Rob ter Horst

• Master of Science
• CeMM Research Center for Molecular Medicine

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy‐related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,...

Background: Rheumatoid Arthritis (RA) is a chronic disease marked by symptoms of inflammation and pain in the joints that eventually lead to joint degeneration, reduction in physical fitness and even disability [1]. It is broadly known that RA predisposition is partially explained by common genetic variants within multiple immune-related loci. Geno...

Background and aims Obesity predisposes to metabolic and cardiovascular diseases. Adipose tissue inflammation and systemic inflammation contribute to these complications. There are strong sex differences in adipose tissue distribution and in systemic inflammation. Women have more subcutaneous adipose tissue (SAT) and less visceral adipose tissue (V...

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. The vast majority of patients have unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Considering this fact, it is urgent to understand the genetic basis of susceptibility to PDAC and to develop more individualized prevention strate...

Leptin is associated with cardiometabolic complications of obesity, such as metabolic syndrome and atherosclerosis. In obese men, the presence of metabolic syndrome is associated with higher circulating leptin and interleukin-6 concentrations, and increased monocyte cytokine production capacity. Here we investigated the effects of leptin on monocyt...

Background: Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal protein...

Background: Although genome-wide association studies (GWAS) have uncovered the germline genetic component underlying chronic lymphocytic leukaemia (CLL) susceptibility, the potential use of GWAS-identified risk variants to predict disease prognosis remains unmet. Methods: We evaluated whether 41 GWAS-identified risk variants for CLL could influence...

Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults worldwide. Although genome-wide association studies (GWAS) have uncovered the germline genetic component underlying CLL susceptibility, the potential use of GWAS-identified risk variants to predict disease progression and patient survival remains unexplored. Here, we evalua...

Simple Summary We investigated the influence of autophagy-related variants in modulating Multiple Myeloma (MM) risk through a meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined the functional m...

Multiple myeloma (MM) is an incurable disease characterized by the presence of malignant plasma cells in the bone marrow that secrete specific monoclonal immunoglobulins into the blood. Obesity has been associated with the risk of developing solid and hematological cancers, but its role as a risk factor for MM needs to be further explored. Here, we...

Rationale To evaluate whether common nonsynonymous variants [single-nucleotide polymorphisms (SNPs) or SNP haplotypes] in the β2-adrenergic receptor render subjects more susceptible to norepinephrine-induced immunosuppression and whether they are associated with dysregulated ex vivo and in vivo inflammatory responses. Methods Peripheral blood mono...

Background Even during long-term combination antiretroviral therapy (cART), people living with HIV (PLHIV) have a dysregulated immune system, characterized by persistent immune activation, accelerated immune ageing and increased risk of non-AIDS comorbidities. A multi-omics approach is applied to a large cohort of PLHIV to understand pathways under...

Background Dietary patterns have been associated with variations in behavior. However, evidence has been limited and mixed, and the underlying mechanism remains unclear. Objective Extend a previous study reporting significant associations between food patterns and behavioral disinhibition and explore whether low-grade inflammation is linked to dis...

Simple Summary We investigated the influence of GWAS-identified variants for T2D in modulating prostate cancer (PCa) risk through a meta-analysis of our data with those from the UKBiobank and FinnGEn cohorts and four large European cohorts. We found that genetic variants within the FTO, HNF1B, and JAZF1 loci were associated with PCa risk. Our resul...

Background: Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among adults in Western countries and remains as an incurable disease with a very heterogeneous clinical course. Traditional clinical prognostic factors include Rai and Binet staging systems and lymphocyte doubling time. Among the biological markers used in clinical practi...

Dietary habits may affect inflammatory status in humans. Here we explore this interaction as well as the potential mediating role of the gut microbiome (GM), given that the GM is both involved in processing of dietary components and influences the immune system. A cross-sectional analysis of a sample of 482 healthy participants (207 males and 275 f...

We aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected markers and evaluated their association with response to...

Male sex and old age are risk factors for COVID-19 severity, but the underlying causes are unknown. A possible explanation for this might be the differences in immunological profiles in males and the elderly before the infection. With this in mind, we analyzed the abundance of circulating proteins and immune populations associated with severe COVID...

