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Objective: SLE is an autoimmune disease, mainly affecting women of childbearing age, with possible impact on pregnancy. In this study, we evaluated pregnancy outcomes in all pregnant patients affected by SLE, followed in the context of a rheumatology/gynaecology multi-disciplinary team., Methods: Since 2008, we evaluated 70 consecutive pregnancies occurring in 50 SLE patients referring to the Lupus Clinic of Sapienza University of Rome; as controls we evaluated 100 consecutive pregnancies in 100 women without autoimmune diseases., Results: By comparing SLE patients and controls, we did not find differences in terms of pregnancy outcomes, except for the occurrence of small for gestational age, which was significantly higher in the SLE group (22.8% vs 11%, P =0.003). Small for gestational age was associated with the positivity for anti-dsDNA, anti-Sm and anti-RNP (P =0.009, P =0.02, P =0.002, respectively). A disease flare was reported in 28 pregnancies (40%) and in 31 puerperium periods (44.3%). Flare during pregnancy was associated with anti-SSA (P =0.02), while puerperium relapse with previous MMF treatment (P =0.01) and haematological flare during pregnancy (P =0.03)., Conclusion: The present study confirms how pre-gestational counselling and a multi-disciplinary approach could result in positive pregnancy outcomes for SLE patients. The high percentage of disease relapse justifies even more the need for multi-disciplinary management., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Systemic lupus erythematosus (SLE) and other autoimmune diseases are propelled by immune dysregulation and pathogenic, disease-specific autoantibodies. Autoimmunity against the lupus autoantigen Sm is associated with cross-reactivity to Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1). Additionally, EBV latent membrane protein-1 (LMP1), initially noted for its oncogenic activity, is an aberrantly active functional mimic of the B cell co-stimulatory molecule CD40. Mice expressing a transgene (Tg) for the mCD40-LMP1 hybrid molecule (containing the cytoplasmic tail of LMP1) have mild autoantibody production and other features of immune dysregulation by 2-3 months of age, but no overt autoimmune disease. This study evaluates whether exposure to the EBV molecular mimic, EBNA-1, stimulates antigen-specific and concurrently-reactive humoral and cellular immunity, as well as lupus-like features. After immunization with EBNA-1, mCD40-LMP1 Tg mice exhibited enhanced, antigen-specific, cellular and humoral responses compared to immunized WT congenic mice. EBNA-1 specific proliferative and inflammatory cytokine responses, including IL-17 and IFN-γ, were significantly increased ( p<0.0001 ) in mCD40-LMP1 Tg mice, as well as antibody responses to amino- and carboxy-domains of EBNA-1. Of particular interest was the ability of mCD40-LMP1 to drive EBNA-1 associated molecular mimicry with the lupus-associated autoantigen, Sm. EBNA-1 immunized mCD40-LMP1 Tg mice exhibited enhanced proliferative and cytokine cellular responses (p<0.0001) to the EBNA-1 homologous epitope PPPGRRP and the Sm B/B' cross-reactive sequence PPPGMRPP. When immunized with the SLE autoantigen Sm, mCD40-LMP1 Tg mice again exhibited enhanced cellular and humoral immune responses to both Sm and EBNA-1. Cellular immune dysregulation with EBNA-1 immunization in mCD40-LMP1 Tg mice was accompanied by enhanced splenomegaly, increased serum blood urea nitrogen (BUN) and creatinine levels, and elevated anti-dsDNA and antinuclear antibody (ANA) levels ( p<0.0001 compared to mCD40 WT mice). However, no evidence of immune-complex glomerulonephritis pathology was noted, suggesting that a combination of EBV and genetic factors may be required to drive lupus-associated renal disease. These data support that the expression of LMP1 in the context of EBNA-1 may interact to increase immune dysregulation that leads to pathogenic, autoantigen-specific lupus inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Munroe, Anderson, Gross, Stunz, Bishop and James.)

Objectives: In SLE, heterogeneous clinical expression and activity may reflect diverse pathogenic and/or effector mechanisms. We investigated SLE heterogeneity by assessing the expression of three gene sets representative of type I IFN (IFN-I), polymorphonuclear neutrophil (PMN) and plasmablast (PB) signatures in a well-characterized, multidisciplinary cohort of SLE patients. We further assessed whether individual gene products could be representative of these three signatures., Methods: Whole blood, serum and clinical data were obtained from 140 SLE individuals. Gene expression was assessed by NanoString technology, using a panel of 37 probes to compute six IFN-I, one PMN and one PB scores. Protein levels were measured by ELISA., Results: Depending on the score, 45-50% of SLE individuals showed high IFN-I gene expression. All six IFN-I scores were significantly associated with active skin involvement, and two of six were associated with arthritis. IFN-induced Mx1 protein (MX1) level was correlated with IFN-I score (P < 0.0001) and associated with a similar clinical phenotype. In all, 25% of SLE individuals showed high PMN gene expression, associated with SLE fever, serositis, leukopoenia and glucocorticoid use. PB gene expression was highly affected by immunosuppressant agents, with no association with SLE features. Combined IFN-I and PMN gene scores were significantly associated with high disease activity and outperformed anti-dsDNA and anti-C1q autoantibody and complement levels for predicting SLE activity., Conclusion: IFN-I and PMN gene scores segregate with distinct SLE clinical features, and their combination may identify high disease activity. MX1 protein level performed similar to IFN-I gene expression., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The generation of systemic lupus erythematosus (SLE)-related autoantibodies have been shown to be T cell dependent and antigen driven with HLA-DR restriction. In this study, the initiating antigen(s) and the mechanism of autoantibody diversification were investigated., Methods: T cell epitopes (T-epitopes) of SmD1 (SmD) were mapped by T-T hybridomas generated from DR3 + AE 0 mice immunised with SmD and with SmD overlapping peptides. TCRs from the reactive hybridomas were sequenced. The core epitopes were determined. Bacterial mimics were identified by bioinformatics. Sera from DR3 + AE 0 mice immunised with SmD peptides and their mimics were analysed for their reactivity by ELISA and immunohistochemistry. Samples of blood donors were analysed for HLA-DR and autoantibody specificities., Results: Multiple HLA-DR3 restricted T-epitopes within SmD were identified. Many T-T hybridomas reacted with more than one epitope. Some of them were cross-reactive with other snRNP peptides and with proteins in the Ro60/La/Ro52 complex. The reactive hybridomas used unique TCRs. Multiple T-epitope mimics were identified in commensal and environmental bacteria. Certain bacterial mimics shared both T and B cell epitopes with the related SmD peptide. Bacterial mimics induced autoantibodies to lupus-related antigens and to different tissues. HLA-DR3 + blood donors made significantly more SLE-related autoantibodies., Conclusions: The unique antigenic structures of the lupus-related autoantigens provide the basis for being targeted and for T and B cell epitope spreading and autoantibody diversification with unique patterns. SLE-related autoantibodies are likely generated from responses to commensal and/or environmental microbes due to incomplete negative selection for autoreactive T cells. The production of SLE-related antibodies is inevitable in normal individuals. The findings in this investigation have significant implications in autoimmunity in general., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To validate the association of thrombotic events with positive lupus anticoagulant (LA) and co-presence of anti-RNP/Sm, as well as the diagnostic accuracy of this combination of antibodies for thrombosis., Methods: Case-control study of patients with systemic lupus erythematosus (SLE) who presented thrombosis after SLE diagnosis and controls with SLE without thrombosis. Comorbidities, traditional risk factors, clinical variables, and treatment were evaluated. Antiphospholipid (aPL) and anti-RNP/Sm antibodies were determined., Results: Sixty-three cases and 63 controls were studied, 88% women, median age of 40 years, and disease duration of 135 months at study inclusion. No differences were found between groups regarding age, comorbidities, or clinical characteristics at SLE diagnosis. Patients with thrombosis were more frequently positive for anti-RNP/Sm (p = 0.001), IgG aCL (p = 0.02), IgG anti-B2GPI (p = 0.02), IgM anti-B2GPI (p = 0.02), LA (p < 0.001), the combination of anti-RNP/Sm + LA (p < 0.001), and aPL triple marker (p = 0.002), compared to controls. The combination of anti-RNP/Sm + LA, SLEDAI-2 K, and prednisone dose was associated with thrombosis (p < 0.05). The combination of anti-RNP/Sm + LA showed 56% sensitivity, 79% specificity, 73% positive predictive value, 64% negative predictive value, positive likelihood ratio (LR) 2.69, and negative LR 0.56 for predicting thrombosis. No difference was found in the comparison of area under the curve between LA alone and the combination of anti-RNP/Sm + LA (p = 0.73)., Conclusion: Thrombosis was associated with disease activity, dose of prednisone, and the combination of anti-RNP/Sm antibodies and LA. This combination of antibodies could be useful in the identification of SLE patients at risk of thrombosis.

