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K Elkon

Publications and source records attributed to K Elkon.

17 recordsLinked to original sources
PubMed1996

Antiribosomal P antibodies in pediatric patients with systemic lupus erythematosus and psychosis.

OBJECTIVE: To study antibodies directed against ribosomal P proteins, a sensitive and specific marker of depression and psychosis in systemic lupus erythematosus (SLE), in pediatric patients with SLE. METHODS: One hundred six serum samples were obtained from 79 patients with SLE. Sixty age- and sex-matched control sera were obtained, and 12 samples were obtained from children with primary psychosis. Antibodies to recombinant ribosomal P (rRP) protein were detected using a standard enzyme-linked immunosorbent assay. RESULTS: All 12 children with non-SLE-associated psychosis had normal levels of anti-rRP antibodies. Elevated levels of anti-rRP were found in 11 of 64 pediatric SLE patients without a history of psychosis (17%). In the group of 13 SLE patients with psychosis, 5 (38%) had increased anti-rRP antibody levels during the time of acute psychosis, and which significantly decreased during remission. In addition, most of the SLE patients without a history of psychosis had a good correlation between anti-rRP antibody levels and disease activity. The patients with psychosis had significantly less renal involvement than the patients without a history of psychosis. This apparent protection from renal disease was not related to the presence or absence of either antiribosomal P or anti-DNA antibodies. CONCLUSION: Elevated serum levels of antibodies to ribosomal P protein can distinguish SLE-associated psychosis from primary psychosis of childhood. In SLE, elevated antiribosomal P antibody levels were not specific for psychosis. Serial assays were useful for monitoring the disease activity.

Antibodies, Anti-Idiotypic↗
PubMed1996

Regulation of Fas and Fas ligand expression in cultured murine renal cells and in the kidney during endotoxemia.

Fas ligand (FasL) and Fas belong to a recently described family of cytokines and receptors with similarities to tumor necrosis factor (TNF) and its receptors. Upon engagement by specific antibodies or by FasL, Fas transduces a signal for apoptosis in permissive cells. Although apoptosis occurs during renal development and following injury to mature cells, the factors responsible for programmed renal cell death are uncertain. We have studied Fas expression by renal cells in vitro and during endotoxemia in mice. Several renal cell types, including glomerular mesangial cells and tubular epithelial cells express a Fas transcript in culture. Lipopolysaccharides (LPS), interleukin-1 beta, interferon-gamma (IFN-gamma), and TNF-alpha increase the levels of Fas mRNA in cultured mesangial and tubular cells. TNF-alpha and LPS raise the level of Fas mRNA in a time- and dose-dependent manner with Fas receptor expression peaking after 72 h of exposure to LPS. Anti-Fas antibodies can induce the death of cultured mesangial cells. This cell death shows the characteristic changes of apoptosis, including DNA fragmentation and pyknotic changes of the nucleus. Increases in Fas by LPS, TNF-alpha, and IFN-gamma enhance the killing induced by the anti-Fas antibody. FasL is also expressed by cultured renal cells, and TNF-alpha treatment of mesangial cells increases its expression. In vivo, Fas mRNA is present at low level in normal kidney. LPS increases the levels of Fas mRNA and protein in kidney and produces evidence of apoptosis along nephrons. These data suggest that transcripts encoding natural FasL and Fas are induced by LPS and may play a role in endotoxemia-induced acute renal failure and organ dysfunction.

Animals↗
PubMed1995

Autoantibodies in systemic lupus erythematosus.

Autoantibodies in systemic lupus erythematosus (SLE) are targeted predominantly to intracellular nucleoprotein particles. Following analysis of the quantitative and qualitative properties of the humoral immune response as well as identification of the major particles recognized as antigens, current studies are addressing the following questions: How is tolerance lost? What accounts for the selection of the antigens? What perpetuates the autoimmune response in SLE?

Animals↗
PubMed1994

Sera from some patients with antibody-associated paraneoplastic encephalomyelitis/sensory neuronopathy recognize the Ro-52K antigen.

