Systemic lupus erythematosus.
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Antibodies, Antinuclear↗
Biomedical subjects
M Reichlin
Publications and source records attributed to M Reichlin.
Progressive systemic sclerosis.
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Antibodies, Antinuclear↗
Molecular definition of the Ro(SSA) particle(s): a frequent target of autoimmunity in systemic lupus erythematosus and Sjögren's syndrome.
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Antibodies, Antinuclear↗
A radioimmunoassay for antibodies to the Ro/SSA particle.
A radioimmunoassay (RIA) for antibodies to the Ro/SSA particle is described using Iodogen to radiolabel the antigenic protein moiety of Ro/SSA with 125I. RIA methods utilizing either 33% saturated ammonium sulfate (NH4)2SO4 or 3.5% polyethylene glycol to separate bound from free antigen are comparable. Either method is similar to ELISA in sensitivity and specificity. This RIA provides a fluid phase assay for the Ro/SSA-anti-Ro/SSA system not previously available.
Autoantibodies↗
HLA-D region genes associated with autoantibody responses to histidyl-transfer RNA synthetase (Jo-1) and other translation-related factors in myositis.
Myositis has been associated with HLA-B8 and DR3, especially in white patients with polymyositis and serum anti-Jo-1 antibodies. Twenty-eight patients with myositis and serum translation-related autoantibodies anti-Jo-1, anti-PL-7, anti-PL-12, anti-KJ, and anti-SRP were studied for HLA class II specificities by Southern blotting with HLA-DR beta, DQ beta, and DQ alpha probes. The association of HLA-DR3 (DRw17) with anti-Jo-1 antibodies in white myositis patients was confirmed (P = 0.003, relative risk 8.9). However, HLA-DRw52 haplotypes, regardless of subtype, were present in all of the white and black patients with serum anti-Jo-1 and other translation-related autoantibodies. Moreover, one anti-Jo-1 positive patient had HLA-DRw8, an HLA-DRw52 haplotype on which the DR beta 3 gene has been partially deleted. No HLA-DQ specificity or allele was common to all patients. The HLA-DR3, DR5, DRw6, and DRw8 haplotypes, which bear the HLA-DRw52 specificity, share the most homology in the DR beta 1 first hypervariable region at amino acid positions 9-13. Thus, this DR beta 1 region appears to be the most likely candidate "epitope" for translation-related autoimmune responses in inflammatory myositis.
Alleles↗
Organ distribution of the Ro (SS-A) antigen in the guinea pig.
Using an anti-Ro (SS-A)-specific "sandwich" enzyme-linked immunosorbent assay (ELISA) and Western immunoblotting, we determined the Ro (SS-A) content (both quantitative and qualitative) in saline-perfused organs of the guinea pig. All tissue extracts contained substantial concentrations of Ro (SS-A) antigen and could be grouped into 3 categories based on quantitative reactivity in the sandwich ELISA. The 60-kd and 52-kd molecular forms of Ro (SS-A) present in tissue extracts were similar to those described in Wi-L2 extracts, and the 54-kd molecular form of Ro (SS-A) in guinea pig erythrocytes was similar to that found in human erythrocytes. The tissue distribution of the isoforms of Ro (SS-A) was shown by Western immunoblotting to vary in different tissues, and the reactivity to the 60-kd Ro (SS-A) was correlated with the activity seen in the ELISA. Both the 60-kd and 52-kd Ro (SS-A) bands in guinea pig liver extracts were very weak on Western immunoblots, in contrast to the high concentration of Ro (SS-A) antigen in the ELISA. Other data suggest the possible existence of a unique form of Ro (SS-A) in the liver. Guinea pig tissues have 4 Y RNA that are equivalent to the 4 human RNA--hY1, hY3, hY4, and hY5--present in HeLa cells, while guinea pig red blood cells have only one Y RNA, which is equivalent in size to human hY4.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Heterogeneity of the Ro/SSA antigen and autoanti-Ro/SSA response: evidence of the four antigenically distinct forms.
