mu and kappa chain cDNA by the Taq 1 polymerase chain reaction (PCR) using specific primers. The 2E7 mu chain variable region is encoded by a VH3 gene segment that is 98% homologous to the germline gene VH1.9III, a D-gene that is not homologous to any of the germline D-genes reported to date, and a JH6 gene segment that is essentially germline. The heavy-chain sequence, save for the unique D-gene, is similar to that of a number of human autoantibodies. The 2E7 kappa variable region is encoded by a Vk1 gene segment linked to a Jk1 gene segment. The Vk1 sequence of 2E7, with the exception of one nucleotide, is identical to that of autoantibody HF2-1/17, a prototype of SLE-associated anti-DNA autoantibodies bearing the 16/6 idiotype. The single base substitution results in a relatively conservative exchange of Asp for Glu at position 70 of the protein sequence. Despite this near identity in sequence, 2E7 does not bind to either single-stranded or double-stranded DNA. From these results, we conclude that specificity of 2E7 is likely to reside in either or both the D-JH region (CDR3) of the mu chain and the Jk region (CDR3) of the kappa chain. In addition to the identification of a novel D-gene, we also provide evidence that the 2E7 VHIII gene is probably a prototype of a VHIII subfamily, that the germline Vk1 gene shared by 2E7 and autoantibodies of the 16/6 idiotype probably represents a separate Vk family, and that this Vk gene cannot itself attribute specificity for DNA.
 ...
PMID:Nucleotide sequence of the human autoantibody 2E7 specific for the platelet integrin IIb heavy chain. 171 98

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.
 ...
PMID:Molecular analysis of a germ line-encoded idiotypic marker of pathogenic human lupus autoantibodies. 212 Mar 34

In order to investigate the genetic basis for natural anti-DNA immune responses, we isolated and sequenced the variable gene elements (VH and VL) encoding an anti-DNA antibody expressed by a human hybridoma of normal origin (Kim4.6) and compared these sequences with those reported for four other human anti-DNA antibodies. The Kim4.6 antibody leader and VH segments were identical in nucleotide sequence with the VH1.9III germ-line VH3 gene, and the Kim4.6VL segment showed 98% nucleotide sequence identity with a V lambda I subgroup gene expressed in a Burkitt's lymphoma. Comparative analysis of Kim4.6 and other human hybridoma anti-DNA antibodies indicated that anti-DNA immune responses are diverse in terms of VH and VL gene utilization but may exhibit a bias toward rearrangement of VH genes that are over-represented in the fetal pre-B cell repertoire. Moreover, Kim4.6 and three of four other sequenced human anti-DNA antibodies appear to use a germ-line diversity gene, DXP'1, which may represent a counterpart of the DFL16.1 segment utilized in murine responses to the hapten nitrophenyl. Taken together, our findings indicate that anti-DNA immune responses can be encoded by nonmutated VH genes and that the elements and molecular mechanisms which engender this response are essentially the same among natural and lupus-associated anti-DNA antibodies. Our data also suggest that natural autoimmune responses originate early in B cell ontogeny as is consistent with the hypothesis that autoreactivity plays a major role in shaping the normal immune repertoire.
 ...
PMID:Analysis of variable region genes encoding a human anti-DNA antibody of normal origin. Implications for the molecular basis of human autoimmune responses. 278 10

Antibodies against double stranded DNA (dsDNA) are characteristic of systemic lupus erythematosus (SLE) and have been implicated in disease pathogenesis. Up to one third of an SLE patient's anti-dsDNA antibodies can express the lambda L chain idiotype 8.12. Serum titers of this idiotype are elevated in 50% of SLE patients, and idiotypic antibodies are present in glomerular immune deposits associated with lupus nephritis. Two EBV transformed B cell lines, KS3 from a patient with SLE and SD6 from an individual without autoimmune disease, secrete 8.12+ IgG antibodies that bind dsDNA. The 8.12+ lambda L chains of these anti-DNA antibodies are encoded by members of the V lambda II gene family; the KS3 heavy chain is encoded by a VH4-DM1-DQ52-JH6b-C gamma 1 gene rearrangement and the SD6 heavy chain is encoded by a VH3-D21/9-JH6b-C gamma 1 rearrangement. Both of these monoclonal antibodies are somatically mutated: the KS3 antibody displays mutations in complementarity determining regions (CDRs) and the SD6 antibody in framework regions (FRs). The significance of these different patterns of mutation in two potentially pathogenic anti-DNA antibodies is discussed.
 ...
PMID:Characterization of two human anti-DNA antibodies bearing the pathogenic idiotype 8.12. 751 Oct 7