Screening a small cell lung cancer cDNA library with serum from a patient with antibody-associated paraneoplastic sensory neuronopathy (Anti-Hu syndrome) resulted in the isolation of a cDNA clone encoding the Ro-52 kD antigen. The Ro-52 kD antigen is one of the major antigens recognized by the sera of patients with Sjögren's syndrome and systemic lupus erythematosus. Further investigation revealed that the sera of only a small percentage (4%) of patients with the Hu syndrome reacted with Ro-52 kD antigen. The cross-reactivity may result from a domain of high homology between Ro-52 kD and HuD antigen. These results emphasize the necessity of using recombinant antigens whenever possible when assaying for assaying for specific antibodies.

Amino Acid Sequence↗
PubMed1993

Cognitive impairment and autoantibodies in systemic lupus erythematosus.

Nervous system involvement in systemic lupus erythematosus (SLE) includes a wide array of manifestations some of which have been associated with specific autoantibodies. These include reactivity to surface neuronal and lymphocyte antigens, ribosomal P and cardiolipin. The aim of the present study was to examine the association between cognitive abnormalities and these autoantibodies in an unselected female population of SLE patients. Using a battery of standardized neuropsychological tests, cognitive impairment was identified in 15/70 (21%) SLE patients compared to 1/25 (4%) patients with rheumatoid arthritis and 1/23 (4%) healthy subjects (P = 0.04). Circulating antineuronal antibodies were measured by indirect immunofluorescence using human neuroblastoma cell lines IMR-6 and SK-N-SH. Lymphocytotoxic antibodies were measured by microcytotoxicity. Antibodies to ribosomal P and cardiolipin were measured by ELISA. Antineuronal antibodies were detected in 34%, lymphocytotoxic antibodies in 47%, anti-P antibodies in 17% and anticardiolipin antibodies in 24% of patients. In the cognitively impaired and unimpaired SLE patients there was no significant difference in the prevalence of antineuronal antibodies (33 vs 35%), lymphocytotoxic antibodies (40 vs 50%), anti-P antibodies (20 vs 17%) or anticardiolipin antibodies (7 vs 29%). The titre and isotype of autoantibodies were also similar in both groups. These results suggest that autoantibodies which have previously been associated with nervous system manifestations of SLE are not likely to be directly involved in the pathogenesis of cognitive dysfunction.

Antibodies, Anticardiolipin↗
PubMed1991

Lupus antiribosomal P antisera contain antibodies to a small fragment of 28S rRNA located in the proposed ribosomal GTPase center.

The ribosomal P proteins are necessary for GTPase activity during protein synthesis. In addition to antibodies to the P proteins, sera from lupus patients contain anti-rRNA activity. To determine whether lupus antiribosomal sera recognize the region of 28S rRNA recently proposed to form part of the ribosomal GTPase center, an rRNA fragment corresponding to nucleotides (nt) 1922-2020 was transcribed in vitro and tested for antigenicity. 18 of 24 (75%) lupus sera containing anti-P antibodies, but only 2 of 24 (8%) lupus sera without anti-P, immunoprecipitated this rRNA fragment (p less than 0.001). The binding was specific, since no significant differences were observed between anti-P positive and negative lupus sera in binding to the RNA fragment transcribed in the antisense orientation or to a control region of rRNA. The majority of sera tested protected a rRNA fragment of approximately 68 nucleotides. To evaluate the fine specificity of the anti-28S antibodies, deletions and site-directed mutations were made in the RNA fragment. The anti-28S antisera required nt 1944-1955 for recognition and were remarkably sensitive to destabilizing as well as nondestabilizing mutations in the stems of the RNA fragments. Detection of antiprotein and anti-RNA antibodies directed against a functionally related domain in the ribosome, together with the remarkable specificity of anti-28S antibodies, strongly suggests a direct role for this region of the ribosome in initiating and/or maintaining antiribosomal autoantibody production.

Antibody Specificity↗
PubMed1991

Anti-P autoantibody production requires P1/P2 as immunogens but is not driven by exogenous self-antigen in MRL mice.

