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Biomedical subjects

M Reichlin

Publications and source records attributed to M Reichlin.

At least 145 records · Page 8Linked to original sources
PubMed1987

Implications of anti-Ro/Sjögren's syndrome A antigen autoantibody in normal sera for autoimmunity.

We have applied a sensitive assay to analyze lupus and Sjögren's syndrome autoantibodies in 40 normal sera. Seven of these bound Ro/Sjögren's syndrome A antigen (SSA). Although this binding was 1,000-fold lower than the highest anti-Ro/SSA level measured from patients, it was inhibited by human Ro/SSA. Positive normal serum-bound Ro/SSA in Western immunoblots and binding activity was demonstrated in the F(ab')2 fragment of IgG. Affinity purification of normal anti-Ro/SSA IgG increased the specific anti-Ro/SSA binding by greater than 17-fold. This purified antibody formed a Ro/SSA precipitin and had a relative affinity for Ro/SSA identical to that of Ro/SSA precipitin-positive patients. These data demonstrate that the anti-Ro/SSA present in healthy normal donors is true autoantibody. Anti-La/Sjögren's syndrome B antigen (SSB) autoantibodies were found in 3 of the 40 normal sera, while none bound nuclear ribonucleoprotein (Sm). Finding low levels of anti-Ro/SSA and anti-La/SSB among normals may indicate that anti-Ro/SSA and anti-La/SSB occur in disease by enhancement of a preexisting immune response.

Adult↗
PubMed1987

Lupus/Sjögren's autoantibody specificities in sera with paraproteins.

Antinuclear antibody and anti-RNA-protein autoantibodies were determined in 143 sera containing paraproteins and 39 control sera. Antinuclear antibodies were commonly present in the paraprotein sera by indirect immunofluorescence. 19 of 143 sera (13%) had elevated anti-Ro/SSA activity in a solid phase Ro/SSA binding assay, and 5 (3.5%) had Ro/SSA precipitating autoantibody. Eighteen sera had La/SSB binding autoantibodies (12%) but only one had an anti-La/SSB precipitin. Anti-nRNP(Sm) was not detected in any of these sera. The solid phase anti-RNA protein assays were repeated using anti-lambda and anti-kappa conjugates. Both lambda and kappa light chain autoantibodies were found in all positive sera consistent with polyclonal anti-Ro/SSA and anti-La/SSB responses. Paraprotein sera containing Ro/SSA precipitins were analyzed by isoelectric focusing followed by exposure to 125I-labeled Ro/SSA and autoradiography. All sera with anti-Ro/SSA binding paraproteins also contained polyclonal anti-Ro/SSA. Our data are consistent with the hypothesis that anti-Ro/SSA paraproteins are common and arise from a previously present polyclonal anti-Ro/SSA response.

Antibodies, Antinuclear↗
PubMed1987

Antibodies to Ro(SSA) and the heterogeneity of systemic lupus erythematosus.

The clinical heterogeneity of systemic lupus erythematosus (SLE) is associated with a multiplicity of autoimmune responses to both cellular and soluble antigens. At least part of the clinical heterogeneity is associated with serological heterogeneity and this is particularly striking among patients with SLE who produce anti-Ro(SSA) and anti-La(SSB). Certain subsets within the lupus spectrum are closely associated with the anti-Ro(SSA) response. These include subacute cutaneous lupus erythematosus, the lupus like syndrome associated with homozygous C2 and C4 deficiency, and neonatal lupus erythematosus. Moreover, among the patients with SLE who produce anti-Ro(SSA) are 2 stable groups, on which produces anti-Ro(SSA) alone and one which produces both anti-Ro(SSA) and anti-La(SSB). Clear clinical and serological differences distinguish these groups and it is hypothesized that these differences are due to genetic differences in the HLA-D region. Exact identification of the genes involved and how they control immune responses should lead to a clearer understanding of the clinical phenomena seen in these patients.

Adolescent↗
PubMed1987

Novel nucleolar antigens in autoimmune disease.

Antinucleolar antibodies are of interest in 2 important areas, namely, autoimmune diseases and specific products involved in the "mitogenic cascade." The former have delineated a series of novel nuclear and nucleolar elements including the recently described proliferating cell nuclear antigens (PCNA), some of which are present in the nucleolus only at specific times in the G1-S phase of the cell cycle. Important new proteins such as "fibrillarin" (34 kD/pI 8.5) and a 125 kD nucleotide containing protein have been identified with antinucleolar antibodies. Protein p145 is a nucleolar PCNA that is present in growing and dividing cells but not in normal resting tissues. Antinucleolar antibodies offer powerful tools, not only for identification of specific nucleolar proteins important in the cell cycle, but also for purification of their genes and analysis of mechanisms of gene control that operate the "time windows" of the cell cycle.

