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Ectodermal dysplasia with immunodeficiency (ED-ID) is a rare primary immunodeficiency syndrome characterized by defects in ectodermal tissues (skin, hair and sweat glands), recurrent infections, impaired response to Toll-like receptor ligands, hypogammaglobulinemia and deficient antibody production. It is caused by defective \(NF\kappa B\) signaling. The most common form of ED-ID is X-linked. It is caused by hypomorphic mutations in the \(NF\kappa B\) essential modifier gene NEMO, which is an important regulatory component in the \(NF\kappa B\) signaling pathway. We report the first case of ED-ID caused by insufficient expression of a NEMO protein of normal sequence, due to a mutation in the 5’ untranslated region of the NEMO gene. Autosomal dominant ED-ID, a rare form of ED-ID, has been reported to be caused by a heterozygous S32I mutation in the \(I \kappa B \alpha\). This mutation prevents IκBα phosphorylation and inhibits its degradation. The mutant sequesters \(NF\kappa B\) in the cytoplasm and acts as a dominant negative. We report the first ED-ID patient with a heterozygous mutation (W11X) that causes N-terminal truncation of \(I \kappa B \alpha\) and results in functional haploinsufficiency. We have constructed a knock-in mouse model of ED-ID caused by a heterozygous S32I mutation in \(I \kappa B \alpha\). The mutant mice had ED, increased mortality, complete lack of lymph nodes and Peyer’s patches, and disorganized spleens that lacked follicles, marginal zone B cells and follicular dendritic cells. T cell proliferation and cytokine production was normal in vitro, but in vivo contact hypersensitivity was severely impaired, B cell function in vitro and specific antibody response to antigens were severely reduced. All immune defects, except those that affected B cell function, were absent in \(I \kappa B \alpha\) S32I mutant \(Rag2^{-/- }\) bone marrow chimeras, indicating that defects in non-lymphiod cells play a major role in the immunodeficiency of patients with ED-ID due to mutations in \(I \kappa B \alpha\). This has important clinical implications, as bone marrow transplant may not be able to correct immune function in such patients. The lessons learned in these chapters may be applicable to other mutations that impair \(NF\kappa B\) signaling and have important implications for the treatment of patients who carry these mutations.

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Background: Tissue factor (TF) is a 47 kDa transmembrane glycoprotein known as the main initiator of blood coagulation. TF is over-expressed on many malignant cells and apart from increasing the risk of thrombosis, the presence of TF/FVIIa also promotes the progression of cancer and metastasis by intracellular signaling. TF expressing microparticles (MP) are, moreover, often found in the circulation of cancer patients. Aim: The aim of this thesis was to study different aspects of TF activity, e.g. the importance of procoagulant MP and TF-induced intracellular signaling pathways, with focus on cell migration (chemotaxis) and apoptosis. Results: The TF signaling complexes were shown to prevent apoptosis induced by serum starvation and TRAIL in cancer cells by reduced activation of caspase-8 in a PI3k/AKT-dependent manner. FVIIa also decreased transcription of pro-apoptotic genes in cancer cells treated with TRAIL. Simvastatin triggered apoptosis by transcriptional reduction of BCL-2 due to cytosolic retention of NFκB. Simvastatin also inactivated the PI3k/AKT pathway and reduced the production of the MP-like prostasomes which, respectively, impaired the anti-apoptotic signaling by TF and reduced the procoagulant activity in the vicinity of prostate cancer cells. Intracellular events conducted by the TF/FVIIa complex selectively enhanced PDGF-BB induced chemotaxis which was partly explained by the TF/FVIIa-induced transactivation of the PDGFβ-receptor. This was dependent on Src-family members and engagement of PAR2. Conclusions: The results presented in this thesis extend the current knowledge of TF-mediated signaling. We report the TF complexes to govern the extrinsic pathway of apoptosis, present data on FVIIa-dependent regulation of apoptosis-related genes, and exclude known surface proteins as transmitters of the anti-apoptotic signals. We moreover describe TF/FVIIa to transactivate the PDGFβ-receptor and play a decisive role in the potentiated chemotaxis toward PDGF-BB in a number of cell types. Finally, we explain the mechanism behind simvastatin-induced apoptosis in cancer cells and how statins interfere with TF-dependent signaling and coagulation.