Considerable evidence supports the idea that autoantibody production in human and murine SLE is Ag driven. To determine whether Ag (the ribosomal P proteins) could initiate autoantibody production in lupus mice, 34 MRL/lpr mice were immunized with mouse riboosomal proteins in Freund's adjuvant. Neither intact ribosomes, denatured total mouse ribosomal proteins, nor the purified mouse ribosomal proteins, P1 and P2, induced the production of anti-P autoantibodies in the MRL/lpr mice. In contrast to these negative findings, MRL/lpr mice immunized with Artemia salina ribosomes produced anti-P antibodies as well as anti-P autoantibodies. Although the induced anti-P autoantibodies bound exclusively to the carboxyl terminus, these anti-P antibodies differed from spontaneously occurring anti-P autoantibodies in their predominant binding to mouse P0 on immunoblots and their preferential reactivity against A. salina synthetic peptides by ELISA. Induction of anti-P antibodies required the presence of P1 and P2 on the ribosome because ribosomal cores devoid of P1 and P2 dimers did not induce anti-P. Despite the presence of approximately 80 ribosomal proteins, autoantibodies to other mouse ribosomal proteins were rarely observed. Immunization of MRL/+ mice and a normal H-2-matched strain of mice, C3H, also resulted in anti-P antibodies reactive with the A. salina P proteins and mouse P0. Whereas anti-P levels gradually declined in C3H mice, anti-P levels either remained elevated (MRL/lpr) or showed a secondary rise (MRL/+) at the onset of autoimmunity. These observations indicate that: i) high levels of autologous Ag are not sufficient to drive antiribosomal autoantibody production in MRL mice, ii) multivalency of the P proteins may explain their potent immunogenicity and ability to break tolerance, and iii) immunized MRL mice show an abnormal persistence of high level anti-P production presumably reflecting T cell activation of presensitized B cells.

Amino Acid Sequence↗
PubMed1991

A human autoantibody specific for a unique conserved region of 28 S ribosomal RNA inhibits the interaction of elongation factors 1 alpha and 2 with ribosomes.

An autoantibody reactive with a conserved sequence of 28 S rRNA (anti-28 S) was identified in serum from a patient with systemic lupus erythematosus. Anti-28 S protected a unique 59-nucleotide fragment synthesized in vitro against RNase T1 digestion. RNA sequence analysis revealed that it corresponded to residues 1944-2002 in human 28 S rRNA and 1767-1825 in mouse 28 S rRNA. These sequences are identical and highly conserved throughout all known eukaryotic 28 S rRNAs. In addition, this fragment is homologous to residues 1052-1110 of Escherichia coli 23 S rRNA that lies within the GTP hydrolysis center of the 50 S ribosomal subunit. Anti-28 S and its Fab fragments strongly inhibited poly(U)-directed polyphenylalanine synthesis, but had no effect on ribosomal peptidyltransferase activity. This effect resulted from inhibition of the binding of elongation factors EF-1 alpha and EF-2 to ribosomes and of the associated GTP hydrolysis. The inhibitory effect was almost completely suppressed by preincubation of anti-28 S with 28 S rRNA or in vitro synthesized RNA fragments containing the immunoreactive region. These results show that the immunoreactive conserved region of 28 S rRNA participates in the interaction of ribosomes with the two elongation factors in protein synthesis.

Animals↗
PubMed1990

Central nervous system function in systemic lupus erythematosus.

Autoantibodies to three eukaryotic 60S ribosomal phosphoproteins P0, P1 and P2 have been found in the sera of 10-20% of patients with systemic lupus erythematosus (SLE). These antibodies inhibit protein synthesis in vitro and when microinjected into cultured human fibroblasts. The three proteins share a common epitope contained within the carboxyl terminal 22 amino acids of each protein. Because a significant number of SLE patients have central nervous system disturbances with major behavioral disorders, the antiribosomal protein autoantibodies were measured in this subset of SLE individuals to determine whether or not there was an association. These antibodies are present in 90% of SLE patients who were diagnosed as having psychosis, secondary to the disease.

