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
OBJECTIVE—In view of the recognised clustering of autoimmune diseases (AID), the chronology of development of other autoimmune diseases in systemic lupus erythematosus (SLE) patients was considered.
METHODS—A retrospective review of a well documented population of 215 patients with SLE was undertaken. The duration of follow up ranged from 2 to 18 years.
RESULTS—Of these 215 patients, 65 (30%) had at least one other AID—including 51 (24%) having one other AID, 12 (6%) having two and two (1%) having three other AID in addition to their SLE. Twelve different autoimmune diseases were identified. The majority of patients developed a further AID after SLE had been diagnosed (62%) reflecting the relatively early age of onset of SLE. There was no significant difference in the age of onset of rheumatoid arthritis, Sjögren's syndrome and hypothyroidism that had developed before SLE compared with those who developed these diseases after SLE. However, those who developed autoimmune thrombocytopenia (AITP) before SLE were significantly younger than those who developed AITP after SLE (16.7 v 38.7 years respectively, p<0.05).
CONCLUSIONS—Physicians caring for SLE patients should remain alert to the possible development of a second AID during follow up. Further well matched case-control studies are required to define the exact relation between SLE and other AID.
Systemic lupus erythematosus (SLE) is a chronic, systemic, and autoimmune disease, whose etiology is still unknown. Although there has been progress in the treatment of SLE through the use of glucocorticoid and immunosuppressive drugs, these drugs have limited efficacy and pose significant risks of toxicity. Moreover, prognosis of patients with SLE has remained difficult to assess. TRIM21/Ro52/SS-A1, a 52-kDa protein, is an autoantigen recognized by antibodies in sera of patients with SLE and Sjögren's syndrome (SS), another systemic autoimmune disease, and anti-TRIM21 antibodies have been used as a diagnostic marker for decades. TRIM21 belongs to the tripartite motif-containing (TRIM) super family, which has been found to play important roles in innate and acquired immunity. Recently, TRIM21 has been shown to be involved in both physiological immune responses and pathological autoimmune processes. For example, TRIM21 ubiquitylates proteins of the interferon-regulatory factor (IRF) family and regulates type I interferon and proinflammatory cytokines. In this paper, we summarize molecular features of TRIM21 revealed so far and discuss its potential as an attractive therapeutic target for SLE.
A selective polyclonal increase in IgG1 has been described previously in a group of patients with connective tissue disease; nine of the 16 patients had a prior diagnosis of systemic lupus erythematosus (SLE). A detailed clinical and serological study of 32 patients with this immunoglobulin abnormality has now been made. Most cases showed a characteristic autoantibody profile of antinuclear antibody, rheumatoid factor, and antibodies to Ro and La. Sjögren's syndrome was diagnosed as 'definite' in 16 cases and 'possible' in seven cases by Fox's criteria. The remainder had unclassified connective tissue disease (three), rheumatoid arthritis with dry eyes (two), SLE (one), scleroderma (two), and Raynaud's disease (one). Extraglandular features were invariably present in patients with primary Sjögren's syndrome. The highest concentrations of IgG1 were found in patients with the shortest disease duration. Selective polyclonal increase of IgG1 should alert the doctor to the development of Sjögren's syndrome, usually with extraglandular disease and antibodies to Ro and La.
The age at onset refers to the time period at which an individual experiences the first symptoms of a disease. In autoimmune diseases (ADs), these symptoms can be subtle but are very relevant for diagnosis. They can appear during childhood, adulthood or late in life and may vary depending on the age at onset. Variables like mortality and morbidity and the role of genes will be reviewed with a focus on the major autoimmune disorders, namely, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes mellitus (T1D), Sjögren's syndrome, and autoimmune thyroiditis (AITD). Early age at onset is a worst prognostic factor for some ADs (i.e., SLE and T1D), while for others it does not have a significant influence on the course of disease (i.e., SS) or no unanimous consensus exists (i.e., RA and MS).
Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is a type I transmembrane protein belonging to the TNFR superfamily. After activated by its ligand GITRL, GITR could influence the activity of effector and regulatory T cells, participating in the development of several autoimmune and inflammatory diseases included rheumatoid arthritis and autoimmune thyroid disease. We previously reported that serum GITRL levels are increased in systemic lupus erythematosus (SLE) patients compared with healthy controls (HC). Here, we tested serum soluble GITR (sGITR) and GITRL levels in 41 primary Sjögren's syndrome (pSS) patients and 29 HC by ELISA and correlated sGITR and GITRL levels with clinical and laboratory variables. GITR and GITRL expression in labial salivary glands was detected by immunohistochemistry. pSS patients had significantly increased serum levels of sGITR and GITRL compared with controls (GITR: 5.66 ± 3.56 ng/mL versus 0.50 ± 0.31 ng/mL; P < 0.0001; GITRL: 6.17 ± 7.10 ng/mL versus 0.36 ± 0.28 ng/mL; P < 0.0001). Serum sGITR and GITRL levels were positively correlated with IgG (GITRL: r = 0.6084, P < 0.0001; sGITR: r = 0.6820, P < 0.0001) and ESR (GITRL: r = 0.8315, P < 0.0001; sGITR: r = 0.7448, P < 0.0001). Moreover, GITR and GITRL are readily detected in the lymphocytic foci and periductal areas of the LSGs. In contrast, the LSGs of HC subjects did not express GITR or GITRL. Our findings indicate the possible involvement of GITR-GITRL pathway in the pathogenesis of pSS. Further studies may facilitate the development of targeting this molecule pathway for the treatment of pSS.
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.
The aim of the present study was to investigate the sensitivity and specificity of anti-Sjögren’s syndrome type B (SSB) antibodies for diagnosing systemic lupus erythematosus (SLE) and to understand the correlation between anti-SSB antibodies and the clinical manifestations of SLE. A line immunoassay (LIA) was used to detect the presence of serum anti-SSB antibodies in SLE patients. The clinical manifestations of the patients were recorded to enable their correlation with the serum anti-SSB antibodies to be analyzed. In 25.7% of the 74 SLE patients, the serum was positive for anti-SSB antibodies, whereas only 3.3% of the 30 control cases were positive. The specificity of anti-SSB antibodies for detecting SLE was 96.7%. In anti-SSB antibody-positive SLE patients, the incidence of cheek erythema, alopecia, serositis, secondary Sjögren’s syndrome (sSS), leukocytopenia, elevated immunoglobulin (Ig)G and positive presence of anti-Sjögren’s syndrome type A (SSA)60 or anti-SSA52 antibodies was higher than in the anti-SSB antibody-negative group (P<0.05). Anti-SSB antibodies are important for the diagnosis of SLE and are associated with cheek erythema, alopecia, serositis, sSS, leukocytopenia, the elevation of IgG and positive presence of anti-SSA60 or anti-SSA52 antibodies.
anti-Sjögren’s syndrome type B antibody; linear immunoblot assay; systemic lupus erythematosus
Based on the revised criteria of the American-European Consensus Group, we retrospectively established the diagnosis of primary or secondary Sjögren's syndrome for 202 patients referred to a Sjögren's syndrome clinic. Of these, 58 patients and 8 patients fulfilled criteria for primary and secondary Sjögren's syndrome, respectively. Of the 58 patients with primary Sjögren's syndrome, one (1.7%) had definite autoimmune hepatitis, as defined by the International Autoimmune Hepatitis Group diagnostic criteria. One additional symptomatic patient who did not fulfill criteria for primary Sjögren's syndrome had definite autoimmune hepatitis. None of the patients with secondary Sjögren's syndrome had definite autoimmune hepatitis. Two (1%) of the 194 patients with primary Sjögren's syndrome or clinical symptoms had primary biliary cirrhosis. These values are lower than those reported by prior studies with smaller patient populations and likely represent a more accurate estimate of the true prevalence of these diseases in patients with primary Sjögren's syndrome.
Autoimmune hepatitis; Sjögren's syndrome; primary biliary cirrhosis
The association of systemic lupus erythematosus (SLE) and myeloproliferative and lymphoproliferative malignancies is widely reported. There is scarce information available with regards to the association of SLE and malignancy in children. Usually, SLE precedes the onset of lymphoproliferative disease, but the neoplasia can occur earlier or even simultaneously. There are only five pediatric cases of SLE and associated acute lymphoblastic leukemia (ALL) reported in literature. All of these except one satisfied the revised American College of Rheumatology Criteria for SLE. Three of these cases developed SLE several years after successful treatment of ALL. While two cases reported had simultaneous onset of SLE and ALL, one of the cases in this two-patient series, did not fulfill ≥4 criteria for diagnosis of SLE. We present a case of a 3-year-old boy with SLE and coexistent ALL. To the best of our knowledge, only two such cases of simultaneous presentation of both these diseases are present in literature.