Background. Dietary habits may influence chronic low-grade inflammation in humans. Here we explore this interaction as well as the potential mediating role of the gut microbiome (GM), given that the GM is both involved in processing of dietary components and influences the immune system. Methods. A cross-sectional analysis of a sample of 482 health...

Different components of the immune response show large variability between individuals, but they also vary within the same individual because of host and environmental factors. In this study, we report an extensive analysis of the immune characteristics of 56 individuals over four timepoints in 1 single year as part of the Human Functional Genomics...

Background The interplay between genetics and drug response in rheumatoid arthritis (RA) has shown that response to biologics varies between individuals and that a large proportion of patients show no clinical improvement (Plenge and Bridges, 2011). Despite the disappointing scenario, to date, only a few genetic markers have been consistently ident...

Activation of immune cells in response to fungal infection involves the reprogramming of their cellular metabolism to support antimicrobial effector functions. Although metabolic pathways such as glycolysis are known to represent critical regulatory nodes in antifungal immunity, it remains undetermined whether these are differentially regulated at...

Background: Male sex and old age are risk factors for COVID-19 severity, but the underlying causes are unknown. A possible explanation for this might be the differences in immunological profiles in males and the elderly before the infection. Given the seasonal profile of COVID-19, the seasonal response against SARS-CoV-2 could also be different in...

Long-term changes in the immune system of successfully treated people living with HIV (PLHIV) remain incompletely understood. In this study, we assessed 108 white blood cell (WBC) populations in a cohort of 211 PLHIV on stable antiretroviral therapy and in 56 HIV-uninfected controls using flow cytometry. We show that marked differences exist in T c...

The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome...

Using a comparative RNA-Sequencing based transcriptional profiling approach, responses of primary human peripheral blood mononuclear cells (PBMCs) to common human pathogenic fungi have been characterized (Bruno et al. Computational and Structural Biology Journal). Primary human PBMCs were stimulated in vitro with the fungi A. fumigatus, C. albicans...

Chronic inflammation and immune dysfunction play a key role in the development of non-AIDS related comorbidities. The aim of our study was to characterize the functional phenotype of immune cells in people living with HIV (PLHIV). We enrolled a cross-sectional cohort study of PLHIV on stable antiretroviral therapy and healthy controls. We assessed...

Human diseases arise in a complex ecosystem composed of disease mechanisms and the whole-body state. However, the precise nature of the whole-body state and its relations with disease remain obscure. Here we map similarities among clinical parameters in normal physiological settings, including a large collection of metabolic, hemodynamic and immune...

The endocrine and the immune systems interact by sharing receptors for hormones and cytokines, cross‐control, and feedback mechanisms. To date, no comprehensive study has assessed the impact of thyroid hormones on immune homeostasis. By studying immune phenotype (cell populations, antibody concentrations, circulating cytokines, adipokines and acute...

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta...

CRELD1 is a pivotal factor for heart development, the function of which is unknown in adult life. We here provide evidence that CRELD1 is an important gatekeeper of immune system homeostasis. Exploiting expression variance in large human cohorts contrasting individuals with the lowest and highest CRELD1 expression levels revealed strong phenotypic,...

Candidiasis, aspergillosis, and mucormycosis cause the majority of nosocomial fungal infections in immunocompromised patients. Using an unbiased transcriptional profiling in PBMCs exposed to the fungal species causing these infections, we found a core host response in healthy individuals that may govern effective fungal clearance: it consists of 15...

We evaluated the association between germline genetic variants located within the 3′‐untranlsated region (polymorphic 3′UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case‐control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recr...

The IL‐1 family member IL‐38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL‐38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL‐38 correlated negatively with age (P = 0.02) and was stable in 48 subjects for one year. In comparison with pr...

Bile acids (BAs) are implicated in the etiology of obesity-related conditions such as non-alcoholic fatty liver disease. Differently structured BA species display variable signaling activities via farnesoid X receptor (FXR) and Takeda G protein-coupled BA receptor 1 (TGR5). This study profiles plasma and fecal BAs and plasma 7α-hydroxy-4-cholesten-...

The Roma people are the largest transnational ethnic minority in Europe and can be considered the last human migration of South Asian origin into the continent. They left Northwest India approximately 1,000 years ago, reaching the Balkan Peninsula around the twelfth century and Romania in the fourteenth century. Here, we analyze whole-genome sequen...

