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Lower expression levels of the programmed death 1 receptor on CD4+CD25+ T cells and correlation with the PD-1.3A genotype in patients with systemic lupus erythematosus
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics. (Genetics of inflammatory diseases)
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2010 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 6, 1702-1711 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE.: A genetic polymorphism, PD1.3A, in the PDCD1 gene encoding the co-inhibitory immunoreceptor PD-1, has been associated with SLE. The aim of the study was to assess PD-1 receptor expression in SLE patients, relatives and controls and correlate with PD-1.3A. METHODS.: Icelandic and Swedish SLE patients, relatives and controls were studied. PBMCs were stimulated with alphaCD3/CD28 and PD-1 expression analyzed by flow cytometry. PD-1.3A/G genotyping was performed by PCR-RFLP. RESULTS: I. PD-1 expression on PBMCs was induced after stimulation, by 2.1-fold in SLE patients, 3.1-fold in relatives and 5.1-fold in controls.II. The frequency of PD-1+ cells was significantly lower in SLE patients compared to relatives and controls. PD-1 expression on PD-1+ cells was significantly lower in SLE patients and relatives.III. PD-1 expression on CD4+CD25+ T cells was significantly lower in SLE patients and relatives.IV. PD-1 expression was significantly higher on CD25(high) compared to CD25(intermediate) and (low) cells.V. PD-1 expression on CD25(high) and CD25(intermediate) cells was significantly lower in SLE patients compared to controls.VI. PD-1 was expressed on both FoxP3- and FoxP3+ cells.VII. Lower PD-1 expression was significantly correlated with the PD-1.3A/G genotype. CONCLUSION.: The study demonstrates significantly lower PD-1 receptor expression in SLE patients and relatives and a significant correlation of lower PD-1 expression with the PD-1.3A allele. We conclude that PD-1.3A may be contributory to abnormalities in PD-1 receptor expression on CD4+CD25+ T-cells in SLE, providing support for an important role for the PD-1 pathway in SLE and possibly other autoimmune diseases.

Place, publisher, year, edition, pages
2010. Vol. 62, no 6, 1702-1711 p.
Keyword [en]
SLE, PD-1.3A, self-tolerance
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-107272DOI: 10.1002/art.27417ISI: 000279432500020PubMedID: 20178125OAI: oai:DiVA.org:uu-107272DiVA: diva2:228501
Available from: 2009-08-03 Created: 2009-08-03 Last updated: 2017-12-13Bibliographically approved
In thesis
1. The PD-1 pathway and the complement system in systemic lupus erythematosus
Open this publication in new window or tab >>The PD-1 pathway and the complement system in systemic lupus erythematosus
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Autoimmune diseases occur in up to 3-5% of the general population and represent a diverse collection of diseases with regards to clinical manifestations. The unifying factor of autoimmune diseases is tissue and organ damage as a result of an immune response mounted against self-antigens.

Systemic lupus erythematosus (SLE) is considered a prototype of human systemic autoimmune diseases. The etiology of SLE is as yet largely unknown, but both epidemiological and genetic data suggest an interplay between numerous and varying genetic and environmental factors.

There is compelling evidence for a strong genetic component in SLE. The disease has a high λsibs value and familial clustering is apparent. Multiple susceptibility loci have been identified, some of which are syntenic between humans and mice and some of which overlap with other autoimmune diseases.

 

This thesis is based on analysis of Icelandic multicase SLE families and Swedish SLE patients.

Paper I is a study of the association of C4A protein deficiency (C4AQ0) with SLE in the multicase families and shows a significantly increased frequency of C4AQ0 in the families. The genetic basis for C4AQ0 varies and C4AQ0 is found on different MHC haplotypes, pointing to C4AQ0 as an independent risk factor for SLE.

Paper II describes the association of low MBL serum levels with SLE in the families and identifies low MBL as risk factor for SLE in families that carry the defect. Low MBL was furthermore found to mediate an additive risk when found in combination with C4AQ0.

In paper III cellular expression the PD-1 co-inhibitory receptor on T cells was studied. A polymorphism in the PDCD1 gene, PD-1.3A was previously associated with SLE in the multicase families. The polymorphism is thought to disrupt expression of the gene and may lead to decreased expression of the PD-1 receptor. The study demonstrates lower PD-1 expression in SLE patients and relatives in correlation to the PD-1.3A genotype.

Paper IV is a compiled analysis of the SLE families, including PD-1.3A, C4AQ0, low MBL, autoimmune diseases and autoantibody profiles. The study demonstrates clustering of different autoimmune diseases and autoantibodies in families that are heterogenic with regards to the genetic susceptibility factors, PD-1.3A, C4AQ0 and low MBL.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 80 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 469
Keyword
SLE, autoimmune diseases, PD-1, C4AQ0, low MBL, multicase family
National Category
Immunology
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-107198 (URN)978-91-554-7570-3 (ISBN)
Public defence
2009-10-10, Waldenströmsalen, Rudbeck Laboratory, Dag Hammarskjölds väg 20, 751 85 Uppsala, 13:15 (English)
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Supervisors
Available from: 2009-09-15 Created: 2009-07-27 Last updated: 2009-09-23Bibliographically approved

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