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Biomedical subjects

M Reichlin

Publications and source records attributed to M Reichlin.

At least 55 records · Page 3Linked to original sources
PubMed1997

Congenital heart block and subsequent connective tissue disorder in adolescence.

A young girl born to a mother with systemic lupus erythematosus (SLE) had congenital heart block and developed symptoms of a connective tissue disorder at the age of 13 y. When first seen at the age of 15 y she was found to have an unclassified connective tissue disorder and to be seropositive for anti Ro/SSA and U1 RNP. This constellation of clinical/serological features has not been described among the reported handful of patients with congenital heart block and subsequent development of a connective tissue disorder.

Adolescent↗
PubMed1997

Immunologically restricted and inhibitory anti-Ro/SSA in monozygotic twins.

A pair of monozygotic twins with Sjögren's syndrome are described who both have large amounts of anti-Ro/SSA in their sera by ELISA, but no precipitin in double immunodiffusion. Unique among previously encountered specimens, sera from the twins inhibit the formation of Ro/SSA-precipitins in double immunodiffusion by known anti-Ro/SSA positive SLE patients. The twins have near identical, clonally restricted anti-Ro/SSA autoantibodies as evaluated by isoelectric focusing and bind the same 60 kD Ro/SSA peptides. Thus, this pair of monozygotic twins has an identical fine specificity in their immune response to 60 kD Ro/SSA, despite potential differences in their immune response generated by random processes in the formation of immunoglobulin molecules and T cell receptors. These data imply that the anti-Ro/SSA found in these sera binds less than three epitopes such that soluble antigen/antibody complexes are formed instead of an insoluble complex that precipitates.

Adult↗
PubMed1996

Lupus autoantibodies to double-stranded DNA cross-react with ribosomal protein S1.

One cDNA clone (G7) was isolated from a lambda gt11 human liver cDNA library by the reaction with a serum containing anti-dsDNA Abs and was ligated into pGEX-1 lambda T vector. All the 10 SLE sera with anti-dsDNA, 2 samples of human monoclonal anti-dsDNA (33.C9 and 33.H11), and 2 affinity-purified anti-dsDNA Abs recognized the glutathione S-transferase fusion protein expressed by G7 (G7-FP). Ab binding to the recombinant protein expressed by G7 (G7-RP) and to G7-FP was inhibited completely by calf thymus dsDNA. The cDNA was 1314 nucleotides in length and contained an open reading frame encoding 352 amino acids. However, it seems to be a partial length cDNA because the affinity-purified Ab from G7-FP recognized only a 104-kDa protein on Western blot using MOLT4 cell extract. The nucleotide sequence of G7 was homologous (99% identity) to a cDNA encoding human ribosomal protein (r-protein) S1 homologue mRNA. The encoded protein contains repeating residues as a feature of r-proteins S1. Cytoplasmic and nucleolar staining of 33.H11 on indirect immunofluorescence (IF) using HEP 2 cells was inhibited by both G7-RP and calf thymus dsDNA. On ELISA, 33.H11 had a higher affinity for G7-RP than for DNA while 33.C9 had a higher affinity for DNA than for G7-RP and binds nuclei on IF. We conclude that G7 encodes a portion of human r-protein S1 and anti-dsDNA Abs cross-react with this protein.

Amino Acid Sequence↗
PubMed1996

Some autoantibodies to Ro/SS-A and La/SS-B are antiidiotypes to anti-double-stranded DNA.

OBJECTIVE: To determine the relationship of anti-Ro/SS-A and anti-La/SS-B antibodies to anti-double- stranded DNA (anti-dsDNA) in sera from patients with systemic lupus erythematosus. METHODS: Sera with anti-Ro/SS-A alone (n = 5) or those with anti-Ro/SS-A and anti-La/SS-B (n = 7) were absorbed with purified Ro/SS-A and La/SS-B, respectively. The absorbed sera were then tested for reactivity with MOLT-4 extract by Western blot and dsDNA by enzyme-linked immunosorbent assay (ELISA). With selected sera, anti-dsDNA was isolated on DNA cellulose columns and anti-Ro/SS-A and anti-La/SS-B were isolated on antigen-affinity columns. Reactivity between anti-dsDNA and autologous anti-Ro/SS-A or anti-La/SS-B, as well as inhibition by cognate antigens, was studied. RESULTS: After absorption, all sera showed reactivity with small nuclear RNP A and D bands in Western blots, and some showed reactivity with dsDNA by ELISA. Anti-dsDNA populations (n = 4) were purified on dsDNA cellulose columns. Anti-Ro/SS-A (n = 1) and anti-La/SS-B (n = 3) were affinity purified from the same sera as the anti-dsDNA. In all cases, anti-dsDNA bound autologous anti-Ro/SS-A and anti-La/SS-B much more strongly than it bound normal pooled IgG. Moreover, dsDNA, but not RNA, blocked these interactions. In addition, Ro/SS-A blocked anti-Ro/SS-A and La/SS-B blocked anti-La/SS-B in these same interactions. CONCLUSION: In sera with anti-Ro/SS-A and anti- La/SS-B, there are subpopulations of these antibodies that bind and mask anti-dsDNA. We hypothesize that these anti-Ro/SS-A and anti-La/SS-B antibodies are antiidiotypes to idiotypes on anti-dsDNA and that they both mask and down-regulate these anti-dsDNA antibodies.

