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1.
Int J Rheum Dis ; 16(6): 674-80, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24330273

ABSTRACT

AIM: Prolidase deficiency is a rare autosomal recessive disease in which one of the last steps of collagen metabolism, cleavage of proline-containing dipeptides, is impaired. Only about 93 patients have been reported with about 10% also having systemic lupus erythematosus (SLE). METHODS: We studied a large extended Amish pedigree with four prolidase deficiency patients and three heterozygous individuals for lupus-associated autoimmunity. Eight unaffected Amish children served as normal controls. Prolidase genetics and enzyme activity were confirmed. Antinuclear antibodies (ANA) were determined using indirect immunofluorescence and antibodies against extractable nuclear antigens were determined by various methods, including double immunodiffusion, immunoprecipitation and multiplex bead assay. Serum C1q levels were determined by enzyme-linked immunosorbent assay. RESULTS: Two of the four homozygous prolidase deficiency subjects had a positive ANA. One had anti-double-stranded DNA, while another had precipitating anti-Ro. By the simultaneous microbead assay, three of the four had anti-Sm and anti-chromatin. One of the three heterozygous subjects had a positive ANA and immunoprecipitation of a 75 000 molecular weight protein. The unaffected controls had normal prolidase activity and were negative for autoantibodies. CONCLUSIONS: Prolidase deficiency may be associated with the loss of immune tolerance to lupus-associated autoantigens even without clinical SLE.


Subject(s)
Antibodies, Antinuclear/blood , Autoantigens/immunology , Autoimmunity , Lupus Erythematosus, Systemic/immunology , Prolidase Deficiency/immunology , Self Tolerance , Amish/genetics , Antigens, Nuclear/immunology , Biomarkers/blood , Case-Control Studies , Complement C1q/analysis , Genetic Predisposition to Disease , Humans , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/ethnology , Lupus Erythematosus, Systemic/genetics , Pedigree , Phenotype , Prolidase Deficiency/blood , Prolidase Deficiency/ethnology , Prolidase Deficiency/genetics , United States/epidemiology
2.
Arthritis Rheum ; 64(11): 3677-86, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23112091

ABSTRACT

OBJECTIVE: Replacement of standard immunofluorescence methods with bead-based assays for antinuclear antibody (ANA) testing is a new clinical option. The aim of this study was to evaluate a large, multiethnic cohort of patients with systemic lupus erythematosus (SLE), blood relatives, and unaffected control individuals for familial aggregation and subset clustering of autoantibodies by high-throughput serum screening technology and traditional methods. METHODS: Serum samples (1,540 SLE patients, 1,154 unaffected relatives, and 906 healthy, population-based controls) were analyzed for SLE autoantibodies using a bead-based assay, indirect immunofluorescence (IIF), and immunodiffusion. Autoantibody prevalence, sensitivity for disease detection, clustering of autoantibodies, and associations between newer methods and standard immunodiffusion results were evaluated. RESULTS: The frequencies of ANAs in the sera from African American, Hispanic, and European American patients with SLE were 89%, 73%, and 67%, respectively, by BioPlex 2200 bead-based assay and 94%, 84%, and 86%, respectively, by IIF. When comparing the serum prevalence of 60-kd Ro, La, Sm, nuclear RNP A, and ribosomal P autoantibodies across assays, the sensitivity of detection ranged from 0.92 to 0.83 and the specificity ranged from 0.90 to 0.79. Autoantibody cluster analysis showed associations of autoantibody specificities in 3 subsets: 1) 60 kd Ro, 52-kd Ro, and La, 2) spliceosomal proteins, and 3) double-stranded DNA (dsDNA), chromatin, and ribosomal P. Familial aggregation of Sm/RNP, ribosomal P, and 60-kd Ro in SLE patient sibling pairs was observed (P ≤ 0.004). Simplex-pedigree SLE patients had a greater prevalence of dsDNA (P = 0.0003) and chromatin (P = 0.005) autoantibodies compared to patients with a multiplex SLE pedigree. CONCLUSION: The frequencies of ANAs detected by a bead-based assay are lower than those detected by IIF in European American patients with SLE. These assays have strong positive predictive values across ethnic groups, provide useful information for clinical care, and provide unique insights into familial aggregation and autoantibody clustering.