Amino Acid Sequence↗
PubMed1990

Analysis of autoantibodies to recombinant La (SS-B) peptides in systemic lupus erythematosus and primary Sjogren's syndrome.

Autoantibodies to a polymerase III transcription factor, La (SS-B), are frequently detected in the serum of patients with Sjogren's syndrome and systemic lupus erythematosus. To define the humoral immune response to this protein, we analyzed the patterns of antibody recognition toward 13 recombinant La peptides by immunoblotting and determined the heterogeneity of antibodies reactive with the immunodominant epitopes. The smallest epitopes that were strongly antigenic and recognized by greater than 70% of sera tested (immunodominant) were encoded by the subclones BgX and XA located in the 5' and 3' halves of the La cDNA, respectively. Conformation of the immunodominant La peptides played a major role in antibody recognition. Although greater diversity in antibody binding to carboxyl-terminal La peptides was observed, the overall pattern of peptide recognition by anti-La antibodies was similar in different diseases. The antibody responses to the immunodominant peptides were strongly correlated (r = 0.68, P less than 0.001). One- and two-dimensional isoelectric focusing of affinity purified IgG anti-La peptide antibodies revealed restricted heterogeneity and oligoclonal bands (kappa light chains). These observations suggest that anti-La antibodies are induced and/or maintained by the self antigen and that their diversity is constrained either by mechanisms related to tolerance or by affinity maturation of the humoral immune response.

Animals↗
PubMed1988

The inhibition of protein synthesis by IgG containing anti-ribosome P autoantibodies from systemic lupus erythematosus patients.

Autoantibodies found in approximately 15% of patients with systemic lupus erythematosus recognize three 60 S ribosomal phosphoproteins P0, P1, and P2. Fab fragments obtained from sera of these patients inhibited globin mRNA translation in an in vitro protein synthesizing system which was reversed by the addition of excess ribosomes. Further studies suggested that these antibodies bind to ribosomes in the intact cell. Thus, when IgG fractions from these sera were microinjected into cultured human fibroblasts [35S]methionine incorporation into cellular proteins was inhibited.

Animals↗
PubMed1988

Frequency and epitope recognition of anti-ribosome P antibodies from humans with systemic lupus erythematosus and MRL/lpr mice are similar.

Autoantibodies reactive against a shared, conserved epitope on the ribosomal phosphoproteins P0, P1, and P2 occur in approximately 15% of patients with SLE and are relatively specific for this disease. To determine whether anti-P antibodies occur in murine lupus, serum from MRL/lpr and NZB/W F1 mice were analyzed by immunoblotting as well as by ELISA using a synthetic peptide Ag. Of those analyzed, 4 of 35 (11%) MRL/lpr, 0 of 25 NZB/W F1 and 0 of 13 control NIH/Swiss mice had anti-P antibodies. Anti-P specificity was confirmed by immunoblotting of ribosomal proteins separated by two-dimensional gel electrophoresis and by inhibition of anti-P reactivity on immunoblots with the synthetic peptide Ag. These findings indicate a striking similarity in the frequency and fine epitope specificity of anti-P antibodies in humans and MRL/lpr mice with SLE.

Animals↗
PubMed1988

Immunoblot analysis of IgG subclasses of multiple lupus autoantibodies.

Sera from 35 patients with systemic lupus erythematosus were analyzed for the subclass distribution of IgG autoantibodies to saline-soluble intracellular proteins. To assess the response to all Ag, an immunoblot technique was used, and strips were sequentially probed with patient sera, monoclonal anti-subclass sera, and a labeled anti-mouse reagent. The relative proportions of each subclass reactive with a specific Ag was determined semi-quantitatively by densitometric scanning. Overall, all of the IgG subclasses were involved in the autoantibody response, although the frequency of detection was highest for IgG1 and lowest for IgG4. When the subclass responses to different Ag were compared, IgG1 was the major subclass reactive with the Ro, La, and U1 ribonucleoprotein Ag, whereas IgG1 and IgG2 were almost equally represented in the responses to the Sm BB' and D Ag as well as to the ribosomal P proteins. Individual patient sera frequently showed discordance between the dominant subclass reactive against apparently unrelated proteins and even against proteins within the same antigenic particle (e.g., the Sm BB' and D proteins). These observations indicate that there are two major patterns of subclass response to the common lupus autoantigens but that considerable variation between patients and even within the same patient (to different Ag) occurs.

