RESUMO
OBJECTIVES: The objective of this paper is to determine the effect of clinical and laboratory manifestations, and medication prescribing, on survival according to patient age at diagnosis in a large academic systemic lupus erythematosus (SLE) cohort. METHODS: We identified SLE patients with a diagnosis at age ≥18, seen between 1970 through 2011, and with more than two visits to our lupus center. Data collection included SLE manifestations, serologies, other laboratory tests, medications, dates, and causes of death. We examined characteristics of those diagnosed before age 50 (adult onset) compared to those diagnosed at or after age 50 (late onset) using descriptive statistics. We used Kaplan-Meier curves with log rank tests to estimate five- and 10-year survival in age-stratified cohorts. Predictors of 10-year survival were assessed using Cox regression models, adjusted for calendar year, race/ethnicity, sex, lupus nephritis, and medication use. RESULTS: Of 928 SLE patients, the mean age at diagnosis was 35. Among the adult-onset group, there was significantly higher prevalence of malar rashes and lupus nephritis. Glucocorticoids, azathioprine, mycophenolate, and cyclophosphamide use were also more frequent in the adult-onset group compared to the late-onset group. Five-year survival rates were 99.5% and 94.9% and 10-year survival rates were 97.8% and 89.5%, among those diagnosed before and at or after age 50. In the entire cohort, increasing age at diagnosis, male sex, and black race were statistically significant predictors of reduced 10-year survival. Compared to those diagnosed before age 50, the late-onset group had a multivariable-adjusted hazard ratio for 10-year risk of death of 4.96 (95% CI 1.75-14.08). The most frequent cause of known death was a lupus manifestation, followed by cardiovascular disease and infection. CONCLUSIONS: In our cohort, several demographic features, SLE manifestations, and medication prescribing differed between those with adult-onset and late-onset SLE. Ten-year survival rates were high for both groups, but relatively lower among late-onset patients. A lupus manifestation as the cause of death was more common among adult-onset compared with late-onset patients.
Assuntos
Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/mortalidade , Adolescente , Adulto , Fatores Etários , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
OBJECTIVE: To identify factors associated with development of systemic lupus erythematosus (SLE) among patients evaluated at a tertiary care Lupus Center for potential SLE. METHODS: We identified patients first seen at the Brigham and Women's Hospital Lupus Center between 1 January 1992 and 31 December 2012 and thought to have potential SLE by a board-certified rheumatologist. All had 1-3 SLE ACR criteria at initial visit and > 2 follow-up visits ≥ 3 months apart. We reviewed medical records through 15 May 2013 for: SLE signs and symptoms, autoimmune serologies, prescriptions and diagnoses by board-certified rheumatologists. Bivariable analyses and multivariable logistic regression models were used to identify independent predictors of developing SLE. RESULTS: Two hundred and sixty four patients met inclusion criteria. At initial visit, mean age was 39.2 (SD 12.4) years, 94% were female and 67% white. Mean number of SLE ACR criteria was 2.7 (SD 1.0) and 88% were antinuclear antibody (ANA) positive at initial consultation. Mean follow-up time was 6.3 (SD 4.3) years and 67% were prescribed hydroxychloroquine in follow-up. At most recent visit, 56 (21%) had been diagnosed with SLE; 47 (18%) were thought not to have SLE and 161 (61%) were still considered to have potential SLE. In multivariable regression models, oral ulcers (OR 2.40, 95% CI 1.03-5.58), anti-dsDNA (OR 2.59, 95% CI 1.25-5.35) and baseline proteinuria or cellular casts (OR 16.20, 95% CI 1.63-161.02) were independent predictors of developing SLE. The most common other final diagnoses included fibromyalgia, Sjögren's syndrome, mixed connective tissue disease and cutaneous lupus. CONCLUSION: Among patients with potential SLE at initial consultation, 21% were diagnosed with definite SLE within 6.3 years. Oral ulcers, anti-dsDNA and proteinuria or cellular casts were independent predictors of developing definite SLE. A better means of accurately identifying those who will develop SLE among those presenting with potential disease is necessary.