Subject(s)
Antibody Specificity/immunology , Autoantibodies/immunology , Ethnicity/statistics & numerical data , Fluorescent Antibody Technique, Indirect/methods , Lupus Erythematosus, Systemic/ethnology , Lupus Erythematosus, Systemic/immunology , Adult , Black or African American/statistics & numerical data , Aged , Antibodies, Antinuclear/blood , Antibodies, Antinuclear/immunology , Asian/statistics & numerical data , Autoantibodies/blood , Family , Female , Hispanic or Latino/statistics & numerical data , Humans , Immunodiffusion/methods , Male , Middle Aged , Native Hawaiian or Other Pacific Islander/statistics & numerical data , Ribosomal Proteins/immunology , Seroepidemiologic Studies , United States/epidemiology , White People/statistics & numerical data
3.
Autoimmune Dis ; 2012: 819634, 2012.
Article in English | MEDLINE | ID: mdl-22988489

ABSTRACT

Purpose. This study evaluates high-throughput autoantibody screening and determines associated systemic lupus erythematosus (SLE) clinical features in a large lupus cohort. Methods. Clinical and demographic information, along with serum samples, were obtained from each SLE study participant after appropriate informed consent. Serum samples were screened for 10 distinct SLE autoantibody specificities and examined for association with SLE ACR criteria and subcriteria using conditional logistic regression analysis. Results. In European-American SLE patients, autoantibodies against 52 kD Ro and RNP 68 are independently enriched in patients with lymphopenia, anti-La, and anti-ribosomal P are increased in patients with malar rash, and anti-dsDNA and anti-Sm are enriched in patients with proteinuria. In African-American SLE patients, cellular casts associate with autoantibodies against dsDNA, Sm, and Sm/nRNP. Conclusion. Using a high-throughput, bead-based method of autoantibody detection, anti-dsDNA is significantly enriched in patienets with SLE ACR renal criteria as has been previously described. However, lymphopenia is associated with several distinct autoantibody specificities. These findings offer meaningful information to allow clinicians and clinical investigators to understand which autoantibodies correlate with select SLE clinical manifestations across common racial groups using this novel methodology which is expanding in clinical use.

4.
J Rheumatol ; 37(7): 1480-7, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20472921

ABSTRACT

OBJECTIVE: Systemic lupus erythematosus (SLE) is more common among women than men, a ratio of about 10 to 1. We undertook this study to describe familial male SLE within a large familial SLE cohort. METHODS: SLE families (2 or more patients) were identified from the Lupus Multiplex Registry and Repository. Genomic DNA and blood samples were obtained using standard methods. Autoantibodies were determined by multiple methods. Medical records were abstracted for SLE clinical data. Fluorescent in situ hybridization (FISH) was performed with X and Y centromere-specific probes, and a probe specific for the Toll-like receptor 7 gene on the X chromosome. RESULTS: Among 523 SLE families, we found 5 families in which all the SLE patients were male. FISH found no yaa gene equivalent in these families. SLE-unaffected primary female relatives from the 5 families with only-male SLE patients had a statistically increased rate of positive antinuclear antibodies compared to SLE-unaffected female relatives in other families. White men with SLE were 5 times more likely to have an offspring with SLE than White women with SLE, but there was no difference in this likelihood among Black men. CONCLUSION: Because women in the all-male families had positive antinuclear antibodies, and men are more likely to have children with SLE, these data suggest genetic susceptibility factors that act only in men.


Subject(s)
Lupus Erythematosus, Systemic/genetics , Black or African American/genetics , Antibodies, Antinuclear/genetics , Antibodies, Antinuclear/immunology , Autoantibodies/blood , Autoantibodies/genetics , Chromosomes, Human, X , Chromosomes, Human, Y , Cohort Studies , Female , Genetic Predisposition to Disease , Humans , In Situ Hybridization, Fluorescence , Lupus Erythematosus, Systemic/blood , Male , Pedigree , Registries , White People/genetics
5.
PLoS One ; 5(3): e9599, 2010 Mar 10.
Article in English | MEDLINE | ID: mdl-20224770

ABSTRACT

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, humoral autoimmune disorder. The unifying feature among SLE patients is the production of large quantities of autoantibodies. Serum samples from 129 patients collected before the onset of SLE and while in the United States military were evaluated for early pre-clinical serologic events. The first available positive serum sample frequently already contained multiple autoantibody specificities (65%). However, in 34 SLE patients the earliest pre-clinical serum sample positive for any detectable common autoantibody bound only a single autoantigen, most commonly 60 kD Ro (29%), nRNP A (24%), anti-phospholipids (18%) or rheumatoid factor (15%). We identified several recurrent patterns of autoantibody onset using these pre-diagnostic samples. In the serum samples available, anti-nRNP A appeared before or simultaneously with anti-nRNP 70 K in 96% of the patients who had both autoantibodies at diagnosis. Anti-60 kD Ro antibodies appeared before or simultaneously with anti-La (98%) or anti-52 kD Ro (95%). The autoantibody response in SLE patients begins simply, often binding a single specific autoantigen years before disease onset, followed by epitope spreading to additional autoantigenic specificities that are accrued in recurring patterns.


