uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Association of three systemic lupus erythematosus susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin, with autoimmune manifestations in Icelandic multicase systemic lupus erythematosus families
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics. (Genetics of inflammatory diseases)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Show others and affiliations
2008 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 58, no 12, 3865-3872 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To study autoimmune diseases and autoantibodies in Icelandic multicase systemic lupus erythematosus (SLE) families and to determine the association of 3 SLE susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin (MBL), with autoimmune disease in this population.

Methods: Eight SLE multicase families were studied, comprising a total of 124 family members (23 patients with SLE and 101 relatives). The diagnosis of an autoimmune disease was established and autoantibodies were measured in each family. In addition, PD-1.3A alleles were genotyped, and C4AQ0 allotypes were established by electrophoresis and haplotype analysis. Low levels of MBL were determined using enzyme-linked immunosorbent assay and variant-allele genotyping.

Results: In the SLE multicase families there was a high frequency of other autoimmune diseases (32.2%) and a high frequency of autoantibodies (53.2%). Of all family members, 59.7% were determined to have SLE, other autoimmune diseases, antinuclear antibodies, and/or other autoantibodies. The families showed genetic heterogeneity for PD-1.3A, C4AQ0, and low MBL levels; the frequency of each factor ranged from 0% to 85%. The frequencies of PD-1.3A and C4AQ0 were significantly increased in patients with SLE, relatives with other autoimmune diseases, and non-autoimmune disease relatives compared with controls. In the 7 families whose members had low levels of MBL, this factor was significantly associated with SLE, but the frequency of low MBL was decreased in relatives with other autoimmune diseases as compared with non-autoimmune disease relatives and controls. There were indications of an additive effect, and 91% of patients with SLE, 78% of relatives with other autoimmune diseases, and 75% of non-autoimmune disease relatives carried at least 1 of the 3 factors.

Conclusion: These results demonstrate a high frequency of autoimmune diseases and autoantibodies in SLE multicase families. PD-1.3A and C4AQ0 are part of a predisposing genetic background. Other genetic and/or environmental factors are necessary for disease expression, demonstrated by a high frequency of PD-1.3A and C4AQ0 in non-autoimmune disease relatives. Low MBL levels may be one such contributing factor. The results of this study provide an example of epistatic genetic effects and overlapping genetics in autoimmune diseases.

Place, publisher, year, edition, pages
2008. Vol. 58, no 12, 3865-3872 p.
Keyword [en]
SLE, PD-1, C4AQ0, low MBL, families, autoimmune disease
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-107268DOI: 10.1002/art.24129ISI: 000261587500025PubMedID: 19035512OAI: oai:DiVA.org:uu-107268DiVA: diva2:228500
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)
Opponent
Supervisors
Available from: 2009-09-15 Created: 2009-07-27 Last updated: 2009-09-23Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Kristjánsdóttir, Helga

Search in DiVA

By author/editor
Kristjánsdóttir, Helga
By organisation
Medical GeneticsDepartment of Genetics and Pathology
In the same journal
Arthritis and Rheumatism
Immunology in the medical area

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 485 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf