Analysis of cellular senescence through detection and assessment of RNAs and proteins important to gene expression: transfer RNAs and autoimmune antigens.
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Adult↗
Biomedical subjects
M Reichlin
Publications and source records attributed to M Reichlin.
Systemic lupus erythematosus: delineation of subpopulations by clinical, serologic, and T cell subset analysis.
Patients with systemic lupus erythematosus (SLE) (n = 194) were analyzed for correlation of clinical features. In addition, the proportions of the two major T cell subsets were determined in 87 subjects. Two patient subgroups were discerned: one in which severe renal disease, leukopenia, and thrombocytopenia predominated, and a second in which sicca syndrome and involvement of the central nervous system, lungs and muscle occurred. The ratio of T helper/inducer to T suppressor/cytotoxic cells was reduced in the first group and increased in the second. We conclude that SLE does not comprise a single disease entity, but rather represents a number of syndromes with overlapping clinical features. The correlation of clinical symptoms with the proportions of circulating T cell subsets suggests that several immunologic mechanisms may underlie the various types of SLE.
Adult↗
T-cell differentiation and maturation.
Understanding of the differentiation and maturation of T cells has been greatly enhanced by several technical developments. Certainly, the most important of these has been the rapid expansion in the availability of monoclonal antibodies to identify surface markers on T cells. Utilization of these antibodies has permitted the description of the developmental sequence of T cells both within the thymus and peripherally. Equally impressive have been the rapid advances in the understanding of the cellular events involved in antigen activation of T cells. These events are MHC restricted. The biochemical description of the class I and class II molecules that are involved in antigen presentation and the biochemical description of the T-cell receptor have provided a framework that should allow a more definitive picture of these specificity-determining molecular structures to emerge in the coming years. Several soluble growth and maturation factors (IL-1, IL-2, and BCGF), which are involved in the generation of cellular immune responses, have also been integrated into the above framework. Finally, ongoing studies on products of activated T lymphocytes (lymphokines) are providing clearer insights into the mechanisms by which immune T cells influence other cells. An additional benefit from the study of T cell development has been a more biochemically based classification of T-cell malignancies. The powerful tools of molecular genetics are beginning to have an impact on research in T-cell differentiation and maturation, and will likely have an ever-growing influence on research into the phenomena surrounding the activities of these immune cells.
Antigens, Surface↗
Anti-DNA antibody idiotypes in systemic lupus erythematosus.
Monoclonal anti-DNA antibodies prepared by the hybridoma technique were used for an analysis of idiotypes of anti-DNA antibodies in systemic lupus erythematosus (SLE). Serum levels of one idiotypic marker, 16/6/R, were higher than normal in 40 of 74 patients (54%) with active SLE, compared with only 6 of 24 patients (25%) with inactive SLE, 9 of 38 patients (25%) with rheumatoid arthritis, and 4 of 96 normal subjects (4%). Levels of the 16/6/R idiotypic marker were determined in serially collected serum samples from 12 patients with SLE. Concordance was found between idiotype levels and clinical activity in 8 of the 12 patients. Levels of the 16/6/R idiotype tended to correlate with levels of antibodies to double-stranded DNA, but in some cases the clinical status was reflected better by the idiotype levels than by the levels of anti-double-stranded-DNA antibodies. Measurement of idiotypes of anti-DNA antibodies may provide information valuable in monitoring the clinical course of patients with SLE.
Antibodies, Monoclonal↗
Anti-threonyl-tRNA synthetase, a second myositis-related autoantibody.
An autoantibody known as PL-7 was found in the serum of four patients with myositis and one with a systemic lupus erythematosus-like syndrome. The PL-7 antigen is an 80,000 dalton polypeptide that coprecipitates with transfer RNA. In aminoacylation reactions, PL-7 IgG inhibited the charging of tRNA with threonine but had little or no effect on charging with other amino acids. Experimental antibodies raised against purified threonyl-tRNA synthetase recognized the same 80,000 dalton polypeptide, but tRNA was not coprecipitated. We conclude that PL-7 antibody is directed at threonyl-tRNA synthetase, and that different antigenic sites are recognized by the human and experimental autoantibodies. Our findings emphasize the link between myositis and autoimmunity to tRNA-related structures.