The present study was performed to elucidate the roles of serum anti-Sm antibodies in the pathogenesis of systemic lupus erythematosus (SLE). Highly purified peripheral blood monocytes obtained from healthy donors were cultured in the presence of monoclonal anti-Sm antibody (anti-Sm mAb), monoclonal anti-U1-RNP antibody (anti-RNP mAb) or control murine IgG1 or IgG3. After various periods of incubation, levels of IL-6 and TNF-α in the culture supernatants were measured by ELISA and the expression of mRNA for various molecules in monocytes was determined using RT-PCR. Flow cytometry analysis confirmed the bindings of anti-Sm mAb and anti-RNP mAb on viable human monocytes. Both anti-Sm mAb and anti-RNP mAb significantly increased the production of IL-6 and TNF-α of human monocytes in a dose-dependent manner, although the latter was more potent than the former. Of note, anti-Sm mAb synergistically enhanced the production and mRNA expression of IL-6 and TNF-α of human monocytes in the presence of anti-RNP mAb. Notably, anti-RNP mAb, but not anti-Sm mAb, significantly enhanced the mRNA expression of RelA in human monocytes. Finally, anti-Sm mAb still up-regulated the IL-6 production of monocytes in the presence of anti-RNP mAb under the influence of N-acetyl cysteine or pyrrolidine dithiocarbamate that totally abrogated the IL-6 production provoked by anti-Sm mAb alone in the absence of anti-RNP mAb. These results demonstrate that anti-Sm and anti-RNP antibodies synergistically up-regulate the expression of IL-6 and TNF-α in human monocytes. The data also suggest that the effect of anti-Sm in the synergy with anti-RNP might not involve NFkB activation., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The present study was carried out to elucidate the roles of serum autoantibodies in the development of blood-brain barrier (BBB) damages in neuropsychiatric systemic lupus erythematosus (NPSLE)., Methods: Paired serum and CSF samples were obtained from 101 SLE patients when they presented active neuropsychiatric manifestations (69 patients with diffuse psychiatric/neuropsychological syndromes [diffuse NPSLE] and 32 patients with neurologic syndromes or peripheral neuropathy [focal NPSLE]). IgG anti-NR2 subunit of NMDA receptor (anti-NR2), anti-Sm, anti-ribosomal P and IgG anti-cardiolipin in sera and albumin in CSF and sera were measured by ELISA. Blood-brain barrier (BBB) function was evaluated by Q albumin (CSF/serum albumin quotient x 1,000)., Results: Q albumin was significantly higher in acute confusional state (ACS) than in non-ACS diffuse NPSLE (anxiety disorder, cognitive dysfunction, mood disorder and psychosis) or in focal NPSLE. Anti-Sm, but not anti-NR2, anti-P or anticardiolipin, was significantly elevated in ACS compared with the other 2 groups of NPSLE, although serum anti-NR2 was significantly higher in ACS than that in focal NPSLE. Multiple regression analysis confirmed the significant contribution of anti-Sm (p=0.0040), but not anti-NR2 (p=0.5023), anti-P (p=0.2651), or anti-cardiolipin (p=0.6769) in the elevation of Q albumin., Conclusions: The data demonstrate that serum anti-Sm antibodies play a most important role in the disruption of BBB in NPSLE.

The aim was to explore possible correlations of antibodies to extractable nuclear antigens (ENA) with clinical manifestations and disease activity indices in systemic lupus erythematosus (SLE) patients. A total of 70 consecutive SLE patients (64 females) were included. Disease activity was assessed by SLE activity index (SLEDAI), and British Isles Lupus Assessment Group (BILAG). Anti-Ro/SSA correlated positively with, headache (r=0.24, p=0.04), blurring of vision (r=0.25, p=0.03) and SLEDAI (r=0.25, p=0.04) and negatively with C3 (r=-0.35, p=0.003). Anti-Ro/SSA correlated with anti La/SSB antibodies (r=0.69, p<0.001), but not with anti-DNA, anti-RNP and anti-Sm antibodies. Anti-La/SSB antibodies correlated with headache (r=0.26, p=0.03), SLEDAI (r=0.25, p=0.03) and negatively with C3 (r=-0.34, p=0.004). Anti-La/SSB did not correlate with anti-RNP or anti-Sm antibodies. Anti-Sm antibodies correlated with disease duration (r=0.34, p=0.003), 24 hours urinary proteins (r=0.31, p=0.008), SLEDAI (r=0.31, p=0.009), BILAG renal score (r=0.29, p=0.02) and negatively with age at onset (r=-0.27, p=0.02), WBCs (r=-0.29, p=0.014) and C4 (r=-0.25, p=0.049). In multivariate analyses, anti-Ro/SSA antibodies remained associated with headache, blurring of vision and C3 and anti-La/SSB antibodies remained associated with C3 and with headache. Anti-Sm antibodies were independently associated with disease duration and total SLEDAI scores, while anti-RNP antibodies remained significantly associated with BILAG mucocutaneous scores only. Antibodies to ENAs are associated with clinical aspects of SLE and may play a role in the assessment of disease activity. Insight into these ENAs may lead to new approaches to diagnostic testing, accurate evaluation of disease activity and lead to target approach for SLE.