Acute lymphoblastic leukemia; myeloproliferative disorder; systemic lupus erythematosus
Polyautoimmunity is one of the major clinical characteristics of autoimmune diseases (ADs). The aim of this study was to investigate the prevalence of ADs in spondyloarthropathies (SpAs) and vice versa. This was a two-phase cross-sectional study. First, we examined the presence of ADs in a cohort of patients with SpAs (N = 148). Second, we searched for the presence of SpAs in a well-defined group of patients with ADs (N = 1077) including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS). Among patients with SpAs, ankylosing spondylitis was observed in the majority of them (55.6%). There were two patients presenting with SS in the SpA group (1.4%) and 5 patients with autoimmune thyroiditis (3.5%). The global prevalence of ADs in SpAs was 4.86%. In the ADs group, there were 5 patients with SpAs (0.46%). Our results suggest a lack of association between SpAs and ADs. Accordingly, SpAs might correspond more to autoinflammatory diseases rather than to ADs.
Antibodies to the ribonucleoprotein (RNP) component of extractable nuclear antigen were measured in patients with systemic lupus erythematosus (SLE) and other connective tissue subgroups by counterimmunoelectrophoresis. Antibodies to RNP were found in the sera of 32% of patients with a primary diagnosis of SLE, 29% of patients with features of SLE and erosive joint disease, none of 9 scleroderma patients, and in 75% of 8 patients with features of SLE and scleroderma. In the SLE patients overall there was an increased frequency of sclerodactyly and severe Raynaud's phenomenon in the patients with antibodies to RNP but no association of antibodies to RNP was found with the presence of erosive joint disease, Sjögren's syndrome, or the absence of renal disease in these patients.
Sjögren's syndrome (SS) is a chronic, progressive autoimmune disease primarily affecting women. Diagnosis of SS requires an invasive salivary gland tissue biopsy and a long delay from the start of the symptoms to final diagnosis has been frequently observed. In this study, we aim to identify salivary autoantibody biomarkers for primary SS (pSS) using a protein microarray approach. Immune-response protoarrays were used to profile saliva autoantibodies from patients with pSS (n=14), patients with systemic lupus erythematosus (SLE, n=13), and healthy control subjects (n=13). We identified 24 potential autoantibody biomarkers that can discriminate patients with pSS from both patients with SLE and healthy individuals. Four saliva autoantibody biomarkers, anti-transglutaminase, anti-histone, anti-SSA, and anti-SSB, were further tested in independent pSS (n=34), SLE (n=34), and healthy control (n=34) subjects and all were successfully validated with ELISA. This study has demonstrated the potential of a high-throughput protein microarray approach for the discovery of autoantibody biomarkers. The identified saliva autoantibody biomarkers may lead to a clinical tool for simple, noninvasive detection of pSS at low cost.
Autoantibody biomarker; Protein arrays; Protein microarray; Sjögren's syndrome
Sjögren’s syndrome (SS) is a systemic autoimmune disease with a variety of presenting symptoms which may delay its diagnosis. We previously discovered a number of candidate salivary biomarkers for primary SS (pSS) using both mass spectrometry and expression microarray analysis (Arthritis Rheumatism, 2007;56(11):3588-3600). In this study, we aim to verify these candidate biomarkers in independent patient populations and to evaluate their predictive values for pSS detection.
In total, 34 patients with pSS, 34 patients with systemic lupus erythematosus (SLE) and 34 healthy individuals were enrolled for the validation studies. Salivary protein biomarkers were measured using either Western blotting or ELISA, and the mRNA biomarkers were measured using quantitative polymerase chain reaction (qPCR). Statistical analysis was performed using R2.9.