Assuntos
Lúpus Eritematoso Sistêmico/epidemiologia , Encaminhamento e Consulta/estatística & dados numéricos , Adulto , Anticorpos Antinucleares/sangue , Causalidade , Feminino , Seguimentos , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/mortalidade , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Antibodies were eluted from the isolated glomeruli prepared from the kidneys of 10 patients with the nephritis of systemic lupus erythematosus. Antibodies reacting primarily with buffer extracts of nuclei were eluted by acid treatment, and antibodies reacting mainly with DNA and nucleoprotein were eluted with deoxyribonuclease. Quantitative immunochemical studies revealed a high concentration of antinuclear antibody per milligram of gamma-globulin in glomerular eluates compared with that in the corresponding serums. The gamma-globulin of two eluates was found to consist predominantly of antinucleoprotein antibody. The selective elution of antinuclear antibodies was also indicated by the absence of other serum antibodies in the eluates. DNA antigen was demonstrated in the glomeruli of two kidneys with nephritis by means of isolated anti-DNA antibody labeled with fluorescein. In one of these cases, anti-DNA antibodies were also found concentrated in the glomeruli and, in the second, circulating anti-DNA antibodies were demonstrated in the patient's serum. The immunochemical evidence for the high specific activity of antinuclear antibodies and the association of DNA antigen with DNA antibody in glomeruli add further support for the antigen-antibody complex hypothesis for renal injury in systemic lupus erythematosus.
Assuntos
Reações Antígeno-Anticorpo , Autoanticorpos/análise , Lúpus Eritematoso Sistêmico/imunologia , Nefrite/imunologia , Animais , Anticorpos Antinucleares , Doenças Autoimunes , Bovinos , Proteínas do Sistema Complemento/análise , DNA/análise , Imunofluorescência , Testes de Hemaglutinação , Humanos , Técnicas In Vitro , Glomérulos Renais/imunologia , Lúpus Eritematoso Sistêmico/complicações , Nefrite/etiologia , Testes de Precipitina , Coelhos , gama-Globulinas/análiseRESUMO
Proteins cleaved by interleukin-1 beta converting enzyme family proteases during apoptosis are common targets for autoantibody production in patients with systemic lupus erythematosus (SLE). We have tested the possibility that proteins phosphorylated in cells undergoing apoptosis are also targets for autoantibody production in patients with autoimmune disease. Sera from 9/12 patients containing antinuclear antibodies (10/12 meeting diagnostic criteria for SLE or a lupus overlap syndrome), precipitated new phosphoproteins from lysates derived from Jurkat T cells treated with apoptotic stimuli (i.e., Fas-ligation, gamma irradiation, ultraviolet irradiation), but not with an activation (i.e., CD3-ligation) stimulus. Sera derived from individual patients precipitated different combinations of seven distinct serine-phosphorylated proteins. None of these phosphoproteins were included in precipitates prepared using sera from patients with diseases that are not associated with autoantibody production or using serum from rheumatoid arthritis patients. Protein phosphorylation precedes, or is coincident with, the induction of DNA fragmentation, and is not observed when apoptosis is inhibited by overexpression of bcl-2. Serum from four patients precipitated a serine/threonine kinase from apoptotic cell lysates that phosphorylates proteins of 23-, 34-, and 46-kD in in vitro kinase assays. Our results suggest that proteins phosphorylated during apoptosis may be preferred targets for autoantibody production in patients with SLE.
Assuntos
Apoptose/imunologia , Autoanticorpos/biossíntese , Autoantígenos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fosfoproteínas/imunologia , Células Cultivadas , Fragmentação do DNA , Humanos , Proteínas Nucleares/imunologia , Fosforilação , Fosfosserina/imunologia , Testes de Precipitina , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/efeitos da radiação , Receptor fas/imunologiaRESUMO
An effective molecule titration for the ninth component of complement in the biologic fluids of man was developed using EAC1-8 cells produced by treating EAC14 cells with a chromatographic fraction of human serum containing C2, C3, C5, C6, C7, and C8. Kinetic studies of the interaction of EAC1-8 with C9 indicated that this component was depleted from the fluid phase, and that the lytic reaction proceeded most rapidly at ionic strength 0.145, and at a temperature of 37 degrees C. The mean value for C9 in normal serum was 52,000 +/-12,000 units/ml. The mean serum C9 for patients with DJD, rheumatoid arthritis, or SLE without active renal disease was approximately twice the mean for normal individuals. Patients with SLE and active renal disease had a mean C9 value which fell within the normal range, but was significantly lower than in patients with SLE who did not have active renal disease. Two instances of absolutely subnormal C9 levels were observed in patients during attacks of florid SLE, including nephritis. Since the usual change in serum C9 in rheumatic diseases is a marked elevation, the occurrence of a subnormal value reflects circumstances in which depletion due to activation of the sequence exceeds the increases associated with the inflammatory response.
RESUMO
OBJECTIVE: To determine the significance of quantitative levels of antibodies to cyclic citrullinated peptides (anti-CCP) in a population of patients with rheumatoid arthritis (RA). METHODS: A total of 241 consecutive sera from patients with RA sent from a large rheumatology clinic for laboratory testing were selected for precisely quantifying anti-CCP antibody titres with the anti-CCP2 assay. Patient charts were reviewed for demographic information, smoking history, clinical diagnosis, rheumatoid factor (RF) titre, radiographic information and other laboratory information (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level). Correlations with anti-CCP titre and RF titre, disease parameters and smoking history were assessed. RESULTS: We confirm previous findings that anti-CCP seropositivity is associated with a higher incidence of erosions in patients with RA (56% vs 20% CCP+ vs CCP-, kappa = 0.297, p<0.001). We also found a moderate correlation between anti-CCP titre and RF titre. However, we failed to find an association between anti-CCP titre and presence of erosions, between anti-CCP titre and CRP or ESR level, or between anti-CCP titre and age or disease duration. Interestingly, we did find significantly higher anti-CCP titres in patients with a history of smoking (452 units/ml vs 229 units/ml, smokers vs non-smokers, respectively; p = 0.02). CONCLUSIONS: Although anti-CCP titres were not associated with clinical parameters of disease, they are increased in patients with RA with exposure to tobacco. By contrast, no elevation in RF was noted in patients with a history of smoking. These observations are consistent with a pathogenic contribution of smoking to RA and suggest the immune stimulus for anti-CCP is distinct from that for RF.
Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Peptídeos Cíclicos/imunologia , Fumar/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/diagnóstico por imagem , Biomarcadores/sangue , Sedimentação Sanguínea , Proteína C-Reativa/análise , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Fator Reumatoide/sangue , Fumar/sangue , Adulto JovemRESUMO
OBJECTIVE: The classification of rheumatoid arthritis (RA) is increasingly important as new therapies can halt the disease in its early stages. Antibodies to cyclic citrullinated peptides (anti-CCP) are widely used for RA diagnosis, but are not in the 1987 American College of Rheumatology (ACR) Criteria for RA Classification. We developed and tested the performance characteristics of new criteria for RA classification, incorporating anti-CCP. METHODS: We identified all subjects seen in our arthritis centre with rheumatoid factor (RF) and anti-CCP tested simultaneously between 1 January and 30 June 2004 and reviewed their medical records for the ACR criteria, rheumatologists' diagnoses, RF and anti-CCP. We revised the ACR criteria in two ways: (a) adding anti-CCP, and (b) replacing rheumatoid nodules and erosions with anti-CCP (CCP 6 criteria). We compared sensitivity and specificity of all criteria, in all subjects and in subjects with arthritis symptoms =6 months. RESULTS: Medical records of 292 subjects were analysed: mean age was 54 years, 82% were women, and mean symptom duration was 4.1 years. 17% were RF positive and 14% were anti-CCP positive at initial testing. 78 (27%) had definite RA per treating rheumatologist at latest follow-up. The CCP 6 criteria increased sensitivity for RA classification for all subjects regardless of symptom duration: 74% vs 51% for ACR criteria with a loss in specificity (81% vs 91%). Sensitivity was greatly improved in subjects with symptoms < or =6 months: 25% vs 63% for ACR criteria with a decrease in specificity. CONCLUSIONS: The CCP 6 criteria improved upon the sensitivity of the ACR criteria, most remarkably for subjects with symptoms < or =6 months and could be used for the classification of subjects for RA in clinical studies.