Objective This article aims to determine the serological biomarkers which can be considered as risk factors of systemic lupus erythematosus (SLE)-associated pulmonary arterial hypertension by a systematic review and meta-analysis. Methods This study was conducted in accordance with the PRISMA statement. The search database included MEDLINE, EMBASE, Cochrane Library and Scopus. The Newcastle-Ottawa scale was used for the quality assessment. The odds ratio was the primary measure of effect of the risk factors. Results Twelve studies were included in this meta-analysis. The results identified the anti-RNP antibody and anti-Sm antibody as risk factors for SLE-associated pulmonary arterial hypertension with the pooled odds ratios 3.68 (95% confidence interval 2.04-6.63, P < 0.0001) and 1.71 (95% confidence interval 1.06-2.76, P = 0.03), respectively. Conclusion Pulmonary arterial hypertension is a serious complication of SLE with a worse prognosis than SLE patients without pulmonary arterial hypertension. The early recognition of pulmonary arterial hypertension with transthoracic echocardiography routinely performed in SLE patients with risk factors is necessary, especially in Asian patients.

Detection of autoantibodies in systemic lupus erythematosus (SLE) plays an important role in timely diagnosis and earlier treatment of SLE. In this study, we used a SmD1 polypeptide-based ELISA to determine anti-SmD1 antibody in 269 SLE, including100 naïve (had not been treated with steroids or immunosuppressants at study inception) SLE patients and 169 non-naive SLE patients; 233 controls with other rheumatic diseases (RDC) (70 RA, 40 AS, 73SSc, and 50 SS), and 110 healthy controls (HC) group. The positive rate of anti-SmD1 among all SLE patients was 60.97%, higher than that in the RDC group (13.30%, P = 0.000) or the HC group (9.09%, P = 0.000). The positive rate of anti-SmD1 in non-naive SLE patients was higher than that for anti-dsDNA antibodies (44.97%, P = 0.03). Positivity for anti-SmD1 only was found in 14.00% of naive SLE patients and 16.00% of non-naive SLE patients. In naive SLE patients, the serum concentration of anti-SmD1 was lower after treatment than before treatment (P = 0.039). Active SLE patients positive for anti-SmD1 were more likely to have malar rash, rash, nonscarring alopecia, PAH and hypocomplementemia. High positivity for anti-SmD1 only in patients with SLE indicated the importance and necessity of detection of anti-SmD1 in patients with SLE.

We describe a 28-year-old man with linear atrophoderma of Moulin (LAM), whose serum immunological markers were abnormal (including antinuclear antibody, ribonucleoprotein, immunoglobulin M and anti-SM antibody). In addition, however, a histological analysis identified unexpected connective tissue disease changes in this patient. We speculate that the pathogenesis of LAM is associated with immunity or that LAM itself is a kind of connective tissue disease., (© 2016 The Australasian College of Dermatologists.)

Objectives: To investigate the clinical value of anti-Sm antibodies in diagnosis and monitoring of systemic lupus erythematosus (SLE) and their ability to predict lupus flares compared with that of anti-dsDNA antibody and complement (C3) assays., Methods: Autoantibodies against Smith antigen (Sm) and double-stranded DNA (dsDNA) in sera from SLE (n=232), myositis (n=26), systemic sclerosis (n=81), Sjögren's syndrome (n=88), and rheumatoid arthritis patients (n=165) and healthy donors (n=400) were determined by using enzyme-linked immunosorbent assays (both from Euroimmun). New thresholds for both autoantibodies were calculated by receiver operating characteristics (ROC) curve analysis. Cross-sectional, longitudinal and predictive analyses of anti-Sm and disease activity were also performed., Results: Sensitivities of 25.9% for anti-Sm (cut-off: 3.6 relative units/ml) and 30.2% for anti-dsDNA (cut-off 157.4 international units/ml) were obtained at a specificity of 99%. 14.8% of anti-dsDNA-negative patients were positive for anti-Sm, and more than half (51.4%) of anti-dsDNA-positive patients were also positive for anti-Sm. Anti-Sm antibodies were associated with age (p=0.0174), the number of ACR criteria (p=0.0242), the ACR criteria renal (p=0.0350) and neurologic disorder (p=0.0239), the BILAG category constitutional symptoms (p=0.0227), fatigue (p=0.0311) and cross-sectional disease activity (r=0.2519, p=0.0224). Although no correlations with lupus activity were observed in the longitudinal and predictive analysis, a remarkable association was found between anti-Sm and proteinuria., Conclusions: Anti-Sm antibodies are essential for diagnosis of SLE, especially in anti-dsDNA-negative patients. However, our data suggest that anti-Sm monitoring is only helpful in SLE patients with active lupus nephritis.