Three protein biomarkers, cathepsin D, alpha-enolase and beta-2-microglobulin (B2M), and three mRNA biomarkers, myeloid cell nuclear differentiation antigen (MNDA), Guanylate binding protein 2 (GIP2) and low affinity IIIb receptor for the Fc fragment of IgG (FCGR3B), were significantly elevated in patients with pSS compared to both SLE patients and healthy controls. The combination of three protein biomarkers, cathepsin D, alpha-enolase and B2M, yielded a receiver operating characteristic (ROC) value of 0.99 in distinguishing pSS from healthy controls. The combination of protein biomarkers B2M and two mRNA biomarkers, MNDA and GIP2, reached an ROC of 0.95 in discriminating pSS from SLE.
We have successfully verified a panel of protein and mRNA biomarkers that can discriminate pSS from both SLE and healthy controls. If further validated in pSS patients and those with sicca symptoms but no autoimmune disease, these biomarkers may lead to a simple yet highly discriminatory clinical tool for diagnosis of pSS.
OBJECTIVE—Firstly, to study the prevalence of ocular and oral sicca symptoms, reduced tear and saliva production, and the minimum frequency of secondary Sjögren's syndrome (sSS) in systemic lupus erythematosus (SLE). Secondly, to compare sicca symptoms and findings with those of matched patients with rheumatoid arthritis (RA), and sicca symptoms with those in healthy controls. Finally, to study possible associations of clinical variables with sicca symptoms and sSS in SLE.
METHODS—Self reported sicca symptoms were recorded in 81 patients with SLE aged ⩽70, 81 matched patients with RA, and 81 matched healthy controls. Other study variables included Schirmer-I test (S1T), unstimulated whole saliva, health status measures (in SLE and RA), disease activity, accumulated organ damage, and serological markers (in SLE).
RESULTS—A significantly higher proportion of patients with SLE reported sicca symptoms than healthy controls. Further, a significantly higher proportion reported ocular sicca symptoms (43 and 21%, respectively) and had pathologically reduced S1T compared with RA (46 and 21%, respectively). No difference was seen in oral sicca symptoms and saliva production. In SLE, sicca symptoms were associated with fatigue, and sSS with anti-SSB or anti-SSA antibodies, or both.
CONCLUSIONS—An increased prevalence of sicca symptoms was found in patients with SLE compared with controls, and a higher prevalence of ocular sicca symptoms and reduced tear production in SLE compared with RA. Sicca problems should be considered in the care of patients with SLE, especially those with anti-SSB and/or anti-SSA antibodies who have sicca symptoms and fatigue.
Anti-Ro/SSA antibodies are among the most frequently detected autoantibodies against extractable nuclear antigens and have been associated with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). Although the presence of these autoantibodies is one of the criteria for the diagnosis and classification of SS, they are also sometimes seen in other systemic autoimmune diseases. In the last few decades, the knowledge of the prevalence of anti-Ro/SSA antibodies in various autoimmune diseases and symptoms has been expanded, and the clinical importance of these antibodies is increasing. Nonetheless, the pathological role of the antibodies is still poorly understood. In this paper, we summarize the milestones of the anti-Ro/SSA autoantibody system and provide new insights into the association between the autoantibodies and the pathogenesis of autoimmune diseases.
Six patients are reported in whom systemic lupus erythematosus (SLE) and thyrotoxicosis coexisted. All had four or more American Rheumatism Association criteria (1982) for the diagnosis of SLE and had clinical manifestations and function test results characteristic of hyperthyroidism (except for one who had been thyroidectomised previously). In three patients the diagnosis of hyperthyroidism preceded that of SLE, in two patients both diseases began simultaneously, and only in one was the diagnosis of thyrotoxicosis made after that of SLE. It is suggested that hyperthyroidism associated with SLE may be a form of presentation of thyroiditis. This association may pass unnoticed because of the similarity of some clinical manifestations.