Animals↗
PubMed1988

Neonatal lupus risk to newborns of mothers with systemic lupus erythematosus.

We prospectively studied 91 infants born to women with systemic lupus erythematosus (SLE) or with SLE-like disease. Thirty-eight infants, including 3 sets of twins, were born to women who had anti-Ro, anti-La, or anti-RNP antibodies. Four infants had definite neonatal lupus, and 4 had possible neonatal lupus. No prospectively studied infant had congenital heart block. The presence of neonatal lupus did not correlate with the titer of anti-Ro antibodies. During the same time period, 2 additional babies with neonatal lupus and congenital heart block were born to mothers not previously known to have SLE. Taken together, these findings confirm the association of anti-Ro antibody with neonatal lupus, but indicate that life-threatening neonatal lupus is rare in children born to mothers who are known to have SLE, even when antibodies to Ro, La, or RNP are present. Prophylactic therapy is therefore not indicated for these women. An important proportion of mothers bearing children with neonatal lupus do not have recognized SLE and, currently, cannot be prospectively identified.

Antibodies↗
PubMed1988

Properties of the ribosomal P2 protein autoantigen are similar to those of foreign protein antigens.

Approximately 15% of patients with systemic lupus erythematosus have autoantibodies that bind to a shared epitope previously shown to be located on the carboxyl-terminal 22 amino acids of three 60S ribosomal proteins, P0, P1, and P2 ("P proteins"). A hydrophilicity plot and fine epitope mapping with seven synthetic peptides revealed that the properties of the antigenic site were similar to certain properties of epitopes on foreign protein antigens--namely, the epitope was located in the most hydrophilic portion of the P2 protein and also in the terminal region of the molecule. However, this site has been highly conserved during evolution. A mouse monoclonal antibody induced by immunization with ribosomal proteins had a fine specificity similar to the lupus antibodies. This finding indicates that a highly conserved region of a lupus autoantigen may also be antigenic in some normal animals. Therefore, lupus autoantibodies may be similar in most, if not all respects, to antibodies produced by immunization.

Amino Acid Sequence↗
PubMed1986

Identification and chemical synthesis of a ribosomal protein antigenic determinant in systemic lupus erythematosus.

The characteristics of eukaryotic ribosomal proteins P0, P1, and P2 (P proteins) and their antigenic determinants were studied using the sera of patients with systemic lupus erythematosus (SLE). P0, P1, and P2 were isolated as a macromolecular complex by preparative isoelectric focusing and anion-exchange chromatography in the presence of 6 M urea. The apparent molecular size of the complex was 140 kDa as determined by gel filtration on a Sephadex G-200 column. P0 may, therefore, be the eukaryotic equivalent of Escherichia coli ribosomal protein L10. In addition, all three P proteins were detected in the postribosomal supernatant of HeLa cells, and P0 and P1 were found to be more acidic than their ribosome-bound counterparts. Partial proteolysis experiments revealed that SLE anti-P sera recognized one or both ends of the P2 equivalent protein from Artemia salina (eL12). Sixteen SLE sera containing antibodies to P0, P1, and P2 reacted with a carboxyl-terminal peptide 22 amino acids in length of eL12 and not with an amino-terminal peptide of 20 amino acids. Even though the carboxyl-terminal peptide completely inhibited the ability of the antiserum to react with all three proteins on an immunological blot, the same peptide produced only small decreases in binding of the SLE antibody to the native, nondenatured P proteins. These findings indicate that SLE anti-P antibodies react with a single sequential (linear) antigenic determinant on all three P proteins, but that additional antibodies recognize a conformational determinant(s).

Amino Acid Sequence↗