Background: Current non-invasive biomarkers for Crohn's disease are limited in their utility. Progress in identifying individual autoantigens and autoantibodies in Crohn's disease has been challenging due to limitations of available immunoassays., Aims: Our aim was to identify autoantibodies associated with Crohn's disease that may be useful in diagnosis and management using an innovative protein array technology, namely nucleic acid programmable protein arrays [NAPPA]., Methods: Serum samples of 96 patients with established Crohn's disease and 96 healthy controls were included and evenly split into discovery and validation sets randomly. Autoantibodies of both IgG and IgA classes were profiled against ~1900 human proteins in the discovery set on NAPPA. Autoantibodies discovered to be Crohn's disease-specific were further validated in the independent validation set by enzyme-linked immunosorbent assay., Results: Overall, reactivity of IgG autoantibodies was stronger than that of IgA autoantibodies; however, IgA autoantibodies showed greater differential reactivity between cases and controls. Four IgA autoantibodies against SNRPB, PRPH, PTTG1 and SNAI1 were newly identified with sensitivities above 15% at 95% specificity, among which anti-SNRPB-IgA had the highest sensitivity of 24.0%. Autoantibodies associated with specific disease subtypes were also found., Conclusions: As one of the first studies to use immunoproteomics for the identification of autoantibodies in Crohn's disease, our results support the utility of NAPPA in implementing future expanded studies with better coverage of the human proteome and microbial proteomes relevant to Crohn's disease and identifying antibody markers that may have clinical impact in diagnosis and management., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Background: SmD1-amino-acid 83-119 peptide (SmD183-119) is the major epitope of Smith (Sm) antigen, which is specific for adult systemic lupus erythematosus (SLE). The anti-SmD183-119 antibody has exhibited higher sensitivity and specificity than anti-Sm antibody in diagnosing adult SLE. However, the utility of anti-SmD183-119antibodies remains unclear in children with SLE (cSLE). This study aimed to assess the characteristics of anti-SmD183-119antibody in the diagnosis of cSLE., Methods: Samples from 242 children with different rheumatological and immunological disorders, including autoimmune diseases (SLE [n = 46] and ankylosing spondylitis [AS, n = 11]), nonautoimmune diseases (Henoch-Schonlein purpura [HSP, n = 60], idiopathic thrombocytopenia purpura [n = 27], hematuria [n = 59], and arthralgia [n = 39]) were collected from Shanghai Children's Medical Center from March 6, 2012 to February 27, 2014. Seventy age- and sex-matched patients were enrolled in this study as the negative controls. All the patients' sera were analyzed for the anti-SmD183-119, anti-Sm, anti-U1-nRNP, anti-double-stranded DNA (dsDNA), anti-nucleosome, anti-SSA/Ro60, anti-SSA/Ro52, anti-SSB, anti-Scl-70, and anti-histone antibodies using the immunoblotting assay. The differences in sensitivity and specificity between anti-SmD183-119 and anti-Sm antibodies were compared by Chi-square test. The correlations between anti-SmD183-119and other auto-antibodies were analyzed using the Spearman's correlation analysis. A value of P< 0.05 was considered statistically significant., Results: Thirty-six out of 46 patients with cSLE were found to be positive for anti-SmD183-119, while 12 patients from the cSLE cohort were found to be positive for anti-Sm. Compared to cSLE, it has been shown that anti-SmD183-119 was only detected in 27.3% of patients with AS and 16.7% of patients with HSP. In comparison with anti-Sm, it has been demonstrated that anti-SmD183-119 had a higher sensitivity (78.3% vs. 26.1%, χ2 = 25.1, P< 0.05) and a lower specificity (90.8% vs. 100%, χ2 = 13.6, P< 0.05) in the diagnosis of cSLE. Further analysis revealed that anti-SmD183-119antibodies were positively correlated with anti-dsDNA, anti-nucleosome, and anti-histone antibodies in cSLE. Moreover, it has been clearly shown that anti-SmD183-119 was more sensitive than anti-Sm in discriminating autoimmune diseases from nonautoimmune disorders in patients with arthralgia or hematuria., Conclusions: Measurement of anti-SmD183-119in patients with cSLE has a higher sensitivity and a marginally lower specificity than anti-Sm. It has been suggested that inclusion of anti-SmD183-119testing in the integrated laboratory diagnosis of cSLE may significantly improve the overall sensitivity in child populations., Competing Interests: There are no conflicts of interest.

Objective: Increased levels of type I interferon (IFN) and type I IFN-regulated genes are found in patients with systemic lupus erythematosus (SLE) and may be central to its pathogenesis. Mitochondrial antiviral signaling protein (MAVS) is a key regulator of type I IFN that undergoes a dramatic prion-like aggregation and self propagates the activation signal from viral RNA to amplify downstream IFN production. We undertook this study to determine whether such MAVS aggregates might play a role in the sustained increased production of type I IFN in SLE., Methods: Peripheral blood mononuclear cells were isolated and mitochondrial extracts were prepared. MAVS aggregation was detected by semidenatured agarose gel electrophoresis and confirmed by immunofluorescence staining. MAVS-associated signaling proteins were analyzed by Western blotting. MAVS aggregation-associated gene expression signature was analyzed by microarray., Results: In blood cells from 22 of 67 SLE patients, essentially all MAVS was in a high molecular weight aggregated form. None of 6 rheumatoid arthritis patients and only 3 of 33 healthy controls had abnormal MAVS. Compared to MAVS aggregate-negative patients, MAVS aggregate-positive SLE patients had significantly higher serum levels of IFNβ and significantly increased levels of autoantibodies against Sm and U1 RNP. Gene array data revealed a characteristic gene expression pattern in these patients, with altered expression of genes involved in IFN signaling and membrane trafficking., Conclusion: Persistent MAVS aggregates may lead to increased type I IFN production and result in unmitigated signals leading to autoimmunity., (© 2016, American College of Rheumatology.)

Aim: We investigated whether anti-Smith (Sm) is associated with the outcome of kidney biopsy-proven lupus nephritis., Methods: We retrospectively analyzed clinical, laboratory and histological results in 90 patients with kidney biopsy-proven lupus nephritis. We defined persistent administration of immunosuppressants for more than 3 months after the kidney biopsy as early poor outcome of lupus nephritis. We compared baseline variables and delta values of lupus nephritis-related variables between patients with and without anti-Sm. The independent predictive values for early poor outcome were analyzed using logistic regression analysis., Results: The median age was 32.0 years old, and 77 patients (85.5%) were women. Anti-Sm was found in 44 of 90 patients (48.8%). When we analyzed the differences in delta values of variables reflecting the kidney function or the early poor outcome between patients with and without anti-Sm, we found significant difference in the early poor outcome between the two groups (80.0% of patients having anti-Sm vs. 56.5% of those not having anti-Sm, P = 0.022). In multivariate logistic regression analysis, along with age and Systemic Lupus Erythematosus Disease Activity Index, the presence of anti-Sm increased the potential of the early poor outcome of lupus nephritis (odds ratio 2.870, 95% confidence interval, 1.033, 7.976, P = 0.043)., Conclusion: Our data suggest that anti-Sm identified at kidney biopsy might have a predictive value for the early poor outcome of biopsy-proven lupus nephritis during the follow-up period., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Pristane-treated mice chronically produce high levels of anti-ribonucleoprotein/Smith (anti-Sm/RNP) and other lupus autoantibodies. The present study addressed how these autoantibody levels are maintained over time., Methods: Lupus was induced in BALB/c mice using pristane. Naïve B cells, switched memory B cells, switched plasmablasts, and plasma cells were flow-sorted and total IgG and anti-U1A (RNP) autoantibodies were determined with ELISA., Results: B cells with a switched "memory-like" (CD19(+)CD138(-)IgM(-)IgD(-)) (sMB) phenotype were increased in pristane-treated mice and expressed higher levels of Toll like receptor 7 (Tlr7) than cells with this phenotype from untreated mice. Flow-sorted sMB cells from pristane-treated mice did not secrete IgG spontaneously, but were hyper-responsive to both synthetic (R848) and natural (apoptotic cells) TLR7 ligands, resulting in increased IgG production in vitro. The flow-sorted sMB cells also could be driven by R848 to produce IgG anti-U1A autoantibodies. Production of IgG was strongly inhibited by both JSH-23 and SB203580, suggesting that the canonical NFκB and p38 MAPK pathways, respectively, contribute to the TLR7 ligand hyper-responsiveness of sMB from pristane-treated mice., Conclusions: The switched memory B cell subset from pristane-treated mice is expanded and shows an increased propensity to undergo terminal (plasma cell) differentiation in response to synthetic and natural TLR7 ligands. The data suggest that the decreased clearance of apoptotic cells characteristic of pristane-treated mice might help maintain high serum levels of anti-RNP/Sm autoantibodies.

