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1.  Selective Involvement of the Amygdala in Systemic Lupus Erythematosus 
PLoS Medicine  2006;3(12):e499.
Antibodies specifically affect the amygdala in a mouse model of systemic lupus erythematosus (SLE). The aim of our study was to investigate whether there is also specific involvement of the amygdala in human SLE.
Methods and Findings
We analyzed a group of 37 patients with neuropsychiatric SLE (NP-SLE), 21 patients with SLE, and a group of 12 healthy control participants with diffusion weighted imaging (DWI). In addition, in a subset of eight patients, plasma was available to determine their anti-NMDAR antibody status. From the structural magnetic resonance imaging data, the amygdala and the hippocampus were segmented, as well as the white and gray matter, and the apparent diffusion coefficient (ADC) was retrieved. ADC values between controls, patients with SLE, and patients with NP-SLE were tested using analysis of variance with post-hoc Bonferroni correction. No differences were found in the gray or white matter segments. The average ADC in the amygdala of patients with NP-SLE and SLE (940 × 10−6 mm2/s; p = 0.006 and 949 × 10−6 mm2/s; p = 0.019, respectively) was lower than in healthy control participants (1152 × 10−6 mm2/s). Mann-Whitney analysis revealed that the average ADC in the amygdala of patients with anti-NMDAR antibodies (n = 4; 802 × 10−6 mm2/s) was lower (p = 0.029) than the average ADC of patients without anti-NMDAR antibodies (n = 4; 979 × 10−6 mm2/s) and also lower (p = 0.001) than in healthy control participants.
This is the first study to our knowledge to observe damage in the amygdala in patients with SLE. Patients with SLE with anti-NMDAR antibodies had more severe damage in the amygdala compared to SLE patients without anti-NMDAR antibodies.
Patients with SLE who also had antibodies against the NMDA receptor had more severe damage in the amygdala as compared with patients with SLE without these antibodies.
Editors' Summary
The human body is continually attacked by viruses, bacteria, fungi, and parasites, but the immune system usually prevents these pathogens from causing disease. To be effective, the immune system has to respond rapidly to foreign antigens (bits of proteins that are unique to the pathogen) but ignore self-antigens. In autoimmune diseases, this ability to discriminate between self and nonself fails for unknown reasons, and the immune system begins to destroy human tissues. In the chronic autoimmune disease systemic lupus erythematosus (SLE or lupus), the immune system attacks the skin, joints, nervous system, and many other organs. Patients with SLE make numerous “autoantibodies” (antibodies are molecules made by the immune system that recognize and attack antigens; autoantibodies attack self-antigens). These autoantibodies start the attack on the body; then other parts of the immune system join in, causing inflammation and forming deposits of immune cells, both of which damage tissues. Common symptoms of SLE include skin rashes and arthritis, but some patients develop NP-SLE, a form of SLE that includes neuropsychiatric symptoms such as amnesia, dementia, mood disorders, strokes, and seizures. There is no cure for SLE, but mild cases are controlled with ibuprofen and other non-steroidal anti-inflammatory drugs; severe cases are kept in check with corticosteroids and other powerful immunosuppressants.
Why Was This Study Done?
In most of the tissues affected by SLE, the damage done by autoantibodies and immune cells can be seen when the tissues are examined with a microscope. But there is little microscopic damage visible in the brains of patients with NP-SLE. More generally, it is unclear how or even whether the immune system affects mental functions and emotion. In this study, researchers used magnetic resonance imaging (MRI) to investigate whether there are any structural changes in the brains of patients with NP-SLE that could explain their neuropsychiatric symptoms. They have also examined whether any changes in the brain can be linked to the presence of autoantibodies that recognize a protein called the NMDA receptor (anti-NMDAR antibodies) that is present on brain cells.
What Did the Researchers Do and Find?
The researchers used an MRI technique called diffusion weighted imaging to examine the brains of several patients with NP-SLE or SLE and the brains of several healthy individuals. Using this technique, it is possible to quantify the amount of structural damage in different regions of the brain. The researchers found no differences in most areas of the brain between the two groups of patients and the healthy controls. However, there were clear signs of damage in the amygdala (the part of the brain that regulates emotions and triggers responses to danger) in the patients with SLE or NP-SLE when compared to the control individuals. The researchers also found that the damage was more severe in the patients who had anti-NMDAR autoantibodies than in those that did not have these autoantibodies.
What Do These Findings Mean?
These findings suggest that autoantibodies produced by patients with SLE specifically damage the amygdala, a discovery that helps to explain some of the neuropsychiatric symptoms of this condition. Previous work has shown that the treatment of mice with anti-NMDAR antibodies and epinephrine, a stress hormone that causes leaks in the blood-brain barrier (antibodies can't usually get into the brain because of this barrier), results in damage to the amygdala and a deficient response to dangerous stimuli. The researchers suggest that a similar series of events might happen in SLE—patients often mention that a period of major stress precedes the development of symptoms. To provide stronger evidence for such a scenario, a detailed study of how stress relates to neuropsychiatric symptoms is needed. The damage to the amygdala (and the lack of damage elsewhere in the brain) and the possible association between brain damage and anti-NMDAR antibodies seen in this small study also need to be confirmed in more patients. Nevertheless, these findings provide an intriguing glimpse into the interplay between the immune system and the brain and into how stress might lead to physical damage in the brain.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia pages on autoimmunity and on systemic lupus erythematosus
US National Institute of Arthritis and Musculoskeletal and Skin Diseases booklet for patients with SLE
American College of Rheumatology information for patients on SLE
NHS Direct Online Health Encyclopedia pages on SLE
The Lupus Foundation of America information and support for patients with SLE
PMCID: PMC1702559  PMID: 17177602
2.  Association of cerebrospinal fluid anti-ribosomal P protein antibodies with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus 
We explored the relationship of antibodies to the whole ribosomal P proteins (P0, P1, and P2) in cerebrospinal fluid (CSF) with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus (SLE). CSF samples were obtained from 71 SLE patients (52 patients with diffuse psychiatric/neuropsychological syndromes [diffuse NP-SLE] and 19 patients with neurological syndromes or peripheral neuropathy [focal NP-SLE]) as well as from 24 patients with non-inflammatory neurological disease. Immunoglobulin G (IgG) antibodies to the C-terminal 22-amino acid ribosomal P synthetic peptide (anti-PC22) and those to purified bovine ribosomal P proteins (P0, P1, and P2) (anti-whole P) were determined by enzyme-linked immunosorbent assay; affinity-purified IgG anti-PC22 were used as the standard. The concentrations of antibodies to epitopes other than the C-terminal 22 amino acids of ribosomal P proteins were calculated by subtracting anti-PC22 from anti-whole P (anti-PEX.C22). CSF anti-whole P levels were significantly elevated in diffuse NP-SLE compared with focal NP-SLE or control patients. By contrast, there were no significant differences in CSF anti-PC22 levels among the three groups. Of note, CSF anti-PEX.C22 levels were significantly elevated in diffuse NP-SLE compared with the other two groups. CSF anti-PEX.C22 levels were not significantly correlated with CSF anti-PC22 levels, but with CSF antibodies against the recombinant ribosomal P0 protein lacking the C-terminal 22 amino acids (C22-depleted rP0). Moreover, levels of CSF anti-PEX.C22 or CSF anti-C22-depleted rP0, but not CSF anti-PC22, were significantly correlated with CSF anti-neuronal cell antibodies (anti-N). These results indicate that CSF IgG antibodies to the epitopes other than the C-terminal 22 amino acids of ribosomal P proteins, which might contain one of the major targets of CSF anti-N, are associated with the development of diffuse NP-SLE.
