Genetic complete deficiency of the early complement components such as C1, C2 and C4 commonly results in a monogenetic form of systemic lupus erythematosus (SLE). However, previous studies have examined groups of complete complement deficient subjects for SLE, while a familial SLE cohort has not been studied for deficiencies of complement. Thus, we undertook the present study to determine the frequency of hereditary complete complement deficiencies among families with two or more SLE patients. All SLE patients from 544 such families had CH50 determined. Medical records were examined for past CH50 values. There were 66 individuals in whom all available CH50 values were zero. All but four of these had an SLE-affected relative with a non-zero CH50; thus, these families did not have monogenic complement deficient related SLE. The four remaining SLE-affected subjects were in fact two sets of siblings in which 3 of the 4 SLE patients had onset of disease at <18 years of age. Both patients in one of these families had been determined to have C4 deficiency, while the other family had no clinical diagnosis of complement deficiency. In this second family, one of the SLE patients had had normal C4 and C3 values, indicating that either C1q or C2 deficiency was possible. Thus, only 2 of 544 SLE families had definite or possible complement deficiency; however, 1 of 7 families in which all SLE patients had pediatric onset and 2 of 85 families with at least 1 pediatric-onset SLE patent had complete complement deficiency. SLE is found commonly among families with hereditary complement deficiency but the reverse is not true. Complete complement deficiency is rare among families with two or more SLE patients, but is concentrated among families with onset of SLE prior to age 18.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that predominantly affects women. Despite Klinefelter's syndrome (47,XXY) and SLE coexisting in isolated cases, no association has been established with SLE or any other autoimmune disease. Methods: Sex chromosome genotyping was performed in 981 SLE patients (213 were men). A first group of 843 SLE patients from 378 multiplex families and a second group of 138 men with non-familial SLE were evaluated. Fluorescent in situ hybridization (FISH) and karyotyping in transformed B cell lines enumerated chromosomes for selected cases.
Of 213 men with SLE, five had Klinefelter's syndrome (or 1 in 43). Four of them were heterozygous at X markers. FISH and karyotyping confirmed Klinefelter’s syndrome in the fifth. An overall rate of 235 47,XXY per 10,000 male SLE patients (95%CI: 77 to 539) was found, a dramatic increase over the known prevalence of Klinefelter's syndrome in an unselected population (17 per 10,000 live male births). Asking men with SLE about fertility was highly sensitive (100%) for Klinefelter’s syndrome. All 768 SLE women were heterozygous at X.
47,XXY Klinefelter's syndrome, often subclinical, is increased in men with SLE by ~14-fold, compared to its prevalence in men without SLE. Diagnostic vigilance for 47,XXY males in SLE is warranted. These data are the first to associate Klinefelter's syndrome with an autoimmune disease found predominantly in women. The risk of SLE in Klinefelter's syndrome is predicted to be similar to the risk in normal 46,XX women and ~14-fold higher than in 46,XY men, consistent with SLE susceptibility being partly explained by a X chromosome gene dose effect.
Autoimmune thyroid disease is common in systemic lupus erythematosus (SLE). About 20% of patients with SLE have secondary Sjögren's syndrome.
Families with more than one patient with SLE were identified. All patients met the revised classification criteria, although SLE‐unaffected relatives were confirmed not to satisfy these criteria. Diagnosis of autoimmune thyroid disease and Sjögren's syndrome was made on the basis of a review of medical records, interview and questionnaire administered to patients with SLE, and by a questionnaire administered to SLE‐unaffected subjects.
Of a total of 1138 patients with SLE, 169 had a diagnosis of Sjögren's syndrome. Of these 50 (29.6%) patients also had autoimmune thyroid disease. Of the 939 patients with SLE with no diagnosis of Sjögren's syndrome, 119 (12.7%) had autoimmune thyroid disease (χ2 = 20.1, p = 0.000009). There was no association of a diagnosis of hypertension with secondary Sjögren's syndrome (42% vss 47%). Among 2291 SLE‐unaffected relatives, 44 had diagnosed primary Sjögren's syndrome and 16 (36.3%) of these also had autoimmune thyroid disease. 265 of 2247 (11.8%) subjects had autoimmune thyroid disease but no Sjögren's syndrome (χ2 = 24.2, p<0.001).