MHC, especially HLA-DR3 and HLA-DR2, is one of the most important genetic susceptibility regions for systemic lupus erythematosus. Human studies to understand the role of specific HLA alleles in disease pathogenesis have been hampered by the presence of strong linkage disequilibrium in this region. To overcome this, we produced transgenic mice expressing HLA-DR3 (DRβ1*0301) and devoid of endogenous class II (both I-A and I-E genes, AE(0)) on a lupus-prone NZM2328 background (NZM2328.DR3(+)AE(0)). Both NZM2328 and NZM2328.DR3(+)AE(0) mice developed anti-dsDNA and glomerulonephritis, but anti-dsDNA titers were higher in the latter. Although kidney histological scores were similar in NZM2328 and NZM2328.DR3(+)AE(0) mice (7.2 ± 4.3 and 8.6 ± 5.7, respectively, p = 0.48), the onset of severe proteinuria occurred earlier in NZM2328.DR3(+)AE(0) mice compared with NZM2328 mice (median, 5 and 9 mo respectively, p < 0.001). Periarterial lymphoid aggregates, classic wire loop lesions, and occasional crescents were seen only in kidneys from NZM2328.DR3(+)AE(0) mice. Interestingly, NZM2328.DR3(+)AE(0) mice, but not NZM2328 mice, spontaneously developed anti-Smith (Sm) Abs. The anti-Sm Abs were seen in NZM2328.DR3(+)AE(0) mice that were completely devoid of endogenous class II (AE(-/) (-)) but not in mice homozygous (AE(+/+)) or heterozygous (AE(+/-)) for endogenous MHC class II. It appears that only HLA-DR3 molecules can preferentially select SmD-reactive CD4(+) T cells for generation of the spontaneous anti-Sm immune response. Thus, our mouse model unravels a critical role for HLA-DR3 in generating an autoimmune response to SmD and lupus nephritis in the NZM2328 background., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy characterized by a highly variable course and outcome. The disease is believed to be driven by B-cell receptor (BCR) signals generated by external antigens and/or cell-autonomous BCR interactions, but direct in vivo evidence for this is still lacking. To further define the role of the BCR pathway in the development and progression of CLL, we evaluated the capacity of different types of antigen/BCR interactions to induce leukemia in the Eμ-TCL1 transgenic mouse model. We show that cell autonomous signaling capacity is a uniform characteristic of the leukemia-derived BCRs and represents a prerequisite for CLL development. Low-affinity BCR interactions with autoantigens generated during apoptosis are also positively selected, suggesting that they contribute to the pathogenesis of the disease. In contrast, high-affinity BCR interactions are not selected, regardless of antigen form or presentation. We also show that the capacity of the leukemic cells to respond to cognate antigen correlates inversely with time to leukemia development, suggesting that signals induced by external antigen increase the aggressiveness of the disease. Collectively, these findings provide in vivo evidence that the BCR pathway drives the development and can influence the clinical course of CLL.

Objective: The aim of this study was to clarify the clinical characteristics and predictors of silent LN (SLN), a type of LN in SLE without abnormal urinalysis or renal impairment., Methods: Of 182 patients who underwent renal biopsy, 48 did not present with abnormal urinalysis or renal impairment at the time of biopsy. The patients with LN (SLN group, n = 36) and those without LN (non-LN group, n = 12) were compared with respect to their baseline characteristics. Bivariate analysis comprised Fisher's exact test and the Mann-Whitney test, whereas multivariate analysis employed binomial logistic regression analysis., Results: LN was histopathologically identified in 36 of 48 patients. According to the International Society of Nephrology/Renal Pathology Society classification, 72% of the SLN patients were classified as having class I/II, with a further 17% having class III/IV. Bivariate analyses indicated that platelet count, serum albumin, complement components (C3 and C4), complement haemolytic activity (CH50), anti-Sm antibody titre and anti-ribonucleoprotein antibody titre were significantly different between groups. Multivariate analysis indicated that CH50 and C3 titres were significantly lower in the SLN group, whereas anti-Sm antibody titre was significantly higher. The cut-off titre, calculated based on the receiver operating characteristic curve for CH50, was 33 U/ml, with a sensitivity and specificity of 89% and 83%, respectively. The cut-off titre for anti-Sm antibodies was 9 U/ml, with a sensitivity and specificity of 74% and 83%, respectively., Conclusion: Low titres of CH50 and C3 and a high titre of anti-Sm antibody were identified as predictors of SLN., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Recent advances in mass spectrometry-based proteomic methods have allowed variable (V)-region peptide signatures to be derived from human autoantibodies present in complex serum mixtures. Here, we analysed the clonality and V-region composition of immunoglobulin (Ig) proteomes specific for the immunodominant SmD protein subunit of the lupus-specific Sm autoantigen. Precipitating SmD-specific IgGs were eluted from native SmD-coated ELISA plates preincubated with sera from six patients with systemic lupus erythematosus (SLE) positive for anti-Sm/RNP. Heavy (H)- and light (L)-chain clonality and V-region sequences were analysed by 2-dimensional gel electrophoresis and combined de novo database mass spectrometric sequencing. SmD autoantibody proteomes from all six patients with SLE expressed IgG1 kappa restricted clonotypes specified by IGHV3-7 and IGHV1-69 H-chains and IGKV3-20 and IGKV2-28 L-chains, with shared and individual V-region amino acid replacement mutations. Clonotypic sharing and restricted V-region diversity of systemic autoimmunity can now be extended from the Ro/La cluster to Sm autoantigen and implies a common pathway of anti-Sm autoantibody production in unrelated patients with SLE., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: Neuropsychiatric manifestation in systemic lupus erythematosus (NPSLE) is one of the most serious complications of the disease. Previous studies revealed the strong association between serum anti-Sm and organic brain syndrome, consisting mainly of acute confusional state (ACS) of diffuse psychiatric/neuropsychological syndromes (diffuse NPSLE). However, the precise mechanism by which anti-Sm causes diffuse NPSLE remains unclear. Of note, recent studies demonstrated that anti-U1 RNP antibodies (anti-RNP) in cerebrospinal fluid (CSF) are associated with NPSLE. The present study was designed to explore the association of anti-Sm antibodies in CSF with NPSLE., Methods: Paired serum and CSF specimens were obtained from 72 patients with NPSLE (49 with diffuse NPSLE, 23 with neurological syndromes or peripheral neuropathy (focal NPSLE) and from 22 control patients with non-SLE neurological diseases. Sera were also obtained from 41 patients with active SLE without neuropsychiatric manifestations (non-NPSLE). Anti-Sm and anti-RNP were measured by enzyme-linked immunosorbent assay (ELISA). Blood-brain barrier (BBB) function and intrathecal anti-Sm production were evaluated by Q albumin and CSF anti-Sm index, respectively. Binding of anti-Sm to neuroblastoma cell lines SK-N-MC and Neuro2a was examined by flow cytometry and by cell ELISA., Results: Anti-Sm and anti-RNP in CSF and sera were elevated in NPSLE compared with non-SLE control. CSF anti-Sm, but not CSF anti-RNP, was significantly elevated in ACS compared with non-ACS diffuse NPSLE or with focal NPSLE. By contrast, there were no significant differences in serum anti-Sm or anti-RNP among subsets of NPSLE and non-NPSLE. Whereas there were no significant differences in CSF anti-Sm index, Q albumin was elevated in ACS compared with non-ACS or with focal NPSLE. Notably, CSF anti-Sm was correlated with Q albumin (r = 0.2373, P = 0.0447) or with serum anti-Sm (r = 0.7185, P <0.0001) in 72 patients with NPSLE. Finally, monoclonal anti-Sm and purified human anti-Sm bound to the surface of SK-N-MC and Neuro2a., Conclusions: These results demonstrate that the elevation of CSF anti-Sm through transudation from systemic circulation due to damaged BBB plays a critical role in the pathogenesis of ACS. More importantly, the data indicate that anti-Sm is yet another autoantibody with presumed neural toxicity, but might not be the last.

