PhD-projects for MD/PhD-traject
Immunity, Infection and Tolerance
January 2015
Content
Page
Infectious diseases
• Topical application of synthetic AMPs has potential for development of novel treatments of
infections………………………………………………………………………………………………………………………………………1
• Developing superior vaccines against a major human infectious disease: tuberculosis…………………2
• HLA-E mediated antigen presentation as Trojan Horse in vaccination against Tuberculosis.…………3
• Discovery of host regulatory networks as targets for novel immunomodulatory drugs to control
intracellular bacterial infections………………………….………………………………………………………………………..4
Molecular cell biology
• Immune escape by Epstein-Barr virus: Underlying mechanisms, impact, and potential
applications……………………………………………………………………………………………………………………………..…..5
• Role of alpha cells in T1D pathogenesis: Targets and mechanisms at the interface of pancreatic
islets and the immune system………………………………………………………………………………………………………6
Nephrology
• Role of Mannan Binding Lectin in delayed graft function and acute kidney injury…………………………7
Neurology
• New moves in Parkinson’s disease…………………………………..……………………………………………………………8
Parasitology
• Helminth-derived molecules and insulin sensitivity: from immunomodulatory properties to direct
regulation of metabolic tissues …………………………..………………………………………….……………………………9
Pediatrics
• Role of B7-H4/VTCN1 in the course of disease in juvenile idiopathic arthritis………………………..……10
Pulmonology
• Role of airway epithelial cells in the pathogenesis of asthma and chronic obstructive pulmonary
disease (COPD)…………………..……………………………………………………………………………………………….………11
• Treatment options for different asthma endotypes……………………………………………………………………12
Radiology
• The value of MRI of hand and foot in juvenile idiopathic arthritis (JIA)…………………………….…………13
Rheumatology
• Early detection and treatment of young adults with axial spondyloarthritis: the international
Spondyloarthritis Caught Early (SPACE)
cohort………………………………………………………….……….……………………………………………………………..……14
• Studies into the effect of intracellular complement activation on immune cell activation in
Rheumatoid
Arthritis……………………………………………………………..……….…………………………………………………….………15
• Diagnostic and prognostic value of autoantibodies in Rheumatoid arthritis…………………..…….……16
• Obesity as risk factor for Osteoarthritis: how does it work? ……….…………………………………….………17
Infectious diseases
Title PhD project:
Developing superior vaccines against a major human infectious disease:
tuberculosis
Department:
Infectious Diseases
Promotor:
Prof Dr Tom HM Ottenhoff
Supervisor (PI):
Prof Dr Tom HM Ottenhoff and Prof dr A Geluk
Email address contact person: t.h.m.ottenhoff@lumc.nl
Description:
Tuberculosis remains a major human infectious disease, causing 9 million new cases and 1,5 million
deaths each year. There is no effective vaccine available, and there is an increasing emergence of drug
resistance. Our mission is to design and develop better vaccines against Mycobacterium tuberculosis
infection, based on insight of Mtb’s infection biology. Mtb is known to alter its gene expression profile
significantly during intracellular stress inside host macrophages, the cells in which it mostly resides in
the human host. This impacts upon the Mtb antigen repertoire which is expressed and presented to the
immune system during infection. A deeper understanding of the real time infection-expressed Mtb
‘antigenome’ and its recognition by the human immune system, including non-classical T and B cells, is
therefore critical to the design of better vaccine strategies. Based upon comprehensive and precise Mtb
gene expression data from Mtb during infection of the lungs of highly susceptible mice –much more
extensive than was available previously- we want to further decipher the Mtb antigenome during its
infection cycle, and study its impact on human protective immune responses using latest immune and
genetic technologies. Studies will involve in vitro experiments with human cells.