Autoimmune thyroid disease is found in excess among patients with SLE with a diagnosis of secondary Sjögren's syndrome, as well as among their SLE‐unaffected relatives with a diagnosis of primary Sjögren's syndrome.
MRL/1 and BXSB male mice have a systemic lupus erythematosus (SLE)-like disease similar to but more acute than that occurring in NZB X W mice. The common elements of lymphoid hyperplasia, B-cell hyperactivity, autoantibodies, circulating immune complex (IC), complement consumption, IC glomerulonephritis with gp70 deposition, and thymic atrophy were found in all three kinds of SLE mice. On the basis of these common elements, SLE seen in these mice can be considered a single disease in the same sense that human SLE is one disease. The differences in the SLE expressed in the different mice are no greater than those found in an unselected series of humans with SLE. However, the significant quantitative and qualitative variations in abnormal immunologic expression suggest that different constellations of factors, genetic and/or pathophysiologic, may operate in the three murine strains and that each constellation is capable of leading, via its particular abnormal immunologic consequences, to the activation of common immunopathologic effector mechanisms that cause quite similar SLE-like syndromes. From an experimental point of view, the availability of several inbred murine strains of commonplace histocompatibility types that express an SLE-like syndrome makes possible innumerable manipulations which should help to elucidate the nature and cause(s) of this disorder.
Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci.
A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex–gene interaction was further validated using parametric and nonparametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients.
A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P = 4.52×10−8) A significant sex–gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men.
The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.
Systemic lupus erythematosus (SLE) is a multifactorial disorder characterized by the presence of autoantibodies. We and others have implicated free radical mediated peroxidative damage in the pathogenesis of SLE. Since harmful free radical products are formed during this oxidative process, including 4-hydroxy 2-nonenol (4-HNE) and malondialdehyde (MDA), we hypothesized that specific HNE-protein adducts would be present in SLE red blood cell (RBC) membranes. Catalase is located on chromosome 11p13 where linkage analysis has revealed a marker in the same region of the genome among families with thrombocytopenia, a clinical manifestation associated with severe lupus in SLE affected pedigrees. Moreover, SLE afflicts African-Americans three times more frequently than their European-American counterparts. Hence we investigated the effects of a genetic polymorphism of catalase on risk and severity of SLE in 48 pedigrees with African American ancestry.
Tryptic digestion followed by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) analysis was used to identify the protein modified by HNE, following Coomassie staining to visualize the bands on the acrylamide gels. Genotyping analysis for the C → T, -262 bp polymorphism in the promoter region of catalase was performed by PCR-RFLP and direct PCR-sequencing. We used a "pedigree disequilibrium test" for the family based association analysis, implemented in the PDT program to analyze the genotyping results.
We found two proteins to be HNE-modified, migrating around 80 and 50 kD respectively. Tryptic digestion followed by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) analysis of the Coomassie stained 80 kD band revealed that the target of HNE modification was catalase, a protein shown to associate with RBC membrane proteins. All the test statistics carried out on the genotyping analysis for the C → T, -262 bp polymorphism in the promoter region of catalase were non-significant (p > 0.05) in our data, which suggested that this SNP is not associated with SLE.