Background: Congenital grouped skin lesions are alarming signs of a variety of threatening diagnoses of quite different origin. The present case report shows an impressive clinical pattern of a neonate and illustrates the difficulty in differential diagnosis of mixed connective tissue disease and neonatal lupus erythematosus in newborns. This reported case is to our knowledge the first description of an unrecognized mixed connective tissue disease in the mother with an unusual clinical manifestation in the newborn, comprising skin lesions, neurological damage and non-typical antibody constellation., Case Presentation: We report on a Caucasian female neonate from a perinatally asymptomatic mother, who presented with grouped facial pustular-like skin lesions, followed by focal clonic seizures caused by multiple ischemic brain lesions. Herpes simplex virus infection was excluded and both the mother and her infant had the antibody pattern of systemic lupus erythematosus and neonatal lupus erythematosus, respectively. However, clinical signs in the mother showed overlapping features of mixed connective tissue disease., Conclusion: This case report emphasizes congenital Lupus erythematosus and mixed connective tissue disease as important differential diagnoses of grouped skin lesions in addition to Herpes simplex virus-infection. The coexistence of different criteria for mixed connective tissue disease makes it difficult to allocate precisely maternal and congenital infantile disease.

Aim: Clinical features of systemic lupus erythematosus (SLE) have been described from different geographical regions around the world. However, data from North African countries, including Tunisia, are scarce., Methods: The aim of this retrospective multicenter study was to analyze demographic, clinical, laboratory features and outcome of SLE in Tunisia throughout 14 Departments of Internal Medicine and to compare them with those of other ethnic and geographic groups., Results: Seven hundred and forty-nine cases of SLE were recorded (American College of Rheumatology criteria) during a 17-year period (1989-2006). They were 676 women and 73 men with an average age at SLE onset of approximately 30.66 years. Our Tunisian patients were characterized by a high frequency of photosensitivity (67.6%), malar rash (68.7%), renal involvement (49.5%) and anti-Sm antibodies (44.8%). Infections were the main complications. Fifty-six (7.5%) patients died during the study period., Conclusion: Potential limitations and biases in our study need discussion. Specific recruitment of patients in tertiary referral centers may be the source of selection bias and adding to the frequency of moderate or even severe diseases. The therapeutic management and outcome monitoring were heterogeneous due to the fact that patients were evaluated by different doctors. However, this study remains the most representative of Tunisian SLE patients recruited from all parts of Tunisia., (© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Objective: To evaluate serum interferon-α (IFNα) activity in the context of autoantibody profiles in patients with juvenile dermatomyositis (JDM)., Methods: Sera from 36 patients with JDM were analyzed. Autoantibody profiles were determined by probing microarrays, which were fabricated with ∼80 distinct autoantigens, with serum and a Cy3-conjugated secondary antibody. Arrays were scanned and analyzed to determine antigen reactivity. Serum IFNα activity was measured using a functional reporter cell assay. Sera were assayed alone or in combination with cellular material released from necrotic U937 cells to stimulate peripheral blood mononuclear cells from healthy donors in vitro, and IFNα production in culture was measured by a dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA)., Results: Reactivity against at least 1 of 41 autoantigens on the microarray, including Ro 52, Ro 60, La, Sm, and RNP, was observed in 75% of the serum samples from patients with JDM. IFNα activity was detected in 7 samples by reporter cell assay. The reporter cell assay showed a significant association of reactivity against Ro, La, Sm, and proliferating cell nuclear antigen with serum IFNα activity (P = 0.005). Significance Analysis of Microarrays (SAM) identified increased reactivity against Sm, RNP, Ro 52, U1-C, and Mi-2 in these sera. Sixteen samples induced IFNα production as measured by DELFIA, and there was a significant association of reactivity against Ro, La, Sm, and RNP with the induction of IFNα by serum and necrotic cell material (P = 0.034). SAM identified increased reactivity against Ro 60 in these sera., Conclusion: These data support the hypothesis that nucleic acid-associated autoantibodies, including the Ro/La and Sm/RNP complexes, may stimulate the production of active IFNα in children with JDM., (Copyright © 2013 by the American College of Rheumatology.)

A 59-year-old woman was referred to our hospital because of severe anemia and leucopenia. Although she developed mild arthralgia without the typical symptoms of systemic lupus erythematosus (SLE), positivity for anti-Sm antibodies led us to a diagnosis of late-onset SLE. Autoimmune hemolytic anemia (AIHA) and suppression of reticulocyte production were considered to have been involved in the etiology of severe anemia. Administration of oral prednisolone (PSL) resulted in a marked improvement of the hematological abnormalities. As late-onset SLE is rare and patients tend to show the typical symptoms less frequently, close attention should be focused on latent symptoms and immunological findings.

Objective: Autoreactive CD4 T cells specific for nuclear peptide antigens play an important role in tolerance breakdown during the course of systemic lupus erythematosus (SLE). However, reliable detection of these cells is limited due to their low frequency in peripheral blood. The authors assess autoreactive CD4 T cells in a representative SLE collective (n=38) by flow cytometry and study the influence of regulatory T cells (Treg) on their antigenic challenge., Methods: CD4 T-cell responses were determined according to intracellular CD154 expression induced after 6-h short-term in-vitro stimulation with the SLE-associated autoantigen SmD1(83-119). To clarify the influence of Treg on the activation of autoreactive CD4 T cells, CD25 Treg were depleted by magnetic activated cell sorting before antigen-specific stimulation in selected experiments., Results: In the presence of Treg, autoreactive CD4 T-cell responses to SmD1(83-119) were hardly observable. However, Treg removal significantly increased the frequency of detectable SmD1(83-119)-specific CD4 T cells in SLE patients but not in healthy individuals. Consequently, by depleting Treg the percentage of SmD1(83-119)-reactive SLE patients increased from 18.2% to 63.6%. This unmasked autoreactivity of CD4 T cells correlated with the disease activity as determined by the SLE disease activity index (p=0.005*, r=0.779)., Conclusions: These data highlight the pivotal role of the balance between autoreactive CD4 T cells and CD25 Treg in the dynamic course of human SLE. Analysing CD154 expression in combination with a depletion of CD25 Treg, as shown here, may be of further use in approaching autoantigen-specific CD4 T cells in SLE and other autoimmune diseases.