See also https://www.lumc.nl/org/infectieziekten/medewerkers/tomottenhoff
[1]
Title PhD project:
Topical application of synthetic AMPs has potential for development of
novel treatments of infections
Department:
Infectious Diseases
Promotor:
Prof dr JT van Dissel
Supervisor (PI):
Dr PH Nibbering
Email address contact person: p.h.nibbering@lumc.nl
Description:
The increase in resistance against antimicrobial drugs is a public health emergency. There is a high
urgency to develop new antimicrobial drugs or develop alternative ways of coping with infectious
microorganisms. The development of conventional antibiotics heavily relies on the concept of each
antibiotic having a single primary target and a single mode of action. Nature appears to have chosen
a very different concept: the evolution of innate host-defense and anti-microbial peptides (AMPs),
favoring the design of ‘drugs’ that disturb many biological functions simultaneously (both bacterial
as mammalian, see attachment) rather than blocking a specific high-affinity target. As a result, AMPs
have been effective for billions of years, and therefore new therapeutic approaches using AMPs
might be of great value to address and overcome antibiotic resistance. We have developed a family
of highly potent AMPs, that are the first in their class to be active in the sub-micromolar range. We
have established a wealth of data on both the efficacy and (pre) clinical safety profiles. Some of our
AMPs combine high antibacterial efficacy against gram- positive and gram-negative bacteria,
including antibiotic resistant strains, and fungi/yeasts with no detectable resistance development.
In addition, our AMPs are effective against bacteria on wounded, 3D human skin equivalents as well
as air-exposed human airway epithelial cell cultures and urine-exposed 3D human urothelial
models. Moreover, our AMPs have proven to be effective in mouse and rabbit models for infections
associated with medical (metal) implants. Clinical efficacy of our first generation synthetic AMP has
been shown in patients with treatment-resistant otitis media and by others for the naturally
occurring parent AMP LL-37 in venous wounds. Our synthetic peptides can be applied in various
formulations (coatings, ointment, gels etc) and at different body locations, e.g. on wounds,
intravesicularly etc. An alternative might be to rely on the host cellular machinery to locally
manufacture the AMPs of interest. In this connection, transfection-enhancing polymers have
recently been described that open a new effective and affordable way to deliver AMP-encoding gene
constructs.
[2]
Title PhD project:
HLA-E mediated antigen presentation as Trojan Horse in vaccination against
Tuberculosis
Department:
Infectious Diseases
Promotor:
Prof Dr Tom HM Ottenhoff
Supervisor (PI):
Dr Simone A Joosten
Email address contact person: t.h.m.ottenhoff@lumc.nl; sajoosten@lumc.nl
Description:
Mycobacterium tuberculosis (Mtb), responsible for tuberculosis (TB), is a major infectious threat to
the world population, still being one of the mostly deadly pathogens for humans. Experts believe
that appropriate vaccination strategies are the sole possibility to limit the disease burden and
thereby subsequently limit spreading of the infection. At present the success of vaccination against
Mtb is limited to protection of young children but poor protection of adults against infection and
disease development. In our laboratory, we have been investigating quantitatively and qualitatively
the immune response in patients with TB and following vaccination with BCG and novel vaccines in
clinical testing for TB, and we focussed mostly on the human T cell responses. We have identified
several novel subsets of human CD8+ T cells that appear involved not only in immune-regulation of
the effector immune response against Mtb, but also in direct killing of Mtb. Interestingly, these CD8+
T cells expressed GATA3, produced Th2 cytokines (IL-4,-5,-10,-13) and activated B-cells via IL-4.
These T cells appeared to recognize their antigen in one of the non-classical HLA-class I family
members, named HLA-E. HLA-E is an antigen presentation molecule expressed by almost all cells and
is invariable between individuals, moreover this molecule is relatively insensitive to modulation by
HIV, therefor peptide vaccination targeting HLA-E would be highly attractive. In TB patients, Mtb
specific cells were detectable by peptide-HLA-E tetramers, and IL-4 and IL-13 were produced
following peptide stimulation. The aim of the current project would be to investigate in great detail
the possibility to apply these antigens presented in HLA-E to the immune system for vaccination
strategies against TB.
