Hodgkin lymphoma and testicular cancer survivors have an increased risk of developing second primary gastrointestinal malignancies. Whether the pathogenesis of the gastrointestinal malignancies in... Show moreHodgkin lymphoma and testicular cancer survivors have an increased risk of developing second primary gastrointestinal malignancies. Whether the pathogenesis of the gastrointestinal malignancies in cancer survivors differs from cancer in the general population is unknown. This thesis investigated the pathogenesis of gastrointestinal malignancies in Hodgkin lymphoma and testicular cancer survivors. Furthermore, the effectiveness of colorectal cancer surveillance is investigated in these cancer survivors. Additionally, this thesis will focus on mismatch repair deficiency, as identification of Lynch syndrome could have implications for the patients and implications for treatment choice. Show less
Rheumatoid arthritis is a heterogeneous disease, which can be, based on data combining genetic risk factors and autoantibodies, sub-classified into ACPA-positive and -negative RA. Presence of ACPA... Show moreRheumatoid arthritis is a heterogeneous disease, which can be, based on data combining genetic risk factors and autoantibodies, sub-classified into ACPA-positive and -negative RA. Presence of ACPA and RF as well as rising CRP-levels in some patients years before onset of clinical symptoms indicate that relevant immune responses for RA development are initiated very early. ACPA are highly specific for RA, whereas RF can also be found among healthy (elderly) individuals and patients with other autoimmune diseases or infection. The most important genetic risk factor for RA development, the shared epitope alleles, resides in the MHC class II region. Shared epitope alleles, however, only predispose to the development of ACPA-positive RA. Smoking is thus far the most important environmental risk factor associated with the development of RA. Studies on synovitis have shown the importance not only of adaptive but also of innate immune responses. In summary of the various results from immunological changes in blood and synovial tissue, the extension of the immune response from a diffuse myeloid to a lympho-myeloid inflammation appears to be associated with a more successful therapeutic response to biologics. With respect to advances in synovitis research, new targets for treatment against pathological subsets of immune cells or fibroblasts are already on the horizon. However, alternative strategies involving the microbiome may play an important role as well and research in this field is growing rapidly. Show less
Cytomegalovirus (CMV) infection is a worldwide common infection that in a considerable proportion of individuals remains unnoticed. The congenital CMV infection (cCMV) can induce a variety of... Show moreCytomegalovirus (CMV) infection is a worldwide common infection that in a considerable proportion of individuals remains unnoticed. The congenital CMV infection (cCMV) can induce a variety of clinical manifestations at birth (symptoms at birth), and of permanent long-term impairments (LTI). Of the total of infected neonates at birth, 13% are symptomatic at birth, and half of them will develop LTI. However, 13% of the asymptomatic neonates will still develop the same LTI. Therefore, a quite high percentage of neonates will develop LTI. This thesis aimed to identify prognostic markers, for short- and long-term clinical outcome, and correlates of protection, for future vaccine development. In order to identify such biomarkers, a retrospective nationwide cohort of children with (n=125) and without (n=263) cCMV was used. The findings of this thesis allowed us to get more insights into cCMV pathogenesis, and into the potential processes leading to immune dysfunction, and therefore to a worse clinical outcome. Several approaches have been used to explore prognostic markers. The neonatal immune markers, through DNA quantification of the most common TCR and BCR rearrangements from DBS, together with the maternal-child HLA background, through typing DNA from buccal swabs, seemed to be quite promising for prognostic markers. Show less
Jansen, A.F.M.; Schoffelen, T.; Textoris, J.; Mege, J.L.; Bleeker-Rovers, C.P.; Roest, H.I.J.; ... ; Deuren, M. van 2017
Until a few years ago, only two human polyomaviruses (JC and BK) were known to infect humans and cause severe illness in immunocompromised hosts. Since 2007, at least eleven new polyomaviruses... Show moreUntil a few years ago, only two human polyomaviruses (JC and BK) were known to infect humans and cause severe illness in immunocompromised hosts. Since 2007, at least eleven new polyomaviruses became known that infect humans. Among them is the polyomavirus associated with trichodysplasia spinulosa (TSPyV). In Chapter 1 of this dissertation, the main focus is on the recent developments in studying the newly identified human polyomaviruses until mid-2014. This introductory chapter sets the stage for further investigation into TSPyV infection, pathogenesis, evolution and host adaptation, which is detailed in Chapter 2. To study causality between TSPyV infection and TS disease, in Chapter 3, the prevalence, load and localization of this virus is described. In Chapter 4, the cellular mechanisms behind disruption of cellular proliferation and TS spicule formation by TSPyV Large T-antigen is investigated. By In-silico analysis, in Chapter 5, the identification of a polyomavirus evolution and adaptation mechanism called COCO-VA is highlighted. Subsequently, in Chapter 6, TSPyV genome sequences are tested to gain more insight into this COCO-VA mechanism. Finally, in Chapter 7, the findings described in this dissertation are discussed with regard to several TSPyV aspects, and compared to existing knowledge about polyomaviruses in a broader context. Show less