Although systemic lupus erythematosus (SLE) is a multigenic autoimmune disorder, HLA-D is the most dominant genetic susceptibility locus. This study was undertaken to investigate the hypothesis that microbial peptides bind HLA-DR3 and activate T cells reactive with lupus autoantigens. Using HLA-DR3 transgenic mice and lupus-associated autoantigen SmD protein, SmD(79-93) was identified to contain a dominant HLA-DR3 restricted T cell epitope. This T cell epitope was characterized by using a T-T hybridoma, C1P2, generated from SmD immunized HLA-DR3 transgenic mouse. By pattern search analysis, 20 putative mimicry peptides (P2-P21) of SmD(79-93,) from microbial and human origin were identified. C1P2 cells responded to SmD, SmD(79-93) and a peptide (P20) from Vibro cholerae. Immunization of HLA-DR3 mice with P20 induced T cell responses and IgG antibodies to SmD that were not cross-reactive with the immunogen. A T-T hybridoma, P20P1, generated from P20 immunized mice, not only responded to P20 and SmD(79-93), but also to peptides from Streptococcus agalactiae (P17) and human-La related protein (P11). These three T cell mimics (P20, P11 and P17) induced diverse and different autoantibody response profiles. Our data demonstrates for the first time molecular mimicry at T cell epitope level between lupus-associated autoantigen SmD and microbial peptides. Considering that distinct autoreactive T cell clones were activated by different microbial peptides, molecular mimicry at T cell epitope level can be an important pathway for the activation of autoreactive T cells resulting in the production of autoantibodies. In addition, the novel findings reported herein may have significant implications in the pathogenesis of SLE., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

MicroRNAs (miRNAs) may play important roles in SLE, but genetic polymorphisms of miRNAs and their relationships with various autoantibodies present in SLE patients remain unclear. Here, we report that 213 SLE patients and 209 healthy individuals of Chinese had been taken into this case-control studies, which had been performed by selecting two miRNAs (hsa-mir-146a rs2910164 G>C, and hsa-mir-499 rs3746444 T>C) to analyze the genetic polymorphisms. The single nucleotide polymorphism (SNP) variants had been analyzed by PCR-RFLP and serum anti-ribonucleoprotein (anti-RNP), anti-Sm nuclear antigen (anti-Sm) antibodies had been determined by an anti-ENA kit and serum anti-double-stranded DNA (anti-dsDNA) antibodies had been assessed by indirect immunofluorescence. We found that hsa-mir-146a rs2910164 and hsa-mir-499 rs3746444 polymorphisms had no significant relationship with SLE susceptibility. The genotype frequencies of rs2910164 (GG, CC, and GC) were 16, 37, and 47% in SLE patients, but 11, 39, and 50% in healthy group (P = 0.397), respectively; The genotype frequencies of rs3746444 (CC, TT, and TC) were 3, 74, and 23% in SLE patients, but 3, 76, and 22% in healthy group (P = 0.892), respectively. The G and C allele frequencies of rs2910164 were 39 and 61% in SLE patients, but 36 and 64% in healthy group (P = 0.990), respectively. The C and T allele frequencies of rs3746444 were 15 and 85% in SLE patients, but 14 and 86% in healthy group (P = 0.702), respectively. In addition, we also showed no significant difference in the distribution of rs2910164 and rs3746444 genotypes in each of the three antibodies (anti-RNP, anti-Sm, and anti-dsDNA).

Introduction: Testing for autoantibodies to extractable nuclear antigens (ENA) is essential in the investigation of connective tissue disease. Counterimmunoelectrophoresis is an early described testing methodology for antibodies to ENAs, but is labour-intensive, only moderately sensitive, and reliant on high-quality reference sera. Enzyme-linked immunosorbent assay (ELISA) is automatable for relatively high sample throughput, but has issues with false positives. The addressable laser bead immunoassay (ALBIA) is a multiplex technology which can assess several antibody specificities simultaneously on a small serum sample. We report performance of an ALBIA system compared with CIE and ELISA., Methods: Samples from 100 systemic sclerosis patients attending Royal Free Hospital in 2007 and 99 SLE patients attending St Thomas's Hospital in 2007-2008 were studied. All samples were tested for antibodies to RNP, Sm, Ro, La, Scl-70, Jo-1 by in-house CIE, FIDIS™ ALBIA (BMD, France), and ELISAs (Phadia, Germany). Cohen's kappa coefficient was used to examine agreement of the different assay methods for the same antibody. McNemar's test was used to detect differences between methodologies., Results: One sample was positive for anti-Jo-1 by CIE, & confirmed by ALBIA & ELISA. All 198 remaining samples were anti-Jo-1 negative by all 3 methods. With respect to RNP, Ro, La, Scl-70 antibodies, there was good agreement in assay performance between CIE, ALBIA, and ELISA. For Sm, agreement was less good between CIE and ELISA (kappa 0.491), and ALBIA and ELISA (kappa 0.403). Using McNemar's test performance was no different between the 3 assays, with the following exceptions: between CIE and ELISA for Ro-60 (p<0.01) and RNP (p<0.05), and between ALBIA and ELISA for RNP (p<0.01)., Conclusions: The FIDIS™ ALBIA produced similar level of performance as CIE, but with advantages of automation, and less dependence on highly skilled operators. ALBIA represents a potential advancement applicable to routine Immunology diagnostics., (Copyright © 2011. Published by Elsevier B.V.)

The release of hemoglobin (Hb) occurs in some infectious and autoimmune diseases characterized by inflammation. As levels of haptoglobin (Hp) fall, free Hb can cause pathology. Humoral autoreactivity to human Hb was demonstrated in the sera of systemic lupus erythematosus (SLE), leishmania and malaria patients. Serum anti-murine Hb antibody levels in lupus-prone mice also exhibited an age-dependent increase, with progressive organ sequestration; significant isotypic correlation was observed with anti-dsDNA antibodies. A suggestive link between anti-Hb and anti-Sm responses was observed: Human lupus sera expressing anti-Sm antibody reactivity preferentially contained heightened levels of anti-Hb autoantibodies, and immunization of lupus-prone mice with Sm led to enhanced anti-murine Hb reactivity. Human and murine anti-Hb monoclonal antibodies were generated, some of which were preferentially reactive toward disease-associated methemoglobin. Epitope-mapping studies revealed evidence of intra-molecular cross-reactivity. One such autoantibody synergized with Hb to enhance the secretion of pro-inflammatory cytokines while eliciting the increased production of monocyte migratory signals from endothelial cells. Preferential usage of specific variable region gene segments was not observed, although somatic mutations were documented. These studies reveal that, while the etiology, specificity and sequences of anti-Hb autoreactive antibodies can vary, they occur quite frequently and can have inflammatory consequences., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

To investigate the association of anti-Sm antibodies with clinical and serological features in systemic lupus erythematosus. A group of 1,584 patients with SLE was recruited. Clinical and laboratory data were compared between patients with and without anti-Sm antibodies. There were 1,424 females and 160 males, the mean age of the patients was 33.2 +/- 12.3 years, and the mean duration of disease was 32.5 +/- 59.4 months. A total of 469 (29.6%) were anti-Sm antibodies positive. The presence of anti-Sm antibodies was associated with arthritis, renal involvement, malar rash, vasculitis and low serum complement C3. The positive rate of anti-nuclear, anti-dsDNA, anti-La/SSB and anti-U1RNP antibodies were significant higher in anti-Sm positive group when compared with anti-Sm negative group. A trend towards a higher presence of anti-Sm antibodies related to an early disease onset was observed. In conclusion, Anti-Sm antibodies are associated with lupus related clinical and laboratory profiles and correlated significantly with disease activity.