PMCID: PMC2206358  PMID: 17472755
3.  Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti–dsDNA Autoantibody Production 
PLoS Genetics  2011;7(3):e1001323.
Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti–dsDNA autoantibody production, a SLE–related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti–dsDNA autoantibody positive (anti–dsDNA +, n = 811) and anti–dsDNA autoantibody negative (anti–dsDNA –, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti–dsDNA + SLE. Far fewer and weaker associations were observed for anti–dsDNA – SLE. For example, rs7574865 in STAT4 had an OR for anti–dsDNA + SLE of 1.77 (95% CI 1.57–1.99, p = 2.0E-20) compared to an OR for anti–dsDNA – SLE of 1.26 (95% CI 1.12–1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti–dsDNA + SLE and were not associated with anti–dsDNA – SLE. In conclusion, we identified differential genetic associations with SLE based on anti–dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti–dsDNA – SLE.
Author Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can involve virtually any organ system. SLE patients produce antibodies that bind to their own cells and proteins (autoantibodies) which can cause irreversible organ damage. One particular SLE–related autoantibody directed at double-stranded DNA (anti–dsDNA) is associated with kidney involvement and more severe disease. Previous genome-wide association studies (GWAS) in SLE have studied SLE itself, not particular SLE manifestations. Therefore, we conducted this GWAS of anti–dsDNA autoantibody production to identify genetic associations with this clinically important autoantibody. We found that many previously identified SLE–associated genes are more strongly associated with anti–dsDNA autoantibody production than SLE itself, and they may be more accurately described as autoantibody propensity genes. No strong genetic associations were observed for SLE patients who do not produce anti–dsDNA autoantibodies, suggesting that other factors may have more influence in developing this type of SLE. Further investigation of these autoantibody propensity genes may lead to greater insight into the causes of autoantibody production and organ damage in SLE.
PMCID: PMC3048371  PMID: 21408207
4.  Elevated Serum Levels of Interferon-Regulated Chemokines Are Biomarkers for Active Human Systemic Lupus Erythematosus 
PLoS Medicine  2006;3(12):e491.
Systemic lupus erythematosus (SLE) is a serious systemic autoimmune disorder that affects multiple organ systems and is characterized by unpredictable flares of disease. Recent evidence indicates a role for type I interferon (IFN) in SLE pathogenesis; however, the downstream effects of IFN pathway activation are not well understood. Here we test the hypothesis that type I IFN-regulated proteins are present in the serum of SLE patients and correlate with disease activity.
Methods and Findings
We performed a comprehensive survey of the serologic proteome in human SLE and identified dysregulated levels of 30 cytokines, chemokines, growth factors, and soluble receptors. Particularly striking was the highly coordinated up-regulation of 12 inflammatory and/or homeostatic chemokines, molecules that direct the movement of leukocytes in the body. Most of the identified chemokines were inducible by type I IFN, and their levels correlated strongly with clinical and laboratory measures of disease activity.
These data suggest that severely disrupted chemokine gradients may contribute to the systemic autoimmunity observed in human SLE. Furthermore, the levels of serum chemokines may serve as convenient biomarkers for disease activity in lupus.
A comprehensive survey of the serologic proteome in human SLE suggests that severely disrupted chemokine gradients may contribute to the systemic autoimmunity observed.
Editors' Summary
The term “lupus,” meaning wolf in Latin, is often used as an abbreviation for the disease systemic lupus erythematosus (SLE). The name may have been given because some people with SLE have a rash that slightly resembles a wolf's face. The condition affects around 50 to 100 people per 100,000, and is much more common in women than men. SLE is a complicated disease that comes about when antibodies inappropriately attack the body's own connective tissues, although it is not known why this happens. Symptoms vary between different people; the disease may get better and then worse, without explanation; and can affect many different organs including the skin, joints, kidneys, blood cells, and brain and nervous system. SLE is difficult for doctors to diagnose. Although the disease cannot be cured, patients who are diagnosed with SLE can be treated for their symptoms, and the right management can slow progress of the disease. One area of SLE research focuses on finding “molecular markers” (e.g., proteins or other compounds) that could be tested for in the blood. Researchers hope this would help doctors to more accurately diagnose SLE initially, and then also help to track progress in a patient's condition.
Why Was This Study Done?
“Gene expression” is a term meaning the process by which a gene's DNA sequence is converted into the structures and functions of a cell. These investigators had found in previous studies that certain genes were more “highly expressed” in the blood cells of patients with SLE. Some of these genes were already known to be regulated by interferons (a group of proteins, produced by certain blood cells, that are important in helping to defend against viral infections). The investigators performing this study wanted to understand more clearly the role of interferon in SLE and to see whether the genes that are more highly expressed in patients with SLE go on to produce higher levels of protein, which might then provide useful markers for monitoring the condition.
What Did the Researchers Do and Find?
This research project was a “case-control” study, in which the researchers compared the levels of certain proteins in the blood of people who had SLE with the levels in people who did not have the condition. Thirty people were recruited as cases, from a group of patients with SLE who have been under evaluation at Johns Hopkins School of Medicine since 1987. Fifteen controls were recruited from a group of healthy people of similar age and sex as the patients with SLE; everyone involved in the study gave their consent to take part. Blood samples were taken from each individual, and the serum (liquid component of blood) was separated out. The serum levels of 160 different blood proteins were then measured. When comparing levels of blood proteins between the groups, the researchers found that 30 specific proteins were present at higher or lower levels in the SLE-affected patients. Many of these proteins are cytokines, which are regulated by interferons and are involved in the process of “signaling” within the immune system. A few proteins were found at lower levels. Levels of the interferon-regulated proteins were, on average, seen at higher levels in people whose condition was more severe.
