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Mannan-binding lectin and complement C4A in Icelandic multicase families with systemic lupus erythematosus
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics. (Genetics of inflammatoru diseases)
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2006 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, Vol. 65, no 11, 1462-7 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To determine whether low mannan-binding lectin (MBL) and C4A null alleles (C4AQ0) are associated with systemic lupus erythematosus (SLE) in multicase families with SLE.

Methods: Low MBL level was determined by measuring serum levels and by genotyping for mutant structural (B/C/D, designated as 0) and promoter (LX) alleles (by real-time polymerase chain reaction). C4AQ0 was detected by protein electrophoresis and corroborated with haplotype and genotype analysis. In nine Icelandic families, 24 patients with SLE were compared with 83 first-degree and 23 second-degree relatives without SLE. Twenty four unrelated family members and a population group of 330 Icelanders served as controls.

Results: Overall, the frequency of low MBL genotypes (0/0, LX/0 and wild-type/0) tended to be higher in patients with SLE than in their first-degree and second-degree relatives (p = 0.06), but the frequency was similar in the families and in the controls (p = 0.6). The frequency of C4AQ0 was, however, increased in patients and their relatives compared with that in the controls (p = 0.04). The combination of low MBL genotypes and C4AQ0 was found more often in the patients than in their relatives (p = 0.03) and controls (p = 0.02). However, low MBL level was observed only in patients and first-degree relatives in five of the nine multicase families. In these five families, patients with SLE had low MBL genotypes more often (64%) than their first-degree (38%) and second-degree (0%) relatives (p = 0.001), and the patients with SLE also had, accordingly, lower MBL levels than their relatives (p = 0.001).

Conclusions: These findings indicate that low MBL levels can predispose people to SLE and highlight the genetic heterogeneity of this disease.

Place, publisher, year, edition, pages
2006. Vol. 65, no 11, 1462-7 p.
National Category
Immunology in the medical area
Research subject
URN: urn:nbn:se:uu:diva-107261DOI: 10.1136/ard.2005.046086PubMedID: 16439442OAI: oai:DiVA.org:uu-107261DiVA: diva2:228493
Available from: 2009-08-03 Created: 2009-08-02 Last updated: 2009-08-04Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 469
SLE, autoimmune diseases, PD-1, C4AQ0, low MBL, multicase family
National Category
Research subject
Medical Genetics
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)
Available from: 2009-09-15 Created: 2009-07-27 Last updated: 2009-09-23Bibliographically approved

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