[3]
Title PhD project:
Discovery of host regulatory networks as targets for
immunomodulatory drugs to control intracellular bacterial infections
Department:
Infectious Diseases
Promotor:
Prof Dr Tom H.M. Ottenhoff
Supervisor (PI):
Dr Mariëlle C. Haks
Email address contact person: m.c.haks@lumc.nl; t.h.m.ottenhoff@lumc.nl
novel
Description:
Tuberculosis (TB) is a health threat of global dimensions. Current interventions (antibiotics, Bacillus
Calmette-Guérin vaccination, diagnostics) fail to reduce TB incidence sufficiently. Together with the
rising frequency of multi-, extensively-, and even totally drug-resistant (MDR/XDR/TDR) bacteria, and
the fact that many drugable targets in pathogens are already inhibited by current antibiotics, it is
imperative to develop innovative out-of-the-box strategies acting by mechanisms different from
those already targeted by current interventions to combat TB. Mycobacterium tuberculosis (Mtb)
has a remarkable ability to manipulate intracellular signaling pathways to escape from host defense
in human cells. We hypothesize that it is critical to counteract these pathogen induced inhibitory
mechanisms, which act on essential host cell signaling pathways, before intracellular (myco)bacteria
can be efficiently controlled and eradicated by host defense mechanisms and chemotherapeutics.
Innovative strategies to achieve this are approaches that target host rather than pathogen
molecules. These approaches are not only less likely to result in drug resistance but also offer new
modalities to combat drug resistant strains such as MDR/XDR/TDR-TB.
The aim of our project is to identify the key host molecules that are manipulated by intracellular
pathogens in human cells (including macrophages, the main targets of Mtb) and to develop novel
chemical compounds that target these key host genes/proteins to eliminate intracellular Mtb, using
similar approaches as we reported earlier (Kuijl et al, Nature 2007). Collectively, supporting host cell
biology in the control of infections is a novel and highly attractive approach of disease control.
[4]
Molecular cell biology
Title PhD project:
Immune escape by Epstein-Barr virus: Underlying mechanisms, impact, and
potential applications
Department:
Molecular Cell Biology
Promotor:
Prof Dr. Rob C Hoeben
Supervisor (PI):
Dr Maaike Ressing
Email address contact person: m.e.ressing@lumc.nl
Description:
Infectious diseases caused by viruses continue to be a major cause of human suffering and death
worldwide. Herpesviruses stand out for their capacity to establish lifelong infections in
immunocompetent hosts. These viruses, including the oncogenic Epstein-Barr virus, encode a variety
of gene products to facilitate infection, replication, and persistence in the face of a functional host
immune system. Viral evasion tactics appear to target virtually any stage of the innate and adaptive
immune response of the infected host. In the context of this research project, the diverse pathways
employed by herpesviruses in general and EBV in particular will be scrutinized, with a focus on the
still enigmatic pathways of how EBV immune evasion strategies target innate immunity. Unraveling
the mechanisms that underlie EBV immune escape allows: 1. interference with these to prevent or
treat virus-associated pathology (malignant tumors, mononucleosis, XLP, PTLD); 2. exploitation of
these strategies to e.g. mask transplants, therapeutic gene products or relieve autoimmunity.
[5]
Title PhD project:
Role of alpha cells in T1D pathogenesis: Targets and mechanisms at the
interface of pancreatic islets and the immune system.
Department:
Molecular Cell Biology
Promotor:
Prof. dr. Rob C Hoeben
Supervisor (PI):
Dr. Arnaud Zaldumbide
Email address contact person: a.zaldumbide@lumc.nl
Description:
Type 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T-cell mediated
destruction of the insulin-producing pancreatic beta cells. During T1D pathogenesis,
proinflammatory cytokines secreted by infiltrated autoreactive immune cells are known to play a
prominent role by inducing endoplasmic reticulum (ER) stress, beta cell dysfunction and ultimately
beta cell death. These danger signals serve as mediator in the dialogue between beta cells and the
immune compartment to initiate T-cell activation, loss of tolerance, induction of beta cell
autoimmunity, and progressive beta cell destruction.
