http://repub.eur.nl/res/aut/16774/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39098/ 2012-06-01T00:00:00Z The lymph nodes (LNs) and spleen have an optimal structure that allows the interaction between T cells, B cells and antigen-presenting dendritic cells (DCs) on a matrix made up by stromal cells. Such a highly organized structure can also be formed in tertiary lymphoid organs (TLOs) at sites of infection or chronic immune stimulation. This review focuses on the molecular mechanisms of TLO formation and maintenance, the controversies surrounding the nature of the inducing events, and the functions of these structures in infection, transplantation and autoimmunity. http://repub.eur.nl/res/pub/25208/ 2009-10-26T00:00:00Z Tertiary lymphoid organs (TLOs) are organized aggregates of B and T cells formed in postem-bryonic life in response to chronic immune responses to infectious agents or self-antigens. Although CD11c+dendritic cells (DCs) are consistently found in regions of TLO, their contribution to TLO organization has not been studied in detail. We found that CD11chiDCs are essential for the maintenance of inducible bronchus-associated lymphoid tissue (iBALT), a form of TLO induced in the lungs after influenza virus infection. Elimination of DCs after the virus had been cleared from the lung resulted in iBALT disintegration and reduction in germinal center (GC) reactions, which led to significantly reduced numbers of class-switched plasma cells in the lung and bone marrow and reduction in protective antiviral serum immunoglobulins. Mechanistically, DCs isolated from the lungs of mice with iBALT no longer presented viral antigens to T cells but were a source of lymphotoxin (LT) β and homeostatic chemokines (CXCL-12 and -13 and CCL-19 and -21) known to contribute to TLO organization. Like depletion of DCs, blockade of LTβ receptor signaling after virus clearance led to disintegration of iBALT and GC reactions. Together, our data reveal a previously unappreciated function of lung DCs in iBALT homeostasis and humoral immunity to influenza virus. http://repub.eur.nl/res/pub/17358/ 2009-09-28T00:00:00Z Natural killer cells are innate effector cells known for their potential to produce interferon-γ and kill tumour and virus-infected cells. Recently, B220+CD11cintNK1.1+ NK cells were found to also have antigen-presenting capacity like dendritic cells (DC), hence their name interferon-producing killer DC (IKDC). Shortly after discovery, it has already been questioned if IKDC really represent a separate subset of NK cells or merely represent a state of activation. Despite similarities with DCs, in vivo evidence that they behave as bona fide APCs is lacking. Here, using a model of influenza infection, we found recruitment of both conventional B220- NK cells and IKDCs to the lung. To study antigen-presenting capacity of NK cell subsets and compare it to cDCs, all cell subsets were sorted from lungs of infected mice and co-cultured ex vivo with antigen specific T cells. Both IKDCs and conventional NK cells as well as cDCs presented virus-encoded antigen to CD8 T cells, whereas only cDCs presented to CD4 T cells. The absence of CD4 responses was predominantly due to a deficiency in MHCII processing, as preprocessed peptide antigen was presented equally well by cDCs and IKDCs. In vivo, the depletion of NK1.1-positive NK cells and IKDCs reduced the expansion of viral nucleoprotein-specific CD8 T cells in the lung and spleen, but did finally not affect viral clearance from the lung. In conclusion, we found evidence for APC function of lung NK cells during influenza infection, but this is a feature not exclusive to the IKDC subset. http://repub.eur.nl/res/pub/37560/ 2009-06-06T00:00:00Z Influenza disease, often referred to as “flu”, is caused by the influenza viruses. These viruses are most only responsible for epidemics of variable severity almost every winter but occasionally cause major pandemic outbreaks. The term “influenza” has been derived from the Italian astrologers in the mid-1300s, who thought the flu was due to the “influence” of the heavenly bodies. Yet, the aetiology of the disease and the explanation for it’s peculiar behavior remained elusive. At the turn of the 19th century, influenza was thought to be due to a bacterial infection with Haemophilus influenzae. It was not until 1931 that Richard Shope showed that the causative agent was a virus. A few years later, Smith and co-workers for the first time isolated an influenza virus from humans with respiratory illness. The burden of influenza virus for the society, not only from a clinical but also from an economic perspective, is often underestimated. This relates particularly to the recurring annual winter epidemics. Fortunately, since the virus was first discovered, efficient means to contain the infection have been developed. Vaccination is the primary method for the prevention of influenza. However, due to the continuous genetic and antigenic variation that influenza viruses undergo, a constant global surveillance is required to identify and select new variants with epidemic or pandemic potential. Therefore, improvement of vaccination strategies against epidemic influenza and development of effective vaccines against potential pandemic viruses are a public health priority. New strategies for influenza vaccines include altering the dose, site or method of delivery of inactivated vaccines, the use of adjuvants