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
Parasitic helminths modulate host immune responses. While the induction of type 2 immune responses is a widely recognized feature of helminth infections, a network of regulatory immune responses is... Show moreParasitic helminths modulate host immune responses. While the induction of type 2 immune responses is a widely recognized feature of helminth infections, a network of regulatory immune responses is often dominant during the chronic phase of infection. Suppression of the host immune system during helminth infections inhibits anti-parasite immunity, prevents tissue damage due to excessive inflammation and conveys spill-over suppression to inflammatory conditions such as allergy and asthma. The first part of this thesis focuses on the role of regulatory B cells, a prominent member of the immune regulatory network, in protection from allergic asthma by chronic Schistosoma (S.) mansoni infections. It furthermore identifies signals required for schistosome-induced regulatory B cell development. The second part of this thesis describes the protective effect of S. mansoni eggs, and a specific egg-derived glycoprotein, against allergic asthma in the absence of chronic infection. A better understanding how helminthes including S. mansoni modulate host immune responses, and the implications this has for inflammatory diseases such as allergic asthma, may provide valuable leads for the development of novel pharmaceutical agents for the treatment of allergic disorders. Show less
The main objective of this thesis is to improve understanding of the role of helminth infections in the development of insulin resistance (IR), hence Type 2 Diabetes (T2D), in the light of... Show moreThe main objective of this thesis is to improve understanding of the role of helminth infections in the development of insulin resistance (IR), hence Type 2 Diabetes (T2D), in the light of increasing urbanization in Indonesia. Our large-scale cluster-randomized controlled trial was performed in a rural area of Indonesia, which is endemic for soil-transmitted helminth (STH), and has been previously reported to have a low prevalence of IR and T2D. In STH-infected subjects, as assessed by microscopy, 12-month anthelmintic treatment increased IR, which was mediated by an increase in BMI and leptin to adiponectin ratio, as well as reduction in eosinophil count. Next, we also aimed to assess the different metabolic profile between populations living in rural and urban area, and to study the relative protective effect of rural environment to high-fat diet (HFD). In comparison to those living in rural area, individuals living in urban area had higher whole body IR, which was mainly mediated by the higher adiposity and leptin level, which were progressively increased with increased duration of time spent in urban area. Different environmental factors (including past or current exposure to STH) did not seem to affect the metabolic response to HFD intervention, independent from adiposity. 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
Madinga, J.; Polman, K.; Kanobana, K.; Lieshout, L. van; Brienen, E.; Praet, N.; ... ; Speybroeck, N. 2017
The work presented in this thesis aimed at increasing our understanding of the effect of helminths on Plasmodium spp. immune response in co-infected individuals living in endemic countries. It... Show moreThe work presented in this thesis aimed at increasing our understanding of the effect of helminths on Plasmodium spp. immune response in co-infected individuals living in endemic countries. It presents data from studies conducted in rural and semi urban areas of Lambaréné (Gabon) where the burden of malaria and helminths is particularly important. Although scarce previous studies have indicated an effect of helminths on malaria outcomes and immune response to Plasmodium spp. parasite in co-infected subjects. However it is still debated how consistent is this effect across study sites and teams and what its immunological basis is. Show less
Nearly one quarter of the world__s population is infected with helminth parasites. A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T... Show moreNearly one quarter of the world__s population is infected with helminth parasites. A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T helper 2 (Th2) cells. In addition to their involvement in anti-helminth immunity, recent studies have shown that components of the type 2 immune responses can have additional functions. For example, recent evidence indicates that multiple facets of the type 2 immune response can regulate tissue-specific metabolic processes and whole-body nutrient homeostasis, and protect against insulin resistance. In this work we use omega-1, a glycosylated RNase excreted from Schistsoma mansoni eggs with strong Th2-inducing capacities, to study the requirements that equip DCs for Th2 skewing. In addition, we analyse the effect of chronic S. mansoni infection and administration of S. mansoni-derived egg antigens on metabolic homeostasis in diet-induced obese mice. Elucidating how helminths generate Th2 responses and contribute to metabolic homeostasis will not only shed light on the mechanisms that promote control of parasite infection, but may provide valuable leads for the development of pharmaceutical agents for the treatment of metabolic disorders. Show less
Recent studies indicate that there is a global rise in the prevalence of asthma and other allergic disorders. Several epidemiological studies conducted in countries endemic for parasitic worms ... Show moreRecent studies indicate that there is a global rise in the prevalence of asthma and other allergic disorders. Several epidemiological studies conducted in countries endemic for parasitic worms (helminths) have reported an inverse association between the presence of helminth infections and allergic disease. The main objectives of the study described in this thesis were to: i. To determine urban-rural differences in allergy outcomes in Ghana, West Africa ii. To examine the association between helminth infections and allergies iii. To characterize IgE responses associated with helminth infections and allergies The thesis describes cross-sectional studies among schoolchildren aged 5-16 years living in urban and rural areas of Southern Ghana. Study findings showed marked urban-rural differences in the prevalence of allergy outcomes with current infection with the waterborne helminth schistosoma being inversely associated with mite skin prick test allergic sensitization. In the study population, elevated levels of allergen specific IgE were observed that did not translate into skin reactivity or reported symptoms. Differences in gene expression profiles were also observed between urban and rural children. Overall, study findings indicate that factors associated with urbanization such as reduced exposure to parasitic worms are associated with the increased prevalence of allergy outcomes in Ghanaian children Show less
