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M Reichlin

Publications and source records attributed to M Reichlin.

At least 19 recordsLinked to original sources
PubMed2006

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus.

Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1,506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, anti-nRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P=1.9 x 10(-6)), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P=3.5 x 10(-6)), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P=3.4 x 10(-4)) and to anti-IgM aPL Abs on chromosome 13q14 (adjusted P=2.3 x 10(-4)). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.

Black or African American↗
PubMed2006

Autoantibodies to the ribosomal P proteins in systemic lupus erythematosus.

This paper describes the clinical significance of antibodies to the ribosomal P proteins in systemic lupus erythematosus. It appears that liver disease due to the lupus process and not attributable to viral infection, alcohol or drugs is associated with anti-ribosomal P. In addition, there is a strong relationship to central nervous system disease and nephritis of antibodies to ribosomal P proteins. The prevalence of the anti-P antibodies is strongly related to disease activity wherein disease remission is associated with disappearance of anti-P antibodies. These phenomena taken together suggest an immunopathogenic role for anti-P antibodies. This idea is strongly supported by the observation that immunoglobulin G containing antiribosomal P activity binds and penetrates living cells with profoundly inhibitory effects on protein synthesis. Finally, a new era of research has been uncovered by the observation that in 54 of 55 instances normal sera passed over a ribosome-sepharose column unmasks anti-P antibodies, which can be eluted from the ribosome column with 3.0 M magnesium chloride. This suggests that anti-idiotypes regulate the expression of anti-P antibodies in normal persons and in lupus patients this regulation is ineffective, with the development of free anti-P antibodies in a proportion of patients with active disease.

Autoantibodies↗
PubMed2003

Ribosomal P antibodies and CNS lupus.

Within two years of the recognition of autoantibodies to ribosomal P proteins in patients with systemic lupus erythematosus (SLE) an association with anti-P autoantibodies with psychosis was noted. While there has been some controversy about this association, ample evidence suggests a meaningful relationship between anti-P antibodies and central nervous system (CNS) disease. This evidence consists of 1) seven independent studies showing a strong relationship between anti-P antibodies and CNS disease; 2) longitudinal studies showing fluctuations of anti-P antibodies with episodes of psychosis; 3) correlation of anti-P antibodies with general disease activity; and 4) acid eluates form lupus renal tissue were found to contain anti-P antibodies enriched 30-fold with respect to their specific activity in serum heralding a direct role of anti-P antibodies in disease expression. Finally, there is evidence that the P protein resides on normal cells in an immunologically accessible way and evidence exists that anti-P antibodies are able to bind and penerate cells in culture, and once inside cells can affect a profound inhibition of protein synthesis in living cells. Taken together, these observations provide evidence linking anti-P antibodies to various forms of CNS disease. While this is true, there are other autoantibodies in SLE patients such as anti-dsDNA and antiglial fibrillary protein which may also play a role in the CNS disease of SLE patients. Continued study will inform us of the relative contribution of these autoantibodies to CNS disease in SLE patients.

Biomarkers↗
PubMed2002

Genome scan stratified by the presence of anti-double-stranded DNA (dsDNA) autoantibody in pedigrees multiplex for systemic lupus erythematosus (SLE) establishes linkages at 19p13.2 (SLED1) and 18q21.1 (SLED2).

Anti-double-stranded DNA (anti-dsDNA) is arguably one of the most specific autoantibodies in systemic lupus erythematosus (SLE). This antibody is associated with more severe SLE and with glomerulonephritis. From 196 pedigrees multiplex for SLE, we selected those that had any SLE affected positive for anti-dsDNA by the Crithidia luciliae kinetoplast imunofluorescence assay. This stratification strategy tested the hypothesis that anti-dsDNA would identify a more genetically homogeneous group of pedigrees, in which previously undetected linkage effects could be established. A genome screen data for linkage to SLE was available at 307 microsatellite markers for this selected group of 71 pedigrees: 37 European-American, 29 African-American, and five others. The most significant results were obtained at 19p13.2 (LOD(max) = 4.93), named SLED1, in the 37 European-American pedigrees using a dominant model with mixed penetrances (92% for females and 49% for males) at 100% homogeneity (theta = 0). A second linkage effect, SLED2, was established in the 29 African-American pedigrees at 18q21.1 (LOD(max) = 3.40) using a recessive model with 100% penetrance (theta = 0.1). Parametric and non-parametric multipoint analyses were performed, which provided further evidence and support of susceptibility genes residing in these regions. In conclusion, two powerful linkages have been detected with SLE based on the presence of anti-dsDNA. These findings show SLE to be a richly complicated disease phenotype that is now ripe for important new discovery through a genetic approach.