The hyperglucagonemia observed in T1D patients and the precise architecture of human islets where
alpha cells and beta cells are largely interconnected, strongly point toward the participation of alpha
cells as a missing link in the communication chain between immune system and beta-cells. This
program should reveal how the alpha cells and beta cells interplay when islets are assaulted by
autoreactive immune cells.
[6]
Nephrology
Title PhD project:
Role of Mannan Binding Lectin in delayed graft function and acute kidney
injury
Department:
Nephrology
Promotor:
Prof Dr C van Kooten, Prof dr JW de Fijter
Supervisor (PI):
Prof Dr C van Kooten
Email contact person: kooten@lumc.nl
Description:
Ischemia/reperfusion is an early and inevitable process in organ transplantation, and the innate
immune system has been implicated as a critical mediator of injury. Complement activation has
been recognized as an important effector arm of the immune system, not only as a defense against
pathogens, but also as a pathogenic mechanism for antibody-mediated processes (humoral
rejection, IgA-nephropathy, SLE) or as a clearance mechanism for the removal of cellular debris.
Interest in complement has strongly increased with the availability of therapeutic agents which can
be applied in the clinical setting. This requires an in depth view of the pathways involved in the
complement activation.
In a combination of clinical, experimental and in vitro experiments we have recently established a
new role for Mannan Binding Lectin (MBL), the initiator of the lectin pathway of complement.
Recipients with low MBL show improved graft survival, whereas therapeutic inhibition of MBL in a
rat model of IRI resulted in a complete protection against injury and maintenance of epithelial
integrity. Deposition of MBL could be demonstrated in renal biopsies of patients with delayed graft
function. The molecular mechanism of MBL-mediated injury is currently unknown, but appears to be
independent of the complement activation and dependent on the molecular composition of the MBL
molecule. In the current project we will further investigate the presence and role of MBL in delayed
graft function and other forms of acute kidney injury.
[7]
Neurology
Title PhD project:
New moves in Parkinson’s disease
Department:
Neurology
Promotor:
Prof. dr. J.J. (Bob) van Hilten
Supervisor (PI):
Prof. dr. J.J. (Bob) van Hilten
Email address contact person: j.j.van_hilten@lumc.nl
Description:
Parkinson’s disease is a neurodegenerative disorder characterized by deteriorating motor function,
which greatly impacts daily life. The motor features of the disease are usually assessed with rating
scales, but these only provide a crude impression of a patient’s motor impairments. Better methods
to quantify the motor deficits are therefore warranted to determine the effect of interventions or to
monitor the course of the disease. Recently new computer vision techniques have been developed
for computer gaming, but this technology is potentially also very useful for motion research. The
applicability of these techniques in this field is the basis of a multi-center project: ‘Technology In
Motion’ (TIM). The new software technologies not only allow collection of information on relevant
aspects of motor function in daily life (e.g. gait, balance, arm function), but also quantification of
movement disorders typically present in Parkinson’s diease, including slowness of movement,
tremor and chorea. Taken together, the current project involves the development of an innovative
protocol for motion research in Parkinson’s disease that is reliable, valid and readily applicable to
patients with Parkinson’s disease. So, if you are interested in motion research, want to improve your
technical skills, and want to contribute to bringing clinical research in Parkinson’s disease at a higher
level, do not hesitate to contact me for further information on this exciting project.