Many autoimmune diseases (ADs) share similar underlying pathology and have a tendency to cluster within families, supporting the involvement of shared susceptibility genes. To date, most of the genetic variants associated with systemic lupus erythematosus (SLE) susceptibility also show association with others ADs. ITGAM and its associated ‘predisposing’ variant (rs1143679, Arg77His), predicted to alter the tertiary structures of the ligand-binding domain of ITGAM, may play a key role for SLE pathogenesis. The aim of this study is to examine whether the ITGAM variant is also associated with other ADs. We evaluated case-control association between rs1143679 and ADs (N=18,457) including primary Sjögren’s syndrome, systemic sclerosis, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, celiac disease, and type-1 diabetes. We also performed meta-analyses using our data in addition to available published data. Although the risk allele ‘A’ is relatively more frequent among cases for each disease, it was not significantly associated with any other ADs tested in this study. However, the meta-analysis for systemic sclerosis was associated with rs1143679 (pmeta=0.008). In summary, this study explored the role of ITGAM in general autoimmunity in seven non-lupus ADs, and only found association for systemic sclerosis when our results were combined with published results. Thus ITGAM may not be a general autoimmunity gene but this variant may be specifically associated with SLE and systemic sclerosis.
ITGAM; autoimmune diseases; genetic susceptibility
Objective. To investigate the association of lipoprotein(a) and atherosclerosis-related autoimmune diseases, to provide information on possible pathophysiologic mechanisms, and to give recommendations for Lp(a) determination and therapeutic options. Methods. We performed a systematic review of English language citations referring to the keywords “Lp(a)” AND “autoimmune disease” AND “atherosclerosis,” “Lp(a)” AND “immune system” OR “antiphospholipid (Hughes) syndrome (APS)” OR “rheumatoid arthritis” OR “Sjögren's syndrome” OR “systemic lupus erythematosus” OR “systemic sclerosis” OR “systemic vasculitis” published between 1991 and 2011 using Medline database. Results. 22 out of 65 found articles were identified as relevant. Lp(a) association was highest in rheumatoid arthritis (RA), followed by systemic lupus erythematosus (SLE), moderate in APS and lowest in systemic sclerosis (SSc). There was no association found between Lp(a) and systemic vasculitis or Sjögren's syndrome. Conclusion. Immune reactions are highly relevant in the pathophysiology of atherosclerosis, and patients with specific autoimmune diseases are at high risk for CVD. Elevated Lp(a) is an important risk factor for premature atherosclerosis and high Lp(a) levels are also associated with autoimmune diseases. Anti-Lp(a)-antibodies might be a possible explanation. Therapeutic approaches thus far include niacin, Lp(a)-apheresis, farnesoid x-receptor-agonists, and CETP-inhibitors being currently under investigation.
While Sjögren’s syndrome (SS) is more common than related autoimmune disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), scientific and medical research in SS has lagged behind significantly. This is especially true in the field of SS genetics, where efforts to date have relied heavily on candidate gene approaches. Within the last decade, the advent of the genome-wide association (GWA) scan has altered our understanding of disease pathogenesis in hundreds of disorders through the successful identification of novel risk loci. With strong evidence for a genetic component in SS as evidenced by familial aggregation of SS as well as similarities between SS and SLE and RA, the application of GWA approaches would likely yield numerous novel risk loci in SS. Here we review the fundamental scientific principles employed in GWA scans as well as the limitations of this tool, and we discuss the application of GWA scans in determining genetic variants at play in complex disease. We also examine the successful application of GWA scans in SLE, which now has more than 40 confirmed risk loci, and consider the possibility for a similar trajectory of SS genetic discovery in the era of GWA scans. Ultimately, the GWA studies that will be performed in SS have the potential to identify a myriad of novel genetic loci that will allow scientists to begin filling in the gaps in our understanding of the SS pathogenesis.
genetics; Sjögren’s syndrome; genome-wide association
Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease of unknown etiology with many clinical manifestations. The skin is one of the target organs most variably affected by the disease. The American College of Rheumatology (ACR) established 11 criteria as a classificatory instrument to operationalise the definition of SLE in clinical trials. They were not intended to be used to diagnose individuals and do not do well in that capacity. Cutaneous lesions account for four of these 11 revised criteria of SLE. Skin lesions in patients with lupus may be specific or nonspecific. This paper covers the SLE-specific cutaneous changes: malar rash, discoid rash, photosensitivity, and oral mucosal lesions as well as SLE nonspecific skin manifestations, their pathophysiology, and management. A deeper thorough understanding of the cutaneous manifestations of SLE is essential for diagnosis, prognosis, and efficient management. Thus, dermatologists should cooperate with other specialties to provide optimal care of SLE patient.