What Do These Findings Mean?
These results suggest that patients with SLE are likely to have a very different pattern of regulation of certain proteins within the blood, particularly the proteins involved in signaling within the immune system. The authors propose that these proteins may be involved in the progression of the disease. There is also the possibility that some of these proteins may prove useful in diagnostic tests, or in tests for monitoring how the disease progresses. However, before any such tests could be used in clinical practice, they would need to be further developed and then thoroughly tested in clinical trials.
Additional Information.
Please access these Web sites via the online version of this summary at
Patient information from the UK National Health Service on systemic lupus erythematosus
Patient handout from the US National Institutes of Health
MedlinePLUS encyclopedia entry on lupus
Information on lupus from the UK Arthritis Research Campaign
PMCID: PMC1702557  PMID: 17177599
5.  Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden 
Autoantibodies have a central role in systemic lupus erythematosus (SLE). The presence of autoantibodies preceding disease onset by years has been reported both in patients with SLE and in those with rheumatoid arthritis, suggesting a gradual development of these diseases. Therefore, we sought to identify autoantibodies in a northern European population predating the onset of symptoms of SLE and their relationship to presenting symptoms.
The register of patients fulfilling the American College of Rheumatology criteria for SLE and with a given date of the onset of symptoms was coanalysed with the register of the Medical Biobank, Umeå, Sweden. Thirty-eight patients were identified as having donated blood samples prior to symptom onset. A nested case-control study (1:4) was performed with 152 age- and sex-matched controls identified from within the Medical Biobank register (Umeå, Sweden). Antibodies against anti-Sjögren's syndrome antigen A (Ro/SSA; 52 and 60 kDa), anti-Sjögren's syndrome antigen B, anti-Smith antibody, ribonucleoprotein, scleroderma, anti-histidyl-tRNA synthetase antibody, double-stranded DNA (dsDNA), centromere protein B and histones were analysed using the AtheNA Multi-Lyte ANA II Plus Test System on a Bio-Plex Array Reader (Luminex200). Antinuclear antibodies test II (ANA II) results were analysed using indirect immunofluorescence on human epidermal 2 cells at a sample dilution of 1:100.
Autoantibodies against nuclear antigens were detected a mean (±SD) of 5.6 ± 4.7 years before the onset of symptoms and 8.7 ± 5.6 years before diagnosis in 63% of the individuals who subsequently developed SLE. The sensitivity (45.7%) was highest for ANA II, with a specificity of 95%, followed by anti-dsDNA and anti-Ro/SSA antibodies, both with sensitivities of 20.0% at specificities of 98.7% and 97.4%, respectively. The odds ratios (ORs) for predicting disease were 18.13 for anti-dsDNA (95% confidence interval (95% CI), 3.58 to 91.84) and 11.5 (95% CI, 4.54 to 28.87) for ANA. Anti-Ro/SSA antibodies appeared first at a mean of 6.6 ± 2.5 years prior to symptom onset. The mean number of autoantibodies in prediseased individuals was 1.4, and after disease onset it was 3.1 (P < 0.0005). The time predating disease was shorter and the number of autoantibodies was greater in those individuals with serositis as a presenting symptom in comparison to those with arthritis and skin manifestations as the presenting symptoms.
Autoantibodies against nuclear antigens were detected in individuals who developed SLE several years before the onset of symptoms and diagnosis. The most sensitive autoantibodies were ANA, Ro/SSA and dsDNA, with the highest predictive OR being for anti-dsDNA antibodies. The first autoantibodies detected were anti-Ro/SSA.
PMCID: PMC3241374  PMID: 21342502
6.  The clinical relevance of antibodies to ribosomal-P common epitope in two targeted systemic lupus erythematosus populations: a large cohort of consecutive patients and patients with active central nervous system disease 
Annals of the Rheumatic Diseases  2000;59(2):99-104.
OBJECTIVES—To develop an enzyme linked immunosorbent assay (ELISA) using as substrate a synthetic 22-aminoacid peptide, corresponding to the ribosomal P0, P1 and P2 common epitope. To study the specificity and sensitivity of the method and evaluate the frequency and clinical associations of anti-P antibodies in two groups of systemic lupus erythematosus (SLE) patients: (a) unselected SLE patients and (b) SLE patients with central nervous system (CNS) involvement.
PATIENTS AND METHODS—The C-terminal 22 aminoacid peptide of the ribosomal P proteins (Lys-Lys-Glu-Glu-Lys-Lys-Glu-Glu-Lys-Ser-Glu-Glu-Glu-Asp-Glu-Asp-Met-Gly-Phe-Gly-Leu-Phe-Asp) was synthesised according to Merrifield's solid phase procedure. Purification of the peptide was performed by preparative high performance liquid chromatography and confirmed by amino acid analysis. Using this peptide, in a concentration 5 µg/ml, an ELISA was developed. The presence of anti-P antibodies was evaluated by western blot using purified ribosomal proteins from rat liver. Sera from 178 consecutive patients with SLE and 28 patients with SLE and CNS manifestations were tested. Sera from 58 patients with rheumatoid arthritis and 57 patients with primary Sjögren's syndrome were used as controls. The cut off point of the assay was defined using 124 normal sera.
RESULTS—The specificity of the assay was evaluated by homologous inhibition. Pretreatment of positive sera with soluble 22mer peptide of the ribosomal P proteins resulted in 88% inhibition. The concordance between the peptide assay and western blot was found to be 83%. Thirty three of 178 (18.6%) of the unselected SLE patients had antibodies to P-protein common epitope. Their presence was associated with more active disease (European Consensus Lupus Activity Measurement, ECLAM scoring system) (p<0.001), higher levels of anti-ds DNA antibodies (p<0.05) and lower levels of the C4 component of complement (p<0.01). Eleven of 28 (39.3%) patients with SLE and active CNS involvement had antibodies to P-protein. The overall prevalence of anti-P antibodies in active CNS disease patients was statistically significantly higher, as compared with unselected SLE patients (χ2=6.04, p<0.05). These antibodies were found in a high proportion of patients without anticardiolipin antibodies (52.4%) and they were associated with diffuse CNS involvement (psychiatric disorders (71%) and epilepsy (75%)).
 CONCLUSIONS—A synthetic analogue of the common epitope of ribosomal P-proteins can be use as an antigen for the detection of anti-P antibodies. These antibodies are associated with active SLE and CNS involvement particularly in patients without anticardiolipin antibodies.

PMCID: PMC1753066  PMID: 10666163
7.  60 kD Ro and nRNP A Frequently Initiate Human Lupus Autoimmunity 
PLoS ONE  2010;5(3):e9599.
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.
PMCID: PMC2835743  PMID: 20224770
8.  Anti-ribosomal P protein IgG autoantibodies in patients with systemic lupus erythematosus: diagnostic performance and clinical profile 
BMC Medicine  2013;11:98.
This study was devised to assess the performance of anti-ribosomal P (anti-Rib-P) antibodies in the diagnosis of systemic lupus erythematosus (SLE) and the association of these antibodies with the clinical features of SLE.
We used a fluorescence enzyme immunoassay to determine anti-Rib-P levels in an SLE group, a rheumatic disease control (RDC) group (rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis), and a healthy control (HC) group. We also determined anti-Smith antigen (anti-Sm) and anti-double-stranded DNA (anti-dsDNA) antibody levels. Receiver operating characteristic (ROC) curves were constructed and the best cut-off points for positivity were determined. Using regression analysis, the relationship between clinical variables and autoantibody levels was analyzed.
In total, 127 patients with SLE, 256 controls with other rheumatic diseases, and 100 HCs were studied. Anti-Rib-P autoantibodies were positive in 18 (14.2%) of the patients with SLE (mean concentration of 30.6 ± 46.9 U/ml) and in 2 patients with RA (0.8% of the RDC group). In addition, 12 patients with SLE (9.4%) were positive for anti-Sm (31.1 ± 40.8 U/ml) and 63 (49.6%) were positive for anti-dsDNA autoantibodies (88.4 ± 88.5 U/ml). When we assessed the 18 patients with SLE who had tested positive for anti-Rib-P, we found that 4 of these were positive for anti-Rib-P only, whereas 12 were positive for anti-Rib-P plus anti-dsDNA, and 2 were positive for all three antibodies. There were no samples positive for anti-Rib-P plus anti-Sm. The specificity, sensitivity, positive likelihood ratio, and negative likelihood ratio of anti-Rib-P for SLE diagnosis were 99.4%, 14.2%, 23.7%, and 0.86%, respectively.
Caucasian ethnicity was associated with lower anti-Rib-P antibody levels. No relation was found between anti-Rib-P levels and neuropsychiatric or other clinical features.
Anti-Rib-P autoantibodies have high specificity for SLE, and measurement of these might improve the accuracy of SLE diagnosis. In this study, we found that Caucasian ethnicity was associated with lower anti-Rib-P antibody levels.
PMCID: PMC3616863  PMID: 23557114
Anti-Rib-P; Systemic lupus erythematosus; Antibodies
9.  IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2011;71(3):463-468.
High serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease.
1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African–American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay.
In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR > 2.56, p >003C; 1.9×10−14 for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained > 70% of the genetic risk of SLE due to IRF5. In African–American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African–American subjects and absent in African patients with SLE.
The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements.
SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population.1 These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness2 and are likely pathogenic in SLE.34
PMCID: PMC3307526  PMID: 22088620
10.  Serum and Cerebrospinal Fluid Autoantibodies in Patients with Neuropsychiatric Lupus Erythematosus. Implications for Diagnosis and Pathogenesis 
PLoS ONE  2008;3(10):e3347.
Despite the uncertainty in the diagnosis of neuropsychiatric involvement in systemic lupus erythematosus (SLE), attempts have been made to record the association of certain antibodies in serum with neuropsychiatric (NP) manifestations. We aimed to assess the behaviour and the association of serum and cerebrospinal fluid (CSF) autoantibodies with NP manifestations in SLE patients (NPSLE).
Methodology/Principal Findings
Forty-seven SLE patients, hospitalized because of NP manifestations were included. They were evaluated at hospitalization and six months later, and serum and CSF samples were obtained at each evaluation. As controls, serum samples were taken from 49 non-NPSLE patients at hospitalization and six months later; serum and CSF samples were also obtained from 6 SLE patients with septic meningitis, 16 surgical SLE patients and 25 patients without autoimmune diseases. Antinuclear, anti-dsDNA, anti-ribosomal P, Anti-N-Methyl-D-Aspartate receptor (NMDAR), anti-cardiolipin, and anti-β2 glycoprotein-I antibodies were measured. In serum, anti-ribosomal P, anti-NMDAR, and other antibodies did not differentiate among SLE groups, and the levels of all antibodies were similar among the SLE groups. Six-months later, this scenario remained unchanged and the decrease in the levels of some autoantibodies reflected a decline in disease activity, rather than a change in NPSLE. In CSF, only the presence and the levels of anti-NMDAR antibodies showed a characteristic distribution in central NPSLE and septic meningitis patients. Six months later the prevalence of most antibodies in CSF did not change, however the levels of anti-dsDNA, anti-ribosomal P, and anti-NMDAR decreased.
In NPSLE, autoantibodies in serum do not reflect their behaviour in CSF. All autoantibodies were elevated in septic meningitis reflecting the global penetration of serum antibodies into the CSF in this condition. Anti-NMDAR antibodies in CSF identified patients with central NPSLE; their continued presence in CSF 6 months after neurologic symptoms raise questions regarding the conditions under which they are pathogenic.
PMCID: PMC2556096  PMID: 18836530
11.  Anti-ribosomal P protein antibodies detected by immunoblotting in patients with connective tissue diseases: their specificity for SLE and association with IgG anticardiolipin antibodies 
Annals of the Rheumatic Diseases  2000;59(12):975-981.
OBJECTIVE—To assess the prevalence and clinical and serological associations of anti-ribosomal P protein antibodies (anti-P antibodies) in patients with connective tissue diseases (CTDs) and investigate the immunobiological nature of autoantibody clustering in which anti-P antibodies play a part.
METHODS—IgG anti-P antibodies in the sera of 267 patients with CTDs and 31 healthy subjects were analysed by immunoblotting performed on cytoplasmic extract of Raji cells. 60 patients with systemic lupus erythematosus (SLE), 32 systemic sclerosis, 46 primary Sjögren's syndrome, 16 poly/dermatomyositis, 11 rheumatoid arthritis, 8 undifferentiated CTD, 72 overlap CTD, and 22 primary antiphospholipid syndrome were studied. Anti-P antibodies were affinity purified by elution from nitrocellulose bound antigen and tested by ELISA for their binding activity to cardiolipin.
RESULTS—Anti-P antibodies were detected in 16 (6%) patients and in none of the controls: 12/60 SLE (20%) and 4/80 undifferentiated/overlap patients with CTD (5%). A close association of IgG antibodies with P proteins and with cardiolipin was seen in lupus sera (p=0.0009, odds ratio 18.33). Anti-P antibodies from 9 of 12 anti-P lupus serum samples could be affinity purified and none of the affinity purified fractions cross reacted with ELISA plate coated cardiolipin.
