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Scooped by
Gilbert C FAURE
April 20, 2018 4:30 AM
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Objective Although systemic lupus erythematosus (SLE) is the most common autoimmune disease associated with antiphospholipid antibodies (aPL), limited data exist on the impact of SLE on the clinical phenotype of aPL‐positive patients. The primary objective was to compare the clinical, laboratory, and treatment characteristics of aPL‐positive patients with or without SLE. Methods A secure web‐based data capture system stores patient demographics, and aPL‐related clinical and laboratory characteristics. Inclusion criteria include aPL positivity according to the Updated Sapporo Classification Criteria. Patients fulfilling the SLE Classification Criteria and those with no other autoimmune diseases were included in the analysis. Results 672 aPL‐positive patients were recruited from 24 international centers; 426 were without other autoimmune diseases and 197 with SLE. The aPL with SLE group had higher rates of thrombocytopenia, hemolytic anemia, low complements, and IgA anti‐β2 glycoprotein‐I antibodies (aβ₂GPI), whereas the aPL only group had higher rates of cognitive dysfunction and IgG aβ₂GPI. The frequency of arterial and venous thromboses (including recurrent) as well as the pregnancy morbidity were similar between the groups. The prevalence of cardiovascular disease risk factors at the registry entry did not differ between the two groups, except current smoking, which was more frequent in aPL with SLE group. Conclusions Although the frequencies of thrombosis and pregnancy morbidity are similar between aPL‐positive patients with or without SLE, the diagnosis of SLE in persistently aPL‐positive patients is associated with an increased frequency of thrombocytopenia, hemolytic anemia, low complements, and IgA aβ₂GPI positivity. This article is protected by copyright. All rights reserved.
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Scooped by
Gilbert C FAURE
April 13, 2018 8:45 AM
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Objectives The association between mutations in TNFAIP3 , encoding the NF-kB regulatory protein A20, and a new autoinflammatory disease has recently been recognised. This study aims at describing the clinical phenotypes and disease course of patients with A20 haploinsufficiency (HA20).
Methods Data for all cases from the initial publication, and additional cases identified through collaborations since, were collected using standardised data collection forms.
Results A total of 16 patients (13 female) from seven families with a genetic diagnosis of HA20 were included. The disease commonly manifested in early childhood (range: first week of life to 29 years of age). The main clinical symptoms were recurrent oral, genital and/or gastrointestinal ulcers (16/16), musculoskeletal (9/16) and gastrointestinal complaints (9/16), cutaneous lesions (8/16), episodic fever (7/16), and recurrent infections (7/16). Clinical phenotypes varied considerably, even within families. Relapsing-remitting disease course was most common, and one patient died. Laboratory abnormalities included elevated acute-phase reactants and fluctuating presence of various autoantibodies such as antinuclear antibodies (4/10 patients tested) and anti-dsDNA (2/5). Tissue biopsy of different sites revealed non-specific chronic inflammation (6/12 patients tested), findings consistent with class V lupus nephritis in one patient, and pustules and normal results in two patients each. All patients were treated: 4/16 received colchicine and 12/16 various immunosuppressive agents. Cytokine inhibitors effectively suppressed systemic inflammation in 7/9 patients.
Conclusions Early-onset recurrent oral, genital and/or gastrointestinal ulcers are the hallmark feature of HA20. Frequency and intensity of other clinical manifestations varied highly. Treatment regimens should be based on disease severity, and cytokine inhibitors are often required to control relapses.
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Scooped by
Gilbert C FAURE
March 23, 2018 12:40 PM
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These data show that a progressive improvement in disease activity is associated with
correction of pro-inflammatory T-cell lineage specification in patients with active
systemic lupus erythematosus during 12 months of sirolimus treatment. Follow-up placebo-controlled
clinical trials in diverse patient populations are warranted to further define the
role of mTOR blockade in treatment of systemic lupus erythematosus.