Tetramethylpentadecane (TMPD, or commonly known as pristane)-induced lupus is a murine model of systemic lupus erythematosus (SLE). Renal disease and autoantibody production strictly depend on signaling through the interferon (IFN)-I receptor. The major source of IFN-I is immature monocytes bearing high levels of the surface marker Ly6C. Interferon production is mediated exclusively by signaling through TLR7 and the adapter protein MyD88. It is likely that endogenous TLR7 ligands such as components of small nuclear ribonucleoprotein complexes are involved in triggering disease. Lupus autoantibodies are produced in ectopic lymphoid tissue developing in response to TMPD. This model is well suited for examining links between dysregulated IFN-I production and the pathogenesis of human SLE, which like TMPD-lupus, is associated with high levels of IFN-I.

Objective: (1) To evaluate the spectrum of serum autoantibodies in pediatric-onset systemic lupus erythematosus (pSLE) with a focus on ethnic differences; (2) using cluster analysis, to identify patients with similar autoantibody patterns and to determine their clinical associations., Methods: A single-center cohort study of all patients with newly diagnosed pSLE seen over an 8-year period was performed. Ethnicity, clinical, and serological data were prospectively collected from 156/169 patients (92%). The frequencies of 10 selected autoantibodies among ethnic groups were compared. Cluster analysis identified groups of patients with similar autoantibody profiles. Associations of these groups with clinical and laboratory features of pSLE were examined., Results: Among our 5 ethnic groups, there were differences only in the prevalence of anti-U1RNP and anti-Sm antibodies, which occurred more frequently in non-Caucasian patients (p < 0.0001, p < 0.01, respectively). Cluster analysis revealed 3 autoantibody clusters. Cluster 1 consisted of anti-dsDNA antibodies. Cluster 2 consisted of anti-dsDNA, antichromatin, antiribosomal P, anti-U1RNP, anti-Sm, anti-Ro and anti-La autoantibody. Cluster 3 consisted of anti-dsDNA, anti-RNP, and anti-Sm autoantibody. The highest proportion of Caucasians was in cluster 1 (p < 0.05), which was characterized by a mild disease with infrequent major organ involvement compared to cluster 2, which had the highest frequency of nephritis, renal failure, serositis, and hemolytic anemia, or cluster 3, which was characterized by frequent neuropsychiatric disease and nephritis., Conclusion: We observed ethnic differences in autoantibody profiles in pSLE. Autoantibodies tended to cluster together and these clusters were associated with different clinical courses.

A growing body of experimental and clinical evidence supports the pivotal role of infections in the induction or exacerbation of systemic lupus erythematosus (SLE). Infections can be responsible for aberrant immune response leading to a loss of tolerance towards native proteins. Molecular mimicry, especially between Sm or Ro autoantigens and EBV Nuclear Antigen-1 response, as well as the over-expression of type 1 INF genes are among the major contributors to SLE development. On the other hand infections are very common in SLE patients, where they are responsible for 30-50% of morbidity and mortality. Several factors, either genetic, including complement deficiencies or mannose-binding lectin deficiency or acquired such as severe disease manifestations or immunosuppressant use, predispose SLE patients to infections. All types of infections, including bacterial, viral and opportunistic infections, have been reported and the most frequently involved sites of infections are the same as those observed in the general population, including respiratory, skin, and urinary tract infections. Some preventive measures could be adopted in order to reduce the rate of infections in SLE patients: i.e. screening for Mycobacterium tuberculosis and for some chronic viral infections before immunosuppressive treatment; adequate prophylaxes or drug adjustments when indicated, and pneumococcal and influenza vaccinations in patients with stable disease.

Autoimmunity is a serious health problem and understanding the maintenance and loss of tolerance to self-antigens are key issues in developing new therapeutic strategies to treat these diseases. Despite considerable progress toward understanding B cell tolerance and tolerance loss, much remains unknown, particularly regarding B cells specific for antigens targeted in disease. Our interest in systemic lupus erythematosus (SLE), a B cell-mediated autoimmune disease characterized by the production of autoantibodies to numerous nuclear antigens, is focused on understanding B cell tolerance and tolerance loss to the SLE-specific autoantigen Sm in mice and humans. Our work aims to provide the cellular and molecular underpinnings for the development of rational therapies to target autoreactive B cells in human SLE.

Systemic lupus erythematosus (SLE) highlights the dangers of dysregulated B cells and the importance of initiating and maintaining tolerance. In addition to central deletion, receptor editing, peripheral deletion, receptor revision, anergy, and indifference, we have described a new mechanism of B cell tolerance wherein dendritic cells (DCs) and macrophages (MPhis) regulate autoreactive B cells during innate immune responses. In part, DCs and MPhis repress autoreactive B cells by releasing IL-6 and soluble CD40L (sCD40L). This mechanism is selective in that IL-6 and sCD40L do not affect Ig secretion by naïve cells during innate immune responses, allowing immunity in the absence of autoimmunity. In lupus-prone mice, DCs and MPhis are defective in secretion of IL-6 and sCD40L and cannot effectively repress autoantibody secretion suggesting that defects in DC/MPhi-mediated tolerance may contribute to the autoimmune phenotype. Further, these studies suggest that reconstituting DCs and MPhis in SLE patients might restore regulation of autoreactive B cells and provide an alternative to immunosuppressive therapies.

To determine the prevalence of antibodies to individual histone components in collagen disease patients with anti-U1RNP antibodies. Serum samples were examined by enzyme-linked immunosorbent assay. Patients with mixed connective tissue disease (MCTD) and systemic sclerosis (SSc) showed similar levels and patterns of antihistone antibody (AHA) reactivities to individual histones: IgG responses to H2B or H3 and IgM responses to H2B were highest. However, both IgG and IgM AHAs against outer portion of chromatin (H1, H2A, or H2B) were generally higher in SLE compared with other diseases. SLE or SSc patients with anti-U1RNP antibodies showed generally higher AHA levels than in those without them. Thus, the pattern of reactivities to each histone component was dependent on the disease, while the intensity was dependent on both the disease and anti-U1RNP antibodies. The antigenic stimulus in SLE may be different from other connective tissue diseases and is more likely to be native chromatin.