Assuntos
Artrite Reumatoide/diagnóstico , Autoanticorpos/sangue , Peptídeos Cíclicos/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/classificação , Biomarcadores/sangue , Diagnóstico Precoce , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/sangue , Sensibilidade e Especificidade , Fatores de TempoRESUMO
C3b inactivator (C3bINA) has been measured in biologic fluids by radial immunodiffusion using a monospecific antiserum prepared in rabbits, and by a hemolytic assay which measures the reduction in the capacity of EAC43 cells bearing limited C3b sites to form C3B, the alternative pathway C3 convertase. The radial immunodiffusion and hemolytic assays show a good correlation (r = 0.86 P less than 0.001). Measurement of C3bINA concentrations in the sera of patients with systemic lupus erythematosus showed that during exacerbations of disease activity C3bINA concentrations tended to be lower, usually in association with reductions in C4, C3, factor B, and properdin, and sometimes with reductions of the alternative pathway proteins, factor B, and properdin alone. Supranormal values for C3bINA were found in the sera of 14 of 20 patients with seropositive rheumatoid arthritis and 3 of 9 seronegative patients, but none of 7 patients with degenerative joint disease. Synovial fluid concentrations of C3bINA, after correction for total synovial fluid protein and serum concentration of the enzyme, were significantly reduced in patients with rheumatoid arthritis compared to patients with degenerative joint disease (P less than 0.05). In both serum and synovial fluid from patients with rheumatoid arthritis, there was a good correlation between the concentrations of C3bINA and those of C3, factor B, and properdin, but not that of C4, suggesting that levels of C3bINA may serve to modulate recruitment of the properdin amplification loop in this disease.
Assuntos
Complemento C3 , Proteínas do Sistema Complemento , Properdina/metabolismo , Doenças Reumáticas/imunologia , Animais , Artrite Reumatoide/imunologia , Complemento C3/antagonistas & inibidores , Complemento C3/metabolismo , Complemento C4 , Proteínas do Sistema Complemento/metabolismo , Esterases/antagonistas & inibidores , Glicoproteínas , Cobaias , Hemólise , Humanos , Imunodifusão , Lúpus Eritematoso Sistêmico/imunologia , Soroglobulinas , Líquido Sinovial/imunologiaRESUMO
36 renal biopsies from patients with nephritis were studied for glomerular localization of the heavy chain subgroups of immunoglobulin G (IgG or gammaG). The deposition pattern of these subgroups was selective and did not reflect the normal serum concentration of these proteins. gammaG2, which comprises 18% of normal serum gammaG, was the predominant or unique subgroup deposited in five cases of lupus nephritis and four biopsies with other forms of nephritis associated with granular gammaG deposits. gammaG3, which normally makes up only 8% of the serum gammaG, was the dominant subgroup seen in one biopsy of lobular glomerulonephritis. Patients with linear gammaG deposits generally had a selective absence of gammaG3 and often had large amounts of gammaG4 (normally 3% of the serum gammaG) deposited. The deposition of complement components C1q, C4, and C3 was variable. One biopsy had only gammaG2 and no complement components in the deposits and had no neutrophile leukocyte infiltration. This latter observation correlates well with the poor ability of gammaG2 to fix complement in vitro. Similarly, deposits containing large amounts of gammaG4, which does not fix complement, also tended to have less inflammatory infiltrate than deposits devoid of this subgroup. The selective deposition of monotypic or restricted gammaG subgroups on the glomerulus supports the likelihood that the gammaG represents antibody. The nature of the subgroup involved in the deposit may represent one variable in the determination of the inflammatory and morphological picture that evolves in human glomerulonephritis.
Assuntos
Glomerulonefrite/imunologia , Imunoglobulina G/análise , Glomérulos Renais/imunologia , Doença Antimembrana Basal Glomerular/imunologia , Membrana Basal/imunologia , Proteína de Bence Jones/isolamento & purificação , Biópsia , Proteínas do Sistema Complemento/análise , Imunofluorescência , Glomerulonefrite/sangue , Glomerulonefrite/patologia , Humanos , Imunodifusão , Imunoeletroforese , Microscopia de Fluorescência , Nefrose/imunologiaRESUMO
The present study was designed to test the possibility that T cell receptor genes are associated/linked to those involved in systemic lupus erythematosus (SLE). Genomic DNA was isolated from 31 unrelated Caucasian SLE patients, 34 unrelated Caucasian normals, 5 multiplex American Caucasian SLE families, 9 multiplex Mexican SLE families, and 13 unrelated Mexican normals. The DNA was digested with Pst I, electrophoresed, and transferred to membranes by the Southern blot method. The blots were probed with a cDNA probe for the alpha chain of the T cell receptor. 13 polymorphic RFLP patterns were recognized. 1.3- and 3.0-kb band pairs were observed in 15 of 31 of American Caucasian patients and 4 of 34 American Caucasian controls (chi square, 8.81; P less than 0.002; relative risk, 7); there was no association of any RFLP pattern with Mexican SLE. The cDNA probe was cut with Rsa I, EcoR I, and Ava II into fragments corresponding to the V, J, C, and 3'UT regions. Only the fragment corresponding to the constant region reacted with the 1.3/3.0-kb band pair. These observations suggest that a genetic marker of the constant region of the alpha chain of the T cell receptor is associated with genes involved in SLE.