Our results indicate that catalase is one of the proteins modified due to oxidative stress. However, catalase may not be a susceptibility gene for SLE. Nonetheless, catalase is oxidatively modified among SLE patients. This suggests a possible role between oxidative modification of catalase and its affects on enzymatic activity in SLE. An oxidatively modified catalase could be one of the reasons for lower enzymatic activity among SLE subjects, which in turn could favor the accumulation of deleterious hydrogen peroxide. Furthermore, HNE-products are potential neoantigens and could be involved in the pathogenesis of SLE. Decrease in catalase activity could affect the oxidant-antioxidant balance. Chronic disturbance of this balance in patients with SLE may work favorably for the premature onset of atherogenesis with severe vascular effect.
Autoantibodies to ribosomal P are found in 15–30% of systemic lupus erythematosus (SLE) patients and are highly specific for SLE. The goal of this study is to assess the temporal association of anti-ribosomal P (anti-P) responses with SLE disease onset, as well as to characterize the humoral ribosomal P (ribo P) epitopes targeted in early, pre-diagnostic SLE samples. Patients with stored serial serum samples available prior to SLE diagnosis were identified from a military cohort. Each sample was tested for antibodies against ribo P utilizing standard C-terminus ribo P ELISAs and a solid phase, bead-based assay with affinity-purified ribo P proteins. In this study, antibodies to ribo P were more common in African American SLE patients (p= 0.026), and anti-P positive patients comprised a group with more measured autoantibody specificities than did other SLE patients (3.5 vs. 2.2, p<0.05). Antibodies against ribo P were present on average 1.7 years before SLE diagnosis and were detected an average of 1.08 years earlier in pre-diagnostic SLE samples using affinity-purified whole protein rather than C- terminal peptide alone (p=0.0019). Furthermore, 61% of anti-P positive patients initially had antibodies to aa 99–113, a known ribosomal P0 antigenic target, at a time point when no antibodies to the clinically used C-terminus were detected. Our findings provide evidence that antibodies against ribosomal P frequently develop before clinical SLE diagnosis and are more broadly reactive than previously thought by targeting regions outside of the C-terminus.
lupus; antibodies; autoimmunity; ribosomal P; epitope
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.
Objectives: This study was undertaken to investigate the role of lipid oxidative-by-product 4-hydroxy-2-nonenal (HNE)-modified human serum albumin (HSA), chromatin, reactive oxygen species (ROS)-modified chromatin and nitric oxide (NO)-modified chromatin in systemic lupus erythematosus (SLE).
Methods: HSA was modified by HNE. Immunogenicity of modified HSA was probed by inducing polyclonal antibodies in rabbits. Chromatin was isolated from goat liver and modified by ROS or NO. Immunocross-reactions of Protein-A purified anti-HNE-HSA-IgG with chromatin, ROS-chromatin and NO-chromatin were determined. Autoantibodies from 74 SLE patients were screened. HSA was isolated from SLE patients (SLE-HSA) and immunocross-reactions of isolated SLE-HSA with HNE-specific antibodies were investigated.
Results: HNE-HSA was found to be highly immunogenic in rabbits. The notable feature of anti-HNE-HSA-IgG showed cross-reactions with chromatin, ROS-chromatin and NO-chromatin (p < 0.01). High degree of specific binding to HNEHSA, chromatin, ROS-chromatin or NO-chromatin was observed with antibodies from 55% of SLE patients. SLE anti-native/oxidized chromatin antibodies showed specificity towards HNE-HSA. Furthermore, SLE-HSAshowed binding with HNE-specific antibodies.
Conclusions: This is the first study to demonstrate that chromatin and its oxidized forms have been recognized by antibodies against HNE modified epitopes. Our results provide an important insight into the immunological basis of the reported HNE-modified epitopes in SLE.
