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Biomedical subjects

M Reichlin

Publications and source records attributed to M Reichlin.

At least 19 recordsLinked to original sources
PubMed1999

Prevalence of autoantibodies to ribosomal P proteins in juvenile-onset systemic lupus erythematosus compared with the adult disease.

OBJECTIVE: To determine the prevalence of anti-ribosomal P (anti-P) proteins in several groups of patients with juvenile-onset systemic lupus erythematosus (SLE) in comparison with the prevalence in adult SLE. METHODS: Serum samples were pooled together from 3 cohorts of patients with juvenile-onset SLE in 3 different medical centers and from a miscellaneous group of juvenile-onset SLE patients whose samples were sent by regional physicians. Sera were studied for the presence of anti-P using 2 assays: Western blot with ribosomes as antigen, and an enzyme-linked immunosorbent assay with the COOH-terminal 22 amino acids of the ribosomal P protein in a multiantigenic peptide format as antigen. Sera found positive by both tests were considered positive for anti-P antibodies. Findings from similar studies involving a large cohort of patients with adult-onset SLE from Oklahoma City were used for comparison. RESULTS: The prevalence of anti-P antibodies in the pooled sample of juvenile-onset SLE sera was 45 of 108, or 42%, while in the adult cohort from Oklahoma City, 20 of 260, or 7.7%, were positive for anti-P (odds ratio [OR] 9.6, P < 10(-8) by Fisher's exact test). In addition, it was shown that 12 of 13 patients with both anti-P and anti-double-stranded DNA (anti-dsDNA) in the juvenile SLE cohort had nephritis, while only 8 of 22 patients without both antibodies were nephritic (OR 21.0, P < 10(-8)). It was also shown that in 9 illustrative cases, the levels of anti-P and anti-dsDNA antibodies usually varied together and in concordance with the clinical activity as measured by the SLE Disease Activity Index (SLEDAI). Finally, anti-P-positive and anti-P-negative patients had a similar prevalence of anti-dsDNA, anti-Ro/SSA, and anti-La/SSB antibodies, but patients with anti-P had a higher prevalence of anti-U1 RNP and anti-Sm (P = 0.041 and P = 0.0385, respectively, by Fisher's exact test). CONCLUSION: Antibodies to ribosomal P protein are more prevalent in juvenile-onset SLE than in adult-onset SLE. Levels of antibodies to ribosomal P protein vary with the clinical disease activity as measured by the SLEDAI, often in concordance with the levels of anti-dsDNA. The presence of both anti-P and anti-dsDNA antibodies was powerfully associated with nephritis in the cohort of patients for whom comprehensive clinical and serologic data were available.

Adolescent↗
PubMed1999

Further characterization of the autoantibody response of Palmerston North mice.

PN mice spontaneously develop, with age, a lupus-like disease. The present study further evaluated autoantibody production in female PN mice. As early as 1 month of age, all PN mice had detectable IgM antibodies to dsDNA and ssDNA and two-thirds produced IgM anticardiolipin antibodies. By 3 months of age, all PN mice exhibited evidence of isotype switch in their autoantibody response; 88-100% had serum IgG antibodies to ssDNA and dsDNA, respectively. By 6-12 months of age, essentially all female PN mice had IgG antibodies to ssDNA, dsDNA, cardiolipin and other phospholipids (PS, PC, PI, and PG), and IgG and 63% produced IgG anti-mouse erythrocyte antibodies. In addition, 50-100% produced IgA antibodies to dsDNA and ssDNA, and one-third produced IgA anti-IgG antibodies. Antibodies to U1RNP and Sm were present in 81% of 6- to 12-month-old PN mice and 39-94% had IgG or IgM antibodies to mouse thymocytes. Although all four IgG isotypes were represented in the anti-dsDNA response, IgG1 antibodies dominated the IgG anticardiolipin response. The presence of IgA autoantibodies and the predominance of IgG1 in the IgG anticardiolipin response suggest that IL-4 and either IL-5 and/or TGF-beta serve as B cell stimulatory cytokines for autoreactive B cells in PN mice.

Aging↗
PubMed1998

The presence of masked antiribosomal P autoantibodies in healthy children.