Assuntos
Lúpus Eritematoso Sistêmico/genética , Receptores de Antígenos de Linfócitos T/genética , Autoanticorpos/análise , DNA/genética , Feminino , Frequência do Gene , Genes , Antígenos HLA-DR/análise , Humanos , Masculino , Polimorfismo de Fragmento de Restrição , Receptores de Antígenos de Linfócitos T alfa-beta , Mapeamento por RestriçãoRESUMO
The relationship of the genes coding for HLA to those coding for properdin Factor B allotypes and for deficiency of the second component of complement (C2) was studied in families of patients with connective tissue disorders. Patients were selected because they were heterozygous or homozygous for C2 deficiency. 12 families with 15 matings informative for C2 deficiency were found. Of 57 informative meioses, two crossovers were noted between the C2 deficiency gene and the HLA-B gene, with a recombinant fraction of 0.035. A lod score of 13 was calculated for linkage between C2 deficiency and HLA-B at a maximum likelihood value of the recombinant fraction of 0.04. 18 families with 21 informative matings for both properdin Factor B allotype and HLA-B were found. Of 72 informative meioses, three recombinants were found, giving a recombinant fraction of 0.042. A lod score of 16 between HLA-B and Factor B allotypes was calculated at a maximum likelihood value of the recombinant fraction of 0.04. A crossover was shown to have occurred between genes for Factor B and HLA-D, in which HLA-D segregared with HLA-A and B. These studies suggest that the genes for Factor B and C2 deficiency are located outside those for HLA, that the order of genese is HLA-A, -B, -D, Factor B allotype, C2 deficiency, that the genes coding for C2 deficiency and Factor B allotypes are approximately 3--5 centimorgans from the HLA-A and HLA-B loci, and that the apparent lack of recombinants between the Factor B gene and C2 deficiency gene suggests that these two genes lie in close proximity to one another.
Assuntos
Complemento C2/deficiência , Proteínas do Sistema Complemento/deficiência , Genes , Antígenos HLA , Antígenos de Histocompatibilidade , Properdina , Mapeamento Cromossômico , Ligação Genética , Humanos , Linhagem , Recombinação GenéticaRESUMO
The prevalence of homozygous and heterozygous deficiency of the second component of complement (C2) was determined in patients with rheumatic disease including 137 with systemic lupus erythematosus (SLE), 274 with juvenile rheumatoid arthritis, and 134 with rheumatoid arthritis. 1 C2 homozygous deficient and 19 possible heterozygous deficient individuals were identified by using both immunochemical and functional assays to determine C2 levels. Of the 20, 8 had SLE (5.9%), 10 had juvenile rheumatoid arthritis (3.7%), and 2 had rheumatoid arthritis (1.4%), the homozygous deficient individual having SLE. The prevalence of C2 deficiency in the SLE and juvenile rheumatoid arthritis patients was significantly increased (P = 0.0009 and P = 0.02, respectively) when compared with controls, 6 (1.2%) of 509 blood donors having C2 levels consistent with heterozygous deficiency. 15 of the 20 C2 deficient patients were HLA typed and found to have antigens A10(Aw25), B18, or both. The patients with C2 deficiency and SLE had earlier age of onset of disease and less antinuclear antibody when compared with the C2 normal SLE patients. 11 families of the propositi were studied and found to have one or more C2 heterozygous deficient individuals. The family members had an equal distribution of rheumatic disease and antinuclear antibody in the C2 deficient and C2 normal groups. C2 deficient individuals were found to have significantly lower levels of properdin Factor B (242 mug/ml+/-54) when compared with the non-C2 deficient family members (282 mug/ml+/-73). These data support the concept that inherited deficiency of C2 is significantly associated with both SLE and juvenile rheumatoid arthritis.