or immunomodulators to enhance immune responses, or targeting of viral proteins that may promote broader, cross protective responses. http://repub.eur.nl/res/pub/14490/ 2008-10-28T00:00:00Z Dendritic cells (DCs) are a heterogenous population of antigen-presenting cells, of which conventional DCs and plasmacytoid DCs are the main subsets. Like DC subsets in the central lymphoid organs, DC subsets in the lungs exert specific functions that can be associated with distinct expression of endocytic receptors, cell-surface molecules, and anatomical location within the lung. In recent years, DC populations are increasingly split up into a seemingly endless number of defined sub-populations. We argue that this is not a "stamp-collecting" activity but essential for a deeper understanding of the immune response to pathogens like respiratory viruses or tolerance to harmless antigens. In homeostatic conditions, a fine-tuned balance exists between the various functions of lung DC subsets, which is necessary for maintaining immune homeostasis in the lung. However, infectious or inflammatory conditions can profoundly alter the functions of steady-state DC subsets and recruit inflammatory type DCs to the lung. This might be important for clearing the inflicting pathogenic stimulus, but could at the same time also be involved in causing immune pathology. http://repub.eur.nl/res/pub/28937/ 2008-07-07T00:00:00Z Although dendritic cells (DCs) play an important role in mediating protection against influenza virus, the precise role of lung DC subsets, such as CD11b-and CD11b+conventional DCs or plasmacytoid DCs (pDCs), in different lung compartments is currently unknown. Early after intranasal infection, tracheal CD11b-CD11chiDCs migrated to the mediastinal lymph nodes (MLNs), acquiring co-stimulatory molecules in the process. This emigration from the lung was followed by an accumulation of CD11b+CD11chiDCs in the trachea and lung interstitium. In the MLNs, the CD11b+DCs contained abundant viral nucleoprotein (NP), but these cells failed to present antigen to CD4 or CD8 T cells, whereas resident CD11b-CD8α+DCs presented to CD8 cells, and migratory CD11b-CD8α-DCs presented to CD4 and CD8 T cells. When lung CD11chiDCs and macrophages or langerin+CD11b-CD11chiDCs were depleted using either CD11c - diphtheria toxin receptor (DTR) or langerin-DTR mice, the development of virus-specif c CD8+T cells was severely delayed, which correlated with increased clinical severity and a delayed viral clearance. 120G8+CD11cintpDCs also accumulated in the lung and LNs carrying viral NP, but in their absence, there was no effect on viral clearance or clinical severity. Rather, in pDC-depleted mice, there was a reduction in antiviral antibody production after lung clearance of the virus. This suggests that multiple DCs are endowed with different tasks in mediating protection against influenza virus. http://repub.eur.nl/res/pub/13427/ 2004-06-23T00:00:00Z CONTEXT: The role of estrogens in ischemic heart disease (IHD) is uncertain. Evidence suggests that genetic variations in the estrogen receptor alpha (ESR1) gene may influence IHD risk, but the role of common sequence variations in the ESR1 gene is unclear. OBJECTIVE: To determine whether the ESR1 haplotype created by the c.454-397T>C (PvuII) and c.454-351A>G (XbaI) polymorphisms is associated with myocardial infarction (MI) and IHD risk. DESIGN, SETTING, AND PARTICIPANTS: In 2617 men and 3791 postmenopausal women from The Rotterdam Study (enrollment between 1989-1993 and follow-up to January 2000), a population-based, prospective cohort study of participants aged 55 years and older, ESR1 c.454-397T>C and c.454-351A>G haplotypes were determined. Detailed interviews and physical examinations were performed, blood samples were obtained, and cardiovascular risk factors were assessed. MAIN OUTCOME MEASURE: The primary outcome was MI and IHD defined as MIs, revascularization procedures, and IHD mortality. RESULTS: Approximately 29% of women and 28.2% of men were homozygous carriers of the ESR1 haplotype 1 (-397 T and -351 A) allele, 49% of women and 50% of men were heterozygous carriers, and 22% of women and 21.4% of men were noncarriers. During a mean follow-up of 7.0 years, 285 participants (115 women; 170 men) had MI, and 440 (168 women; 272 men) had an IHD event, of which 97 were fatal. After adjustment for known cardiovascular risk factors, female heterozygous carriers of haplotype 1 had an increased risk of MI (event rate, 2.8%; relative risk [RR], 2.23; 95% confidence interval [CI], 1.13-4.43) compared with noncarriers (event rate, 1.3%), whereas homozygous carriers had an increased risk (event rate, 3.2%; RR, 2.48; 95% CI, 1.22-5.03). For IHD events, we observed a similar association. In women, the effect of haplotype 1 on fatal IHD was larger than on nonfatal IHD. In men, the ESR1 haplotypes were not associated with an increased risk of MI (event rate, 5.7%; RR, 0.93; 95% CI, 0.59-1.46 for heterozygous carriers; and event rate, 5.1%; RR, 0.82; 95% CI, 0.49-1.38 for homozygous carriers) compared with noncarriers (event rate, 5.8%) and were not associated with an increased risk of IHD. CONCLUSIONS: In this population-based, prospective cohort study, postmenopausal women who carry ESR1 haplotype 1 (c.454-397 T allele and c.454-351 A allele) have an increased risk of MI and IHD, independent of known cardiovascular risk factors. In men, no association was observed.