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The role of Dickkopf-3 in the adaptive immune system

Ludwig, Julia

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Abstract

Lymphocytes express highly specific receptors to recognize pathogens and malignant cells. At the same time, lymphocytes recognizing self-antigens also develop. These need tight regulation in order to prevent autoimmunity. The elimination or control of self-reactive cells is ensured by central and peripheral tolerance mechanisms. A detailed understanding of tolerance induction and maintenance is indispensable for the establishment of novel therapeutic strategies to treat autoimmune diseases and to prevent rejection of transplanted tissue. Recently, we identified Dickkopf 3 (Dkk3) as a novel immune-mediator in a transgenic model of peripheral T cell tolerance. To further clarify the immune-modulatory capacity of Dkk3 we investigated the influence of this secreted protein on T and B cell function. Experimental autoimmune encephalomyelitis (EAE) is a T cell mediated mouse model of the human autoimmune disease multiple sclerosis. Dkk3 deficient mice developed more persistent symptoms of EAE with increased numbers of brain infiltrating CD4 and CD8 T cells as well as myeloid cells in comparison to wild type mice. Lack of environmental Dkk3 was responsible for the observed phenotype as shown by adoptive T cell transfers using Dkk3 deficient T cells. Disease persistence in Dkk3 deficient mice was associated with an altered local cytokine profile. Absence of Dkk3 did not change the differentiation of Th1 and Th17 T cells but led to increased levels of Th2 associated cytokines. The role of Dkk3 on B cell function was analyzed by investigating antibody and cytokine secretion. Both assay systems showed that B1 related functions were increased in Dkk3 deficient mice, such as antibody secretion to the antigens LPS and phosphorylcholine and IL-10 production. Indeed, Dkk3 deficient mice yielded increased numbers of B1 cells. B2 cell development was supported by Dkk3 at the step from the pre- to immature B cell stage, whereas Dkk3 negatively regulated B1 cell generation. The murine MRL/LPR strain, a mouse model of human systemic lupus erythematosus (SLE), was used to investigate the role of Dkk3 in a B cell mediated autoimmune disease. Treatment of these mice with a Dkk3 neutralizing antibody led to increased numbers of B1 cells and higher pathology of SLE, including enlarged lymph nodes, higher levels of autoantibodies, increased glomerulonephritis and inflammation in pancreas and lung. Among the Dkk protein family, only Dkk3 and Soggy share the unique sgy-domain. To address the question whether this sgy-domain may be responsible for the immune-modulatory capacity we investigated immune functions of Soggy deficient mice. Alterations in the T cell compartment were observed, such as decreased numbers of regulatory T cells in comparison to wild type mice. Furthermore, Soggy deficiency led to an earlier onset and stronger symptoms of EAE in comparison to the disease course in C57BL/6 and Dkk3-/- mice. In summary, Dkk3 regulates T and B cell mediated autoimmunity. In addition, we were able to identify Soggy as a novel immune-mediator suggesting that the shared sgy-domain is contributing to the immune-suppressive capacity of Dkk3 and Soggy.

Document type: Dissertation
Supervisor: Hämmerling, Prof. Dr. Günter
Date of thesis defense: 22 July 2013
Date Deposited: 02 Sep 2013 09:14
Date: 2013
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
DDC-classification: 500 Natural sciences and mathematics
Controlled Keywords: Dickkopf-3, Autoimmunity, T cells, B cells, Soggy
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