Adult↗
Multiplicity of antibodies in myositis sera.
Serologic studies on 114 patients with polymyositis and dermatomyositis revealed that 89% had either a precipitating antibody to antigens in calf thymus extract or a positive immunofluorescent reaction on HEp-2 cells, a human tissue culture line. Previously, the greatest proportion of polymyositis sera demonstrating positive serologic results (i.e., the proportion of patients' sera forming precipitates with calf thymus extract) was reported to be 60%. Use of the HEp-2 cell as immunofluorescent substrate enabled the detection of antibody in 89 (78%) of the sera, providing the additional probe which demonstrated specific antibody. Nuclear, cytoplasmic, and nucleolar staining are the most common patterns of immunofluorescence. The immunofluorescent patterns and individual precipitin reactions are related to each other and to the clinical syndromes in which they appear.
Animals↗
Antibodies to a nuclear/nucleolar antigen in patients with polymyositis overlap syndromes.
A precipitating antigen-antibody system has been characterized that occurs in patients with polymyositis. At least half of the patients not only have polymyositis but also have scleroderma. The proposed name for this antigen found in calf thymus extract (CTE) is PM-Scl, to indicate the almost universal presence of polymyositis and the frequent occurrence of scleroderma in the patients who make antibodies to this antigen. The antigen is probably nucleolar since all sera which precipitate with the PM-Scl antigen stain the nucleoli of Hep2 cells by indirect immunofluorescence. The PM-Scl immune system is a distinctive one different from the other known precipitins that occur in patients with polymyositis and dermatomyositis including Jo1, nRNP, and Mi. This PM-Scl antigen and its antibody represent one system which constitutes part of the reactions previously designated as PM1. Interlaboratory exchange of sera and extracts have established the unique nature of this reaction which occurs in patients with inflammatory myopathy.
Antigen-Antibody Reactions↗
Polymyositis and interstitial lung disease in a patient with anti-Jo1 prototype.
The most common marker autoantibody among patients with polymyositis is anti-Jo1. The patient (John P.) providing the prototype serum for this specificity had both interstitial lung disease and polymyositis. A preliminary survey by Ouchterlony analysis and counter immunoelectrophoresis of serum from 15 patients with idiopathic interstitial lung disease revealed no anti-Jo1 or other precipitating autoantibodies. This provides no evidence to suggest that anti-Jo1 has specificity for interstitial lung disease per se. However, this autoantibody may serve as a possible marker for some patients with overlap of polymyositis and interstitial lung disease. The several interesting features about this patient's diseases and course are discussed.
Antibody Specificity↗
Molecular properties of the Ro/SSA antigen and enzyme-linked immunosorbent assay for quantitation of antibody.
Antibodies to the Ro/SSA antigen occur in patients with systemic lupus erythematosus and Sjögren's syndrome. An immunoaffinity method for the preparation of electrophoretically homogeneous Ro/SSA antigen is described. Several molecular properties of the antigen have been determined. The native RNA protein particle has a molecular weight of approximately 100,000 D determined by gel filtration. Sodium dodecyl sulfate-analysis of the purified Ro/SSA antigen and analysis by staining of bands with silver and Coomassie Blue, Western blotting, and RNAase treatment leads to a hypothesis for the structure of the particle in which an antigenic 60,000 protein is bound to 24,000-27,000 RNA molecules which are not antigenic. An enzyme-linked immunoabsorbent assay method for assay of anti-Ro/SSA is also described which sensitively measures antigen binding at dilutions of sera containing anti-Ro/SSA precipitins up to 10(7) fold. Normal sera on average have 10(3) less binding activity.
Animals↗
Anti-La/SSB antibody is present in some normal sera and is coincident with anti-Ro/SSA precipitins in systemic lupus erythematosus.