Systemic lupus erythematosus; autoimmunity; 4-hydroxy-2-nonenal; chromatin; free radicals
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies to a wide range of self-antigens. Recent genome screens have implicated numerous chromosomal regions as potential SLE susceptibility loci. Among these, the 1q41 locus is of particular interest, because evidence for linkage has been found in several independent SLE family collections. Additionally, the 1q41 locus appears to be syntenic with a susceptibility interval identified in the NZM2410 mouse model for SLE. Here, we report the results of genotyping of 11 microsatellite markers within the 1q41 region in 210 SLE sibpair and 122 SLE trio families. These data confirm the modest evidence for linkage at 1q41 in our family collection (LOD = 1.21 at marker D1S2616). Evidence for significant linkage disequilibrium in this interval was also found. Multiple markers in the region exhibit transmission disequilibrium, with the peak single marker multiallelic linkage disequilibrium noted at D1S490 (pedigree disequilibrium test [PDT] global P value = 0.0091). Two- and three-marker haplotypes from the 1q41 region similarly showed strong transmission distortion in the collection of 332 SLE families. The finding of linkage together with significant transmission disequilibrium provides strong evidence for a susceptibility locus at 1q41 in human SLE.
1q41; autoimmunity; linkage; systemic lupus erythematosus; transmission disequilibrium
The hepatic involvement of 57 patients with systemic lupus erythematosus (SLE) was studied with special reference to liver membrane autoantibody (LMA). Liver abnormalities were found predominantly in patients with active SLE (27/48 (56%) in active SLE v 3/20 (15%) in inactive SLE). They were, however, rather mild or moderate and tended to disappear as the disease activity of SLE decreased. In this respect the liver abnormalities observed in this study differed from those in patients with lupoid hepatitis. The incidence of LMA in active SLE (8/11 (73%] was significantly greater than that in inactive SLE (4/12 (33%)). The mean LMA index value in active SLE was 8.3, which was also greater than the 2.9 in inactive SLE. Furthermore, in active SLE the mean LMA titre was significantly higher in patients with liver abnormalities than in those without. These results suggest that LMA may be associated with the activity of SLE and may be one of the factors which cause transient liver abnormalities.
Objective: To examine the contribution of genetic and environmental factors to disease occurrence in 26 families with two or more members affected with systemic lupus erythematosus (SLE).
Methods: Genetic and environmental factors were examined by HLA-A, B, C/DR typing and by determining the presence of lymphocytotoxic antibodies (LCA) in patients and their consanguineous and non-consanguineous relatives.
Results: No association between SLE and HLA-A, B, C antigens was found. There was, however, a significant association with HLA-DR2 in white subjects with SLE. The most striking finding was that HLA sharing was increased among the affected members, suggesting genetic similarities. Seven of 14 sib pairs (50%) who had concordant SLE were HLA identical as opposed to an expected 25%. Another interesting finding was that 15/18 (83%) patients with SLE and 11/22 (50%) consanguineous relatives had LCA, while 1/9 (11%) spouses, and 2/42 (5%) healthy controls had these antibodies.
Conclusion: Genetic factors have a role in the development and expression of SLE. Environmental factors may trigger the disease in genetically susceptible hosts.
A cardinal feature of systemic lupus erythematosus (SLE) is the development of autoantibodies. The first autoantibodies described in patients with SLE were those specific for nuclei and DNA, but subsequent work has shown that individuals with this disease produce a panoply of different autoantibodies. Thus, one of the constant features of SLE is a profound breakdown in tolerance in the antibody system. The appearance of self-reactive antibodies in SLE precedes clinical disease, but where in the B cell pathway tolerance is first broken has not been defined. In healthy humans, autoantibodies are removed from the B cell repertoire in two discrete early checkpoints in B cell development. We found these checkpoints to be defective in three adolescent patients with SLE. 25–50% of the mature naive B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5–20% in controls. We conclude that SLE is associated with abnormal early B cell tolerance.