[8]
Parasitology
Title PhD project:
Helminth-derived molecules and insulin sensitivity: from
immunomodulatory properties to direct regulation of metabolic tissues
Department:
Parasitology
Promotor:
Prof M. Yazdanbakhsh
Supervisor (PI):
Dr B. Guigas
Email address contact person: b.g.a.guigas@lumc.nl
Description (max 10 sentences):
Chronic low-grade inflammation associated with obesity is one of the major contributors to insulin
resistance, increasing the risk for developing type 2 diabetes. Helminths are strong natural inducers
of Type-2 immune responses. Both helminth infection and helminth-derived molecules (HDMs) were
shown to improve glucose/lipid homeostasis and insulin sensitivity in obese mice, at least partly by
promoting M2 macrophage polarization in adipose tissue. Some HDMs were also recently found to
directly target metabolic cells, such as adipocytes and hepatocytes, via glycan-mediated interaction
with specific receptors. Collectively, this suggests that HDMs can constitute a source of unique
molecules for manipulating metabolic processes. The overall objective of the project will be to
elucidate the immune cell-dependent and/or -independent mechanism(s) whereby HDMs improve
insulin sensitivity and restore glucose/lipid homeostasis in metabolic disease states.
[9]
Pediatrics
Title PhD project:
Role of B7-H4/VTCN1 in the course of disease in juvenile idiopathic arthritis
Department:
Pediatrics
Promotor:
Prof Dr E.H.H.M. Rings / Prof Dr T.W.J. Huizinga
Supervisor (PI):
Dr M.W. Schilham / Dr R. ten Cate
Email address contact person: m.w.schilham@lumc.nl / r.ten_cate@lumc.nl
Description:
In juvenile idiopathic arthritis (JIA) genetic evidence has been collected that a polymorphism in the
VTCN1 gene is associated with the course of disease. The VTCN1 gene encodes the B7-H4 protein
which belongs to the B7 gene family and provides a negative signal to T cells through an as yet
undefined ligand. Therefore, it is attractive to speculate that this gene plays a role in disease
progression. To replicate this genetic association, collaborations have been started with other
centers to genotype DNA from patients of whom sufficient clinical data are available. The soluble (s)
B7-H4 molecule has been detected in sera of patients with rheumatoid arthritis. Levels of sB7-H4 will
be measured in a cohort of patients with JIA treated in the LUMC to investigate correlations with
disease activity. Sera and detailed clinical data are available at the Department of Pediatrics. The
correlation between genotype and expression and/or function of the VTCN1 gene will be studied in
PBMC from healthy bloodbank donors.
[10]
Pulmonology
Title PhD project:
Role of airway epithelial cells in the pathogenesis of asthma and chronic
obstructive pulmonary disease (COPD)
Department:
Pulmonology
Promotor:
Prof Dr Pieter S. Hiemstra
Supervisor (PI):
Prof Dr Pieter S. Hiemstra
Email address contact person: p.s.shiemstra@lumc.nl
Description:
Airway epithelial cells play a central role in the pathogenesis of inflammatory lung diseases such as
asthma and COPD. They not only form a barrier to inhaled substances and provide mucociliairy
clearance, they also are actively involved in host defence against infection and regulating immunity
by secreting a large array of mediators and effector molecules, and interacting with e.g. dendritic
cells. Within this research line, we are using state-of-the-art culture system of differentiated human
airway epithelial cells obtained from patients and controls, to explore the response of these cells to
allergens, air pollutants, cigarette smoke, inflammatory mediators and respiratory pathogens. In
addition, the effect of a range of drugs is evaluated in this system. Current focuses include the role
of epithelial cells in producing anti-inflammatory mediators and antimicrobial peptides, and the role
of oxidative stress, endoplasmic reticulum stress and the integrated stress response in this immune
function of epithelial cells.