Amino Acid Sequence↗
PubMed1987

Familial systemic lupus erythematosus: evidence for separate loci controlling C4 deficiency and formation of antibodies to DNA, nRNP, Ro and La.

A family has been identified in the Canadian province of Prince Edward Island in which 2 sisters have systemic lupus erythematosus in a sibship of 14. Studies are reported on 11 of the siblings and 16 other family members. The affected siblings, and 4 other members of their sibship, are halfnull homozygotes for the C4A component of complement. We studied the distribution in family members of antibodies to ss and dsDNA, and to Ro(SSA), La(SSB), Sm and nRNP. Eight of 11 members of the affected sibship are antibody producers, compared to only 3 of 13 members of the parental generation. Our study provides further evidence for an association between null genes for C4A and familial lupus, and suggests, in an unusually large kindred, that several other genetic factors are involved in the production of antinuclear antibodies.

Adult↗
PubMed1987

Antinuclear and anti-single-stranded DNA antibodies in morphea and generalized morphea.

The clinical features of localized scleroderma have allowed investigators to distinguish three morphologic variants: morphea, generalized morphea, and linear scleroderma. The latter has been reported to have a higher frequency of antinuclear antibodies and has been associated with antibodies to single-stranded DNA (ssDNA). In this study we determined the frequency of antinuclear antibodies and anti-ssDNA antibodies in 22 patients with morphea or generalized morphea. None had Raynaud's phenomenon or evidence of a systemic connective-tissue disease. Antinuclear antibodies were present in 18% of patients when serum samples were tested on mouse kidney substrate but were found in 50% of HEp-2 cells. The serum samples contained anti-ssDNA antibodies in 59% of the patients, with the highest levels of ssDNA binding observed in patients with generalized morphea. The frequency of antibodies to ssDNA was higher in patients with clinical evidence of active compared with inactive disease. Discordance in immune reactivity indicates that at least three distinctive serum autoantibodies exist in morphea and generalized morphea: anti-ssDNA antibodies and antinuclear antibodies with either homogeneous or speckled immunofluorescence patterns. These findings are similar to those recently described in linear scleroderma and suggest that comparable serum autoantibody abnormalities are present in all the variants of localized scleroderma.

Adolescent↗
PubMed1986

Gene interaction at HLA-DQ enhances autoantibody production in primary Sjögren's syndrome.

Primary Sjögren's syndrome is an autoimmune disorder characterized by dryness of the mouth and eyes. The human leukocyte antigen (HLA) locus DQ is related to the primary Sjögren's syndrome autoantibodies that bind the RNA proteins Ro/SSA and La/SSB. Both DQ1 and DQ2 alleles are associated with high concentrations of these autoantibodies. An analysis of all possible combinations at DQ has shown that the entire effect was due to heterozygotes expressing the DQ1 and DQ2 alleles. These data suggest that gene interaction between DQ1 and DQ2 (or alleles at associated loci), possibly from gene complementation of trans-associated surface molecules, influences the autoimmune response in primary Sjögren's syndrome.

Alleles↗
PubMed1986

Anti-Ro (SS-A) and anti-La (SS-B) in patients with Sjögren's syndrome.

Clinical, serologic, and genetic findings in Sjögren's syndrome patients were correlated with quantitative determinations for antibody against Ro (SS-A), La (SS-B), and nRNP (Sm) using newly developed, sensitive solid-phase assays. In 86 Sjögren's syndrome patient sera, more than 96% had anti-Ro (SS-A), and 87% had anti-La (SS-B), spanning a 4.8 log10 range of autoantibody concentration, whereas only 95% of the patients had anti-nRNP (Sm). Low levels of anti-Ro (SS-A) and anti-La (SS-B) were found in 10% and 12.5%, respectively, of the 40 normal control sera. In Sjögren's syndrome patients, the level of anti-Ro (SS-A) correlated strongly with that of anti-La (SS-B) (r = 0.80; P less than 0.0001) but not with the level of anti-nRNP (Sm). We found much higher levels of anti-Ro (SS-A) and anti-La (SS-B) in patients with purpura, leukopenia, lymphopenia, and increased polyclonal gamma globulins than in those without these conditions (between 4.3-fold and 17-fold higher; P less than 0.001 to P less than 0.05). Anti-Ro (SS-A) and anti-La (SS-B) levels correlated with the rheumatoid factor titer and with the concentrations of total globulin, IgG, and IgA, but not with the IgM concentration. The association of rheumatoid factor titer with levels of anti-Ro (SS-A) and anti-La (SS-B) occurred only in patients with primary Sjögren's syndrome. Antinuclear antibody titers correlated with levels of anti-Ro (SS-A) and anti-nRNP (Sm). HLA-DR3-positive patients had higher levels of anti-Ro (SS-A) and anti-La (SS-B).