Antibodies, Anti-Idiotypic↗
PubMed1996

Development of the anti-Ro autoantibody response in a patient with systemic lupus erythematosus.

OBJECTIVE: To characterize the initial events in anti-Ro production by a patient with systemic lupus erythematosus, in whom this autoantibody is developing. METHODS: The immune response to the Ro ribonucleoprotein and other autoantigens were studied by enzyme-linked immunosorbent assay for IgG and IgM, by isoelectric focusing, and by inhibition studies to determine apparent avidity. RESULTS: The patient's sera showed an oligoclonal response to Ro that increased in complexity and affinity with time. IgM anti-Ro appeared shortly before IgG anti-Ro, and disappeared as IgG anti-Ro increased in titer and affinity. IgG antiribosomal P autoantibodies also appeared during the patient's course, but in contrast to anti-Ro, were not preceded by IgM antiribosomal P. CONCLUSION: These data are consistent with the Ro autoantigen being presented and processed in a manner similar to heterologous antigen, and with differences in the mechanisms that lead to the production of IgG anti-Ro autoantibodies as opposed to antiribosomal P autoantibodies.

Adult↗
PubMed1996

Antibodies to carbonic anhydrase in endometriosis: prevalence, specificity, and relationship to clinical and laboratory parameters.

OBJECTIVE: To investigate the presence and clinical association of serum autoantibodies to carbonic anhydrase (CA) in women with and without endometriosis. DESIGN: Sera were tested in an ELISA against human and bovine CAI and/or CAII isoenzymes and by Western immunoblotting of trypsin-digested fragments of human CAII as antigens. The ELISA positivity was defined as mean + 2 SD of 100 control sera. Positive sera also were tested for the presence of antiendometrial antibodies and antinuclear antibodies (ANA) by indirect immunofluorescence assays (IFA) on endometrial (ECC) and HEp-2 cells, antibodies to single-stranded (ss) and double-stranded (ds) DNA by the Farr-type RIA and Crithidia IFA, and extractable nuclear antigens (Sm, nRNP, Ro, and La) by an ELISA. PATIENTS: Sera from 319 patients with laparoscopic diagnosed pelvic endometriosis (100 stage I, 95 stage II, 67 stage III, and 57 stage IV), 100 with other gynecologic disorders, and 100 control women were used. RESULTS: In the ELISA, 113 of 319 (35.4%) endometriosis sera had elevated immunoglobulin G antibodies against nondenatured CA isoenzymes. The reactivity of sera from the endometriosis group was significantly higher (35%) in all four subgroups of patients than each of the nonendometriosis sera (< 12% and < 6%, respectively). No stage-dependent variation of an autoantibody pattern was evident. However, anti-CA autoantibodies were present in 66.3% of women with endometriosis-associated infertility. The frequency of anti-CA autoantibodies was significantly higher (by 51.7%) in women with antiendometrial antibodies detectable by IFA. In addition, in sera positive for anti-CA antibodies, the frequency of ANA also was increased (20/113 [17.6%]) with titers of 1:40 to 1:1,080. The ANA-positive sera were negative for anti-ssDNA, anti-dsDNA, anti-Sm, anti-nRNP, and anti-La. However, three sera were positive for anti-Ro antibodies. Immunoblotting study of autoantibody reactivity with trypsin-digested subfragments of human CAII revealed consistent immunoreactivity with 14 to 6.2-kd range CAII peptides. CONCLUSIONS: [1] A subgroup of patients with endometriosis have autoantibodies directed to native and linear epitopes of the CA protein. [2] Prevalence of anti-CA antibodies was associated with antiendometrial antibodies and ANA. [3] Anti-CA antibodies were associated with a higher predictive value of the disease when all patient subgroups were considered together.

Animals↗
PubMed1996

Autoantibodies to double-stranded (ds)DNA immunoprecipitate 18S ribosomal RNA by virtue of their interaction with ribosomal protein S1 and suppress in vitro protein synthesis.