Interferon α (IFN-α) levels are elevated in many patients with systemic lupus erythematosus (SLE); however it is not known whether high serum IFN-α activity is a cause or a result of the disease. We studied 266 SLE patients and 405 of their healthy relatives, and frequently found high serum IFN-α activity in both patients and healthy relatives as compared to healthy unrelated individuals. High IFN-α activity was clustered in specific families in both SLE patients and their healthy first-degree relatives, suggesting a heritable trait. Heritability was also supported by quantitative familial correlation of IFN-α activity, concordance in affected sib pairs and frequent transmission of the high IFN-α activity trait from parents to offspring. Autoantibodies to RNA-binding proteins and double-stranded DNA were associated with high IFN-α activity in SLE patients; however these autoantibodies were very uncommon in healthy family members and did not explain the observed familial correlations. The frequency of high IFN-α activity was similar across all studied ethnic backgrounds. These data suggest that high serum IFN-α activity is a complex heritable trait, which plays a primary role in SLE pathogenesis.
interferon α; systemic lupus erythematosus; genetics; epidemiology; autoantibodies
Women with systemic lupus erythematosus (SLE) have premature and accelerated atherosclerosis. Although percutaneous coronary intervention (PCI) is utilized frequently to treat coronary artery disease (CAD) in SLE, little is known regarding PCI outcomes immediately post-PCI and after discharge.
Methods and Results
Baseline demographic, procedure-related and adverse outcome data on consecutive patients undergoing PCI during 5 recruitment “waves” of the National Heart, Lung, and Blood Institute Dynamic Registry across 23 clinical centers were collected. SLE patients (n= 28) were compared to nonSLE patients (n=3385). SLE patients were younger and more often female in comparison to nonSLE patients undergoing PCI. SLE patients were less likely than nonSLE patients to have hyperlipidemia, but had a similar prevalence of hypertension, diabetes mellitus, and tobacco use. The prevalence of multi-vessel disease was similar between groups. Initial intervention success (by angiographic definition) was not significantly different between groups. At one year, SLE patients were more likely to suffer a myocardial infarction (MI) (15.6% vs. 4.8%, p=0.01), and more often required repeat PCI (31.3% vs. 11.8%, p=0.009) than nonSLE patients, even following adjustment for important covariates.
SLE patients had significantly worse CV outcomes at one year than nonSLE patients. Even considering the small number of SLE patients, these differences were striking. Further study is warranted to explore other factors potentially accounting for this disparity, including SLE disease activity and duration, presence of hypercoagulable state, and immunosuppressive therapy.
angioplasty; catheterization; restenosis; revascularization; systemic lupus erythematosus
A high prevalence of autoimmune disease (AD) has been documented in relatives of adult patients with systemic lupus erythematosus (SLE). However, data on familial inheritance patterns in pediatric SLE patients is scarce.
The charts of 69 patients with pediatric-onset SLE were reviewed retrospectively. The primary aim was to describe the prevalence and types of AD in relatives of children with SLE. The secondary aims were: 1) to compare severity of SLE in children with and without relatives affected by AD, and 2) to evaluate the impact of baseline demographics on severity of SLE in subjects. At diagnosis, 42% of subjects had one or more first, second, or third degree relative(s) with AD; and 32% of subjects had one or more first degree relative(s) with AD. The most common diseases in relatives of children with SLE were SLE (21%) and thyroid disease (15%). Subjects with no family history of AD were more likely to have severe SLE. SLE severity in subjects did not differ by gender. Children presenting with SLE at an earlier age were found to have more severe disease.
This study demonstrated a high prevalence of AD in families of children with SLE, although a family history of AD did not correlate with more severe SLE in subjects. Future larger studies are necessary to elucidate patterns of familial inheritance and baseline patient characteristics that may affect severity of disease in pediatric SLE.
Pediatric systemic lupus erythematosus; Severity; Inheritance patterns
Autoantibodies may be found years before an autoimmune disease becomes clinically apparent. For systemic lupus erythematosus (SLE), those to RNA-binding proteins, to phospholipids, and to double-stranded DNA, in particular, have been found in sera of SLE patients years before the diagnosis was made. New data now show in an unbiased way that, in patients with early SLE, no single antibody class or specificity is associated with progression to SLE. Rather, an increasing number of autoantibody specificities, such as to thyroid antigens, was observed in patients progressing. This points to more generalized B cell autoreactivity during progression to SLE, underlying lupus disease manifestations.