Two human IgM lambda monoclonal antibodies (MAb) derived from the splenic lymphocytes of patients with idiopathic thrombocytopenia (Ben) and systemic lupus erythematosus (Wri) were studied. BEN-27 and WRI-170 hybridoma supernatants were screened for binding to ssDNA, dsDNA, poly (ADP-ribose), cardiolipin, histone subclasses and Klebsiella K30 cell wall antigen. Of this panel of antigens, BEN-27 and WRI-170 antibodies reacted only with histone H1. Their fine specificity was defined by direct and inhibition ELISA with synthetic peptides of the major human H1b variant. Antibody WRI-170 was shown to bind to both the N- and C-terminal peptides encompassing residues 1-16 and 204-218 of H1b whereas BEN-27 reacted only with peptide 204-218. To analyse the genetic origin of these autoantibodies, we determined the nucleotide sequence of the heavy (H) and light (L) chain variable regions of these two hybridomas. BEN-27 and WRI-170 MAbs were found to use VH1-DN1-JH4/V lambda 3-J lambda 2 and VH3-DIR2-D21/9-JH1/V lambda 2-J lambda 2 gene segment combinations respectively. Between 70 and 95% homology was demonstrated when the mRNA sequences for BEN-27 and WRI-170 were compared with published VH and V lambda germline sequences. This finding suggests that BEN-27 heavy and light chains and WRI-170 light chain use unidentified VH and V lambda germline gene segments whereas WRI-170 heavy chain derives from a VH gene segment recently identified. It is noteworthy that the CDRs of the two MAbs contain several negatively charged amino acids which are assumed to be of critical importance in antigen binding. Moreover, striking similarities are observed between BEN-27 heavy chain CDR2 and a previously described murine anti-H1 Ab heavy chain CDR2.
 ...
PMID:Sequence analysis and fine specificity of two human monoclonal antibodies to histone H1. 751 Dec 11

To determine the molecular and functional properties of human rheumatoid factors (RF), we established stable hybridomas and Epstein-Barr virus-transformed B cell lines from the synovial fluid or peripheral blood of three patients with rheumatoid arthritis and one patient with systemic lupus erythematosus. 17 cell lines were obtained that produced high-titer immunoglobulin M (IgM) RF that reacted exclusively with rabbit but not human IgG or IgG of other mammalian species. Certain anti-rabbit IgG RF also had specificity for other mammalian antigens (Ag), including cytoskeletal proteins and intracellular proteins found in HeLa cells, as well as for Ag present in an extract prepared from the cell wall of group A streptococci. 13 of the 17 RF contained lambda-type light (L) chains, of which 12 were classified serologically as members of the lambda-L chain variable region (V lambda) subgroup, designated V lambda III. The heavy chain V region (VH) and V lambda sequences of nine of these IgM lambda RF were determined at the cDNA level. Five VH genes in three VH families were used by these antibodies (Ab), including VH1 (dp21/1-4b and dp10 [51p1]/hv1051), VH3 (dp38/3-15 and dp77/13-21), and VH4 (dp70/4-4b). The deduced V gene-encoded amino acid sequences of the lambda chains of these IgM lambda RF confirmed their serological classification as lambda III, and they were further classified as members of the relatively uncommon V lambda III subgroup, designated V lambda IIIb. Based on cDNA analyses, nine were the product of three different V lambda III b germline genes. Two such genes, designated hsiggll150 and hsiggll295, were cloned and sequenced from genomic DNA. Unique combinations of these VH and V lambda III b genes could be related to distinctive patterns of reactivity among the IgM lambda RF. Although the VH and V lambda regions of these Abs were expressed primarily as germline-encoded sequences, four of nine multireactive Abs had extensive V region mutation, indicative of an Ag-driven process. The finding that lambda IIIb L chains are preferentially found among anti-rabbit IgG RF, and that some of these Ab have specificity for other protein, cellular, and bacterial Ag, provides new insight into the pathogenesis of RA and related diseases.
 ...
PMID:Human rheumatoid factors with restrictive specificity for rabbit immunoglobulin G: auto- and multi-reactivity, diverse VH gene segment usage and preferential usage of V lambda IIIb. 754 20