CONCLUSIONS—Anti-P immunoreactivity is a specific marker of SLE and lupus-like disease and its detection is recommended as a powerful diagnostic tool. Anti-P antibodies are strongly clustered with IgG anticardiolipin antibodies in lupus sera, even if they are independently elicited. This suggests that their cognate autoantigens play a part in a common pathogenetic pathway in SLE.

PMCID: PMC1753043  PMID: 11087701
12.  Diagnostic value and clinical laboratory associations of antibodies against recombinant ribosomal P0, P1 and P2 proteins and their native heterocomplex in a Caucasian cohort with systemic lupus erythematosus 
In this study, we sought to determine the diagnostic value and clinical laboratory associations of autoantibodies against recombinant ribosomal P0, P1 and P2 proteins and their native heterocomplex in systemic lupus erythematosus (SLE).
Autoantibodies against recombinant ribosomal P proteins (aRibPR0, aRibPR1 and aRibPR2) and antibodies against native ribosomal P heterocomplex (aRibPNH) were determined in sera from patients with SLE (n = 163), systemic sclerosis (n = 66), Sjögren's syndrome (n = 54), rheumatoid arthritis (n = 90) and healthy donors (n = 100) using enzyme-linked immunosorbent assay. Test results were correlated to medical records, including the American College of Rheumatology criteria, the Systemic Lupus Erythematosus Disease Activity Index 2000, laboratory data and medications of all SLE patients.
Sensitivities of 22.0% for aRibPR0, 14.9% for aRibPR2, 14.3% for aRibPNH and 10.7% for aRibPR1 were obtained at a specificity of 99%. The assay for aRibPR0 detection demonstrated the best performance in receiver-operating characteristics analysis, with aRibPR0 detectable in 10% of anti-Smith antibody and anti-double-stranded DNA-negative sera at a specificity of 100%. ARibPR0 positivity was associated with lymphocytopenia. ARibPR1+ patients had significantly higher γ-glutamyl transpeptidase (GGT) levels than their aRibPR1- counterparts. No specific damage occurred in aRibP+ lupus patients compared with a group of age-, sex- and nephritis-matched aRibP- lupus patients within 3 years.
The determination of antibodies against ribosomal P proteins improves the diagnosis of SLE and should therefore be implemented in upcoming criteria for the diagnosis or classification of SLE. High titers of aRibPR0 can be associated with lymphocytopenia, and high titers of aRibPR1 can be associated with elevated GGT levels. So far, there is no evidence for a prognostic value of aRibPs for damage.
PMCID: PMC3241364  PMID: 21310064
13.  Genetic contributions to the autoantibody profile in a rabbit model of systemic lupus erythematosus (SLE) 
For the development of rabbit models of Systemic Lupus Erythematosus (SLE), immunoglobulin allotype-defined pedigreed rabbits from the National Institute of Allergy and Infectious Diseases rabbit resource more closely approximate human populations due to their non-inbred pedigreed structure. In an initial study from this laboratory, peptides (SM and GR) from the spliceosomal Smith (Sm) and the NMDA glutamate receptor NR2b, on branched polylysine backbones (BB) elicited antinuclear and anti-dsDNA autoantibodies typical of SLE, as well as seizures and nystagmus sometimes observed as neurological manifestations in SLE patients. This suggested the feasibility of further selective breeding to develop a more reproducible rabbit model for investigations of SLE. Here we report the results of GR-MAP-8 and control BB immunization on autoantibody responses in a group of 24 rabbits specifically bred and developed from parents and ancestors tested for autoantibody responses. The changes in hematological profile and blood chemistry in the experimental rabbits were evaluated along with autoantibody responses. Elevations of total white blood cell (WBC), monocyte, eosinophil and basophil counts that developed following immunizations were moderately influenced by litter and presence of the antibody heavy chain allotype VH1a1. Autoantibody development followed a sequential pattern with anti-nuclear antibodies (ANA) followed by anti-dsDNA and subsequently anti-Sm and anti-RNP similar to SLE patients. High autoantibody levels to one autoantigen were not always associated with antibody response to another. Female rabbits had higher prevalence and levels of autoantibodies similar to human SLE. Higher autoantibody levels of anti-dsDNA and -ANA were observed among some full sibs and the presence of high responder ancestors in the pedigree was associated the augmented responses. We observed significant association between highest antibody responses to GR-MAP-8 and highest anti-dsDNA levels. Naturally occurring autoantibodies were found in some pre-immune sera and some unique ANA fluorescent staining patterns within the experimental group were observed. Background immunofluorescence in pre-immune sera, distinct patterns of programmed autoantibody responses unique among individual rabbits may have been modulated by genetic constitution, gender and environmental factors including exposure to antigens. The high incidence and intensity of autoantibody responses among descendants of high responders suggest that there may be an additive mode of inheritance with high heritability. It is conceivable that further rigorous pedigree selection for autoantibody responses could lead to development of rabbit models with spontaneous occurrence of SLE like serology and disease phenotypes.
PMCID: PMC2561998  PMID: 18602165
Rabbits; Autoantibodies; Antibody heavy chain allotypes; Genetics; Lupus
14.  Serology of Lupus Erythematosus: Correlation between Immunopathological Features and Clinical Aspects 
Autoimmune Diseases  2014;2014:321359.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the aberrant production of a broad and heterogenous group of autoantibodies. Even though the presence of autoantibodies in SLE has been known, for more than 60 years, still nowadays a great effort is being made to understand the pathogenetic, diagnostic, and prognostic meaning of such autoantibodies. Antibodies to ds-DNA are useful for the diagnosis of SLE, to monitor the disease activity, and correlate with renal and central nervous involvements. Anti-Sm antibodies are highly specific for SLE. Anti-nucleosome antibodies are an excellent marker for SLE and good predictors of flares in quiescent lupus. Anti-histone antibodies characterize drug-induced lupus, while anti-SSA/Ro and anti-SSB/La antibodies are associated with neonatal lupus erythematosus and photosensitivity. Anti-ribosomal P antibodies play a role in neuropsychiatric lupus, but their association with clinical manifestations is still unclear. Anti-phospholipid antibodies are associated with the anti-phospholipid syndrome, cerebral vascular disease, and neuropsychiatric lupus. Anti-C1q antibodies amplify glomerular injury, and the elevation of their titers may predict renal flares. Anti-RNP antibodies are a marker of Sharp's syndrome but can be found in SLE as well. Anti-PCNA antibodies are present in 5–10% of SLE patients especially those with arthritis and hypocomplementemia.