One hundred and twenty-four sera from Greek patients with autoimmune rheumatic diseases (29 with systemic lupus erythematosus (SLE), 24 with scleroderma, 11 with primary Sjögren's syndrome (SS), and 60 with rheumatoid arthritis (RA) were tested for antibodies to nRNP, Sm, Scl-70, Ro(SSA), and La(SSB) cellular antigens. The incidence of these antibodies in the different groups of patients examined, did not differ overall from that described previously. It was noted, however, that antibodies to Sm were very infrequently found in Greek patients with SLE and anti-Ro positive patients with SLE did not have the clinical manifestations described by other workers. Finally, it was found that anti-Ro positive patients with RA experienced a high frequency of side effects from penicillamine-D. The significance of these findings is discussed.
TREX1 (DNase III) is an exonuclease involved in response to oxidative stress and apoptosis. Heterozygous mutations in TREX1 were previously observed in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). We performed a mutational analysis of the TREX1 gene on three autoimmune diseases: SLE (210 patients) and SS (58 patients), to confirm a TREX1 involvement in the Italian population, and systemic sclerosis (SSc, 150 patients) because it shares similarities with SLE (presence of antinuclear antibodies and connective tissue damage). We observed 7 variations; two of these are novel nonsynonymous variants (p.Glu198Lys and p.Met232Val). They were detected in one SS and in one SSc patient, respectively, and in none of the 200 healthy controls typed in this study and of the 1712 published controls. In silico analysis predicts a possibly damaging role on protein function for both variants. The other 5 variations are synonymous and only one of them is novel (p.Pro48Pro).
This study contributes to the demonstration that TREX1 is involved in autoimmune diseases and proposes that the spectrum of involved autoimmune diseases can be broader and includes SSc. We do not confirm a role of TREX1 variants in SLE.
The type I interferon (IFN) pathway is activated in many patients with systemic lupus erythematosus (SLE), and high serum levels of IFN are associated with anti-SSA/Ro autoantibodies. To investigate the clinical features associated with type I IFN production in vivo, we compared serum IFN activity in individuals with anti-SSA/Ro antibodies who were asymptomatic with that in individuals with clinical manifestations of SLE or Sjögren's syndrome (SS).
Antibody-positive sera from 84 mothers of children with manifestations of neonatal lupus were studied for type I IFN activity, using a functional reporter cell assay. Maternal health status was characterized as asymptomatic, SS, SLE, pauci-SLE, or pauci-SS, based on a screening questionnaire, telephone interview, and review of medical records. The prefix “pauci-” indicates symptoms insufficient for a formal classification of the disease.
Only 4% of asymptomatic mothers had high serum type I IFN activity, compared with 73% with pauci-SLE (P = 5.7 × 10−5), 35% with SLE (P = 0.011), and 32% of patients with SS (P = 0.032). One of the 4 patients with pauci-SS had high levels of IFN. The majority of patients for whom longitudinal data were available had stable type I IFN activity over time, and changes in IFN activity were not clearly accompanied by changes in the clinical diagnosis.
Patients with SLE, patients with pauci-SLE, and patients with SS are more likely to have high serum IFN activity than asymptomatic individuals with SSA/Ro autoantibodies, suggesting that these autoantibodies are insufficient for activation of the type I IFN pathway, and that disease-specific factors are important for type I IFN generation in vivo.
Inhibitory coreceptors are thought to play important roles in maintaining immunological homeostasis, and a defect in the negative signals from inhibitory coreceptors may lead to the development of autoimmune diseases. We have recently identified B and T lymphocyte attenuator (BTLA), a new inhibitory coreceptor expressed on immune cells, and we suggest that BTLA may be involved in the development of autoimmune diseases using BTLA-deficient mice. However, the role of BTLA in the pathogenesis of autoimmune diseases in humans remains unknown. We, therefore, examined the possible association between BTLA and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS) by conducting a case-control genetic association study. We found that 590C single-nucleotide polymorphism (SNP) of BTLA gene was significantly associated with susceptibility to RA, but not to SLE or SS. Furthermore, RA patients bearing this 590C SNP developed the disease significantly earlier than the patients without this allele. We also found that BTLA with 590C allele lacked the inhibitory activity on concanavalin A- and anti-CD3 Ab-induced IL-2 production in Jurkat T cells. These results suggest that BTLA is an RA-susceptibility gene and is involved in the protection from autoimmunity in humans.