Precipitating antibodies to the Ro/SSA antigen occur in the sera of 40% of patients with systemic lupus erythematosus (SLE) and in 40-70% of the sera of patients with primary Sjögren's syndrome. Previous work has shown that lymphocyte extracts contain two Ro/SSA antigens with protein moieties of 60 kD and 52 kD and that erythrocyte haemolysate contain two analogous but antigenically distinct Ro/SSA molecules of 60 kD and 54 kD. Frequency analysis of the various specificities in 43 sera with precipitating anti-Ro/SSA and studies with affinity-eluted antibodies suggest that the lymphocyte 60 kD and erythrocyte 60 kD Ro/SSA molecules are related as are the lymphocyte 52 kD and erythrocyte 54 kD Ro/SSA proteins. Anti-Ro/SSA sera when accompanied by other precipitins (anti-La/SSB and anti-U1RNP) react preferentially with certain Ro/SSA isoforms. Evidence is also presented for a 45 kD form of Ro/SSA. These data suggest that the antigenic heterogeneity of the Ro/SSA antigen is immunologically relevant and that there are two families of Ro/SSA antigens; one comprising of the two 60-kD proteins in the erythrocyte and lymphocyte and the other the erythrocyte 54 kD and lymphocyte 52 kD Ro/SSA proteins, respectively.
Antibody Specificity↗
Molecular cloning, expression, and chromosome 19 localization of a human Ro/SS-A autoantigen.
Ro/SS-A antibodies are found in a number of human autoimmune disorders including Sjogren's syndrome and several systemic lupus erythematosus-related disorders. These heterogeneous autoantibodies are known to recognize several distinct cellular antigens. With synthetic oligonucleotides corresponding to amino acid sequence information we have isolated a full-length cDNA clone which encodes a human Ro ribonucleoprotein autoantigen. The 1,890-base pair clone contains an open reading frame that encodes a 417-amino acid, 48-kD polypeptide that migrates aberrantly at 60 kD by SDS-PAGE. Rabbit antibodies raised against this protein's recently described amino-terminal epitope react with a previously identified 52-kD human Ro protein and immunoprecipitate the human cytoplasmic RNAs. Ultraviolet light cross-linking studies suggest that this Ro protein binds each of the four major human cytoplasmic RNAs. The deduced amino acid sequence is 63% homologous to an Onchocerca volvulus antigen. Southern filter hybridization analysis indicates that this gene is not highly polymorphic and exists as a single copy in the human genome. Chromosomal localization studies place this gene on the short arm of chromosome 19 near the gene encoding the low density lipoprotein receptor.
Amino Acid Sequence↗
HLA-DQ gene complementation and other histocompatibility relationships in man with the anti-Ro/SSA autoantibody response of systemic lupus erythematosus.
A strong gene interaction between HLA-DQ1 and DQ2 alleles has been associated with anti-Ro/SSA autoantibodies (Harley, J.B., M. Reichlin, F. C. Arnett, E. L. Alexander, W. B. Bias, and T. T. Provost. 1986. Science [Wash. DC]. 232:1145-1147; Harley, J. B., A. S. Sestak, L. G. Willis, S. M. Fu, J. A. Hansen, and M. Reichlin. 1989. Arthritis Rheum. 32:826-836; Hamilton, R. G., J. B. Harley, W. B. Bias, M. Roebber, M. Reichlin, M. C. Hochberg, and F. C. Arnett. 1988. Arthritis Rheum. 31:496-505). To test a gene complementation mechanism for these results, restriction fragment length polymorphisms (RFLP) of the DQ alpha and DQ beta genes have been related to Ro/SSA precipitins in patients with systemic lupus erythematosus. In this study Ro/SSA precipitins are related to the simultaneous presence of a particular pair of RFLPs. A DQ alpha RFLP associated with HLA-DQ1 and a DQ beta RFLP associated with HLA-DQ2 predict that the alpha beta heterodimer in HLA-DQ1/DQ2 heteroxygotes is most closely related to anti-Ro/SSA autoantibodies, thereby supporting a gene complementation mechanism. Beyond this effect, an RFLP associated with HLA-DQ2 and/or DR7 is also related to Ro/SSA precipitins. Multiple molecular histocompatibility mechanisms are implicated, therefore, in the production of anti-Ro/SSA autoantibodies in autoimmune disease. For anti-Ro/SSA autoantibodies in SLE, and perhaps more generally, these data show that the histocompatibility antigens are among the elements that confer autoimmune response specificity and restrict the production of particular autoantibodies among patients with systemic lupus erythematosus.