Assuntos
Artrite Reumatoide , Complemento C2/deficiência , Proteínas do Sistema Complemento/deficiência , Lúpus Eritematoso Sistêmico , Adulto , Artrite Juvenil/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Pessoa de Meia-IdadeRESUMO
Evidence has been sought for a genetically determined predisposition among children with juvenile rheumatoid arthritis (JRA) who are also at particular risk for the development of inflammatory eye disease.45 unrelated Caucasian patients (41 female) with early-onset pauciarticular JRA were human leukocyte antigen (HLA) types. 28 of the study group were found to be HLA-DRw5 compared with 16 of 84 controls (X(2), 24.3, P = <0.001). 9 patients were HLA-DRw8 compared with 4 of 84 controls (X(2), 7.51, P = <0.01). Iritis developed in 24 of the 45 children studied, 17 of whom were typed as HLA-DRw5 when compared to controls (X(2), 26.76, P = <0.001) and 6 with iritis typed as HLA-DRw8 (X(2), 9.10, P = <0.01). Antinuclear antibody was found in the serum of 17 of the 28 patients typing as HLA-DRw5 compared with 4 of the 17 who did not have this antigen (X(2), 5.88, P = <0.02). No such association was seen in patients with HLA-DRw8. In a study of linked genes, a delta value of 0.090 was found for HLA-DRw5 with HLA-B12, of 0.070 for DRw5 with HLA-Cw4, and a value of 0.050 for DRw5 and HLA-Bw35. This suggests a linkage disequilibrium between HLA-DRw5 and these two B series alleles, a conclusion which was supported by haplotype analysis in families of 11 of the disease probands. HLA-DRw5 has not previously been reported to be increased in any rheumatic disease group. It is proposed that HLA-DRw5 is a genetic marker defining those at risk for early-onset pauciarticular JRA with iritis.
Assuntos
Anticorpos Antinucleares/análise , Artrite Juvenil/imunologia , Antígenos HLA/análise , Irite/etiologia , Artrite Juvenil/complicações , Artrite Juvenil/genética , Feminino , Antígenos HLA/classificação , Haploidia , Humanos , Irite/genética , Irite/imunologia , MasculinoRESUMO
To determine whether imbalance among subsets of human T cells exists in patients with systemic lupus erythematosus (SLE), we analyzed peripheral blood lymphocytes in SLE patients during active and inactive stages of disease. For this analysis, we used monoclonal antibodies to the surface antigens of inducer (T4) and suppressor (T5/T8) T cell subsets, as well as a common T cell antigen (T3). In contrast to normal and inactive SLE patients, the percentage of T3+ cells was reduced in all active SLE patients. More importantly, there was a selective decrease in T5+/T8+ suppressor T cells in 12 of 14 active patients, including 1 of 2 patients with drug-induced SLE. Serial analysis of three SLE patients showed a significant correlation between the presence of T5+/T8+ subset and clinical disease activity in all patients. We conclude that aberrations in suppressor T cell subsets are an important correlate of disease in patients with SLE.
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Lúpus Eritematoso Sistêmico/sangue , Linfócitos T/imunologia , Imunofluorescência , Humanos , Linfócitos T/classificaçãoRESUMO
A 29-yr-old woman with systemic lupus erythematosus (SLE) was found to have no detectable C3b/C4b receptors (CR1) on her erythrocytes (E) when they were assayed by the binding of rabbit polyclonal and murine monoclonal (Yz-1) anti-CR1. Analysis by two-color fluorescent flow cytometry of CR1 expression on the patient's B lymphocytes that had been stained indirectly with monoclonal anti-B1 and rabbit F(ab')2 anti-CR1 also revealed a marked deficiency of CR1. Total cellular CR1 of neutrophils, assessed by a sandwich radioimmunoassay, was about half that of neutrophils from normal individuals. Because her E had expressed 173 sites/cell 2 yr before, the CR1 deficiency was considered to be acquired and a possible mechanism was sought. Autoantibody to CR1 was measured by a radioimmunoassay in which serum or its fractions were incubated in microtiter wells that had been coated with purified CR1, and binding of immunoglobulin to the wells was quantitated with 125I-labeled goat IgG antihuman F(ab')2. The CR1-specific binding of immunoglobulin from the patient's serum was 19.1 ng/well of the detecting antibody when her E had eight CR1 sites per cell; that of 28 healthy donors was 1.3 +/- 0.5 ng/well (mean +/- SEM), and that of 34 additional patients with SLE was 0.5 +/- 0.3 ng/well. The activity was present also in purified IgG and its F(ab')2 fragment, indicating that the binding of serum immunoglobulin to CR1 was not mediated by C3 fragments. The specificity of the patient's IgG for CR1 was confirmed when pretreatment of the CR1-coated wells with affinity-purified rabbit F(ab')2 anti-CR1 was shown to inhibit by 68% the binding of the IgG. The autoantibody also interacted with CR1 in cell membranes, as assessed by its capacity to inhibit the binding of indirectly fluoresceinated Yz-1 to neutrophils, and, when combined with goat IgG antihuman F(ab')2, to diminish the binding of dimeric C3b to normal E. During the period of the marked deficiency of CR1 the patient experienced an exacerbation of disease activity which was treated with prednisone. Clinical improvement was accompanied by a decrease in the serum concentration of anti-CR1 to levels present 2 yr earlier, and an increase of CR1 to 170 sites/E. The temporal association between high titers of an autoantibody to CR1, absence of CR1 from E, and heightened activity of SLE suggest that the former may have had a role in the other manifestations of the patient's disease.