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Rescooped by
Gilbert C FAURE
from Immune-Monitoring
March 21, 2018 3:55 AM
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B cells play a central role in systemic lupus erythematosus (SLE) pathophysiology but dysregulated pathways leading to a break in B cell tolerance remain unclear. Since Toll-like receptor 9 (TLR9) favors the elimination of autoreactive B cells in the periphery, we assessed TLR9 function in SLE by analyzing the responses of B cells and plasmacytoid dendritic cells (pDCs) isolated from healthy donors and patients after stimulation with CpG, a TLR9 agonist. We found that SLE B cells from patients without hydroxychloroquine treatment displayed defective in vitro TLR9 responses, as illustrated by the impaired upregulation of B cell activation molecules and the diminished production of various cytokines including antiinflammatory IL-10. In agreement with CD19 controlling TLR9 responses in B cells, decreased expression of the CD19/CD21 complex on SLE B cells was detected as early as the transitional B cell stage. In contrast, TLR7 function was preserved in SLE B cells, whereas pDCs from SLE patients properly responded to TLR9 stimulation, thereby revealing that impaired TLR9 function in SLE was restricted to B cells. We conclude that abnormal CD19 expression and TLR9 tolerogenic function in SLE B cells may contribute to the break of B cell tolerance in these patients.
Via Marcelo de Carvalho Bittencourt
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Suggested by
Société Francaise d'Immunologie
February 27, 2018 1:12 PM
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Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the loss of adaptive immune tolerance to nucleic acid containing antigens. The resulting autoantibodies form immune complexes that promote inflammation and tissue damage. Defining the signals that drive pathogenic autoantibody production is an important step in the development of more targeted therapeutic approaches for lupus, which is currently treated primarily with non-specific immunosuppression. Here, we review the contribution of Bruton’s tyrosine kinase (Btk), a component of B and myeloid cell signaling pathways, to disease in murine lupus models. Both gain- and loss-of-function genetic studies have revealed that Btk plays multiple roles in the production of autoantibodies. These include promoting the activation, plasma cell differentiation, and class switching of autoreactive B cells. Small molecule inhibitors of Btk are effective at reducing autoantibody levels, B cell activation, and kidney damage in several lupus models. These studies suggest that Btk may promote end organ damage both by facilitating the production of autoantibodies and by mediating the inflammatory response of myeloid cells to these immune complexes. While Btk has not been associated with SLE in GWAS studies, SLE B cells display signaling defects in components both upstream and downstream of Btk consistent with enhanced activation of Btk signaling pathways. Taken together, these observations indicate that limiting Btk activity is critical for maintaining B cell tolerance and preventing the development of autoimmune disease. Btk inhibitors, generally well-tolerated and approved to treat B cell malignancy, may thus be a useful therapeutic approach for SLE.
To the Editor:
Innate immune receptors have been found to be involved in the pathogenesis of systemic lupus erythematosus (SLE)1. The binding of nucleic acids to the endosomal Toll-like receptors (TLR) 7 and TLR9 is considered as a triggering mechanism for the production of antinuclear antibodies2,3. Also, the cell membrane-bound TLR (mbTLR) might contribute to enhance immune cell responses in SLE. Besides detecting microorganisms, these receptors engage molecules exposed upon apoptosis, such as the DNA-binding high mobility group protein B1, which is thought to facilitate self-DNA antigenicity4. The contribution of the mbTLR TLR2 and TLR4 to loss of tolerance and development of nephritis has been consistently found in SLE models conducted in transgenic mice5,6,7. However, there is little information about the activation of mbTLR during SLE flares in humans.