OBJECTIVE: To determine if antiribosomal P (anti-P) autoantibodies are present in healthy children. METHODS: Sera from healthy children were screened for anti-P by conventional enzyme-linked immunosorbent assay and immunoblot techniques. Sera were also treated with immobilized ribosomal P antigens on nitrocellulose strips; affinity-purified fractions were tested for anti-P by high-sensitivity immunoblot. The relative binding affinities were compared for affinity-purified anti-P antibodies from healthy children and adults, and patients with systemic lupus erythematosus. IgG fractions of anti-P-depleted sera from healthy children were assessed for inhibition of autologous anti-P activity. RESULTS: Conventional serologic screening showed no IgG nor IgM anti-P in 88 untreated sera. IgG anti-P were unmasked in all 79 sera treated by the membrane batch affinity technique. IgM anti-P were identified in 27 of the treated sera; the percentage of positive sera decreased with increasing age (chi(2) for linear trend P = 0.00081). Affinity-purified anti-P from children had relative binding affinities similar to those of anti-P from other groups. Sera from healthy children contained inhibitory IgG antibodies to anti-P. CONCLUSION: These results show that anti-P autoantibodies are present in all healthy children. The majority of these autoantibodies are masked by IgG antibodies, suggesting concordant development of a regulatory network.

Adolescent↗
PubMed1998

The association between anti-ribosomal P antibodies and active nephritis in systemic lupus erythematosus.

Autoantibodies to anti-ribosomal P protein have been recognized in patients with systemic lupus erythematosus (SLE) in widely variable proportions of unselected patients. Presence of anti-ribosomal P antibodies was retrospectively studied in 69 patients with SLE during disease exacerbations and remissions or during continuously active disease. Anti-ribosomal P antibodies were positive in 21/69 patients during active disease, with an overall prevalence of 30.4%. Prevalence in patients with active nephritis was 75.0% (15/20), P value by Fisher's exact test of 8.39 x 10(-7). In 12/13 patients (92.3%), anti-P disappeared during periods of disease remission, P = 0.0002. In 17/21 patients (81.0%) with anti-ribosomal P antibodies, anti-dsDNA antibodies were also positive. In 47 patients without anti-P, 23/47 (48.9%) were also positive for anti-dsDNA. In 9/12 patients (75.0%) titers of anti-dsDNA antibodies correlated with anti-P during disease exacerbations and remissions, P = 0.004. The higher prevalence of anti-P in patients with lupus nephritis with disappearance during disease remissions supports the hypothesis of an immunopathogenetic role of these antibodies in lupus nephritis. There was also a strong association between anti-dsDNA and anti-P antibodies.

Autoantibodies↗
PubMed1998

Cellular dysfunction induced by penetration of autoantibodies into living cells: cellular damage and dysfunction mediated by antibodies to dsDNA and ribosomal P proteins.

Antibodies to dsDNA and ribosomal P proteins are disease specific for systemic lupus erythematosus (SLE) and vary with disease activity. It is thought that antibodies to dsDNA are involved in the pathogenesis of lupus nephritis and clinical data consistent with that hypothesis also exist for anti-ribosomal P antibodies; these two specific antibodies both bind and penetrate cells in culture. In the case of anti-P antibodies, the cellular receptor appears to be a membrane form of the Po 38 kDa phosphoprotein, which is present on several cell types and appears to mediate the binding and penetration of anti-P antibodies which then localize in the cytoplasm. In the case of anti-dsDNA, numerous cellular receptors exist on various cell types which may account for the three types of behavior demonstrated by antibodies towards dsDNA. These include (a) localization and prolonged residence on the membrane, with prompt cytolysis upon addition of hemolytic complement, (b) penetration and cytoplasmic localization and (c) penetration and nuclear localization. Both anti-P and anti-dsDNA are potent inhibitors of protein synthesis and are likely to mediate cellular dysfunction via this pathway.

Animals↗
PubMed1998

Rheumatoid hyperviscosity: analysis of a patient with intermediate complexes that block other autoantibodies and a review of the literature.