Subject(s)
Autoantigens/chemistry , Autoimmunity , Lupus Erythematosus, Systemic/immunology , Ribonucleoproteins/chemistry , Autoantigens/blood , Case-Control Studies , Epitopes/chemistry , Female , HeLa Cells , Humans , Lupus Erythematosus, Systemic/blood , Male , Ribonucleoproteins/blood
6.
Arthritis Rheum ; 54(1): 360-8, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16385527

ABSTRACT

OBJECTIVE: New examples support the concept that host immune responses to pathogenic organisms can act as the nidus for autoimmunity. Two such examples implicate the Epstein-Barr virus (EBV) in systemic lupus erythematosus (SLE), i.e., data consistent with SLE anti-Sm and anti-60-kd Ro autoantibodies emerging from distinct humoral immune responses to Epstein-Barr nuclear antigen 1 (EBNA-1). We undertook this study to further test whether the humoral immune response to EBNA-1 is a risk factor for pediatric SLE. METHODS: Sera from pediatric lupus patients and healthy matched controls were tested for anti-EBNA-1 by Western blotting and enzyme-linked immunosorbent assay (ELISA). To define the fine specificity of their anti-EBNA-1 humoral immune response, fragments of EBNA-1 and the maximally overlapping unique octapeptides of EBNA-1 were tested by modified ELISAs. RESULTS: All 36 pediatric SLE patient sera tested recognized EBNA-1, while sera from only 25 of 36 matched EBV-positive controls targeted EBNA-1 (P < 0.005). Epitope mapping revealed that the humoral anti-EBNA-1 response in pediatric SLE was distinct from and less restricted than that in matched normal individuals. Meanwhile, no significant differences between SLE patient sera and control sera were observed in the responses to other herpesviruses or in binding to sequential epitopes from cytomegalovirus immediate-early antigen or EBNA-2. CONCLUSION: Anti-EBNA-1 antibodies are associated with pediatric-onset SLE. Furthermore, an altered humoral immune response to EBNA-1, characteristic of SLE, has been found and may be an important SLE susceptibility factor.


Subject(s)
Epstein-Barr Virus Nuclear Antigens/immunology , Lupus Erythematosus, Systemic/immunology , Adolescent , Child , Epitopes/immunology , Female , Humans , Male , Risk Factors
7.
Ann N Y Acad Sci ; 1051: 390-403, 2005 Jun.
Article in English | MEDLINE | ID: mdl-16126981

ABSTRACT

Autoantibodies binding the ribosomal P phosphoproteins are highly specific for systemic lupus erythematosus (SLE) and can be found in precipitating levels in approximately 15% of these patients. Anti-ribosomal P antibodies are directed against three proteins, and the primary autoimmune target of this response has been described as a common 22-amino acid sequence. Sera from 31 anti-ribosomal P immunodiffusion-positive SLE patients were tested for C-terminal P-peptide reactivity by ELISA. Sera from three patients (9.7%) were negative for the peptide ELISA, despite having anti-ribosomal P by immunodiffusion and Western blot. In addition, inhibition experiments showed that the common P-peptide response accounts for a variable amount of anti-ribosomal P0 reactivity (52-89% of the response dependent upon the patient serum). Based upon these findings, fine-specificity sequential humoral epitope mapping of ribosomal P0 was performed. Several common sequential antigenic targets were defined dispersed throughout the molecule. The most commonly targeted epitopes included RDMLLANKVPAAARA (amino acids 99-113, 11 of 12 patients reactive) and QALGITTKISRGT (amino acids 139-151, 9 of 12 patients reactive). This study confirms that the P22 ribosomal peptide is commonly targeted in SLE and accounts for a variable percentage of the anti-ribosomal P response. Additional anti-ribosomal P humoral epitopes are described.


Subject(s)
Autoantigens/immunology , Lupus Erythematosus, Systemic/immunology , Ribosomal Proteins/immunology , Amino Acid Sequence , Antibody Specificity , Blotting, Western , Enzyme-Linked Immunosorbent Assay , Epitope Mapping , Humans , Molecular Sequence Data , Ribosomal Proteins/chemistry
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