Animals↗
PubMed2002

Production and characterization of human monoclonal anti-idiotype antibodies to anti-dsDNA antibodies.

Anti-dsDNA autoantibodies are the hallmark of systemic lupus erythematosus (SLE) and frequently correlate with disease activity. In this study we report the isolation and characterization of human anti-Id monoclonal antibody fragments as single-chain Fv fragments (scFv) against anti-dsDNA antibody. The anti-Id monoclonal antibodies, specific for anti-dsDNA antibodies, have been cloned from phage display antibody scFv libraries derived from a patient with SLE. The V gene repertoires were derived from the RNA obtained from the B cells of an SLE patient with anti-Ro/SSA and anti-La/SSB antibodies. Affinity-purified anti-dsDNA antibodies were used for selection of bacterial clones producing specific scFv antibody fragments against anti-dsDNA antibodies and little reactivity with normal IgG and other IgG antibodies by ELISA. The anti-Id antibody recognizes a public idiotope that is broadly cross-reactive with polyclonal and monoclonal anti-dsDNA antibodies. This binding was largely inhibited by dsDNA antigen. The anti-Id antibody inhibited anti-dsDNA binding to dsDNA antigen in immunoassays and in the Crithidia luciliae assay. The anti-Id scFv antibody fragments derived from human genes could modulate the pathogenicity of anti-dsDNA autoantibodies and may have therapeutic implications in SLE. They may also be used as probes in studies of the structure of the idiotype.

Animals↗
PubMed2001

Cross-reaction of lupus anti-dsDNA antibodies with protein translation factor EF-2.

This report elucidates a new cross-reactive intracellular target of anti-dsDNA antibodies. Previous experiments have demonstrated that some anti-dsDNA antibodies penetrate cells grown in tissue culture and all inhibit in vitro translation. Data implicate a cross-reactive antigen directly involved in protein synthesis: elongation factor-2 (EF-2). EF-2 was identified by N-terminal sequencing of a band identified with an antibody to the ribosomal protein S1 from Leuconostoc lactis in Western blot assay. Anti-DNA antibodies bind directly to purified EF-2 from bovine liver in dot blot assays. Anti-dsDNA antibodies were shown to inhibit in vitro translation. This inhibiting effect of anti-dsDNA antibodies was partially restored by EF-2 and abrogated by dsDNA, suggesting this cross-reactive specificity. These data demonstrate a cross-reaction between anti-dsDNA antibodies and EF-2 which may lead to cellular dysfunction, as evidenced by inhibition of protein synthesis, and provide a direct pathogenic role for cell penetrating anti-dsDNA antibodies.

Animals↗
PubMed2001

Isolation of human anti-idiotypes broadly cross reactive with anti-dsDNA antibodies from patients with Systemic lupus erythematosus.

Antibodies to double stranded (ds)DNA play a central role in clinical diagnosis and disease expression in Systemic lupus erythematosus (SLE). This paper describes the isolation of anti-idiotype reagents (anti/antidsDNA) from four SLE sera and the demonstration of broad and quantitatively similar cross reactivity to both polyclonal and monoclonal anti-dsDNA antibodies isolated from SLE patients. Seven affinity-purified polyclonal and three monoclonal human anti-dsDNA preparations reacted preferentially with anti-idiotype F(ab')(2) coated plates compared to normal immunoglobulin (Ig)G F(ab')(2) coated plates in ELISA. In contrast, autoantibodies of other specificities (anti-Ro/SSA, anti-La/SSB, and anti-U(1)RNP) reacted equally with anti/anti-dsDNA F(ab')(2) and normal IgG F(ab')(2) coated plates. Such anti-idiotypic antibodies could play a significant role in the regulation of anti-dsDNA antibody levels in SLE.