PMCID: PMC3932647  PMID: 24649358
15.  Autoantibodies against the replication protein A complex in systemic lupus erythematosus and other autoimmune diseases 
Replication protein A (RPA), a heterotrimer with subunits of molecular masses 70, 32, and 14 kDa, is a single-stranded-DNA-binding factor involved in DNA replication, repair, and recombination. There have been only three reported cases of anti-RPA in systemic lupus erythematosus (SLE) and Sjögren syndrome (SjS). This study sought to clarify the clinical significance of autoantibodies against RPA. Sera from 1,119 patients enrolled during the period 2000 to 2005 were screened by immunoprecipitation (IP) of 35S-labeled K562 cell extract. Antigen-capture ELISA with anti-RPA32 mAb, immunofluorescent antinuclear antibodies (ANA) and western blot analysis with purified RPA were also performed. Our results show that nine sera immunoprecipitated the RPA70–RPA32–RPA14 complex and all were strongly positive by ELISA (titers 1:62,500 to 1:312,500). No additional sera were positive by ELISA and subsequently confirmed by IP or western blotting. All sera showed fine speckled/homogeneous nuclear staining. Anti-RPA was found in 1.4% (4/276) of SLE and 2.5% (1/40) of SjS sera, but not in rheumatoid arthritis (0/35), systemic sclerosis (0/47), or polymyositis/dermatomyositis (0/43). Eight of nine patients were female and there was no racial predilection. Other positive patients had interstitial lung disease, autoimmune thyroiditis/hepatitis C virus/pernicious anemia, or an unknown diagnosis. Autoantibody specificities found in up to 40% of SLE and other diseases, such as anti-nRNP, anti-Sm, anti-Ro, and anti-La, were unusual in anti-RPA-positive sera. Only one of nine had anti-Ro, and zero of nine had anti-nRNP, anti-Sm, anti-La, or anti-ribosomal P antibodies. In summary, high titers of anti-RPA antibodies were found in nine patients (1.4% of SLE and other diseases). Other autoantibodies found in SLE were rare in this subset, suggesting that patients with anti-RPA may form a unique clinical and immunological subset.
PMCID: PMC1779422  PMID: 16846524
16.  T cell reactivity against the SmD183–119 C terminal peptide in patients with systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2002;61(9):779-785.
Background: The SmD183–119 peptide is a major target of the B cell response in patients with systemic lupus erythematosus (SLE).
Objective: To investigate the T cell response directed against this peptide, its disease specificity, and possible impact on SLE pathogenesis.
Methods: Peripheral blood mononuclear cells derived from 28 patients with SLE and 29 healthy and disease controls were stimulated by the SmD183–119 and the recombinant (r)SmD1 protein, and [3H]thymidine incorporation was measured. Patients with SLE were simultaneously tested for autoantibodies, disease activity, clinical symptoms, and medical treatments.
Results: T cell reactivity against the SmD183–119 peptide was detected in 11/28 (39%) patients with SLE and against the rSmD1 protein in 10/28 (36%) patients. In contrast, only 2/29 (7%) controls exhibited SmD1 reactivity. An analysis of proliferation kinetics showed that SmD1 reactive T cells are activated in vivo, as additionally confirmed by cytometric analysis. Addition of mammalian dsDNA to rSmD1 enhanced the rSmD1-specific T cell response. SmD183–119-specific T cell reactivity was significantly more common in patients with cardiac and pulmonary symptoms. No correlation between T and B cell responses and disease activity was seen.
Conclusion: SmD183–119 is a major T cell epitope of SmD1, commonly recognised by T cells from patients with SLE and much less commonly found by healthy or disease controls. This strong T cell reactivity as well as the high frequency and specificity of anti-SmD183–119 antibodies in SLE suggest a possible role in SLE pathogenesis, at least in a subset of patients.
PMCID: PMC1754211  PMID: 12176801
17.  The Homogeneous Multiplexed System-a New Method for Autoantibody Profile in Systemic Lupus Erythematosus 
Systemic lupus erythematosus (SLE) is a multi-systemic autoimmune disease leading to immunological aberrations and excessive multiple autoantibody production. The aim of this study was to investigate the prevalence of multiple autoantibodies in SLE patients utilizing the multiplex system method.
We analyzed the presence of elevated titers of anti-Ro, anti-La, anti-RNP, anti-Sm, anti-Jo1, anti-centromere, anti-Scl-70, anti-histone, and anti-dsDNA antibodies in 199 serum samples (113 SLE patients, 86 healthy donors). We compared the type, level and number of autoantibodies and the correlation between the autoantibody profile and disease severity utilizing the SLEDAI score.
Elevated titers of at least one autoantibody were detected in 48% of 42 SLE patients. Elevated titers of anti-Ro antibodies were most commonly detected. The distribution of specific autoantibodies was: anti-Ro- 23.8%, anti-dsDNA- 19%, anti-histone- 19%, anti-RNP- 14.2%, anti-La antibodies- 11.9%, anti-Sm- 7.1%, anti-Scl 70-4.7%, and anti-centromere- 2.4%. Utilizing ROC analysis, the sensitivity and specificity of anti-DNA antibodies at a cutoff value of 34 IU/ml were 87.1% and 79.4% respectively. Elevated titers of anti-Jo1 antibody were not detected. There was a correlation with the titer of anti-Ro antibodies and disease activity by the SLEDAI score. Seven patients harbored one autoantibody only, 15 patients harbored 2-3 autoantibodies, 3 patients harbored 4-5 autoantibodies, and one patient harbored 6 autoantibodies. A correlation between the number of autoantibodies per patient and disease severity was found. One patient with a multitude of autoantibodies had severe lupus and a myriad of clinical manifestations.
In conclusion, the multiplex system is specific and sensitive, provides an autoantibody profile in a single test, and may be useful as a diagnostic test for SLE. Elevated anti-Ro antibodies are associated with severe disease. An autoantibody load may be indicative of more severe disease.
PMCID: PMC2270732  PMID: 16050141
18.  Double positive CD4+CD8+ T cells: key suppressive role in the production of autoantibodies in systemic lupus erythematosus 
Background & objectives:
The presence of CD4+CD8+ (double positive) T cells (DPT) in the target organs of several autoimmune diseases has been reported. The aim of this study was to investigate the pathogenic role of DPT in systemic lupus erythematosus (SLE).
