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Functional study of proteins associated with systemic lupus erythematosus (SLE) Juliana Imgenberg-Kreuz

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Functional study of proteins associated with systemic lupus erythematosus (SLE)

Juliana Imgenberg-Kreuz

The major role of the immune system is to protect us against infectious organisms. In this process it is crucial to distinguish between self and non-self antigens. In autoimmune diseases this capability to differentiate between self and foreign is not given, which in turn leads to an inappropriate immune response against self-antigens.

Systemic lupus erythematosus (SLE), also known as lupus, is a complex autoimmune disease characterized by loss of tolerance to self nuclear antigens, such as DNA and RNA. As these antigens can be found all over the body, the disease is systemic, and virtually any organ can be affected. Clinical manifestation of SLE is highly variable and reaches from mild symptoms to severe tissue inflammation and destruction. Common symptoms are the so- called ‘butterfly rash’ of the skin, as well as joint, heart and kidney problems. Women during their reproductive years are almost 10 times more frequently affected than men, and the disease is more common in African-Caribbean populations than in European. The precise cause of the disorder remains unclear. Environmental factors, various viral infections and some medication have been associated with the disease, and studies in siblings and twins suggest that complex genetic inheritance plays a critical role in the development and progress of SLE.

During the last years, so-called genome wide association studies (GWAS) of small variations throughout the genome of SLE patients and healthy controls identified numerous risk genes for the disease. However, the individual contribution of these factors to SLE is relatively low in general, and it is presumably the complex interaction of multiple risk variants that accounts for the disease. Thus, in more recent studies one looks specifically for genetic interactions, so-called epistatic effects. In such a study a genetic interaction between BANK1 and SID1 variants was detected to increase the risk for SLE. However, the identification of genetic association is only the first step towards a better understanding of the disease. Functional characterization of these genes and the pathways they are involved in may lead to the identification of novel therapeutic strategies for SLE.

The aim of this project was to investigate the interaction between BANK1 and SID1.

To address this question the SID1 coding sequence was amplified and cloned into an expression vector containing a tag that can be used later on to detect direct protein-protein binding via immunoprecipitation and immunoblotting. As a preliminary result no such physical interaction between BANK1 and SID1 was observed. To allow visualization of protein expression and localization in the cell, I inserted fluorescent proteins into the expression vectors. Via laser scanning confocal microscopy protein expression is reported by emission of fluorescent light upon appropriate excitation. Co-localization of two different proteins points to possible interaction. SID1 was not found to be co-localized with BANK1.

Instead, I found SID1 to co-localize completely with an intracellular Toll-like receptor, another factor known to play an important role in autoimmunity.

More works needs to be done to fully dissect the role of SID1 in pathways of immune- regulation in general and in SLE in particular.

Degree project in Biology, 30hp, Uppsala University, 2010

Biology Education Centre and Department of Genetics and Pathology, Uppsala University Supervisors: Prof. Marta E. Alarcón-Riquelme and Casimiro Castillejo-López

References

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