Autoantibodies↗
The evolution of red blood cell and lymphocyte Ro/SSA.
Recent studies have demonstrated that the Ro/SSA autoantigen is heterogeneous as is the corresponding autoimmune response. In addition the autoimmune responses is highly species specific and preferentially reactive with the human antigen. Quantitative ELISA study shows that red blood cell Ro/SSA evolves much more rapidly than lymphocyte Ro/SSA and Western Blot analysis shows that the quantitative ELISA results are mirrored by changes in the 60 kD Ro/SSA molecules but not the 52 kD and 54 kD Ro/SSA molecules. The 52 kD and 54 kD Ro/SSA molecules seem to be relatively conserved as indicated by the Western immunoblotting experiments. These studies add weight to the concept that the antigenic epitopes of these related proteins are under the control of separate genes which have undergone different rates of evolution.
Animals↗
C4 null genes in American whites and blacks with myositis.
The frequencies of C4A and C4B alleles were determined in 66 adults with myositis in relation to HLA class I and II. In whites with myositis, the C4A*Q0 allele occurred in 13/31 (47%) as compared to 25/101 (25%) normal controls (p = 0.08, relative risk = 2.7). Only 11/35 (31%) of black patients with myositis had a C4A*Q0 allele compared to 11/55 (20%) of controls (p = NS, RR = 1.8). Thus, the MHC class III genes do not appear to be the primary genetic risk factors for myositis in adults.
Alleles↗
Genetic studies of Ro (SS-A) and La (SS-B) autoantibodies in families with systemic lupus erythematosus and primary Sjögren's syndrome.
Using enzyme-linked immunosorbent assays, autoantibodies to Ro (SS-A) were detected in the sera of 21% of the first-degree relatives and 11% of the second-degree relatives of anti-Ro-positive probands with systemic lupus erythematosus (SLE) or primary Sjögren's syndrome, as compared with 3% of normal control subjects (P = 0.003 and P = 0.09, respectively). In a parallel study, anti-Ro occurred in 28% of the first-degree relatives of unselected members of families of SLE patients, regardless of the proband's serologic status, compared with 6% of the relatives from normal healthy families. Antibodies to La and to Sm/nuclear RNP were infrequent. Anti-Ro occurred in 41% of the relatives considered to have a dominant, non-HLA-linked "autoimmune trait" by virtue of having any autoimmune disorder and/or serologic abnormality (antinuclear antibodies, anti-single-stranded DNA, or biologic false-positive VDRL test result), as compared with only 2% of the healthy, seronegative relatives without the trait (P = 0.009). Moreover, HLA-DR2 and/or DR3 occurred in 90% of anti-Ro-positive subjects, regardless of their clinical status. These results demonstrate that the Ro autoantibody response occurs frequently in relatives of patients with SLE and is genetically mediated by both major histocompatibility complex and non-major histocompatibility complex effects.
Adult↗
Maternal antibodies to Ro (SS-A) are associated with both early onset of disease and male sex among children with systemic lupus erythematosus.
In this study of 71 children with systemic lupus erythematosus (SLE) and 188 of their first-degree relatives, we demonstrated that the development of SLE in male children younger than age 18, and in all children younger than age 10 at the time of diagnosis, is strongly correlated with the presence of antibodies to Ro (SS-A) in the mother's serum. When the relative antibody concentration was quantified, increased quantities of antibody to Ro (SS-A) were also found in mothers of male probands and mothers of probands whose SLE was diagnosed before age 10. No similar association was found for the presence or amount of antibody to Ro (SS-A) in other first-degree relatives or for antibody to La (SS-B) or nuclear RNP in any relative. The explanation for the association of maternal anti-Ro (SS-A) antibodies and early diagnosis of SLE or male sex is not apparent. These findings extend the association of maternal antibodies to Ro (SS-A) from transient "neonatal" SLE to SLE in childhood, and suggest that maternal antibodies to Ro (SS-A) may be of fundamental importance in the pathogenesis of some cases of childhood SLE.
Adolescent↗
Differences in the fine specificity of anti-Ro (SS-A) in relation to the presence of other precipitating autoantibodies.
In sera from patients with systemic lupus erythematosus or Sjögren's syndrome, we determined the fraction of antibody that remained reactive with human Ro (SS-A) after absorption with bovine spleen extract, and the reactivity with the 60-kd and 54-kd red blood cell Ro (SS-A) bands by Western blot. Of the 3 groups of sera studied, those containing anti-Ro (SS-A) alone had the highest degree of reactivity with human Ro (SS-A) after absorption with bovine spleen extract, followed, in descending order, by sera containing anti-Ro (SS-A) and anti-La (SS-B), and sera containing anti-Ro (SS-A) and anti-nuclear RNP. The groups of sera could be distinguished on this basis. Sera with anti-Ro (SS-A) and anti-nuclear RNP could also be distinguished from the other 2 types of sera by their uniform and preferential reactivity with the 60-kd red blood cell Ro (SS-A), by Western blot analysis. These findings indicate that there are both qualitative and quantitative differences, associated with the presence of other autoantibodies, in the fine specificity of anti-Ro (SS-A) sera.
Animals↗
Autoantibodies to the Ro/SS-A particle react preferentially with the human antigen.
The measurement of autoantibodies frequently employs animal extracts as antigen, and it is widely observed that the autoimmune response to soluble antigens is not species-specific. Published Ouchterlony experiments with anti-Ro/SS-A sera revealed a qualitative reaction of identity when bovine and human extracts are utilized as antigen source [1]. Quantitative studies of the Ro/SS-A-anti-Ro/SS-A reaction employing a sandwich ELISA with human anti-Ro/SS-A to capture antigen coupled with absorption studies reveal that the anti-Ro/SS-A response is directed to the human Ro/SS-A antigen. Quantitative reactivity is best when the sandwich is charged with human spleen or lymphocyte extracts while rat and mouse spleen extracts are far less effective. Anti-Ro/SS-A sera which react well in Ouchterlony experiments with bovine Ro/SS-A could be shown to prefer a human antigen source by quantitative ELISA and to have strong residual reactivity with human Ro/SS-A after absorption with bovine spleen extract. This is the first autoimmune response to a soluble tissue antigen which is recognized to be preferentially reactive with the human antigen. These data support the ideas that the autoimmune response is antigen driven and that the antigen could be involved in the initiation of the response.
Antibodies, Antinuclear↗
Alteration by heat shock and immunological characterization of Drosophila small nuclear ribonucleoproteins.