We report that four systemic lupus erythematosus (SLE) patient sera containing anti-dsDNA antibodies, three affinity-purified anti-dsDNA IgG, and a human anti-dsDNA MoAb (33.H11) immunoprecipitate 18S ribosomal RNA from DNase-treated 32P-labelled MOLT4 cell extract. This 18S RNA precipitation was inhibited completely by preincubating 33.H11 with calf thymus dsDNA or the recombinant human ribosomal protein S1, which was reported to cross-react with anti-dsDNA antibodies (J Immunol 1996; 156:1668-75). Whole IgG from three SLE sera with anti-dsDNA antibodies, 33.H11, and three affinity-purified anti-dsDNA IgG inhibited in vitro translation of globin mRNA (percent inhibition was 36-50%). This translation inhibition by anti-dsDNA antibodies was enhanced (67-79%) when the reticulocyte lysate was treated with DNase. Suppression of protein synthesis could be a pathogenic mechanism of anti-dsDNA antibodies, since it has also been shown that anti-dsDNA penetrates living cells (J Immunol 1995; 154:4857-64) in culture.

Antibodies, Antinuclear↗
PubMed1996

Fluctuations of antibody to ribosomal P proteins correlate with appearance and remission of nephritis in SLE.

Antibodies to ribosomal P proteins are found in widely variable proportions (up to 42%) of patients with SLE depending on the ethnic background of the patient population. Neuropsychiatric disease was first recognized to have increased prevalence with anti-P and more recently liver and renal disease. We describe four patients with SLE and circumscribed episodes of nephritis of relatively short duration. In two patients, antibodies to ribosomal P protein were the only specificity detected at the time of appearance of active nephritis; and in the other two patients, the appearance and disappearance of anti-ribosomal P was simultaneously found with similar fluctuations in anti-dsDNA titers. Anti-ribosomal P antibodies were measured by Western blot and a P peptide-specific ELISA. These data raise the possibility for a pathogenic role for anti-ribosomal P antibodies in lupus nephritis.

Adult↗
PubMed1996

Anti-PM/Scl autoantibodies in patients without clinical polymyositis or scleroderma.

OBJECTIVE: To characterize patients with anti-PM/Scl but no definite myositis-scleroderma (PM/SSc) overlap or either polymyositis/dermatomyositis (PM/DM) or systemic sclerosis (SSc) alone. METHODS: Review of all patients with anti-PM/Scl identified at a reference serologic clinical laboratory. RESULTS: We identified 5 patients with anti-PM/Scl not considered to have either PM, SSc, or PM/SSc. One had primary Sjögren's syndrome but the other 4 had some feature(s) of illness consistent with PM/DM or SSc, such as hypertensive crisis or interstitial lung disease. These 5 patients represented 10% of the total number of patients with anti-PM/Scl identified in our clinical laboratory. CONCLUSION: Anti-PM/Scl may be a marker for atypical or subclinical presentations of the usually associated disease, or this autoantibody may precede expression of the underlying disease. The antibody may also be present in patients who never express PM, SSc, or PM/SSc. Anti-PM/Scl without the usually described illnesses is not uncommon in our series of 55 patients with anti-PM/Scl.

Adult↗
PubMed1996

Clinical significance of specific autoantibodies in juvenile dermatomyositis.

OBJECTIVE: To determine the prevalence and clinical association of myositis specific antibodies in an unselected group of patients with juvenile dermatomyositis (DM). METHODS: The sera of 42 subjects, representing an unselected group of patients from a single center, with juvenile DM and 7 others with idiopathic inflammatory myopathy (IIM) were examined for the presence of myositis specific antibodies by immunodiffusion against calf thymus extract and immunoprecipitation with HeLa extract. RESULTS: Of the subjects with juvenile DM, only 2 had evidence of antibodies specific to myositis (anti-Mi2). Three other patients with juvenile DM had defined autoantibodies not usually considered to be specific to myositis. Two of the 3 subjects had anti-PM-Scl; both developed features of scleroderma after the juvenile DM remitted. The 5 subjects with defined autoantibodies did not differ clinically from the remainder of the subjects with the exception of the late development of scleroderma features in 2. Fourteen other subjects with juvenile DM had unidentified bands on immunoprecipitation, which may represent as yet undiscovered myositis specific antibodies. No myositis specific antibodies were detected in any of the 7 subjects with other IIM syndromes. CONCLUSION: Based on our findings, we do not recommend routine clinical testing for these antibodies in children with typical juvenile DM. Further study of the unidentified bands seen in our subjects may lead to better understanding of the clinical groupings and etiopathogenesis of childhood myositis.