We have studied TLR2 and TLR4 protein levels in peripheral blood mononuclear cells from patients with SLE (n = 35) and healthy controls (n = 11) using flow cytometry. Patients were receiving stable medication at the time of the study, and had no signs of active infection. Whereas no global differences in the levels of the mbTLR were noted between the cohorts, the density of TLR4 was significantly increased in the B cells of patients with active (n = 20) …
Address correspondence to Dr. O. Sánchez-Pernaute, Division of Rheumatology, Jiménez Díaz Foundation Health Research Institute and University Hospital, Avda. Reyes Católicos 2, 28040 Madrid, Spain. E-mail: osanchez{at}fjd.es
Via Krishan Maggon
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Suggested by
Société Francaise d'Immunologie
February 17, 2018 3:19 AM
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Background: B-cell differentiation and B-cell tolerance checkpoints may be different in antiphospholipid syndrome (APS) from systemic lupus erythematosus (SLE) and can help to understand differences between them. Our aim was to define alterations of B-cell subsets in patients with primary APS (pAPS) and to compare them with SLE patients and healthy controls (HC). Methods: Cross-sectional study including three study groups: 37 patients with pAPS, 11 SLE patients, and 21 age- and gender-matched HC. We determined the frequencies of different B-cell subsets in peripheral blood naïve and memory compartments. In addition, we measured serum B cell-activating factor (BAFF) levels and circulating pro-inflammatory cytokines, such as IL-6, by commercial ELISA and CBA, respectively. Results: Patients with pAPS showed a lower percentage of immature and naïve B cells than patients with SLE (p = 0.013 and p = 0.010, respectively) and a higher percentage of non-switched memory B cells than patients with SLE (p = 0.001). No differences either in the percentage of switched memory cells or plasma cells were found among the different groups. Serum BAFF levels were higher in SLE patients than in healthy controls and pAPS patients (p = 0.001 and p = 0.017, respectively). A significant increase in the serum BAFF levels was also observed in pAPS patients compared to HC (p = 0.047). Circulating IL-6 levels were higher in SLE and pAPS patients than HC (p = 0.036 and p = 0.048, respectively). A positive correlation was found between serum BAFF and IL-6 levels in patients with SLE but not in pAPS (p = 0.011). Conclusions: Our characterization of peripheral blood B-cell phenotypes in pAPS demonstrates different frequencies of circulating B cells at different stages of differentiation. These differences in the naïve B-cell repertoire could explain the higher number and variety of autoantibodies in SLE patients in comparison to pAPS patients, especially in those with obstetric complications.
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Scooped by
Gilbert C FAURE
January 31, 2018 2:18 PM
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Objectives Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, subtyped according to clinical manifestations and autoantibodies. Evidence concerning cigarette smoking and SLE risk has been conflicting. We investigated smoking and SLE risk, overall and by anti-double stranded DNA (dsDNA) presence, in two prospective cohort studies.
Methods The Nurses’ Health Study (NHS) enrolled 121 701 US female nurses in 1976; Nurses’ Health Study II (NHSII) enrolled 116 430 in 1989. Lifestyle, environmental and medical data were collected through biennial questionnaires. Incident SLE was confirmed by medical record review. Cox regression models estimated HRs of SLE, overall and by dsDNA subtype, in association with time-varying smoking status and cumulative smoking pack-years through the 2-year cycle prior to diagnosis, controlling for potential confounders.
Results Among 286 SLE cases identified (159 in NHS (1978–2012) and 127 in NHSII (1991–2013)), mean age was 49.2 (10.3) years and 42% were dsDNA+ at SLE diagnosis. At baseline, 45% of women had ever smoked, 51% of whom currently smoked. Compared with never smokers, current smokers had increased dsDNA+ SLE risk (HR 1.86 (1.14–3.04)), whereas past smokers did not (HR 1.31 (0.85–2.00)). Women who smoked >10 pack-years (vs never) had an elevated dsDNA+ SLE risk (HR 1.60(95% CI 1.04 to 2.45)) compared with never smokers. No associations were observed between smoking status or pack-years and overall SLE or dsDNA− SLE.
