scholarly journals Siglec-H protects from virus-triggered severe systemic autoimmunity

2016 ◽  
Vol 213 (8) ◽  
pp. 1627-1644 ◽  
Author(s):  
Heike Schmitt ◽  
Sabrina Sell ◽  
Julia Koch ◽  
Martina Seefried ◽  
Sophia Sonnewald ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Murine Cytomegalovirus ◽  
Systemic Autoimmune Disease ◽  
Type I ◽  
Type I Ifn ◽  
Virus Infections ◽  
Systemic Lupus ◽  
Mcmv Infection ◽  
Systemic Autoimmunity

It is controversial whether virus infections can contribute to the development of autoimmune diseases. Type I interferons (IFNs) are critical antiviral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus. Type I IFN is mainly produced by plasmacytoid dendritic cells (pDCs). The secretion of type I IFN of pDCs is modulated by Siglec-H, a DAP12-associated receptor on pDCs. In this study, we show that Siglec-H–deficient pDCs produce more of the type I IFN, IFN-α, in vitro and that Siglec-H knockout (KO) mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo. This did not impact control of viral replication. Remarkably, several weeks after a single mCMV infection, Siglec-H KO mice developed a severe form of systemic lupus–like autoimmune disease with strong kidney nephritis. In contrast, uninfected aging Siglec-H KO mice developed a mild form of systemic autoimmunity. The induction of systemic autoimmune disease after virus infection in Siglec-H KO mice was accompanied by a type I IFN signature and fully dependent on type I IFN signaling. These results show that Siglec-H normally serves as a modulator of type I IFN responses after infection with a persistent virus and thereby prevents induction of autoimmune disease.

scholarly journals Autoantigen TRIM21/Ro52 as a Possible Target for Treatment of Systemic Lupus Erythematosus

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Ryusuke Yoshimi ◽  
Yoshiaki Ishigatsubo ◽  
Keiko Ozato
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Immunosuppressive Drugs ◽  
Systemic Autoimmune Disease ◽  
Type I ◽  
Systemic Lupus ◽  
Molecular Features ◽  
Attractive Therapeutic Target ◽  
Autoimmune Processes

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.

scholarly journals Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections

2021 ◽  
Vol 12 ◽  
Author(s):  
Nadine Szumilas ◽  
Odilia B. J. Corneth ◽  
Christian H. K. Lehmann ◽  
Heike Schmitt ◽  
Svenia Cunz ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Inflammatory Responses ◽  
Type I Interferon ◽  
Acute Infection ◽  
Murine Cytomegalovirus ◽  
Type I ◽  
Virus Infections ◽  
Mcmv Infection ◽  
Interferon Responses ◽  
Deficient Mice

Siglec-H is a DAP12-associated receptor on plasmacytoid dendritic cells (pDCs) and microglia. Siglec-H inhibits TLR9-induced IFN-α production by pDCs. Previously, it was found that Siglec-H-deficient mice develop a lupus-like severe autoimmune disease after persistent murine cytomegalovirus (mCMV) infection. This was due to enhanced type I interferon responses, including IFN-α. Here we examined, whether other virus infections can also induce autoimmunity in Siglec-H-deficient mice. To this end we infected Siglec-H-deficient mice with influenza virus or with Lymphocytic Choriomeningitis virus (LCMV) clone 13. With both types of viruses we did not observe induction of autoimmune disease in Siglec-H-deficient mice. This can be explained by the fact that both types of viruses are ssRNA viruses that engage TLR7, rather than TLR9. Also, Influenza causes an acute infection that is rapidly cleared and the chronicity of LCMV clone 13 may not be sufficient and may rather suppress pDC functions. Siglec-H inhibited exclusively TLR-9 driven type I interferon responses, but did not affect type II or type III interferon production by pDCs. Siglec-H-deficient pDCs showed impaired Hck expression, which is a Src-family kinase expressed in myeloid cells, and downmodulation of the chemokine receptor CCR9, that has important functions for pDCs. Accordingly, Siglec-H-deficient pDCs showed impaired migration towards the CCR9 ligand CCL25. Furthermore, autoimmune-related genes such as Klk1 and DNase1l3 are downregulated in Siglec-H-deficient pDCs as well. From these findings we conclude that Siglec-H controls TLR-9-dependent, but not TLR-7 dependent inflammatory responses after virus infections and regulates chemokine responsiveness of pDCs.

