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Clinical and Experimental Studies in Primary Sjögren’s Syndrome and Systemic Lupus Erythematosus
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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. , p. 76
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 73
Keywords [en]
Medicine, Sjögren’s syndrome, SLE, α-fodrin, interferon-α, single nucleotide polymorphism, dehydroepiandrosterone
Keywords [sv]
Medicin
National Category
Dermatology and Venereal Diseases
Identifiers
URN: urn:nbn:se:uu:diva-5943ISBN: 91-554-6349-5 (print)OAI: oai:DiVA.org:uu-5943DiVA, id: diva2:167007
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
List of papers
1. Autoantibodies to α-fodrin in primary Sjögren's syndrome and SLE detected by an in vitro transcription and translation assay
Open this publication in new window or tab >>Autoantibodies to α-fodrin in primary Sjögren's syndrome and SLE detected by an in vitro transcription and translation assay
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2003 In: Clinical and Experimental Rheumatology, Vol. 21, p. 49-56Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-93508 (URN)
Available from: 2005-10-05 Created: 2005-10-05Bibliographically approved
2. Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism
Open this publication in new window or tab >>Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism
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2005 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, no 4, p. 1185-1195Article 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-94952 (URN)10.1002/art.20998 (DOI)
Available from: 2006-10-13 Created: 2006-10-13 Last updated: 2018-02-27Bibliographically approved
3. Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus
Open this publication in new window or tab >>Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus
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2005 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, American Journal of Human Genetics, Vol. 76, no 3, p. 528-537Article in journal (Refereed) Published
Abstract [en]

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms ( SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes - the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes - we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P < 10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93510 (URN)10.1086/428480 (DOI)000226851900016 ()
Available from: 2005-10-05 Created: 2005-10-05 Last updated: 2017-12-14Bibliographically approved
4. Effects of Dehydroepiandrosterone Supplement on Health-related Quality of Life in Glucocorticoid Treated Female Patients with Systemic Lupus Erythematosus
Open this publication in new window or tab >>Effects of Dehydroepiandrosterone Supplement on Health-related Quality of Life in Glucocorticoid Treated Female Patients with Systemic Lupus Erythematosus
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2005 (English)In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 38, no 7, p. 531-540Article in journal (Refereed) Published
Abstract [en]

The objective of this study was to evaluate the efficacy of low dose dehydroepiandrosterone (DHEA) on health-related quality of life (HRQOL) in glucocorticoid treated female patients with systemic lupus erythematosus (SLE). Forty one women ( >or= 5 mg prednisolone/day) were included in a double-blind, randomized, placebo-controlled study for 6 months where DHEA was given at 30 mg/20 mg ( or= 46 years) daily, or placebo, followed by 6 months open DHEA treatment to all patients. HRQOL was assessed at baseline, 6 and 12 months, using four validated questionnaires and the patients' partners completed a questionnaire assessing mood and behaviour at 6 months. DHEA treatment increased serum levels of sulphated DHEA from subnormal to normal. The DHEA group improved in SF-36 "role emotional" and HSCL-56 total score (both p<0.05). During open DHEA treatment, the former placebo group improved in SF-36 "mental health" (p<0.05) with a tendency for improvement in HSCL-56 total score (p=0.10). Both groups improved in McCoy's Sex Scale during active treatment (p<0.05). DHEA replacement decreased high-density lipoprotein (HDL) cholesterol and increased insulin-like growth factor I (IGF-I) and haematocrit. There were no effects on bone density or disease activity and no serious adverse events. Side effects were mild. We conclude that low dose DHEA treatment improves HRQOL with regard to mental well-being and sexuality and can be offered to women with SLE where mental distress and/or impaired sexuality constitutes a problem.

Keywords
Adjuvants; Immunologic/pharmacology/*therapeutic use, Adult, Aged, Androgens/blood, Corticotropin/blood, Dehydroepiandrosterone/pharmacology/*therapeutic use, Double-Blind Method, Female, Humans, Insulin-Like Growth Factor I/metabolism, Lupus Erythematosus; Systemic/blood/*drug therapy/*physiopathology, Middle Aged, Prednisolone/pharmacology/*therapeutic use, Quality of Life, Research Support; Non-U.S. Gov't, Sex Characteristics, Sex Hormone-Binding Globulin/metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93511 (URN)10.1080/08916930500285550 (DOI)16373258 (PubMedID)
Available from: 2005-10-05 Created: 2005-10-05 Last updated: 2017-12-14Bibliographically approved

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