Assuntos
Autoanticorpos/imunologia , Eritrócitos/imunologia , Lúpus Eritematoso Sistêmico/sangue , Receptores de Complemento/imunologia , Adulto , Anticorpos Monoclonais , Especificidade de Anticorpos , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Peso Molecular , Neutrófilos/imunologiaRESUMO
The pathogenesis of systemic lupus erythematosus (SLE) is multifactorial and multigenetic. The apoptosis genes, fas and fas ligand (fasL), are candidate contributory genes in human SLE, as mutations of these genes result in autoimmunity in several murine models of this disease. In humans, fas mutations result in a familial autoimmune lymphoproliferative syndrome, but defects in FasL have not yet been identified. In this study, DNA from 75 patients with SLE was screened by single-stranded conformational polymorphism analysis for potential mutations of the extracellular domain of FasL. A heterozygous single-stranded conformational polymorphism for FasL, was identified in one SLE patient, who exhibited lymphadenopathy. Molecular cloning and sequencing indicated that the genomic DNA of this patient contained an 84-bp deletion within exon 4 of the fasL gene, resulting in a predicted 28 amino acid in-frame deletion. Analysis of PBMC from this patient revealed decreased FasL activity, decreased activation-induced cell death, and increased T cell proliferation after activation. This is the first report of defective FasL-mediated apoptosis related to a mutation of the human Fasl, gene in a patient with SLE and suggests that fasL mutations are an uncommon cause of the disease.
Assuntos
Lúpus Eritematoso Sistêmico/genética , Transtornos Linfoproliferativos/genética , Glicoproteínas de Membrana/genética , Mutação , Deleção de Sequência , Sequência de Aminoácidos , Apoptose/genética , Sequência de Bases , População Negra/genética , Proteína Ligante Fas , Testes Genéticos , Heterozigoto , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo Conformacional de Fita Simples , Síndrome , População Branca/genéticaRESUMO
Naturally occurring antibodies to left-handed Z-DNA have been shown to be present in the sera of human patients with systemic lupus erythematosus (SLE). These antibodies are of two types. One type reacts with both denatured DNA and Z-DNA. The other type is specific for Z-DNA and remained in the serum after removal of the cross-reactive antibody by extensive absorption on a denatured DNA affinity column. The antibodies appear to be specific for SLE and do not appear frequently in other rheumatic diseases. The presence of the antibody in SLE is correlated with the clinical manifestations of the disease, in parallel with antibodies to native and denatured DNA.
Assuntos
Autoanticorpos/isolamento & purificação , DNA/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Conformação de Ácido Nucleico , Especificidade de Anticorpos , Autoanticorpos/classificação , Cromatografia em Agarose , Humanos , Concentração Osmolar , RadioimunoensaioRESUMO
22 of 61 systemic lupus erythematosus (SLE) patients produced antibodies to the p24 gag protein of HIV-1 demonstrated by Western blotting. 20 of these 22 patients (91%) also express the 4B4 idiotype (Id 4B4) previously identified on a human anti-Sm monoclonal antibody called 4B4. This represents an enrichment for this Id (seen in only 52% of SLE patients generally). Eight of these 22 SLE patients also have anti-Sm antibody activity. Sm partially inhibits the antibody binding of p24 gag suggesting immunologic cross-reactivity between the retroviral antigen p24 gag and the autoantigen Sm. Anti-Id 4B4 also inhibits p24 gag antibody binding by as much as 40%. Finally the monoclonal antibody 4B4 showed cross-reactivity to Sm and p24 gag. The following points emerge from our studies: (a) SLE patients make antibodies to p24 gag of HIV-1, (b) there is a relationship between immunity to p24 gag and a conserved idiotype, and (c) anti-Sm antibodies can cross-react with p24 gag.