OBJECTIVES: To report a patient who rheumatoid arthritis presented with hyperviscosity syndrome, analyze this patient's rheumatoid factor, and review the previously reported patients. METHODS: Immunofluorescence for antinuclear antibodies, double immunodiffusion, enzyme-linked immunosorbent assay, and size exclusion chromatography were used before and after plasmapheresis to study the patient's rheumatoid hyperviscosity, and polyclonal gammopathy and references in identified papers was used to identify previously reported patients. RESULTS: Similar to several previous patients, this patient's sera contained both IgG and IgM rheumatoid factor and abundant intermediate complexes. Other autoantibodies, either from the patient or from other patients, were masked by rheumatoid factor or intermediate complexes from the reported patients sera. Rheumatic hyperviscosity is seen uncommonly, being reported in only 18 patients with rheumatoid arthritis and nine with other rheumatic illnesses. CONCLUSIONS: There are two mechanisms by which rheumatoid factor can lead to hyperviscosity, both of which require large amounts of rheumatoid factor. Rheumatoid hyperviscosity must be recognized because this life-threatening syndrome usually can be successfully treated with plasmapheresis acutely and immunosuppressives for long-term control.

Adult↗
PubMed1998

Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry.

OBJECTIVES: The present study describes the demographics, mortality, morbidity and recurrence rates of autoimmune-associated congenital heart block (CHB) using information from the Research Registry for Neonatal Lupus. BACKGROUND: Isolated CHB detected at or before birth is strongly associated with maternal autoantibodies to 48-kD SSB/La, 52-kD SSA/Ro and 60-kD SSA/Ro ribonucleoproteins and is a permanent manifestation of the neonatal lupus syndromes (NLS). Available data are limited by the rarity of the disease. RESULTS: The cohort includes 105 mothers whose sera contain anti-SSA/Ro or anti-SSB/La antibodies, or both, and their 113 infants diagnosed with CHB between 1970 and 1997 (56 boys, 57 girls). Of 87 pregnancies in which sufficient medical records were available, bradyarrhythmia confirmed to be CHB was initially detected before 30 weeks of gestation in 71 (82%) (median time 23 weeks). There were no cases in which major congenital cardiac anatomic defects were considered causal for the development of CHB; in 14 there were minor abnormalities. Twenty-two (19%) of the 113 children died, 16 (73%) within 3 months after birth. Cumulative probability of 3-year survival was 79%. Sixty-seven (63%) of 107 live-born children required pacemakers: 35 within 9 days of life, 15 within 1 year, and 17 after 1 year. Forty-nine of the mothers had subsequent pregnancies: 8 (16%) had another infant with CHB and 3 (6%) had a child with an isolated rash consistent with NLS. CONCLUSIONS: Data from this large series substantiate that autoantibody-associated CHB is not coincident with major structural abnormalities, is most often identified in the late second trimester, carries a substantial mortality in the neonatal period and frequently requires pacing. The recurrence rate of CHB is at least two- to three-fold higher than the rate for a mother with anti-SSA/Ro-SSB/La antibodies who never had an affected child, supporting close echocardiographic monitoring in all subsequent pregnancies, with heightened surveillance between 18 and 24 weeks of gestation.

Autoimmune Diseases↗
PubMed1998

Systemic lupus erythematosus and pregnancy.

Systemic lupus erythematosus (SLE) may improve, exacerbate or be unchanged during pregnancy. The activity of SLE at the time of conception has a major influence on pregnancy outcome: SLE patients with quiescent disease do well, while those with active, uncontrollable disease have a high abortion rate. There are specific autoantibodies that confer a high risk of abortion (e.g., IgG antiphospholipid antibodies). There are others, such as anti-Ro/SSA and anti-La/SSB, which confer a risk for neonatal lupus that includes lupus dermatitis, congenital complete heart block, thrombocytopenia and cholestatic jaundice, in order of their relative frequencies.

Abortion, Spontaneous↗
PubMed1997

Autoantibodies to ribosomal P proteins penetrate into live hepatocytes and cause cellular dysfunction in culture.