Sera from 42 patients with systemic lupus erythematosus (SLE) and precipitating antibody to the La/SSB antigen contained 80,000 to 28,800,000 times the minimum detectable binding activity (units) in a solid phase ELISA assay using purified La/SSB antigen. Three normal sera (of 40 tested) had 7,200,21,600 and 21,100 units, respectively, while the log average of the 40 normals was 270 units. Binding activity in normal sera was in the F(ab')2 fragments of IgG, inhibited by purified La/SSB antigen, and bound the major La/SSB peptides. The average apparent relative binding affinity to La/SSB in normal donors was 10-fold lower than in SLE patients with anti-La/SSB precipitins. Analysis of other SLE sera revealed a high incidence of anti-La/SSB in association with anti-Ro/SSA precipitins.
Antibodies, Antinuclear↗
Seroreactivity in myositis patients.
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Antibody Specificity↗
Antibody to Jo-1 in polymyositis/dermatomyositis: association with interstitial pulmonary disease.
Forty-four patients with polymyositis/dermatomyositis (PM/DM) were studied for precipitating antibody to Jo-1. Ten (23%) had anti-Jo-1 antibodies including 8 (47%) of 17 PM patients and 2 (15%) of 13 PM-overlap patients. None of the 11 DM nor 3 PM/DM-cancer patients had anti-Jo-1 antibody. Interstitial pulmonary disease was present in 5 (50%) of the 10 anti-Jo-1 positive compared to 5 (13%) of the 34 anti-Jo-1 negative patients (odds ratio = 5.8, p = 0.05). No differences in other demographic or clinical features or survivorship were noted between these groups. These data confirm the association of anti-Jo-1 antibody with an increased frequency of interstitial pulmonary disease in PM/DM patients.
Adult↗
A mammalian tRNAHis-containing antigen is recognized by the polymyositis-specific antibody anti-Jo-1.
The mammalian cell antigen reactive with the autoantibody anti-Jo-1 has been shown to contain tRNAHis. The RNA sequence of this human and mouse cell tRNA was determined in a search for unusual features that might be related to antigenicity. The 5' terminal nucleotide is unique among other sequenced tRNAs in that it is a methylated guanine. The presence of the hypermodified base queuine, which occurs in the wobble position of the anticodon of tRNAHis from several species, was not detected in the tRNAHis immunoprecipitated by anti-Jo-1 from either human HeLa or mouse Friend erytholeukemia cell extracts. The binding of protein(s) appears to confer antigenicity on tRNAHis since either proteinase K treatment or phenol extraction resulted in the loss of immunoprecipitability. However, we have not succeeded in identifying an antigenic protein, and we find that the antigenic complex is not resolved from purified tRNAHis by Sephacryl S-200 column chromatography. Immunofluorescence studies indicate that the antigenic form of tRNAHis is located preferentially in the mammalian cell cytoplasm. The results presented here are discussed in light of an earlier report (1) on the nature of the Jo-1 antigen.
Animals↗
Homozygous C2 deficiency, lupus erythematosus, and anti-Ro (SSA) antibodies.
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Antibodies, Antinuclear↗
Clinical and biologic significance of antibodies to Ro/SSA.
Study of the clinical associations of antibodies to the soluble antigens Ro/SSA and La/SSB leads to several conclusions. Production of such antibodies are linked to the D locus antigens DR2 and DR3, suggesting involvement of disease susceptibility or immune response genes in the regulation of their synthesis. Genetics therefore provides one of the factors that contribute to the disease expression and the clinical heterogeneity that characterize systemic lupus erythematosus (SLE). The uniform presence of anti-Ro/SSA in neonatal lupus and the almost uniform presence of these antibodies in the vasculitis of Sjögren's syndrome suggest the participation of these antibodies in the immunopathogenesis of these particular clinical manifestations. Finally, identification of the molecular nature of these antigens as RNA-protein conjugates and the ability of the antibodies to La/SSB to bind viral-specific RNA-protein conjugates provide clues that may lead to elucidation of etiologic events in the development of SLE.
Antigen-Antibody Reactions↗
Serologic studies in patients with lupus erythematosus and psoriasis.