Antibodies, Anti-Idiotypic↗
PubMed2001

Significance of histologic patterns of glomerular injury upon long-term prognosis in severe lupus glomerulonephritis.

BACKGROUND: Patients with systemic lupus erythematosus have a spectrum of glomerular disease, but the different patterns of glomerular injury identified within the general category of "severe" lupus glomerulonephritis are responsible for much of the morbidity and mortality in this disease. The glomerular injury patterns seen with severe lupus glomerulonephritis have been separated into distinct histopathologic groups to determine whether they can predict long-term patient outcome. METHODS: We analyzed the clinical follow-up of 85 patients participating in a controlled prospective therapeutic trial for the treatment of severe lupus glomerulonephritis conducted from April 1981 to December 1988, with an average follow-up of 10 years. Patients were classified according to the 1982 World Health Organization classification for lupus glomerulonephritis. RESULTS: During the course of follow-up [120 +/- 65 (SD) months], 60% of patients with category IV (diffuse proliferative glomerulonephritis) lesions entered a remission compared with only 38% of patients with category III (> or =50%, focal and segmental glomerulonephritis) lesions and 27% of patients with category Vc (> or =50%) and Vd (P < 0.05). Renal survival at 10 years was 75% for those with category IV lesions, 47% for patients with category Vc (> or =50%) and Vd, and 52% for patients with category III (> or =50%) lesions (P < 0.05). Based on multivariate analysis, patients with category III (> or =50%) or Vc (> or =50%) and Vd lesions had a relative risk of progression to end-stage renal disease 2.9 times that of category IV patients (P < 0.01), while the likelihood of entering a remission was 8.2 times greater for category IV patients (P = 0.0001). CONCLUSION: The histopathologic categorization among patients with severe lupus glomerulonephritis provides information relevant to their long-term outcome.

Adult↗
PubMed2001

Dual binding capabilities of anti-double-stranded DNA antibodies and anti-ribosomal phosphoprotein (P) antibodies.

The aim of this study is to identify distinctive properties of pathogenic anti-double stranded DNA antibodies and anti-ribosomal P antibodies. The binding activity of anti-dsDNA and anti-ribosomal P antibodies to their cognate antigens in 0.15 M and 1.5 M NaCl solutions on ELISA was examined. All anti-dsDNA and anti-ribosomal P antibodies exhibited a loss of their binding activity from 37.5 to 100% and from 2.3 to 97.4% in high ionic strength buffers, respectively. In contrast, anti-U1RNP antibodies and anti-Ro/SSA antibodies lost from 0 to 32.7% and from 0 to 40.1% of their binding activity, respectively. Anti-dsDNA and anti-ribosomal P antibodies from patients with nephropathy showed significantly higher binding activity in high ionic strength buffers than those from patients without nephropathy. Study of paired sera from lupus nephritis patients revealed that anti-dsDNA and anti-ribosomal P antibodies from patients during disease flare show stronger binding activity in high ionic strength buffer than those during remission. Most anti-dsDNA and anti-ribosomal P antibodies bind their antigens by ionic interactions that are sensitive to high salt. Such dual binding capability of anti-dsDNA and anti-ribosomal P antibodies may underlie their multiple cross reactivities to various epitopes and help elucidate the pathogenic potential of autoantibody subsets.

Antibodies, Antinuclear↗
PubMed2000

Evaluation of assays for the detection of autoantibodies to the ribosomal P proteins.