Rheumatoid factors (RFs) are autoantibodies that are produced by approximately 75% of patients with rheumatoid arthritis (RA). Their role in pathogenesis is not well understood. In this study of 81 human hybridoma IgM antibodies derived from unstimulated peripheral blood B-cells of patients with RA and systemic lupus erythematosus (SLE), we have demonstrated that idiotypes associated with RFs derived from patients with mixed cryoglobulinemia were expressed by approximately 60% of RFs and 6% of IgM antibodies lacking RF activity. The specificity of the RFs for the Fc portion of IgG only (monospecificity) or for Fc and additional self antigens (polyreactivity) was found to correlate with the expression of specific heavy chain associated idiotypes. The VH3 associated RF idiotypes, D12 and B6, were expressed by 0/16 (0%) of monospecific RFs compared with 6/22 (27%) of polyreactive RFs. The predominant use of VH3 was verified by analysis of the expressed Ig with VH family specific anti-peptide antibodies. The light chains expressed by both populations of IgM RFs were found to be predominantly VKIII, both by detection of specific epitopes/idiotypes and V family analysis. This non-random gene usage of both the heavy and light chains suggests that there is a selective expression of V regions in the RF producing B-cells in patients with RA and SLE. We suggest that different antigen-driven, clonal selection events may occur which result in either monospecific RFs or polyreactive RFs.
 ...
PMID:Restricted immunoglobulin variable region gene usage by hybridoma rheumatoid factors from patients with systemic lupus erythematosus and rheumatoid arthritis. 767 67

Idiotype (Id) 16/6 marks a variable (V) region structure that occurs frequently in the human immunoglobulin repertoire. The basis of the Id has been traced to a germline heavy chain gene segment, VH18/2 (VH26). To pursue the molecular basis for the frequency of Id 16/6, we have analyzed polymerase chain reaction-generated C mu, C gamma, and VH3 family V gene libraries derived from the circulating and tonsillar B cells of four normal individuals and from the B cells of two patients with active systemic lupus erythematosus (SLE). The frequency of VH18/2 in these libraries was compared with three control VH genes, VH56P1, VH21/28, and VHA57. Plaque lifts from C mu and C gamma VH cDNA libraries were screened with gene-specific oligonucleotide probes. The frequency of VH18/2 ranged from 4 to 10% of JH+ plaques (two of five times that of control VH genes). In four VH3 family-specific libraries derived from rearranged DNA, VH18/2 represented 19-33% of VH3+ plaques. Hybridizing VH18/2 plaques were 98-100% homologous to the germline VH gene; mutations when present were often in framework 3. Extensive variation was seen in the complementarity determining region 3 sequences of these rearranged V genes. The high frequency of VH18/2 expression in the B cell repertoire was confirmed by sequencing randomly picked JH+ plaques. In two patients with active SLE the frequency of use of VH18/2 was not greater than that observed in normal subjects. These results show that VH18/2 is overrepresented in the B cell repertoire of normal subjects and suggest that the immune repertoire may be dominated by relatively few V genes.
 ...
PMID:High-frequency representation of a single VH gene in the expressed human B cell repertoire. 845 18


1 2 Next >>