We present four patients with coexistent lupus erythematosus (LE) and psoriasis. This is an unusual combination. All four patients had antibodies to Ro, which were absent in twenty-four control psoriatics. Antibodies to Ro occur in only 25% to 30% of unselected SLE patients, but occur in approximately 60% of "antinuclear antibody (ANA)-negative" LE patients, many of whom are highly photosensitive. The increased frequency of anti-Ro in our patients suggests that this may be a specific serologic marker for the LE/psoriasis overlap. Also, since anti-Ro correlates with photosensitivity, LE/psoriasis overlap patients may be at increased risk for photosensitivity, which occurred in two of our patients, one of whom developed severe systemic disease following ultraviolet (UVB) phototherapy. Screening for anti-Ro antibodies may be appropriate in psoriatics prior to UVB phototherapy.
Adult↗
Antibodies to Mi-1 in SLE: relationship to other precipitins and reaction with bovine immunoglobulin.
Precipitating antibodies to Mi-1, a protein antigen purified from calf thymus nuclear extract, have been reported in a small percentage of patients with dermatomyositis (DM) but not in patients with other connective tissue diseases or controls. Mi-1 shares certain characteristics with immunoglobulin, including the ability to react with rabbit anti-bovine immunoglobulin G (BIgG). A more extensive survey for anti-Mi-1 has been performed, involving 51 normal controls, 67 patients with polymyositis (PM) or DM, 47 patients with rheumatoid arthritis (RA), 41 SLE patients without any other precipitating antibodies to saline extractable tissue antigens on routine testing, and 247 patients, many with SLE, known to have other precipitins. Anti-Mi-1 was found in 13 patients from the latter group (5.25%) and two patients with PM or DM (3.0%), and was not found in other groups. It was found in seven of 95 (7.4%) with anti-nRNP, three of 32 (9.4%) with anti-Sm (with or without anti-nRNP) and three of 120 (2.5%) with anti-Ro (SSA). Anti-Mi-1 cross-reacts directly with BIgG but differs from ordinary rheumatoid factor in its frequent reaction with Fab2 fragments and restricted species specificity. Thus, anti-Mi-1 can be found in patients with diseases other than DM, including SLE, most often in patients with antibodies to nRNP.
Arthritis, Rheumatoid↗
Generation of low m.w., C3-bearing immunoglobulin in human serum.
The generation of low m.w. C3-bearing immunoglobulin (lg) in normal human serum by an immune complex (IC) model was investigated in vitro by using discontinuous sucrose density gradient centrifugation (DGC) and an assay that measures C3-bearing Ig. In this method developed to measure circulating IC, all C3 and C3-bearing material is precipitated from serum by using anti-C3 sera in C3d antibody excess, and immune precipitated, C3-bearing Ig is quantitated by the uptake of 125I-5S-anti-IgG. When plasma from patients with clinically active systemic lupus erythematosus was assayed after DGC, most of the reactive material was low m.w. (7S), rather than greater than or equal to 19S as expected for IC, in agreement with a previous report. Low m.w., C3-bearing Ig was found in normal EDTA plasma after extended storage at -29 degrees C but not after storage at -70 degrees C. Such material was also generated in normal human serum during incubation at 37 degrees C and its generation was stimulated by the addition of an IC model, high m.w., heat-aggregated IgG (HMW-HAIgG). In experiments in which the participation of serum IgG was monitored by the addition of 125I-7S-IgG and 131I-HMW-HAIgG was used as an IC model, low m.w., C3-bearing Ig was generated exclusively from serum IgG and the amount generated was proportional to the concentration of 131I-HMW-HAIgG. No significant decrease in sedimentation of 131I-HMW-HAIgG was observed, but the ability of anti-C3 sera to precipitate 131I-HMW-HAIgG decreased 66% 4 hr after initial C activation. These results indicate that generation of nascent C3b in serum results in its interaction with monomeric serum IgG, producing low m.w., C3-bearing IgG. In addition, the data indicate that circulating IC that activate C have a brief time span during which they can be detected by methods that depend upon the binding of C3.
Animals↗