Antibodies, Antinuclear↗
PubMed1986

An animal model of antibody binding in cutaneous lupus.

To study antibody binding in cutaneous lupus, we used human skin grafted onto nude mice. By immunofluorescence examination, mice injected with anti-Ro (SS-A) sera from subacute cutaneous or neonatal lupus erythematosus patients showed evidence of human IgG deposited in the skin, while mice injected with anti-native DNA or normal sera did not. We present evidence that there is specific binding of anti-Ro (SS-A) antibodies to Ro (SS-A) antigen in the skin, and we propose that these antibodies may be directly involved in cutaneous disease.

Adult↗
PubMed1986

Significance of the Ro antigen system.

Knowledge about antibodies to the Ro/SSA and La/SSB antigens has expanded greatly. Recognition of these antibodies was probably achieved 25 years ago but their macromolecular structure, clinical associations, and genetic relationships have come to light only in the past 7 years. It seems clear that these antibodies have a special place in the nosology of SLE and SS and that in certain instances (e.g., neonatal LE) the antibodies play a direct pathogenic role, while in other circumstances (e.g., vasculitis, nephritis, SS) tissue damage might result from immune complex deposition on vascular structures. Certainly, the latter problems will be active areas of investigation in the coming years. If the pace of recent progress continues, many of the questions raised in this review should soon have clear answers.

Antibodies, Antinuclear↗
PubMed1986

Linear scleroderma. Clinical spectrum, prognosis, and laboratory abnormalities.

The clinical features and natural history of linear scleroderma in 53 patients and the laboratory tests helpful in the management of this disease are described. No patient had Raynaud's phenomenon or signs of systemic connective tissue disease in a mean follow-up of 10 years. Blood eosinophilia (greater than 300 cells/mm3) was present in half the patients, usually those with clinically active disease rather than inactive disease (p less than 0.02). An elevated serum IgG level correlated with the presence of joint contractures (p less than 0.02). Antinuclear antibodies, commoner in patients with extensive and prolonged disease, were present in 31% and 46% of patients whose sera were tested on mouse kidney and HEp-2 cells, respectively. Antibodies to single-stranded DNA, present in 50% of patients, were associated with extensive disease, joint contractures (p less than 0.001), and active disease of greater than 2 years' duration (p less than 0.001). Discordance in immune reactivity indicates that at least three serum autoantibodies exist in these patients: antibodies to single-stranded DNA and antinuclear antibodies with homogeneous and nucleolar immunofluorescence patterns.

Adolescent↗
PubMed1986

Complement C4 fixation by the anti-La(SSB) found in normal donors and in patients with systemic lupus erythematosus.

The discovery that a common systemic lupus erythematosus (SLE) autoantibody (anti-La/SSB) occurs in normal individuals has made it possible to compare the specific complement binding capacity of normal autoantibody with SLE patient autoantibody. Normal donors with elevated levels of anti-La(SSB) binding were compared to negative normal donors and to 3 patients with SLE with high levels of anti-La(SSB) binding in assays for anti-La(SSB) and for the capacity of anti-La(SSB) to bind C4. The anti-La(SSB) found in normal sera and in SLE patient sera had no identical specific capacity to fix C4. For the case of anti-La(SSB), the autoantibody structure in relation to its specific capacity to activate complement, at least to the extent of fixing C4, does not differentiate SLE patients from normal individuals with this autoantibody.

Antibodies, Antinuclear↗
PubMed1986

Detection by ELISA of antibodies to small RNA protein particles in systemic lupus erythematosus patients whose sera lack precipitins.

Three hundred five consecutive patients with systemic lupus erythematosus (SLE) have been evaluated for antibodies to the RNA protein particles, Sm, nRNP, Ro/SSA, and La/SSB. Precipitating antibodies were found in 224 (73.1%). With the use of ELISA methodology with affinity-purified antigens, 76 sera from precipitin-negative patients were assayed and 35 had elevated levels of one or more of the autoantibodies. Of these, 27 (36%) had elevated anti-nRNP and 17 (22%) had elevated anti-Ro/SSA. Six of the seven patients with anti-La/SSB (18%) also had anti-Ro/SSA paralleling the close association of these two antibodies noted by precipitin analysis in which 38 of 39 patients with anti-La/SSB precipitins also have anti-Ro/SSA precipitins. Thus, 258 of the 305 SLE sera (84.6%) have elevated anti-RNA protein levels. This represents a minimum estimate of the frequency of these antibodies since longitudinal study of individual patients shows that anti-RNA protein levels may vary from normal to 1000 times over background at different times. Quantitative studies over time in two patients with both anti-Sm and anti-nRNP show that anti-nRNP increased 10- to 100-fold while anti-Sm changed little. These quantitative changes may relate to clinical phenomena.