Many papers have been published on the lupus band in systemic lupus erythematosus (SLE), but little information exists on the possible diagnostic value of the lupus band and other microscopic immunofluorescence phenomena found in clinically normal skin of patients with SLE. In a study of 297 subjects (66 patients with SLE, 81 patients with other forms of LE, and 150 patients with other systemic connective tissue disorders) it was found that: (a) granular deposits of IgA, IgG, and IgM in the basal membrane zone and in the deeper blood vessels were more common in patients with SLE than in the other two groups; (b) depending on the clinical differential diagnosis, IgA and IgG deposits at the epidermal basal membrane can be specific for SLE; (c) using logistic regression analysis sets of variables can be selected with a high potential to discriminate between SLE and the other groups; and (d) immunofluorescence variables do not duplicate the information for the diagnosis of SLE given by the American Rheumatism Association (ARA) criteria or other laboratory methods. From these results, it is concluded that immunofluorescence microscopy of clinically normal skin is a valuable diagnostic method which should be reconsidered as a potential criterion for the diagnosis of SLE in the next evaluation of the ARA criteria.
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
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.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving critical genetic and environmental risk factors. SLE is a relatively common disease among African American women, affecting as many as one in 250. A collection of more than 250 African American and European American pedigrees multiplex for SLE have been collected in Oklahoma over the past decade for the purpose of identifying the genetic risk factors involved in the pathogenesis of SLE. A genome scan has been performed, and interestingly, the linkage results usually dominate in families from one or the other of these ethnicities. For example, the linkage effect at 1q21-22 near FcgammaRIIA is much stronger in the African American pedigrees than in the European American pedigrees. On the other hand, a gene near the top of chromosome4 (at 4p l6-15) contributes to SLE in the European American pedigrees, but not in the African American pedigrees. The racially-specific results lead to the tentative conclusion of genetic differences associated with SLE in African Americans and European Americans. The identification of the genes responsible for the observed linkage effects will provide fundamental knowledge concerning SLE and may even provide new targets for therapy and strategies to defeat this enigmatic and difficult disease.
In human systemic lupus erythematosus (SLE), diverse autoantibodies accumulate over years before disease manifestation. Unaffected relatives of SLE patients frequently share a sustained production of autoantibodies with indiscriminable specificity, usually without ever acquiring the disease. We studied relations of IgG autoantibody profiles and peripheral blood activated regulatory T-cells (aTregs), represented by CD4+CD25bright T-cells that were regularly 70–90% Foxp3+. We found consistent positive correlations of broad-range as well as specific SLE-associated IgG with aTreg frequencies within unaffected relatives, but not patients or unrelated controls. Our interpretation: unaffected relatives with shared genetic factors compensated pathogenic effects by aTregs engaged in parallel with the individual autoantibody production. To study this further, we applied a novel analytic approach named coreferentiality that tests the indirect relatedness of parameters in respect to multivariate phenotype data. Results show that independently of their direct correlation, aTreg frequencies and specific SLE-associated IgG were likely functionally related in unaffected relatives: they significantly parallelled each other in their relations to broad-range immunoblot autoantibody profiles. In unaffected relatives, we also found coreferential effects of genetic variation in the loci encoding IL-2 and CD25. A model of CD25 functional genetic effects constructed by coreferentiality maximization suggests that IL-2-CD25 interaction, likely stimulating aTregs in unaffected relatives, had an opposed effect in SLE patients, presumably triggering primarily T-effector cells in this group. Coreferentiality modeling as we do it here could also be useful in other contexts, particularly to explore combined functional genetic effects.
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.