Aim: To investigate whether a history of severe hypoglycaemia (SH) or the associated presence of impaired awareness of hypoglycaemia (IAH) is characterized by a pro-inflammatory profile in people with type 1 diabetes. Research design and methods: We measured circulating inflammatory markers and pro- and anti-inflammatory cytokine production afte...

Background: The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. Results: In a pooled analysis of cohort stu...

Context Not all obese individuals develop cardiovascular disease (CVD). Hyperaldosteronism is suggested to cause inflammation and metabolic dysregulation, and might contribute to CVD development in obese individuals. Objective We aimed to investigate the association of aldosterone concentrations with inflammation, metabolic disturbances, and ather...

Objective: Metabolic dysregulation and inflammation are important consequences of obesity and impact susceptibility to cardiovascular disease. Anti-inflammatory therapy in cardiovascular disease is being developed under the assumption that inflammatory pathways are identical in women and men, but it is not known if this is indeed the case. In this...

In response to infection, macrophages adapt their metabolism rapidly to enhance glycolysis and fuel specialized antimicrobial effector functions. Here we show that fungal melanin is an essential molecule required for the metabolic rewiring of macrophages during infection with the fungal pathogen Aspergillus fumigatus. Using pharmacological and gene...

We recently demonstrated that the sympathetic nervous system can be voluntarily activated following a training program consisting of cold exposure, breathing exercises, and meditation. This resulted in profound attenuation of the systemic inflammatory response elicited by lipopolysaccharide (LPS) administration. Herein, we assessed whether this tra...

This study sought to evaluate the association of 28 single nucleotide polymorphisms (SNPs) within NFKB and inflammasome pathway genes with the risk of rheumatoid arthritis (RA) and response to TNF inhibitors (TNFi). We conducted a case-control study in a European population of 1194 RA patients and 1328 healthy controls. The association of potential...

Here, we assessed whether 41 SNPs within steroid hormone genes associated with erosive disease. The most relevant finding was the rheumatoid factor (RF)-specific effect of the CYP1B1, CYP2C9, ESR2, FCGR3A, and SHBG SNPs to modulate the risk of bone erosions (P=0.004, 0.0007, 0.0002, 0.013 and 0.015) that was confirmed through meta-analysis of our d...

Background Although most patients recover from acute Q fever, around 20% develop Q fever fatigue syndrome (QFS), a debilitating fatigue syndrome that lasts at least six months. This study investigated transcriptional profiles of circulating monocytes and circulating cytokines as a subsequent mirror of myeloid cell function, one and six months after...

Secondary infections are a major complication of sepsis and associated with a compromised immune state, called sepsis-induced immunoparalysis. Molecular mechanisms causing immunoparalysis remain unclear; however, changes in cellular metabolism of leukocytes have been linked to immunoparalysis. We investigated the relation of metabolic changes to an...

Background Q fever fatigue syndrome (QFS) is a well-documented state of prolonged fatigue following around 20% of acute Q fever infections. It has been hypothesized that low grade inflammation plays a role in its aetiology. In this study, we aimed to identify transcriptome profiles that could aid to better understand the pathophysiology of QFS. Me...

Immunopathology contributes to high mortality in tuberculous meningitis (TBM) but little is known about the blood and cerebrospinal fluid (CSF) immune response. We prospectively characterised the immune response of 160 TBM suspects in an Indonesian cohort, including 67 HIV-negative probable or definite TBM cases. TBM patients presented with severe...

Sepsis involves simultaneous hyperactivation of the immune system and immune paralysis, leading to both organ dysfunction and increased susceptibility to secondary infections. Acute activation of myeloid cells induced itaconate synthesis, which subsequently mediated innate immune tolerance in human monocytes. In contrast, induction of trained immun...

A hallmark of obesity is chronic low‐grade inflammation, which plays a major role in the process of atherosclerotic cardiovascular disease (ACVD). Gut microbiota is one of the factors influencing systemic immune responses, and profound changes have been found in its composition and metabolic function in individuals with obesity. This systematic rev...

Tissue culture medium routinely contains fetal bovine serum (FBS). Here we show that culturing human hepatoma cells in their native, adult serum (human serum, HS) results in the restoration of key morphological and metabolic features of normal liver cells. When moved to HS, these cells show differential transcription of 22-32% of the genes, stop pr...