Abs to ribosomal P protein have been shown to bind a membrane form of the P0 38-kDa ribosomal phosphoprotein. This study shows that after affinity-purified Abs to ribosomal P proteins bind living HepG2 cells, they then penetrate these live cells and cause cellular dysfunction. Binding and penetration of anti-P Abs is the property of F(ab')2 fragments as well as whole IgG molecules showing that neither binding nor penetration depends on Fc fragments or their cognate receptors. Confocal microscopy shows that internalized Ab concentrates in perinuclear vesicles (presumably lysosomes), but substantial quantities of Ab are also found in the cytosol. This intracellular Ab adversely affects the synthesis of apolipoprotein B resulting in a threefold increase in cellular cholesterol with lipid droplet accumulation as seen in some chronic liver diseases. It also has a profound inhibitory effect on global protein synthesis as measured by [35S]methionine incorporation. These studies therefore describe a model of cellular injury effected by specific Ab to ribosomal "P" protein that may underlie certain forms of autoimmune hepatic diseases.

Amino Acid Sequence↗
PubMed1997

Reference sera for antinuclear antibodies. II. Further definition of antibody specificities in international antinuclear antibody reference sera by immunofluorescence and western blotting.

OBJECTIVE: To define the fine specificity of the 10 reference sera used for determination of antinuclear antibodies (ANA) and ANA subsets which are available from the Arthritis Foundation (AF) and from the Centers for Disease Control and Prevention (CDC). METHODS: AF/CDC sera were assessed by experienced laboratory staff, using indirect immunofluorescence and Western blotting. RESULTS: The original assignment of fluorescence patterns to 4 reference sera was confirmed, and the fluorescence intensities were determined using reference fluorescent beads. On Western blots, sera AF/CDC2 (anti-SS-B/La) and AF/CDC7 (anti-SS-A/Ro) did not detect Ro antigens, sera AF/CDC9 and AF/CDC10 appeared to be monospecific anti-Scl-70 and anti-Jo-1 sera, respectively, serum AF/CDC4 (anti-U1 small nuclear RNP) recognized the 70-kd band, and serum AF/CDC5 recognized the Sm antigen with its multiple bands. Semiquantitative analyses revealed that AF/CDC5, AF/CDC2, and AF/CDC10 were strongly reactive sera, whereas AF/CDC4 and AF/CDC9 were much weaker and should be used at lower dilutions on Western blots. CONCLUSION: The AF/CDC ANA reference sera, originally described as reference reagents for indirect immunofluorescence and double immunodiffusion techniques, are also useful for Western blotting. The data presented herein further support the use of these sera for reference purposes.

Antibodies, Antinuclear↗
PubMed1997

Persistent vegetative state: a presumption to treat.

The article briefly analyzes the concept of a person, arguing that personhood does not coincide with the actual enjoyment of certain intellectual capacities, but is coextensive with the embodiment of a human individual. Since in PVS patients we can observe a human individual functioning as a whole, we must conclude that these patients are still human persons, even if in a condition of extreme impairment. It is then argued that some forms of minimal treatment may not be futile for these patients; they may constitute a form of respect for their human dignity and benefit these patients, even if they are not aware of that. Moreover, it is important to consider the symbolic significance of care: while many believe that PVS is a kind of imprisonment, for others providing food and fluids is the only way to testify our proximity to these persons. The best policy would be to provide, as a general rule, artificial nutrition and hydration to PVS patients: this treatment could be withdrawn, after a period of observation and reflection by the family and proxies, on the basis of the proxies' objection to the continuation or of the patient's advance directives specifically referring to this situation.

Advance Directives↗
PubMed1997

Long-term follow-up of autoantibody profiles in black female lupus patients and clinical comparison with Caucasian and Asian patients.

The aim was to determine whether the autoantibody profile in Black female lupus patients is associated with clinical subsets, fluctuates over time and/or reflects disease activity. A clinical comparison with Caucasian and Asian patients matched for age of onset and disease duration was also undertaken. Up to seven serial bleeds from Black female lupus patients who had been followed up for periods of 3.15 yr were tested for antibodies to Ro/SSA, La SSB. Sm, RNP and ribosomal P using ELISA research assays. Significant differences in both clinical and serological profiles between the ethnic groups were found. Varying aspects of disease activity were linked to anti-DNA (renal, cardiovascular, global score), anti-ribosomal P (musculoskeletal, haematology) and anti-Sm (general) antibodies. There are differences in clinical and serological profiles amongst systemic lupus erythematosus patients of different ethnic origin. However, using the BILAG system, relatively few antibodies were found to reflect disease activity accurately in serial measurements.

Adult↗
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↗