Assuntos
Produtos do Gene gag/imunologia , Anticorpos Anti-HIV/imunologia , Antígenos HIV/imunologia , HIV-1/imunologia , Idiótipos de Imunoglobulinas/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Proteínas dos Retroviridae/imunologia , Ribonucleoproteínas Nucleares Pequenas , Proteínas do Core Viral/imunologia , Autoantígenos/imunologia , Western Blotting , Reações Cruzadas , Proteína do Núcleo p24 do HIV , Humanos , Proteínas Centrais de snRNPRESUMO
To determine whether genetic factors influence the human antibody response to polysaccharides, we correlated Ig allotypes with the concentrations of antibody to 14 bacterial capsular antigens in 130 actively immunized Caucasian adults. The 88 individuals possessing G2m(n), an allotype antigen of IgG2 subclass heavy chains, had significantly higher postimmunization antibody levels to Haemophilus influenzae type b (Hib) and 8 of 11 pneumococcal types (P less than 0.05) than the 42 lacking this antigen. For Hib, pneumococcus type 14, and meningococcus group C, an increased response was observed in IgG class but not in IgM or IgA classes of antibody. The G2m(n) positive individuals also had higher preimmunization antibody levels to most polysaccharide antigens. Total IgG2 concentrations were correlated with the mean postimmunization antibody concentrations to pneumococci (P = 0.005), but this correlation was independent of G2m(n) by multiple regression analysis. To determine if the lack of G2m(n) was associated with increased susceptibility to infection, we compared the frequencies of various Ig allotypes in 98 children infected with Hib and 98 matched controls. Caucasian children with Hib infections other than epiglottitis were significantly more likely to lack the G2m(n) allotype than controls (P less than 0.05). G2m(n) negative Caucasian children less than or equal to 18 mo old have a 5.1-fold higher risk of nonepiglottitic Hib infections than G2m(n) positive children (P less than 0.01). We conclude that allotypic variants of the gamma-2 heavy chain genes, or genes in linkage equilibrium with them, exert a regulatory influence on the caucasian antibody response to a variety of immunologically distinct bacterial polysaccharide antigens. Young Caucasian children of the low responder phenotype, i.e., those lacking the G2m(n) allotype, are genetically predisposed to Hib and perhaps other bacterial infections.
Assuntos
Anticorpos Antibacterianos/biossíntese , Infecções por Haemophilus/imunologia , Alótipos de Imunoglobulina/imunologia , Cadeias Pesadas de Imunoglobulinas/imunologia , Cadeias gama de Imunoglobulina/imunologia , Polissacarídeos Bacterianos/imunologia , Adulto , Anticorpos Antibacterianos/imunologia , Feminino , Haemophilus influenzae/imunologia , Humanos , Lactente , Masculino , Neisseria meningitidis/imunologia , Streptococcus pneumoniae/imunologia , VacinaçãoRESUMO
The cytoskeleton is a complex network of proteins that maintain cell shape, mobility, and organelle function. Its components can be divided into three distinct classes: microfilaments, microtubules, and intermediate filaments. Fimbrins are microfilament proteins, a family of cytoplasmic phosphoproteins. Expression of the L-fimbrin isoform is restricted to replicating blood cells and expression of the T-fimbrin isoform to replicating cells of solid tissues. Sera from normals and from patients with systemic lupus erythematosus (SLE), juvenile arthritis, rheumatoid arthritis, Sjögren's syndrome, osteoarthritis, vasculitis, scleroderma, and mixed connective tissue disease were tested for the presence of antibodies to T- and L-fimbrin by ELISA, using purified recombinant fimbrin. The mean OD of sera from SLE patients was significantly higher than in normals (T-fimbrin, P less than 0.0001; L-fimbrin, P less than 0.001). 48 of 98 SLE sera had antibodies to T-fimbrin; 32 had antibodies to L-fimbrin; 20 had antibodies to both; 28 had only anti-T, and 12 had only anti-L-fimbrin. The mean OD for sera of the other rheumatic diseases was not significantly different from normals. The presence of either L- or T-fimbrin antibody was associated with pleuropericarditis (P = 0.015), photosensitivity (P = 0.011), and anti-Sm antibody (P = 0.010). Central nervous system SLE was associated with the presence of the L-fimbrin antibody alone (P = 0.016). There was a strong association between DR7 (but not other MHC alleles) and anti-L-fimbrin antibodies in SLE patients (chi square = 18; P less than 0.00002). No MHC association was observed with anti-T-fimbrin antibodies.