Chronic energy surplus causes obesity and promotes insulin resistance and type 2 diabetes (T2D). A major contributor to insulin resistance is chronic, low-grade inflammation in metabolic tissues,... Show moreChronic energy surplus causes obesity and promotes insulin resistance and type 2 diabetes (T2D). A major contributor to insulin resistance is chronic, low-grade inflammation in metabolic tissues, also coined metaflammation. In this context, white adipose tissue and liver-resident innate and adaptive immune cells produce proinflammatory cytokines that exacerbate inflammation and inhibit canonical insulin signaling. Among them, macrophages and dendritic cells were shown to play central roles in metaflammation, although the environmental and cellular changes dictating proinflammatory activation in the context of obesity are not fully understood. This thesis describes novel mechanisms by which macrophages and dendritic cells control metabolic homeostasis in obese mice. In addition, we show that immunomodulatory molecules derived from parasitic worm eggs promote an immune response in metabolic tissues that maintains insulin sensitivity. Finally, we describe the pleiotropic beneficial effects of a novel plant-derived nutritional supplement on metaflammation and metabolic homeostasis in obese mice. Altogether, this work may provide new leads for interventions aimed at improving immunological control of metabolic dysfunctions. Show less
Transplantation is the golden standard for the treatment of end-stage renal disease. During this process, the transplanted organ is often damaged. In this thesis, we investigated whether activation... Show moreTransplantation is the golden standard for the treatment of end-stage renal disease. During this process, the transplanted organ is often damaged. In this thesis, we investigated whether activation of the complement system, part of our innate immune system, plays a local role. We reviewed that properdin, the only known positive regulator of the complement system, was detected in serum, plasma and urine from patients with various complement-mediated renal diseases. In protocol biopsies obtained 10 days after transplantation, properdin was found deposited in addition to complement activation markers. Next, we showed that dendritic cells secrete properdin and a decrease in properdin levels during dendritic cell- T-cell interaction resulted in reduced T-cell proliferation and activation. We also showed that properdin is able to bind to surfaces of both viable and dead cells, contributing to complement activation. Macrophages can also produce properdin and negative regulators factor H and its splice variant FHL-1. Increasing knowledge on complement factor production by other cells than hepatocytes, including immune cells, hints towards a local role of the complement system in various processes. These findings contribute to a better understanding of the local role of the complement system and are important for the applications of (new) complement-inhibiting drugs. Show less
Dendritic cells are the canonical professional antigen-presenting cell and are therefore crucial in the generation of efficient adaptive T cell responses. It is now well described that immune cells... Show moreDendritic cells are the canonical professional antigen-presenting cell and are therefore crucial in the generation of efficient adaptive T cell responses. It is now well described that immune cells – including dendritic cells – make drastic changes to their biology to transition between different life stages and to deal efficiently with the threat of infection. However, an unanswered question was if DCs with different T cell polarizing properties - that is to say they preferentially skew T cells towards a specific specialization (for example T helper 1 cells over T helper 2 cells) - rely on distinct metabolic characteristics for their T cell polarizing ability. This thesis tries to address that question by studying the metabolism of dendritic cells after in vitro stimulation with antigens or immunomodulatory compounds that are known to prime either T helper 1 cells, T helper 2 cells, T helper 17 cells or regulatory T cells. In addition, we interrogate the role of liver kinase B1 (LKB1) and mechanistic target of rapamycin complex 1 (mTORC1) in DC biology. Show less
In the current thesis, we provide novel insights in antigen uptake, storage, processing, and sustained cross-presentation mechanisms in dendritic cells (DCs) in vitro and in vivo. We have studied... Show moreIn the current thesis, we provide novel insights in antigen uptake, storage, processing, and sustained cross-presentation mechanisms in dendritic cells (DCs) in vitro and in vivo. We have studied antigen handling functions by dendritic cells in three different antigen delivery routes: antibody targeting involving Fcγ receptors and complement factor C1q, C-type lectin receptor targeting, and toll-like receptor ligand targeting systems. Our data highlights that antigen storage in specialized compartments in DCs, despite the chosen uptake route, is beneficial for prolonged antigen cross-presentation by DCs and sustained T cell activation. Further in vivo studies in different antigen presenting cell (APC) subsets confirmed the presence of antigen storage compartments by isolating APC subsets after in vivo antigen uptake. Besides, we revealed a dominant role of C1q in antigen-antibody immune complex uptake and cross-presentation in vivo in contrast to the crucial role of Fcγ receptors in vitro. Furthermore, we demonstrated that autophagosomes have a negative impact on the storage of antigen in those specialized compartments and thereby affecting DC cross-presentation efficiency. With the current studies, we unraveled some mechanics of antigen processing in DCs which contribute to future vaccine designs against diseases such as cancer. Show less
