The CGGGG insertion/deletion polymorphism of the <i>IRF5</i> promoter is a strong risk factor for primary Sjögren's syndrome

Miceli‐Richard, Corinne; Gestermann, Nicolas; Ittah, Marc; Comets, Emmanuelle; Loiseau, Pascale; Puéchal, Xavier; Hachulla, É.; Gottenberg, Jacques-Éric; Lebon, Pierre; Becquemont, Laurent; Mariette, Xavier

doi:10.1002/art.24662

Cited by 93 publications

(54 citation statements)

References 14 publications

(15 reference statements)

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“…Melting curve analysis was performed to assess the specificity of PCR product. PKR cDNA levels were determined as previously described [15] with the amplification primers 5 -GTTTCAAAAGCAGTGTCACA-3 and 5 -CGATACATGAGCCCAGAACA-3 .…”

Section: Rna Extraction and Real-time Quantitative Rt-pcrmentioning

confidence: 99%

Induction of B Cell-Activating Factor by Viral Infection Is a General Phenomenon, but the Types of Viruses and Mechanisms Depend on Cell Type

Ittah¹,

Miceli‐Richard²,

Lebon³

et al. 2010

J Innate Immun

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B cell-activating factor of the TNF family (BAFF) plays a key role in promoting B lymphocyte activation and survival. We previously showed in primary Sjögren’s syndrome that salivary gland epithelial cells (SGECs), the resident targeted cells of autoimmunity in this disease, can produce BAFF after infection with a double-stranded RNA (dsRNA) virus by a protein kinase RNA (PKR)-dependent mechanism. This study aimed to assess the effect of different viruses on various cell types – SGECs but also dendritic cells (DCs) and monocytes – in the induction of BAFF. BAFF induction was observed after Sendai virus infection of monocytes and SGECs, as well as poly(I:C) stimulation of DCs. However, PKR inhibition by 2-aminopurine failed to reduce BAFF expression in these infected or stimulated cells. Conversely, in Sendai virus-infected monocytes, blocking type 1 interferon (IFN) receptor by anti-IFNAR1 antibody strongly inhibited BAFF expression. These results provide additional data suggesting that both dsRNA virus stimulation of DCs and single-stranded RNA virus infection of SGECs or monocytes can induce BAFF expression, but through a PKR-independent mechanism for these 3 cell types and a type 1 IFN-dependent mechanism in monocytes and SGECs. Thus, BAFF induction by viral infection is a general phenomenon, but the types of viruses and mechanisms of the induction depend on the cell type.

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Section: Rna Extraction and Real-time Quantitative Rt-pcrmentioning

confidence: 99%

Induction of B Cell-Activating Factor by Viral Infection Is a General Phenomenon, but the Types of Viruses and Mechanisms Depend on Cell Type

Ittah¹,

Miceli‐Richard²,

Lebon³

et al. 2010

J Innate Immun

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“…The exploratory cohort was genotyped for this polymorphism, 4 which allowed for studying the effect of gene-gene interactions on susceptibility for pSS.…”

Section: Stat4 Rs7582694 Polymorphism Is Significantly Associated Witmentioning

confidence: 99%

“…These observations have provided new insights into the genetics of pSS by focusing on genes involved in innate immunity and the IFN pathway; the same interferon regulatory factor 5 (IRF5) polymorphism has been found associated with both pSS and systemic lupus erythematosus. [4][5][6] STAT4 is not classically considered as a factor involved in the type 1 IFN pathway. Conversely, it has a critical role in cellular growth and T-helper 1 differentiation, with interleukin 12 binding to its receptor.…”