Conclusion Strong and specific associations of current smoking and >10 pack-years of smoking with dsDNA+ SLE were observed. This novel finding suggests smoking is involved in dsDNA+ SLE pathogenesis.
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Scooped by
Gilbert C FAURE
January 17, 2018 11:47 AM
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Scooped by
Gilbert C FAURE
January 10, 2018 3:13 PM
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PLoS One. 2018 Jan 5;13(1):e0186475. doi: 10.1371/journal.pone.0186475. eCollection 2018.
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Scooped by
Gilbert C FAURE
December 31, 2017 10:58 AM
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Journal of Immunology Research is a peer-reviewed, Open Access journal that provides a platform for scientists and clinicians working in different areas of immunology and therapy. The journal publishes research articles, review articles, as well as clinical studies related to classical immunology, molecular immunology, clinical immunology, cancer immunology, transplantation immunology, immune pathology, immunodeficiency, autoimmune diseases, immune disorders, and immunotherapy.
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Scooped by
Gilbert C FAURE
December 12, 2017 8:23 AM
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Lupus Sci Med. 2017 Aug 21;4(1):e000236. doi: 10.1136/lupus-2017-000236. eCollection 2017. Review
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Suggested by
LIGHTING
November 22, 2017 1:53 PM
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Type I IFN and nucleic acid–sensing TLRs are both strongly implicated in the pathogenesis of lupus, with most patients expressing IFN-induced genes in peripheral blood cells and with TLRs promoting type I IFNs and autoreactive B cells. About a third of systemic lupus erythematosus patients, however, lack the IFN signature, suggesting the possibility of type I IFN–independent mechanisms. In this study, we examined the role of type I IFN and TLR trafficking and signaling in xenobiotic systemic mercury-induced autoimmunity (HgIA). Strikingly, autoantibody production in HgIA was not dependent on the type I IFN receptor even in NZB mice that require type I IFN signaling for spontaneous disease, but was dependent on the endosomal TLR transporter UNC93B1 and the endosomal proton transporter, solute carrier family 15, member 4. HgIA also required the adaptor protein-3 complex, which transports TLRs from the early endosome to the late endolysosomal compartments. Examination of TLR signaling pathways implicated the canonical NF-κB pathway and the proinflammatory cytokine IL-6 in autoantibody production, but not IFN regulatory factor 7. These findings identify HgIA as a novel type I IFN–independent model of systemic autoimmunity and implicate TLR-mediated NF-κB proinflammatory signaling from the late endocytic pathway compartments in autoantibody generation.
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Suggested by
LIGHTING
April 17, 2018 6:52 AM
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iral infection could predispose some to at least seven disorders
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Scooped by
Gilbert C FAURE
April 8, 2018 4:59 AM
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Research ArticleImmunologyInflammation Free access | 10.1172/JCI97333 Galectin-9 inhibits TLR7-mediated autoimmunity in murine lupus models Santosh K. Panda,1,2 Valeria Facchinetti,3 Elisaveta Voynova,1 Shino Hanabuchi,1,2 Jodi L. Karnell,1 Richard N. Hanna,1 Roland Kolbeck,1 Miguel A.
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Scooped by
Gilbert C FAURE
March 23, 2018 10:15 AM
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Suggested by
Société Francaise d'Immunologie
February 27, 2018 1:12 PM
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Type I interferons (IFNs) have a prominent role in many aspects of normal innate and adaptive immunity and autoimmunity. However, cell-type specific information about type I IFN expression and autocrine/paracrine signaling is sparse and mostly focused on non-lymphocyte and non-immune .