Immunotherapy of cancer has established itself in recent years as a promising novel approach to treat cancer patients. One of the experimental approaches is based on therapeutic vaccination. We... Show moreImmunotherapy of cancer has established itself in recent years as a promising novel approach to treat cancer patients. One of the experimental approaches is based on therapeutic vaccination. We have previously developed vaccines consisting of synthetic long peptides (SLP) which successfully eradicated premalignant lesions in 50% of patients. To further improve these vaccines, a Toll-like receptor ligand (TLR-L) was conjugated to SLP which enables targeting of the SLP to relevant antigen-presenting cells while concomitantly activating these cells. In fact, the research described in this thesis shows that TLR-L SLP conjugates induce enhanced antitumor immunity. Furthermore, optimization of the TLR-L led to even furher improved antitumor responses in mice. Using human cancer patient-derived lymph node cells, we show that lymph node-derived T cells are favorably activated by the TLR-L SLP conjugates. Finally, we combine multiple innate immune stimulatory agonists (TLR2-L and NOD2-L) in one molecule to establish synergistic immune activation. Overall, the research described in this thesis demonstrates the potency of TLR-L SLP conjugates as cancer vaccines, which could strongly contribute to the treatment of cancer patients. Show less
Parasitic helminths are important organisms to study because their infections have both adverse and beneficial effects on the human host. Helminth infections are considered a burden, as these... Show moreParasitic helminths are important organisms to study because their infections have both adverse and beneficial effects on the human host. Helminth infections are considered a burden, as these infections cause significant morbidity in a large proportion worldwide. However, helminth infections, by means of their ability to modify host immune responses can also provide protection against inflammatory diseases (inflammatory bowel disease, diabetes, and asthma). It is important to better understand the underlying mechanisms of these Yin (positive) and Yang (negative) consequences of helminth infections. The general objective of this thesis is to track helminths at different levels. On the one hand to improve the detection of helminth infections, essential for the studying helminths and the interaction with their human host. Moreover, a more sensitive diagnostics is instrumental for monitoring the distribution of helminth infections and to evaluate the helminth infections elimination program. On the other hand, to understand the mechanistic insights of the interplay between helminths and the host immune system results in priming of Th2 and regulatory T cell responses. This could contribute to the identification of targeted pathways to manipulate immune responses, as part of developing therapeutics to treat inflammatory disorders characterized by deregulated Th2 and/or Treg responses. Show less
In this thesis, we have addressed aspects of two main arms of the adaptive immune system; the B cell and antibody arm and the T cell arm. This led to a division in the presentation of the... Show more In this thesis, we have addressed aspects of two main arms of the adaptive immune system; the B cell and antibody arm and the T cell arm. This led to a division in the presentation of the results described in this thesis into two sections. In the first section, we present the results regarding the characterization of ACPA responses, B cells and ACPA secreting plasmablasts/-cells in RA as well as autoantibody responses and their regulation by an effective anti-rheumatic drug, abatacept, in the arthritis mouse model; Collagen Induced Arthritis (CIA). The second section is compiled of results obtained from studies examining the regulatory and other aspects of CD49b+CD4+ T cells on proinflammatory responses involved in the pathogenesis of arthritis. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammation of the synovial membrane of the joints, culminating in destruction of cartilage and deformity of the joints if remains untreated. Infiltration of inflammatory immune cells such as B cells and T cells into the inflamed joints is a characteristic feature of RA. These immune cells are in continuous interaction with each other and create a viscous circle that sustains persistent synovitis and damage to articular cartilage. Show less
