Co-stimulatory molecules : Genes to protein in autoimmune and inflammatory disorders

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Medicine

Sammanfattning: Co ]stimulatory molecules are antigen ]independent generators of secondary signals which aid in maintaining the homeostasis of the immune system. The most extensively studied costimulatory pathway is CD28/CTLA ]4, expressed on the T cells, interacting with CD80/CD86, expressed on the antigen presenting cells (APC). The interaction between CD28 and CD80/CD86 initiates the activation of T cells, whereas subsequent interaction between CTLA ]4 and CD80/CD86 inhibits the activated T lymphocytes. Also, there exist several other costimulatory pathways. The co ]stimulatory molecules analyzed, in this study are B7H3, CD28, CD80, CD86, CTLA ]4, PD ]1, PD ]L1 and PD ]L2. This study involves both with genetic associations and protein expression of co ]stimulatory molecules (either stimulatory or inhibitory) in case ]control and population ]based studies. In the case ]control study, we categorized two types of model diseases: 1) the B ]cell induced autoantibody mediated disease, myasthenia gravis (MG) and 2) the T ]cell mediated inflammatory diseases, abdominal aortic aneurysm (AAA). In the population based study, we have selected subjects aged above 70 in the county of Uppsala, Sweden. At the genetic level, the key role of inhibitory receptors, B7H3 and Programmed Death ]1 (PD ]1), were evaluated in MG. No significant differences in genotype frequencies or allele frequencies in MG patients when compared with controls were found. The study, with PD ]1, was extended at mRNA and protein expression levels. Though we could not demonstrate any significant differences at mRNA levels, there was an increased expression of PD ]1 and PD ]L1 on T cells and monocytes, respectively. This demonstrates the existence regulatory mechanism behind MG. The soluble (s) forms of co ]stimulatory molecules sCD28, sCD80, sCD86, sCTLA ]4 were evaluated in patients with AAA and in general population. We could demonstrate increased circulating levels of soluble forms of CD28, CD86 and decreased levels of soluble forms of CTLA ]4 among AAA patients when compared with controls. In the general population, levels of soluble forms of co ]stimulatory molecules were positively related to pro ]inflammatory cytokines such as TNF ]alpha, IL ]6, IL ]1alpha, IL ]1beta, IFN ]gamma and chemokines such as IL ]8, but inversely related to CC chemokine, MCP ]1. We could not demonstrate any direct relation of soluble costimulatory molecules to adhesion molecules and other atherosclerotic factors. The detection of soluble forms of PD ]1 could be demonstrated neither in the patients with MG nor in the controls. In conclusion, we suggest that the co ]stimulatory molecules have a significant impact on the status of the immune activation behind the two types of disorders. Therefore, we suggest that sCD28, sCD80, sCD86, sCTLA ]4 could be used as biomarkers for evaluating the process of inflammation. Furthermore, our study suggests a natural regulation of MG through the interaction between PD ]1/PD ]L1.

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