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
February 24, 2018 11:05 AM
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Background The clinical utility of testing for antiphospholipid antibodies (aPL) of IgA isotype remains controversial. Methodology/Principal Findings To address this issue, we reasoned that if IgA aPL contribute to the clinical manifestations of the antiphospholipid syndrome, then an association with thromboembolic events should manifest in patients whose only aPL is of IgA isotype. We performed a retrospective chart review of 56 patients (31 with systemic lupus erythematosus [SLE] and 25 without SLE) whose only positive aPL was IgA anti-β2-glycoprotein I (isolated IgA anti-β2GPI) and compared their clinical features with 56 individually matched control patients without any aPL. Patients with isolated IgA anti-β2GPI had a significantly increased number of thromboembolic events, as compared to controls. When patients were stratified into those with and without SLE, the association between isolated IgA anti-β2GPI and thromboembolic events persisted for patients with SLE, but was lost for those without SLE. Titers of IgA anti-β2GPI were significantly higher in SLE patients who suffered a thromboembolic event. Among patients with isolated IgA anti-β2GPI, there was an increased prevalence of diseases or morbidities involving organs of mucosal immunity (i.e., gastrointestinal system, pulmonary system, and skin). Conclusions/Significance The presence of isolated IgA anti-β2GPI is associated with an increased risk of thromboembolic events, especially among patients with SLE. IgA anti-β2GPI is associated with an increased prevalence of morbidities involving organs of mucosal immunity.
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
January 31, 2018 1:50 PM
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EMBODY 1 (NCT01262365) and EMBODY 2 (NCT01261793) investigated the efficacy and safety of epratuzumab, a CD22‐targeted humanized monoclonal IgG1 antibody, in patients with systemic lupu
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Scooped by
Gilbert C FAURE
January 12, 2018 1:08 PM
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Int J Rheum Dis. 2018 Jan 4. doi: 10.1111/1756-185X.13249. [Epub ahead of print]
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Scooped by
Gilbert C FAURE
January 3, 2018 11:48 AM
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Endogenous pathogenic antibodies can be enzymatically converted into anti-inflammatory mediators in inflamed tissues, revealing a new strategy to treat autoimmune diseases.
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Scooped by
Gilbert C FAURE
December 26, 2017 3:40 AM
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Journal of Immunology Research is a peer-reviewed, Open Access journal that provides a platform for scientists and clinicians working in different areas of immunology and therapy. The journal publishes research articles, review articles, as well as clinical studies related to classical immunology, molecular immunology, clinical immunology, cancer immunology, transplantation immunology, immune pathology, immunodeficiency, autoimmune diseases, immune disorders, and immunotherapy.
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Scooped by
Gilbert C FAURE
November 24, 2017 2:27 AM
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Background: Systemic Lupus Erythematosus (SLE) is a chronic systemic inflammatory autoimmune disease, the aetiology of which remains only partially characterised. Strong evidence implicates chronic infections in the development and chronicity of autoimmune conditions. Recently, an association has been demonstrated between periodontitis and rheumatoid arthritis. Such observations have led to the investigation of the possible role of periodontitis and oral dysbiosis in other systemic inflammatory conditions, including SLE. The aim of this study was to examine whether there is an association between SLE and periodontitis. Methods: MEDLINE via OVID, EMBASE via OVID, and PsycINFO via OVID databases were searched to identify eligible studies, screened by two independent authors and verified by a third. Studies comparing presence of periodontitis in SLE cases to controls without SLE were included. Data was extracted using a predefined table and papers were appraised using Down’s and Black tool. Mantel–Haenszel meta-analysis was performed using RevMan. Results: Eight case-control studies were included, with 487 SLE cases and a total of 1,383 participants. On meta-analysis of four studies, risk of periodontitis in SLE cases compared to controls was significantly greater with a risk ratio of 1.76 (95% CI 1.29-2.41, p=0.0004). No statistical difference was found in individual measures of periodontitis, such as probing depth or clinical attachment loss, between SLE cases and controls. Conclusion: Our study found a statistically significant increased risk of periodontitis in patients with SLE compared to controls. This finding suggests a possible association between these two conditions. Larger longitudinal studies are needed to confirm this possible association.
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