A total of 175 SLE cases and 125 matched healthy controls were investigated for CD3+, CD4+, CD8+ lymphocytes and DPT by flow cytometry. Serum samples from SLE patients and controls were tested for antinuclear antibody (ANA), anti-double strain deoxyribonucleic acid (anti-dsDNA), anti-U1 ribonucleoprotein (anti-U1 RNP), anti-sjogren syndrome A (anti-SSA), anti-ribosomal P protein (anti-rib-P), anti-Smith (anti-Sm), anti-Sjogren syndrome B (anti-SSB), complement 3 (C3) and complement 4 (C4).
The DPT median and 5-95 per cent range of SLE cases and healthy controls were 0.50 [0.10-2.60] and 0.80 [0.20-2.74] respectively (P<0.001). SLE patients were divided into a ≥1:1000 subgroup and a <1:1000 subgroup according to the ANA titre. The DPT of the former subgroup was significantly lower than that of the latter (P=0.032). The DPT medians of positive subgroups with anti-dsDNA (P<0.001), anti-U1RNP (P=0.018), anti-SSA (P=0.021) or anti-rib-P (P=0.039) were also significantly lower than the negative subgroups. Likewise, DPT was significantly lower in SLE subgroups with low concentration of C3 or C4 than those with high concentration (P<0.006).
Interpretation & conclusions:
Our findings show that the DPT cells may play a key suppressive role in the production of autoantibodies in SLE. Direct evidence that DPT regulates the pathogenesis of SLE needs to be investigated in future work.
PMCID: PMC4277137  PMID: 25488445
Antinuclear antibody; double positive; pathogenic role; SLE; CD4+CD8+; T cell
19.  Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients 
Annals of the rheumatic diseases  2010;70(1):151-156.
Systemic lupus erythematosus (SLE) is a chronic, multiorgan, autoimmune disease that affects people of all ages and ethnicities.
To explore the relationship between age at disease onset and many of the diverse manifestations of SLE. Additionally, to determine the relationship between age of disease onset and genetic risk in patients with SLE.
The relationship between the age at disease onset and SLE manifestations were explored in a multiracial cohort of 1317 patients. Patients with SLE were genotyped across 19 confirmed genetic susceptibility loci for SLE. Logistic regression was used to determine the relationships between the number of risk alleles present and age of disease onset.
Childhood-onset SLE had higher odds of proteinuria, malar rash, anti-dsDNA antibody, haemolytic anaemia, arthritis and leucopenia (OR=3.03, 2.13, 2.08, 2.50, 1.89, 1.53, respectively; p values <0.0001, 0.0004, 0.0005, 0.0024, 0.0114, 0.045, respectively). In female subjects, the odds of having cellular casts were 2.18 times higher in childhood-onset than in adult-onset SLE (p=0.0027). With age of onset ≥50, the odds of having proteinuria, cellular casts, anti-nRNP antibody, anti-Sm antibody, anti-dsDNA antibody and seizures were reduced. However, late adult-onset patients with SLE have higher odds of developing photosensitivity than early adult-onset patients. Each SLE-susceptibility risk allele carried within the genome of patients with SLE increased the odds of having a childhood-onset disease in a race-specific manner: by an average of 48% in Gullah and 25% in African-Americans, but this was not significant in Hispanic and European-American lupus patients.
The genetic contribution towards predicting early-onset disease in patients with SLE is quantified for the first time. A more severe SLE phenotype is found in patients with early-onset disease in a large multi-racial cohort, independent of gender, race and disease duration.
PMCID: PMC3034281  PMID: 20881011
20.  Activation of the Interferon Pathway is Dependent Upon Autoantibodies in African-American SLE Patients, but Not in European-American SLE Patients 
Background: In systemic lupus erythematosus (SLE), antibodies directed at RNA-binding proteins (anti-RBP) are associated with high serum type I interferon (IFN), which plays an important role in SLE pathogenesis. African-Americans (AA) are more likely to develop SLE, and SLE is also more severe in this population. We hypothesized that peripheral blood gene expression patterns would differ between AA and European-American (EA) SLE patients, and between those with anti-RBP antibodies and those who lack these antibodies.
Methods: Whole blood RNA from 33 female SLE patients and 16 matched female controls from AA and EA ancestral backgrounds was analyzed on Affymetrix Gene 1.0 ST gene expression arrays. Ingenuity Pathway Analysis was used to compare the top differentially expressed canonical pathways amongst the sample groups. An independent cohort of 116 SLE patients was used to replicate findings using quantitative real-time PCR (qPCR).
Results: Both AA and EA patients with positive anti-RBP antibodies showed over-expression of similar IFN-related canonical pathways, such as IFN Signaling (P = 1.3 × 10−7 and 6.3 × 10−11 in AA vs. EA respectively), Antigen Presenting Pathway (P = 1.8 × 10−5 and 2.5 × 10−6), and a number of pattern recognition receptor pathways. In anti-RBP negative (RBP−) patients, EA subjects demonstrated similar IFN-related pathway activation, whereas no IFN-related pathways were detected in RBP−AA patients. qPCR validation confirmed similar results.
Conclusion: Our data show that IFN-induced gene expression is completely dependent on the presence of autoantibodies in AA SLE patients but not in EA patients. This molecular heterogeneity suggests differences in IFN-pathway activation between ancestral backgrounds in SLE. This heterogeneity may be clinically important, as therapeutics targeting this pathway are being developed.
PMCID: PMC3787392  PMID: 24101921
systemic lupus erythematosus; interferon alpha; autoantibodies; ancestral background; interferon gamma
21.  Anti-idiotypic antibodies prevent the serologic detection of antiribosomal P autoantibodies in healthy adults. 
Journal of Clinical Investigation  1998;102(1):215-222.
A subset of SLE patients has serologically detectable autoantibodies to the ribosomal P proteins (anti-P). We reported the discovery of covert anti-P antibodies and their masking IgG-inhibitory antibodies in the sera of healthy adults. The aim of this study was to determine if these IgG-inhibitory antibodies are anti-idiotypic antibodies (anti-Ids). IgG and IgG-depleted fractions of plasma from two healthy adults were assayed for inhibition of anti-P F(ab')2 binding to the ribosomal P proteins in immunoblot. Anti-P antibody activity was completely inhibited by plasma IgG, whereas there was no inhibition by IgG-depleted plasma. IgG-inhibitory antibodies recognized a cross-reactive epitope among anti-P from different SLE patients. Plasma IgG from one healthy adult was depleted of pepsin agglutinators and generic anti-F(ab')2 antibodies by adsorption with an affinity column prepared with normal IgG F(ab')2. Unretained IgG bound exclusively to anti-P F(ab')2 in ELISA. Using four affinity columns, we isolated IgG anti-Ids to anti-P antibodies from four healthy adults. These purified anti-Ids bound to anti-P F(ab')2 from a healthy adult and SLE patients. They did not bind to F(ab')2 fragments prepared from normal IgG or anti-dsDNA. Ribosomal antigens blocked this anti-Id-Id interaction. Purified anti-Ids inhibited the binding of anti-P F(ab')2 from patients to ribosomal P proteins. SLE patients without overt anti-P antibodies also possessed IgG anti-Ids to anti-P antibodies. We conclude that IgG-inhibitory antibodies are anti-Ids to anti-P antibodies, and are directed to public idiotopes on anti-P antibodies. These anti-Ids may be part of an Id network that regulates anti-P antibody expression, and perhaps pathogenicity.
PMCID: PMC509083  PMID: 9649575
22.  Multiple Autoantibodies Display Association with Lymphopenia, Proteinuria, and Cellular Casts in a Large, Ethnically Diverse SLE Patient Cohort 
Autoimmune Diseases  2012;2012:819634.
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.
PMCID: PMC3439936  PMID: 22988489
23.  IgG and IgM autoantibody differences in discoid and systemic lupus patients 
Systemic lupus (SLE) patients with discoid lupus (DLE) were reported to have milder disease. To test this observation, we employed sandwich arrays containing 98 autoantigens to compare autoantibody profiles of SLE subjects without DLE (DLE−SLE+) (N=9), SLE subjects with DLE (DLE+SLE+) (N=10), DLE subjects without SLE (DLE+SLE−) (N=11), and healthy controls (N=11). We validated differentially expressed autoantibodies using immunoassays in DLE−SLE+ (N=18), DLE+SLE+ (N=17), DLE+SLE− (N=23), and healthy subjects (N=22). Arrays showed 15 IgG autoantibodies (ten against nuclear antigens) and four IgM autoantibodies that were differentially expressed (q-value<0.05). DLE−SLE+ subjects had higher IgG autoantibodies against dsDNA, ssDNA, dsRNA, histone H2A and H2B, and SS-A (52 kDa) than all other groups including DLE+SLE+ subjects (p<0.05). Immunoassays measuring anti-dsDNA, -ssDNA, and -SS-A (52 kDa) IgG autoantibodies showed similar trends (p<0.05). Healthy and DLE+SLE−subjects expressed higher IgM autoantibodies against alpha beta crystallin, lipopolysaccharide, heat shock cognate 70, and desmoglein-3 than DLE+SLE+ and DLE−SLE+ subjects. IgG:IgM ratios of autoantibodies against nuclear antigens progressively rose from healthy to DLE−SLE+ subjects. In conclusion, lower IgG autoantibodies against nuclear antigens in DLE+SLE+ versus DLE−SLE+ subjects suggest that DLE indicates lower disease severity. Higher IgM autoantibodies against selected antigens in healthy and DLE+SLE−subjects may be non-pathogenic.
PMCID: PMC3465644  PMID: 22763789
24.  Anti-Ro/SS-A and anti-La/SS-B antibodies associated with cardiac involvement in childhood systemic lupus erythematosus 
Annals of the Rheumatic Diseases  1997;56(4):272-274.
OBJECTIVES—To determine the frequency and type of cardiac manifestations in children with systemic lupus erythematosus (SLE) and investigate whether cardiac involvement of SLE in children was associated with any autoantibody pattern.
METHODS—Retrospective analysis of the medical records of all children with SLE (31 patients) seen between January 1984 and January 1994 by the paediatric rheumatology service at Children's Hospital in New Orleans. All patients satisfied the American College of Rheumatology criteria for the diagnosis of SLE. Paediatric SLE patients with cardiac manifestations based on echocardiogram were identified. Autoantibody tests at diagnosis were identified retrospectively by chart review, and the correlation between autoantibodies and cardiac involvement was analysed using the two tailed Fisher's exact test.
RESULTS—Thirteen (42%) of 31 SLE patients had cardiac manifestations of SLE. Seven (22%) had pericarditis without myocarditis, five (16%) had pericarditis and myocarditis, and one (3%) had myocarditis without pericarditis. Two patients (6%) with pericarditis had cardiac tamponade. Cardiac manifestations of SLE usually occurred at the time of diagnosis or within six months. Anti-Ro/SS-A antibodies were present in serum samples of nine of 11 (82%) patients with cardiac involvement and in five of 15 (33%) without cardiac involvement (p=0.02). Anti-La/SS-B antibodies were present in serum samples of six of 10 (60%) patients with cardiac involvement and two of 15 (13%) without cardiac involvement (p=0.03). Anti-Sm and anti-RNP antibodies showed no correlation with the presence of cardiac disease.
CONCLUSIONS—Cardiac involvement in our paediatric SLE population was frequently found and correlated significantly with the presence of anti-Ro/SS-A and anti-La/SS-B antibodies.

PMCID: PMC1752359  PMID: 9166002
25.  Major Trypanosoma cruzi antigenic determinant in Chagas' heart disease shares homology with the systemic lupus erythematosus ribosomal P protein epitope. 
Journal of Clinical Microbiology  1990;28(6):1219-1224.
A Trypanosoma cruzi lambda gt11 cDNA clone, JL5, expressed a recombinant protein which was found to react predominantly with chronic Chagas' heart disease sera. The cloned 35-residue-long peptide was identified as the carboxyl-terminal portion of a T. cruzi ribosomal P protein. The JL5 13 carboxyl-terminal residues shared a high degree of homology with the systemic lupus erythematosus (SLE) ribosomal P protein epitope. Synthetic peptides comprising the 13 (R-13), 10 (R-10), and 7 (R-7) carboxyl-terminal residues of the JL5 protein were used to study, by enzyme-linked immunosorbent assay, the specificity of the Chagas' disease anti-JL5 and SLE anti-P antibodies. The R-13 peptide defined a linear antigenic determinant of the JL5 recombinant protein. As was proved for JL5, R-13 defined antibody specificities which were significantly increased in chronic Chagas' heart disease patients. Only SLE anti-P positive sera were found to react with JL5 and R-13. Fine epitope mapping showed that Chagas' disease anti-JL5 and SLE anti-P antibodies define similar epitopes within the R-13 peptide. The binding of the SLE sera to JL5 was completely blocked by the R-13 peptide, indicating that the shared specificity between anti-JL5 and anti-P autoantibodies was exclusively limited to the conserved linear epitope(s) within the R-13 peptide. The prevalence of high anti-R-13 antibody titers in Chagas' heart disease patients supports the hypothesis that postulates the existence of autoimmune disorders in Chagas' heart disease.
PMCID: PMC267908  PMID: 1696282

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