Sera from systemic lupus erythematosus patients that had antibodies to the ribosomal P proteins were compared in several different assays. The enzyme-linked immunosorbent assay (ELISA) method was compared to the Western immunoblotting method using either affinity purified human or bovine ribosomal P proteins. All 30 normal sera had no significant reactivity with these antigens. The most sensitive test was the ELISA using the human P protein, where 31/32 patients were positive (97%). The assay with bovine proteins in ELISA yielded 28/32 (88%) positive results. Immunoblotting with either bovine or human P protein was equally effective with 30/32 (94%) positive. An ELISA incorporating human P proteins is a more sensitive assay for clinical diagnosis than an ELISA with the bovine protein. Immunoblotting is a sensitive method, but is less convenient and is not quantitative. The ELISA with the human protein appears to be the method of choice.

Animals↗
PubMed2000

Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group.

In 1992, we published the results of a prospective, controlled trial of aggressive therapy (high-dose prednisone plus oral cyclophosphamide alone or with plasmapheresis) in 86 patients with severe lupus nephritis. During this study, remission (serum creatinine < or =1.4 mg/dL [< or =123 micromol/L] and proteinuria < or =330 mg/d of protein) in renal disease occurred in 37 patients (43%). To assess the long-term effect of remission on patient and renal survival, we now report the results of our extended follow-up of these patients. After an average of 10 years of follow-up in the 86 patients, patient survival rates at both 5 and 10 years were 95% in the group that had a remission and 69% at 5 years and 60% at 10 years in the no-remission group (P < 0.001). Renal survival rates were 94% at both 5 and 10 years in the remission group compared with 46% at 5 years and 31% at 10 years in the no-remission group (P < 0. 0001). Features predictive of remission included stable renal function after 4 weeks on therapy, category IV lesion, lower chronicity index, white race, lower urine protein excretion level at baseline, and lower baseline serum creatinine level. The features predictive of end-stage renal disease were higher baseline serum creatinine level, presence of anti-Ro antibodies, and failure to attain a remission. Thus, in patients with the most severe forms of lupus nephritis, a remission of clinical renal abnormalities is associated with dramatic improvement in long-term patient and renal survival.

Adult↗
PubMed2000

Solidarity and the role of the state in Italian health care.

The article deals with the issue of solidarity in health care, with particular reference to the Italian context. It presents the difficulties of the Italian NHS and assesses the current proposal to counter the crisis of the Welfare State by giving up institutional arrangements, in order to favour the so-called 'social private'. Moreover, it addresses the question of prioritization and targeting in the context of health care, arguing for the insufficiency of the standard approach of neutral liberalism, and showing how the concept of solidarity might help to develop a different account. Lastly, it discusses the case of organ transplantation in Italy, as an example of solidarity-inspired health care policy.

Civil Rights↗
PubMed2000

ANA negative systemic lupus erythematosus sera revisited serologically.

OBJECTIVE: To better define the serology of a panel of sera from patients with a clinical diagnosis of systemic lupus erythematosus (SLE) or subacute cutaneous lupus erythematosus (SCLE) with a negative antinuclear antibody (ANA) test on mouse liver. METHODS: Sensitive ELISA methods for anti-Ro/SSA, anti-La/SSB, and anti-U1RNP were applied to a panel of 76 sera with either SLE or SCLE and a negative ANA test on mouse liver. RESULTS: These sera had previously been shown to have a high prevalence of anti-Ro/SSA (68%) and anti-La/SSB (27%) precipitins respectively. None had precipitins to U1RNP or Sm. ELISA methodology revealed that all of the sera 76/76 (100%) had elevated levels (> mean +/- 2 SD of a panel of 21 normal sera) of anti-Ro/SSA, 36/76 (46%) had elevated levels of anti-La/SSB, and 27 of 76 (35%) had elevated levels of anti-U1RNP. CONCLUSION: The subset of patients with SLE and SCLE with a negative ANA test on mouse liver almost uniformly have antibodies to the Ro/SSA antigen by a sensitive ELISA. This adds evidence to the idea that this is a more homogeneous disease subset within the spectrum of SLE.

Animals↗
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↗