Sera from human patients with systemic lupus erythematosus (SLE) have been shown to react with snRNP particles of both mammals and Drosophila (Mount, S. M. and J. A. Steitz. 1981. Nucleic Acids Res. 9:6351-6368). We have utilized fully characterized monospecific sera and specifically purified antibodies to carry out indirect immunofluorescence experiments with frozen sections of Drosophila embryos. Embryos subjected to severe heat shock before sectioning showed reduced binding of anti-Sm sera. Anti-nRNP sera reacted identically with antigens of heat shocked and non-heat-shocked sections. The reduction in anti-Sm fluorescence was restored by a brief salt wash. These results imply a noncovalent alteration in the conformation of Sm antigens with the administration of heat shock that can revert with exposure to salt. Drosophila antigens have been compared to mammalian standards, showing partial identity with bovine spleen extract (BSE) antigens when reacted with anti-Sm sera. The antigenic relatedness between affinity-purified heat-shocked and non-heat-shocked Drosophila antigens and their mammalian homologues was examined by quantitative ELISA methodology. In all cases, the Drosophila antigens from heat-shocked and non-heat-shocked embryos were identical. We theorize that the heat shock-induced alteration of Sm antigen reverst during extraction. Because the snRNP antigens have been shown to be involved in splicing, and because splicing is inhibited during heat shock (Yost, H. J., and S. Lindquist. 1986. Cell. 45:185-193), our results provide information on the nature and stability of a change in these antigens which may be a central element in control of the heat shock response.
Animals↗
The immunogenetic relationship between anti-Ro(SS-A)/La(SS-B) antibody positive Sjögren's/lupus erythematosus overlap syndrome and the neonatal lupus syndrome.
We have described previously the clinical features of a unique group of anti-Ro(SS-A) antibody positive Sjogren's patients who have cutaneous features of lupus erythematosus, most commonly subacute cutaneous lupus erythematosus, defined as the Sjogren's/lupus erythematosus overlap syndrome. Three of these patients are also mothers of infants with the neonatal lupus erythematosus syndrome, characterized by cutaneous lesions resembling subacute cutaneous lupus erythematosus or congenital heart block. Patients with Sjogren's/lupus erythematosus overlap syndrome, subacute cutaneous lupus erythematosus, and mothers of infants with the neonatal lupus syndrome characteristically have autoantibodies to Ro(SS-A), and in many cases, La(SS-B) antigens. The present study was designed to test the hypothesis that anti-Ro(SS-A)/La(SS-B) positive Sjogren's/lupus overlap patients and mothers of infants with neonatal lupus erythematosus syndrome are immunogenetically homogenous and closely related. We report a strong association with HLA-B8, DR3, DQw2, and DRw52 phenotypes and the HLA-B8, DR3, DQw2, DRw52 extended haplotype in both patient cohorts. Furthermore, we describe disease associations with HLA-DR3/DRw6 heterozygotes in both patient groups. These data demonstrate that anti-Ro(SS-A)/La(SS-B) positive Sjogren's/lupus overlap patients and neonatal lupus syndrome mothers are immunogenetically closely related to each other and appear to be more closely related to both primary Sjogren's syndrome and subacute lupus erythematosus, than to classical systemic lupus erythematosus.
Antibodies, Antinuclear↗
Heterogeneity of the Ro/SSA antigen. Different molecular forms in lymphocytes and red blood cells.
Ro(SSA) is an intracellular ribonucleoprotein against which autoantibodies are found in a portion of patients with Sjögren's syndrome and systemic lupus erythematosus. A form of Ro(SSA) is described in red blood cells that shares a line of identity with purified Ro(SSA) from bovine spleen and human lymphocytes in counterimmunoelectrophoresis, but has different molecular properties. Ro(SSA) from red blood cells exists in association with only two small RNAs as opposed to four in other cell types, as determined by RNA extraction of protein A-assisted immunoprecipitates. In addition to the common 60-kD Ro(SSA) protein, Western blot analysis revealed an additional 52-kD protein in lymphocytes and a 54-kD protein in red blood cells. The 60-kD form of Ro(SSA) in red cells was found to be antigenically distinct from that in the lymphocyte, because sera were identified that bound each exclusively. Finally, a rabbit antibovine Ro(SSA) serum distinguished red cell from lymphocyte Ro(SSA). These results suggest two distinctive populations of Ro(SSA) proteins and distributions of Ro(SSA) RNAs in the lymphocyte and red blood cell.
Animals↗