Numerous studies have contributed to our current understanding of autoimmune diseases (AIDs), however, pathogenesis of many AIDs can still not be fully explained. Both genetic factors and... Show moreNumerous studies have contributed to our current understanding of autoimmune diseases (AIDs), however, pathogenesis of many AIDs can still not be fully explained. Both genetic factors and environmental factors are involved in the onset of autoimmunity. Which mechanisms explain the contribution of these genetic and environmental factors to disease pathogenesis, and how the different factors interplay remain unanswered key questions. The studies presented in this thesis aimed at identifying and unravelling some of the enigmatic mechanisms in rheumatoid arthritis (RA) and systemic sclerosis (SSc). Show less
In this thesis two diseases that share a common feature of hypomethylation of repetitive DNA are studied: facioscapulohumeral muscular dystrophy (FSHD) and immunodeficiency, centromeric... Show moreIn this thesis two diseases that share a common feature of hypomethylation of repetitive DNA are studied: facioscapulohumeral muscular dystrophy (FSHD) and immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. In FSHD there is hypomethylation of the macrosatellite repeat D4Z4 and the associated DUX4 gene, which is caused by a repeat contraction and/or variants in chromatin modifiers essential for a repressive D4Z4 chromatin structure in somatic cells. In ICF there is hypomethylation of centromeric repeats, which is caused by recessive variants in one of four ICF genes, of which two are established chromatin modifiers. In this thesis, the mutation spectrum of FSHD and ICF has been expanded. The SMCHD1 mutation spectrum in FSHD2 has been expanded with the discovery of exonic SMCHD1 variants, intronic SMCHD1 variants, and whole SMCHD1 gene deletions. In addition, we identified heterozygous variants in a new FSHD2 gene, DNMT3B, in two FSHD2 families. For ICF syndrome we expanded the mutation spectrum in the two most common ICF genes, DNMT3B and ZBTB24. Show less
The work presented in this thesis provides important new clues on the neurobiology of juvenile psychopathic traits in clinically antisocial juveniles. The data specifically shows that these... Show moreThe work presented in this thesis provides important new clues on the neurobiology of juvenile psychopathic traits in clinically antisocial juveniles. The data specifically shows that these traits are ostensibly underpinned by highly specific corticolimbic network dysfunctions, in which amygdala subregional networks seem particularly relevant. That data additionally suggests that some of these network dysfunctions and their associated neurocognitive deficits are possibly driven by alterations in the oxytocinergic system. Interestingly, the data also provides preliminary neurobiological support for the scientific utility of using juvenile psychopathic traits to subtype the highly heterogeneous group of clinically antisocial teens. While these data may represent important new steps towards a deeper understanding of clinical youth antisociality, their significance has to be evaluated by replication studies that further explore and validate the findings presented here. Show less
