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Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2005 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, no 4, 1185-1195 p.Article in journal (Refereed) Published
Abstract [en]

Objective

The etiopathogenesis of primary Sjögren's syndrome (SS) is largely unknown. In other autoimmune diseases, type I interferon (IFN) may play a pivotal role by triggering and sustaining the disease process. We therefore aimed to determine whether patients with primary SS had an activated type I IFN system.

Methods

Salivary gland biopsy specimens and sera from patients with primary SS were investigated for the occurrence of IFNα-producing cells and measurable IFNα levels, respectively. The ability of primary SS sera together with apoptotic or necrotic cells to induce IFNα production in normal peripheral blood mononuclear cells was examined. The IFNα inducer was characterized, and IFNα-producing cells were identified. Clinical data were correlated with the IFNα-inducing capacity of primary SS sera.

Results

Numerous IFNα-producing cells were detected in salivary gland biopsy specimens, despite low serum IFNα levels. Autoantibodies to RNA-binding proteins, combined with material released by necrotic or late apoptotic cells, were potent inducers of IFNα production in plasmacytoid dendritic cells (PDCs). This appeared to be attributable to RNA-containing immune complexes triggering PDCs by means of RNA and interaction with Fcγ receptor IIa. The IFNα-inducing capacity of sera was associated with positive results of a labial salivary gland biopsy (focus score ≥1) and with dermatologic, hematologic, and pulmonary manifestations.

Conclusion

Patients with primary SS have an activated type I IFN system. Although virus may initiate the production of IFN, the continued IFNα synthesis is caused by RNA-containing immune complexes that activate PDCs to prolong IFNα production at the tissue level. This IFNα promotes the autoimmune process by a vicious circle–like mechanism, with increased autoantibody production and formation of more endogenous IFNα inducers.

Place, publisher, year, edition, pages
2005. Vol. 52, no 4, 1185-1195 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94952DOI: 10.1002/art.20998OAI: oai:DiVA.org:uu-94952DiVA: diva2:168985
Available from: 2006-10-13 Created: 2006-10-13 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Endogenous Type I Interferon Inducers in Systemic Autoimmune Diseases
Open this publication in new window or tab >>Endogenous Type I Interferon Inducers in Systemic Autoimmune Diseases
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Patients with systemic lupus erythematosus (SLE) have elevated levels of interferon (IFN)-α in blood and IFN-α-producing cells in tissues. In the present thesis, we investigate the mechanisms behind the upregulated IFN-α-production in SLE and also show that the IFN-α system is activated in primary Sjögren’s syndrome (pSS), with IFN-α-producing cells in the major affected organ, the salivary glands. The IFN-α is a type I IFN, a family of cytokines counteracting especially viral infections, by acting directly on infected cells, and via many immunomodulatory effects. The latter may also contribute to autoimmune processes.

The type I IFNs are usually produced upon recognition of microbial structures. In SLE, however, DNA-containing immune complexes (ICs) that induce IFN-α production are found. Many autoantibodies in SLE and pSS are directed to nucleic acids or to DNA/RNA-binding proteins. We show that also RNA in complex with autoantibodies from SLE or pSS patients (RNA-IC) induces IFN-α-production. The RNA could be either in the form of RNA-containing material released from apoptotic or necrotic cells or as a pure RNA-containing autoantigen, the U1 small nuclear ribonucleoprotein particle.

The IFN-α-production induced by RNA-IC occurred in plasmacytoid dendritic cells (PDCs), also termed natural IFN-producing cells (NIPCs), via binding to Fcγ-receptor IIa, endocytosis and triggering of Toll-like receptors (TLRs), probably TLR7 and TLR9. The RNA-IC may also have other effects, and we found that they induce prostaglandin E2 (PGE2) production in monocytes and tumor necrosis factor (TNF)-α in both monocytes and NIPC/PDC. The PGE2 downregulated the IFN-α induction in NIPC/PDC, and the IFN-α induction was increased in monocyte-depleted cell cultures.

The findings presented in this thesis aids in the understanding of the mechanisms behind the activated IFN-α system in SLE and other autoimmune diseases, and shows that also pSS is one of these diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 180
Keyword
Medicine, Systemic lupus erythematosus, Sjögren's syndrome, type I interferon, plasmacytoid dendritic cell, natural interferon-producing cell, immune complex, RNP, Ro/SSA, La/SSB, Medicin
Identifiers
urn:nbn:se:uu:diva-7181 (URN)91-554-6675-3 (ISBN)
Public defence
2006-11-03, Sal IX, Universitetshuset, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-10-13 Created: 2006-10-13Bibliographically approved
2. Clinical and Experimental Studies in Primary Sjögren’s Syndrome and Systemic Lupus Erythematosus
Open this publication in new window or tab >>Clinical and Experimental Studies in Primary Sjögren’s Syndrome and Systemic Lupus Erythematosus
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Autoimmune mechanisms and genetic susceptibility contribute to the pathogenesis of primary Sjögren’s syndrome and SLE. These chronic systemic autoimmune diseases have many serological and clinical features in common and have an impact on daily life. The studies in this thesis aim to elucidate their autoimmune mechanisms, define susceptibility genes and evaluate effects of androgen supplement on health-related quality of life.

Autoantibodies against α-fodrin, a widely distributed cytoskeletal protein, were detected at similar frequencies in sera from patients with primary and secondary Sjögren’s syndrome and SLE. Consequently, testing for antibodies against α-fodrin would not add diagnostic value compared to conventional serological analysis and does not discriminate between these diseases.

The type I interferon (IFN) system was found to be activated in primary Sjögren’s syndrome. IFN-α containing cells were detected in minor salivary gland biopsies, while sera from patients with primary Sjögren’s syndrome induced IFN-α production in the presence of apoptotic and necrotic cell material. This ability of sera correlated with the presence of antibodies against RNA-binding proteins and IFN-α production was dependent on RNA in immune complexes. The natural interferon producing cells/plasmacytoid dendritic cells (NIPC/PDC) were the IFN-α producers and blocking of FcγRIIa inhibited the production. Single nucleotide polymorphisms (SNPs) in two genes in the type I IFN signalling pathway, those for tyrosine kinase 2 and interferon regulatory factor 5, were strongly associated with SLE in a Swedish, Finnish and Icelandic population. The minor allele frequencies were lower in SLE patients than in healthy controls. These SNPs may decrease the function of the type I IFN system, thereby conferring protection against SLE.

Supplementation with dehydroepiandrosterone (DHEA) in glucocorticoid treated women with SLE led to mild improvements in health-related quality of life in respect of mental well-being and sexuality, whereas physical well-being was unaffected.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 73
Keyword
Medicine, Sjögren’s syndrome, SLE, α-fodrin, interferon-α, single nucleotide polymorphism, dehydroepiandrosterone, Medicin
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:uu:diva-5943 (URN)91-554-6349-5 (ISBN)
Public defence
2005-10-28, Rudbecksalen, Rudbecklaboratoriet, Uppsala, 13:15
Opponent
Supervisors
Available from: 2005-10-05 Created: 2005-10-05 Last updated: 2012-03-30Bibliographically approved

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Nordmark, GunnelRönnelid, JohanEloranta, Maija-LeenaRönnblom, Lars

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