scholarly journals The Role of Genetic Variation Near Interferon-Kappa in Systemic Lupus Erythematosus

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Isaac T. W. Harley ◽  
Timothy B. Niewold ◽  
Rebecca M. Stormont ◽  
Kenneth M. Kaufman ◽  
Stuart B. Glenn ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Systemic Autoimmune Disease ◽  
Type I ◽  
Nucleotide Polymorphisms ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Genome Wide

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated theIFNKlocus in SLE susceptibility. We studiedIFNKsingle nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio=1.93,P=2.5×10−4), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific.IFNKSNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association betweenIFNKSNPs and SLE and skin phenotypes. The serum IFN association suggests thatIFNKvariants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.

scholarly journals OP0005 ELEVATED STAT1 EXPRESSION BUT NOT PHOSPHORYLATION IN LUPUS B CELLS CORRELATES WITH DISEASE ACTIVITY AND INCREASED PLASMABLAST SUSCEPTIBILITY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 4-5
Author(s):  
A. Aue ◽  
F. Szelinski ◽  
S. Weißenberg ◽  
A. Wiedemann ◽  
T. Rose ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Autoimmune Diseases ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
B Cell Subsets

Background:Systemic lupus erythematosus (SLE) is characterized by two pathogenic key signatures, type I interferon (IFN) (1.) and B-cell abnormalities (2.). How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT).Objectives:JAK-STAT inhibition is an attractive therapeutic possibility for SLE (3.). We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared to other autoimmune diseases and healthy controls (HD) and related it to disease activity.Methods:Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T-cells of 21 HD, 10 rheumatoid arthritis (RA), 7 primary Sjögren’s (pSS) and 22 SLE patients was analyzed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs of SLE patients and HD after IFNα and IFNγ incubation were further investigated.Results:SLE patients showed substantially higher STAT1 but not pSTAT1 in B and T-cell subsets. Increased STAT1 expression in B cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker (4.). STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.Figure 1.Significantly increased expression of STAT1 by SLE B cells(A) Representative histograms of baseline expression of STAT1, pSTAT1, STAT3 and pSTAT3 in CD19+ B cells of SLE patients (orange), HD (black) and isotype controls (grey). (B) Baseline expression of STAT1 and pSTAT1 or (C) STAT3 and pSTAT3 in CD20+CD27-, CD20+CD27+ and CD20lowCD27high B-lineage cells from SLE (orange) patients compared to those from HD (black). Mann Whitney test; ****p≤0.0001.Figure 2.Correlation of STAT1 expression by SLE B cells correlates with type I IFN signature (Siglec-1, CD169) and clinical activity (SLEDAI).Correlation of STAT1 expression in CD20+CD27- näive (p<0.0001, r=0.8766), CD20+CD27+ memory (p<0.0001, r=0.8556) and CD20lowCD27high (p<0.0001, r=0.9396) B cells from SLE patients with (A) Siglec-1 (CD169) expression on CD14+ cells as parameter of type I IFN signature and (B) lupus disease activity (SLEDAI score). Spearman rank coefficient (r) was calculated to identify correlations between these parameters. *p≤0.05, **p≤0.01. (C) STAT1 expression in B cell subsets of a previously undiagnosed, active SLE patient who was subsequently treated with two dosages of prednisolone and reanalyzed.Conclusion:Enhanced expression of STAT1 by B-cells candidates as key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold promise to block STAT1 expression and control plasmablast induction in SLE.References:[1]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.[2]Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130-44.[3]Dorner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645-57.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136-45.Disclosure of Interests:Arman Aue: None declared, Franziska Szelinski: None declared, Sarah Weißenberg: None declared, Annika Wiedemann: None declared, Thomas Rose: None declared, Andreia Lino: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen

scholarly journals Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Norzawani Buang ◽  
Lunnathaya Tapeng ◽  
Victor Gray ◽  
Alessandro Sardini ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

scholarly journals Type I IFN signature in childhood-onset systemic lupus erythematosus: a conspiracy of DNA- and RNA-sensing receptors?

2018 ◽  
Vol 20 (1) ◽  
Author(s):  
M. Javad Wahadat ◽  
Iris L. A. Bodewes ◽  
Naomi I. Maria ◽  
Cornelia G. van Helden-Meeuwsen ◽  
Annette van Dijk-Hummelman ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I ◽  
Type I Ifn ◽  
Childhood Onset ◽  
Systemic Lupus ◽  
Dna And Rna ◽  
Onset Systemic Lupus Erythematosus

scholarly journals Drug-Induced Gingival Overgrowth in an 8-Year-Old Girl: A Case Report

2021 ◽  
Vol 13 (3) ◽  
pp. 109-112
Author(s):  
Parviz Torkzaban ◽  
Amir Talaie
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Case Report ◽  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Immunological Tolerance ◽  
Systemic Autoimmune Disease ◽  
Channel Blockers ◽  
Systemic Lupus ◽  
Drug Induced ◽  
Gingival Overgrowth

Systemic lupus erythematosus is a systemic autoimmune disease that involves multi organs. Genetic, endocrine, immunological, and environmental factors influence the loss of immunological tolerance against self-antigens leading to the formation of pathogenic autoantibodies that cause tissue damage through multiple mechanisms. The gingival overgrowth can be caused by three factors: noninflammatory, hyperplastic reaction to the medication; chronic inflammatory hyperplasia; or a combined enlargement due to chronic inflammation and drug-induced hyperplasia. Drug-Induced Gingival Overgrowth is associated with the use of three major classes of drugs, namely anticonvulsants, calcium channel blockers, and immunosuppressants. Due to recent indications for these drugs, their use continues to grow.

scholarly journals Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes

2020 ◽  
Author(s):  
Laura Barnabei ◽  
Hicham Lamrini ◽  
Mathieu Castela ◽  
Nadia Jeremiah ◽  
Marie-Claude Stolzenberg ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Early Onset ◽  
Molecular Mechanisms ◽  
Type I Interferon ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Consensus Sequences ◽  
Expression Of Genes

AbstractSystemic Lupus Erythematosus (SLE) is an autoimmune and inflammatory disease characterized by uncontrolled production of autoantibodies and inflammatory cytokines such as the type-I interferons. Due to the lack of precise pathophysiological mechanisms, treatments are based on broad unspecific immunossupression. To identify genetic factors associated with SLE we performed whole exome sequencing and identified two RELA heterozygous activating mutations in 3 early-onset and familial SLE cases. The corresponding RELA/p65 mutant were abundant in the nucleus but poorly activate transcription of genes controlled by NF-κB consensus sequences. The co-expression of the mutant and wild-type RELA/p65 strongly activated the expression of genes controlled by the IFNα-consensus sequences. These molecular mechanisms lead to the overproduction of type-I IFN in the patients’ cells. Our findings highlight a novel mechanism of autoimmunity where these new RELA mutants are transactivating the type-I IFN genes and are thus promoting type-I interferon production and early-onset SLE, thereby paving the way to the identification of new and specific therapeutic targets.SummaryHeterozygous RELA mutations are associated with Systemic Lupus Erythematosus, with increased expression of genes controlled by the IFNα-consensus sequences.

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