Understanding the physiology and genetics of human hypoxia tolerance has important medical implications, but this phenomenon has thus far only been investigated in high-altitude human populations. Another system, yet to be explored, is humans who engage in breath-hold diving. The indigenous Bajau people (“Sea Nomads”) of Southeast Asia live a subsi...

Innate immune cells can develop long-term memory after stimulation by microbial products during infections or vaccinations. Here, we report that metabolic signals can induce trained immunity. Pharmacological and genetic experiments reveal that activation of the cholesterol synthesis pathway, but not the synthesis of cholesterol itself, is essential...

Monocytes are innate immune cells that play a pivotal role in antifungal immunity, but little is known regarding the cellular metabolic events that regulate their function during infection. Using complementary transcriptomic and immunological studies in human primary monocytes, we show that activation of monocytes by Candida albicans yeast and hyph...

Transcriptome analysis after stimulation of PBMCs with C. albicans. (A and B) Pathway map of the gene expression in the main metabolic pathways in PBMCs stimulated with heat-killed C. albicans yeast 4 h (A) and 24 h (B) after the stimulation. The transcripts marked in red were significantly upregulated in C. albicans versus RPMI. (TIF)

Glycolysis, glutaminolysis and oxidative phosphorylation differentially affected Th1/Th17-derived cytokine production in PBMCs. (A-B) IL-17, IL-22 and IFNγ production by human PBMCs treated with different metabolic inhibitors and stimulated with heat-killed C. albicans yeast (A) or heat-killed C. albicans hyphae (B) for 7 days. IL-10 production was...

Viability of human PBMCs treated with metabolic inhibitors. PBMCs were stained for Annexin V and propidium iodide. Annexin V+ cells were considered as early apoptotic cells and Annexin V+ / PI+ cells were considered as late apoptotic cells. (mean ± SEM, n = 3). Similar results were obtained in 3 independent experiments. (TIF)

OCR/ECAR ratios. Basal and maximum OCR/ECAR ratios obtained after 4 h and 24 h stimulation of monocytes with medium or heat-killed C. albicans yeast (mean ± SEM, n = 6–8; pooled from 2 independent experiments). (TIF)

C-type lectins triggered glycolysis after stimulation with Candida yeast. (A-B) Lactate production by human monocytes was measured after adding the corresponding isotype controls of the blockers used in Fig 4 and the subsequent 24 h-stimulation with medium, heat-killed C. albicans yeast or heat-killed C. albicans hyphae (A) or hgc1 or Δhgc1 live C....

ROS production by monocytes involved glycolysis and the pentose phosphate pathway. (A-D) Human monocytes were treated with DMSO (A), Torin1 (B), AICAR (C) or BPTES (D) and subsequently stimulated with medium, heat-killed C. albicans yeast or heat-killed C. albicans hyphae. Luminescence generated from ROS production was measured every 145 seconds du...

Phagocytic capacity of monocytes after 2-DG treatment. (mean ± SEM, n = 12; pooled from 4 independent experiments). (TIF)

Direct effects of 2-DG on mouse neutrophils. (A-B) Candidacidal activity of neutrophils isolated from blood of non-infected C57BL/6 mice following the protocol described in (A) after in vitro treatment of cells with PBS or 11 mM 2-DG (mean ± SEM, n = 6). *p< 0.05, Student’s t test. Each dot represents one mouse. (TIF)

Primers for real-time PCR. (DOCX)

Tissue culture medium routinely contains fetal bovine serum (FBS). Here we show that culturing human hepatoma cells in their native, adult serum (human serum, HS) results in the restoration of key morphological and metabolic features of normal liver cells. When moved to HS, these cells show differential transcription of 22-32% of the genes, stop pr...

Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable...

Despite the importance of immune variation for the symptoms and outcome of Lyme disease, the factors influencing cytokine production during infection with the causal pathogen Borrelia burgdorferi remain poorly understood. Borrelia infection-induced monocyte- and T cell-derived cytokines were profiled in peripheral blood from two healthy human cohor...

Differences in susceptibility to immune-mediated diseases are determined by variability in immune responses. In three studies within the Human Functional Genomics Project, we assessed the effect of environmental and non-genetic host factors of the genetic make-up of the host and of the intestinal microbiome on the cytokine responses in humans. We a...