Section: Introductionmentioning

confidence: 99%

STAT4 is a confirmed genetic risk factor for Sjögren's syndrome and could be involved in type 1 interferon pathway signaling

et al. 2010

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Signal transducer and activator of transcription 4 (STAT4) is a transcription factor mainly activated by interleukin 12, which promotes the secretion of type 2 interferon (IFN) by T-helper 1 cells. We assessed the association of STAT4 gene polymorphism and primary Sjö gren's syndrome (pSS) and its functional relevance. We analyzed STAT4 rs7582694 polymorphism in an exploratory cohort of 186 pSS patients and 152 controls, and in a replication cohort of 192 pSS patients and 483 controls, all Caucasian. mRNA levels of STAT4a, STAT4b, STAT1, and the type 1 IFN-induced genes PKR, MX1 and IFITM1 were assessed in peripheral blood mononuclear cells (PBMCs) from 30 pSS patients. STAT4 rs7582694 C allele was associated with pSS in both cohorts (odds ratio (OR) 1.57, 95% confidence interval (CI) 1.27-1.93, P ¼ 2.3 Â 10 À5 ). The association was increased for homozygous subjects, which suggests a recessive effect of the STAT4 at-risk allele. STAT4a, STAT4b and STAT1 mRNA levels in PBMCs were not significantly associated with rs7582694 genotypes, however the mRNA levels of STAT4a and type 1 IFN-induced genes were strongly correlated: PKR (P ¼ 4 Â 10 À3 , r ¼ 0.51), MX1 (P ¼ 2 Â 10 À4 , r ¼ 0.63) and IFITM1 (P ¼ 8 Â 10 À3 , r ¼ 0.47), suggesting that STAT4 might be involved in not only type 2 IFN production but also in type 1 IFN-mediated effects.

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“…Recent genome-wide association studies have identified alleles associated with susceptibility to a number of autoimmune diseases some of which encode proteins involved in IFN induction or IFN signaling [Hellquist et al 2009;Kyogoku et al 2009;Miceli-Richard et al 2009;Nordmark et al 2009;Suarez-Gestal et al 2009a, 2009bCunninghame Graham et al 2007;MiceliRichard et al 2007;Graham et al 2006]. Thus, there are a number of reports of the induction or exacerbation of systemic lupus erythematosus (SLE) in patients treated with recombinant IFNa Nordmark et al 2009;Yilmaz and Cimen, 2009].…”

Section: Therapeutic Advances In Drug Safety 2 (3)mentioning

confidence: 99%

Immunogenicity and other problems associated with the use of biopharmaceuticals

Tovey¹,

Lallemand

2011

Therapeutic Advances in Drug Safety

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Biopharmaceuticals are used widely for the treatment of cancer, chronic viral hepatitis, inflammatory, and autoimmune diseases. Biopharmaceuticals such as interferons are well tolerated for the most part with the most common adverse events observed being 'flu-like' symptoms that resolve rapidly after initial treatment. Prolonged treatment is associated, however, with more serious adverse events including leucopenia, thrombocytopenia, and neuropsychiatric effects, which may necessitate dose reduction or even cessation of treatment in some patients. Recombinant growth factors, such as erythropoietin (EPO), granulocyte colony-stimulating factor, or granulocyte macrophage colony-stimulating factor, are for the most part well tolerated, although severe complications have been reported in patients with cancer or chronic kidney disease treated with EPO. Similarly, treatment of patients with cancer with high doses of interleukin-2 is associated with significant toxicity. Treatment of chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, and Crohn's disease, with antitumor necrosis factor-alpha monoclonal antibodies is associated with an increased risk of granulomatous infections and, in particular, tuberculosis. The monoclonal antibody, natalizumab, that targets alpha4 integrins is effective in the treatment of multiple sclerosis but is associated with the activation of JC virus and development of progressive multifocal leukoencephalopathy. Repeated administration of recombinant proteins can cause a break in immune tolerance in some patients resulting in the production of a polyclonal antibody response that can adversely affect pharmacokinetics and clinical response. In addition, neutralizing antibodies that cross react with nonredundant essential proteins such as EPO can cause severe autoimmune reactions.

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The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndrome

Cited by 93 publications

References 14 publications

Induction of B Cell-Activating Factor by Viral Infection Is a General Phenomenon, but the Types of Viruses and Mechanisms Depend on Cell Type

Induction of B Cell-Activating Factor by Viral Infection Is a General Phenomenon, but the Types of Viruses and Mechanisms Depend on Cell Type

STAT4 is a confirmed genetic risk factor for Sjögren's syndrome and could be involved in type 1 interferon pathway signaling

Immunogenicity and other problems associated with the use of biopharmaceuticals

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