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Accelerating the induction of tolerance to cow’s milk (CM) reduces the burden of cow’s milk allergy (CMA). In this randomised controlled intervention study, we aimed to investigate the tolerance induction of a novel heated cow milk protein, the iAGE product, in 18 children with CMA (diagnosed by a paedriatric allergist). Children who tolerated the iAGE product were included. The treatment group (TG: n = 11; mean age 12.8 months, SD = 4.7) consumed the iAGE product daily with their own diet, and the control group (CG: n = 7; mean age 17.6 months, SD = 3.2) used an eHF without any milk consumption. In each group, 2 children had multiple food allergies. The follow-up procedures consisted of a double-blind placebo-controlled food challenge (DBPCFC) with CM t = 0, t = 1 (8 months), t = 2 (16 months), and t = 3 (24 months). At t = 1, eight (73%) of 11 children in the TG had a negative DBPCFC, versus four out of seven (57%) in the CG (BayesFactor = 0.61). At t = 3, nine of the 11 (82%) children in the TG and five of seven (71%) in the CG were tolerant (BayesFactor = 0.51). SIgE for CM reduced from a mean of 3.41 kU/L (SD = 5.63) in the TG to 1.24 kU/L (SD = 2.08) at the end of intervention, respectively a mean of 2.58 (SD = 3.32) in the CG to 0.63 kU/L (SD = 1.06). Product-related AEs were not reported. CM was successfully introduced in all children with negative DBPCFC. We found a standardised, well-defined heated CM protein powder that is safe for daily OIT treatment in a selected group of children with CMA. However, the benefits of inducing tolerance were not observed.

This thesis describes novel insights in the human immune responses to Staphylococcus aureus wall teichoic acid (WTA), a polysaccharide that is abundantly present in the bacterial cell wall. S. aureus WTA is composed of a poly-ribitolphosphate (RboP) backbone, co-decorated with D-alanine and N-acetylglucosamine (GlcNAc) residues. Three distinct WTA glycosyltransferases have been described that can modify the RboP backbone with GlcNAc in different configurations (α- or β-GlcNAc). Based on the strain-specific expression of WTA glycosyltransferases; different WTA glycosylation profiles exist, which can greatly impact host immune responses. In chapter 2, we expand on previous findings that S. aureus interacts with skin resident antigen-presenting cells, namely Langerhans cells (LCs), through the C-type lectin receptor langerin and describe the interaction between langerin and β-GlcNAc WTA expressing S. aureus. Using synthetic WTA oligomers as a novel tool to study host lectin responses to S. aureus WTA, we confirm that human langerin interacts with β-GlcNAc, but not α-GlcNAc, modifications on WTA. In chapter 3, we highlight the use of fully synthetic WTA oligomers as powerful tools to perform in-depth structure binding analysis of glycan-specific monoclonal antibodies (mAbs). We show that WTA-mAb binding and subsequent complement activation are not only affected by GlcNAc linkage type (α- or β-GlcNAc) but also by the position of the GlcNAc moiety on the WTA backbone. Chapter 4 provides an extensive overview of the antibody repertoire to the different WTA-GlcNAc modifications in healthy donors, and ICU patients with culture-confirmed S. aureus bacteremia. For the first time we report WTA-specific IgM responses in these two human cohorts. By matching the WTA glycoprofile of the infecting S. aureus isolate to WTA-specific antibody responses within individual patients, we highlight the importance of raising antibodies to all three WTA-GlcNAc modifications. In chapter 5, we describe the identification of S. aureus-specific tissue-resident memory T cells in healthy human skin. Upon activation, these cells proliferate rapidly and produce pro-inflammatory cytokines thereby possibly contributing to protective immunity during skin infection. In conclusion, the findings presented in this thesis provide novel insights in immunity against S. aureus WTA, which could contribute in the development of a future vaccine that provides protection against S. aureus infections.

Background Atrial fibrillation (AF) is the most frequent arrhythmia, and its prevalence is increasing with aging. We aimed to compare the long-term outcome data of patients < 65 years vs. ≥ 65 years who underwent catheter ablation (CA) for drug-refractory AF. Methods Consecutive patients with primary pulmonary vein isolation performed between March 2001 and December 2011, and those who completed a five-year of follow-up were divided into two groups: patients aged < 65 years into group 1, and patients aged ≥ 65 into group 2. Long-term outcome data concerning mortality, thromboembolic events (TE) and success rates were compared between these groups. Results A total number of 390 patients were included, group 1 contained 310 patients, and 80 patients in group 2. In group 2, patients had more often impaired renal function (P < 0.001) and thyroid disease (P = 0.047). A total of fifteen patients died during the 6.63 ± 2.1 years of follow-up, with a significantly higher incidence in the older group (8/80 vs. 7/310 patients, P = 0.004). The majority of fatal outcome was due to cancerous diseases in both groups. No difference was observed concerning the long-term TE rate (12/310 vs. 4/80 patients, P = 0.75). Rhythm control failed in 25.9% of the patients, with no difference between the groups: 26.4% in group 1 vs. 23.7% in group 2 (P = 0.67). Conclusions Despite growing prevalence of AF in aging population, the elderly patients are underrepresented in CA procedures. Similar clinical success and TE complication rate are observed between the age-groups. Our data suggest more liberal criteria might be applied while selecting patients for AF ablation.

Outflow Tract PVC Termination After AP Ablation. Background: Multiple mechanisms have been proposed for idiopathic premature ventricular contractions (PVCs) originating from the outflow tracts (OTs). Recent observations such as the coexistence of these arrhythmias with atrioventricular nodal reentrant tachycardias and the association between discrete prepotentials and successful ablation sites of ventricular arrhythmias (VAs) from the OTs suggest a common link.