Hysterectomy is one of the most common surgical procedures performed in United States, and currently, one in three women in United States has had a hysterectomy by the age of 60 years. Systemic lupus erythematosus (SLE) is a common autoimmune disease and especially targets women of childbearing age at least 10 times higher than men, which reflects the major role of female sex hormones. In this retrospective study, we evaluate the potential effects of previous hysterectomy in our lupus cohort.Data collected fromstudy subject questionnaires were obtained fromthe Lupus Family Registry and Repository (LFRR) at the OklahomaMedical Research Foundation. Hysterectomy data were available from 3389 subjects. SLE patients with a positive history of hysterectomy have been selected and compared with matched lupus patients with a negative history of hysterectomy and healthy controls. Association analyses were performed, and the P values and adjusted odds ratios (ORs) were calculated. SLE patients with a negative history of hysterectomy more likely had kidney nephritis or positive anti-dsDNA than age-matched SLE patients with a history of hysterectomy before disease onset. This effect was independent of ethnicity with an OR of 6.66 (95% CI = 3.09–14.38, P = 1.00 × 10−8) in European patients and 2.74 (95% CI = 1.43–5.25, P = 0.001) in African-Americans. SLE patients with a positive history of hysterectomy before disease onset also had a later age of disease onset (P = 0.0001) after adjustment for age and race. Our findings support the notion that the influence of female sex hormones in SLE and various clinical findings are tremendous and that surgical menopause such as this could significantly affect the outcome of disease and clinical manifestations
A role for helper T cells in the induction of pathogenic lupus autoantibodies is increasingly supported by data from studies of murine lupus and patients with systemic lupus erythematosus (SLE). However, the poor in vitro function of SLE T cells has hampered the identification and characterization of autoantigen-specific T cells. We used recombinant fusion proteins to study the T cell proliferative response of 31 lupus patients and 27 healthy subjects to a well-characterized SLE autoantigen, the ribosomal P2 protein. Although PBMC from SLE patients showed marked impairment in the proliferative response to the common recall antigen tetanus toxoid when compared with normal subjects, a significantly greater proportion of SLE patients (32%) than normal individuals (0%) showed a T cell response to a recombinant P2 fusion protein. When the SLE patients were subgrouped according to the presence of serum anti-P autoantibody, 7 of 10 anti-P antibody-positive patients, but 0 of 20 anti-P antibody-negative SLE patients, demonstrated > 2,000 cpm [3H]thymidine incorporation and a P2 stimulation index > 5. The specificity of the T cell proliferative response for the P2 protein was confirmed by studies using a second recombinant human P2 fusion protein and by the specific activation of P2-primed T cells by recombinant P2 in secondary cultures. Moreover, the T cell proliferative response to the P2 autoantigen was mediated by CD4-positive T cells and was inhibited by anti-MHC class II antibodies. These data demonstrate the presence of autoantigen-specific T helper cells in patients with SLE and suggest that these T cells drive the production of autoantibodies by B lymphocytes.
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by the presence of a plethora of autoantibodies and immune complex formation. Virtually every system and organ can be affected by SLE. Gastrointestinal symptoms are common in SLE patients, and more than half of them are caused by adverse reactions to medications and viral or bacterial infections. Though not as common as lupus nephritis, SLE-related gastrointestinal involvement is clinically important because most cases can be life-threatening if not treated promptly. Lupus mesenteric vasculitis is the most common cause, followed by protein-losing enteropathy, intestinal pseudo-obstruction, acute pancreatitis and other rare complications such as celiac disease, inflammatory bowel diseases, etc. No specific autoantibody is identified as being associated with SLE-related gastroenteropathy. Imaging studies, particularly abdominal computed tomography scans, are helpful in diagnosing some SLE-related gastroenteropathies. Most of these complications have good therapeutic responses to corticosteroids and immunosuppressive agents. Supportive measures such as bowel rest, nutritional support, antibiotics and prokinetic medications are helpful in facilitating functional recovery and improving the outcome.
Systemic lupus erythematosus; Systemic; Vasculitis; Gastroenteropathy