Adolescent↗
PubMed1985

Purification and partial characterization of a nucleolar scleroderma antigen (Mr = 34,000; pI, 8.5) rich in NG,NG-dimethylarginine.

A new scleroderma antigen of Mr = 34,000; pI, 8.5 has been identified. This 34-kDa protein is a nucleolar protein as determined by immunostaining procedures with affinity-purified antibodies. The 34-kDa protein was shown to localize to the fibrillar regions of the nucleolus by immunoelectron microscopy. Antibodies against the 34-kDa protein precipitate U3 RNA-containing particles. The 34-kDa protein has been isolated from Novikoff hepatoma cell nucleoli by ion exchange and reverse-phase column chromatography. The protein contains 4.1 mol % NG,NG-dimethylarginine (DMA) and 22.8 mol % glycine. It is the most highly arginine-methylated protein thus far detected in higher eukaryotes. This nucleolar 34-kDa protein resembles several nucleoplasmic proteins that are associated with heterogeneous nuclear RNA with respect to isoelectric point, Mr, presence of NG,NG-dimethylarginine, and its high glycine content. The amino-terminal sequence of the first 31 residues of the 34-kDa protein is: Met-Lys-Pro-Gly-Phe-Ser-Pro-DMA-Gly-Gly-Gly-Phe-Gly-Gly-DMA-Gly-Gly- Phe-Gly-Asp-DMA-Gly-Gly-DMA-Gly-Gly-Gly-DMA-Gly-Gly-DMA. In the first 31 residues, there are 16 glycine, 6 DMA, and 3 phenylalanine residues. This is a novel demonstration of clusters of glycine and DMA in a protein.

Amino Acid Sequence↗
PubMed1985

High titers of antibodies to single-stranded DNA in linear scleroderma.

Seven patients with severe linear scleroderma were initially found to have antibodies to double-stranded DNA (dsDNA) in higher titers, using the Farr technique. These patients, however, lacked the systemic involvement normally accompanying such antibodies. A detailed investigation of their sera using Crithidia luciliae assay and single-stranded DNA (ssDNA) labeled with iodine 131 disclosed high titers of antibodies to ssDNA and absent dsDNA antibodies. The ssDNA antibody titer was considerably higher than the mean for unselected patients with systemic lupus erythematosus. It is possible that these antibodies define a subgroup of patients with linear scleroderma who have more severe and extensive involvement of skin and underlying tissues.

Adolescent↗
PubMed1985

The association between Mi-2 antibodies and dermatomyositis.

Antibodies to Mi, an antigen in calf thymus extract, have been demonstrated by complement fixation inhibition in polymyositis (PM) and dermatomyositis (DM) sera but not in the sera of individuals without myositis. The original Mi reference serum defined 2 precipitating antibodies, using immunodiffusion (ID). Anti-Mi-1 was not active in complement fixation. We have now studied in further detail anti-Mi-2, which appears to be the antibody in Mi serum that fixes complement. Mi-2 antigen was purified by immuno-affinity chromatography. An enzyme-linked immunosorbent assay (ELISA) to measure Mi-2 antibody, using this antigen, was used to test the sera of 139 myositis patients: 52 had DM and 87 had PM. Control sera from 35 normal subjects and 93 patients with other connective tissue diseases were also tested. Only 13 sera were considered definitely positive for anti-Mi-2. All were from patients who had myositis, 11 of whom had DM. Only DM sera had anti-Mi-2 by ID, and all sera with anti-Mi-2 by ID were positive by ELISA. A number of other sera, including many from patients with other connective tissue diseases and 2 from normal subjects (all without precipitating antibodies) had lower elevations which were of uncertain significance. Detection of anti-Mi-2 by ID as well as by ELISA was significantly more frequent in DM than in PM. Anti-Mi-2 appears to be closely linked to DM, and is the first specific serologic marker for this form of myositis.

Antibody Specificity↗
PubMed1985

Ro (SS-A) antibody and antigen in a patient with congenital complete heart block.

Congenital complete heart block is closely associated with the presence of anti-Ro (SS-A) autoantibodies. Quantitative solid-phase assays for Ro (SS-A) autoantigen and autoantibody have established the presence of Ro (SS-A) in cardiac tissues and have been used to evaluate an informative pedigree. The propositus we describe here had complete congenital heart block and showed anti-Ro (SS-A) binding of 13-fold less than his normal HLA-identical twin sister. Both had identical titers of antinuclear antibody. These data support the hypothesis that anti-Ro (SS-A) may be directly involved in the pathogenesis of congenital complete heart block.

Adult↗