Adolescent↗
PubMed1995

Unmasking of anti-ribosomal P autoantibodies in healthy individuals.

Autoantibodies to the ribosomal P proteins (anti-P) are found almost exclusively in a subset of patients with systemic lupus erythematosus. To determine if anti-P autoantibodies are present in healthy individuals but in a masked state, sera from healthy adults were applied to affinity columns coated with ribosomes, and the affinity-purified fractions were analyzed for anti-P Abs by ELISA and immunoblot. Anti-P Abs were detectable in serum only after affinity chromatography, were predominantly of the IgG isotype, stained HEp-2 cells in the characteristic anti-P pattern, and demonstrated specificity for all three ribosomal P phosphoproteins. Using batch affinity chromatography, we identified anti-P autoantibodies in the affinity-purified serum fractions of 54 of 55 healthy individuals. Anti-P Abs from healthy adults generally bound less ribosomal P Ag per mg/ml IgG than anti-P from patients. Inhibition studies revealed that autologous serum contained an IgG inhibitor of anti-P Ab. We conclude that masked anti-P autoantibodies are present in the healthy population and hypothesize that detection of these autoantibodies in systemic lupus erythematosus represents disruption of these regulatory networks.

Adolescent↗
PubMed1995

Murine and human antibodies to native DNA that cross-react with the A and D SnRNP polypeptides cause direct injury of cultured kidney cells.

Murine monoclonal and human affinity-purified Abs to native DNA (anti-nDNA) that cross-react with the A and D SnRNP polypeptides were analyzed for direct injurious effects against cultured pig kidney (PK15) cells under ordinary cell-culture conditions. Of the two murine nephritogenic Abs derived from NZB/NZW F1 mice (BWds1 and BWds3), BWds1 initially bound to the cell surface and subsequently penetrated into cells localizing in nuclei and cytoplasm. BWds3 was consistently and abundantly associated with the surface of live cells without penetration. In the presence of rabbit C, BWds3 caused massive cell lysis (85% dead cells) whereas BWds1 had only a modest lytic effect (24% dead cells). One of the nonpathogenic murine anti-nDNA Abs (5GD5) that did not cross-react with the A and D polypeptides showed no interaction with PK-15 cells and had no injurious effects. Affinity-purified autoantibodies to nDNA isolated from two SLE patients with high anti-nDNA titers and clinically active lupus nephritis showed properties similar to the murine mAbs. They both strongly cross-reacted with the A and D SnRNP polypeptides and interacted with live PK-15 cells. One of them (Cr) penetrated into live cells and localized within cytoplasm and nuclei whereas the other (Pe) bound mostly to the cell surface and caused significant cell lysis in the presence of C. Results of this study suggest that the nephritogenic murine anti-nDNA as well as subpopulations of human anti-nDNA Abs could exert their injurious influence through direct interactions with kidney cells using two different pathogenic mechanisms (i.e., C-mediated cytotoxicity and potential cell cycle dysfunctions. Interestingly, cross-reactivity of anti-nDNA Abs with the A and D SnRNP polypeptides appears to be a prerequisite for their direct pathogenicity.

Animals↗
PubMed1995

IgM anti-A and D SnRNP proteins and IgM anti-dsDNA are closely associated in SLE sera.

U1RNP and Sm precipitins occur in systemic lupus erythematosus (SLE) and in overlap syndromes, while precipitins to Ro/SSA and La/SSB occur in SLE and its variants as well as Sjögren's syndrome. In studying IgM and IgG antibodies to these polypeptides by Western blot, we found the expected frequency of antibodies to the A protein of the U1RNP specificity and the D protein of the Sm specificity in sera with precipitins to U1RNP and Sm, but also found the frequent occurrence of both IgM and IgG anti-A and D in SLE sera with no precipitins, and in sera with anti-Ro/SSA and/or anti-La/SSB precipitins, but not in sera from patients with rheumatoid arthritis, polymyositis, scleroderma, or normals. We have studied the sera which bind the A and D polypeptides on Western blot to test their ability to bind native U1RNP (which contain the A and D proteins) in ELISA. The results indicate that most anti-Ro/SSA alone, anti-Ro/SSA, and anti-La/SSB sera as well as SLE sera with no precipitins react preferentially with the denatured A and D proteins. Further study of sera with IgM anti-A and D in Western blot reveals that these sera also frequently contain anti-double-stranded DNA antibodies. These results show that the anti-A and D responses, especially IgM anti-A and D, occur not only in patients with precipitating antibodies to SnRNPs, but in almost half of patients across the lupus spectrum. The extended prevalence of antibodies to the denatured A and D proteins in Western blot is associated with the cross-reaction of antibodies to dsDNA.

Autoantibodies↗