Cell culture system used:
[11]
Title PhD project: Treatment options for different asthma endotypes
Department: Pulmonology & Parasitology
Promotor: Prof C. Taube
Supervisor (PI): Prof C. Taube & Dr H. H. Smits
Email address contact person: c.taube@lumc.nl; h.h.smits@lumc.nl
Description:
In the past 50 years a strong increase in inflammatory diseases, including asthma, has occurred in
westernized countries and it has been hypothesized that a rapid decline in environmental exposure
by microbes and parasites is in part underlying this alarming shift in disease. Asthma is an
heterogeneous airway disease consisting of different phenotypes, possibly evolving from different
pathophysiological origins. There is increasing effort to identify these different phenotypes and to
develop and offer specific (personalised) treatments to these patients. A range of new biologicals
have been developed to target different effector arms of the immune system, such as
immunoglobulins (IgE) or cytokines (IL-5, IL-13), which seem to be effective in specific endotypes of
asthma. Although extensive information about these targets has been gathered in mouse models for
allergic airway disease, these models are often artificial and not representative for the different
asthma endotypes found in patients. Therefore these new biologicals may not only provide new
(though very costly) treatment options, they may also offer a wealth of new information about the
immunological mechanisms and characteristics of the various endotypes of asthma, when applied as
a treatment. Most information so far is coming from peripheral blood analyses, but close insight in
the diseased organs itself is often lacking. Therefore the challenge would be to combine new studies
on biologicals in patients with different endotypes with biobanking of precious tissue material
derived from (upper or lower) airways to provide novel insights in the pathophysiology of this
heterogeneous disease. In addition, this material will offer an unique access to ex vivo explant
cultures and tissue-based test systems to screen new (and less costly) molecules targeting relevant
inflammatory conditions found only in the diseased organ. Both at the Dept of Pulmonology and
Parasitology, overlapping programs are running to identify interesting therapeutic molecules derived
from protective microbes or parasites that would form ideal candidates to determine their efficacy
in reducing inflammation in tissues cultures of different asthma endotypes.
[12]
Radiology
Title PhD project:
The value of MRI of hand and foot in juvenile idiopathic arthritis (JIA)
Department:
Radiology and Paediatrics/Rheumatology
Promotor:
Prof Dr JL Bloem
Supervisor (PI):
Dr M. Reijnierse
Email address contact person: m.reijnierse@lumc.nl
Description:
Since effective medication is available, the early diagnosis and follow up in treatment of Rheumatoid
Arthritis (RA) is of importance. Magnetic Resonance Imaging (MRI) is a relatively new tool in the field
of RA and the value of hand and foot MRI is explored by several PhD students
(Radiology/Rheumatology departments LUMC). The presence of bone marrow edema on MR images
is an important parameter in the early diagnosis of RA and the development of erosions after a year;
the detection of subclinical inflammation is a major advantage. The use of a dedicated 1.5T
extremity MRI scanner is a patient friendly method, however, until now, its application in children
for the early diagnosis and follow-up in JIA is not done. To establish the additional value of MRI of
the hand and foot in the early diagnosis and follow up of therapy in children with JIA, consecutive
children visiting the out-patient clinic of the paediatrics/rheumatology department are eligible for
this study. After informed consent, extremity MRI of one hand and one foot will be added to the
standard patient care. The PhD student involved will learn to perform the MRI and to score the MR
images based on the OMERACT-RAMRIS scorings method in cooperation with other PhD students.
Clinical and laboratory data and RAMRIS scorings MR data available from the (very) early arthritis
cohort as well as normal individuals, will be used as a reference for statistical analysis. A patient
friendly MRI might aid in the early diagnosis of JIA and evaluation of therapy and thus prevent delay
in effective treatment in a vulnerable patient group.
[13]
Rheumatology
Title PhD project:
Early detection and treatment of young adults with axial spondyloarthritis:
the international Spondyloarthritis Caught Early (SPACE) cohort
Department:
Rheumatology
Promotor:
Prof Dr D.M.F.M. (Désirée) van der Heijde
Supervisor (PI):
Dr F.A.(Floris) van Gaalen
Email address contact person: f.a.van_gaalen@lumc.nl
Description:
Axial spondyloarthritis (axSpA) and its most severe sub form ankylosing spondylitis is a chronic,
deforming inflammatory disease involving the spine and the pelvis. It is estimated that around 1.5
million Europeans suffer from axSpA. In many patients the disease is a multiorgan disease with
inflammation affecting the eye (uveitis), skin (psoriasis), joint (arthritis) and/or gut (inflammatory
bowel disease). AxSpA is patient is a disease of young adults but often remains undiagnosed for
many years until irreversible damage to the spin is noted. This is undesirable because effective antiinflammatory treatment is available. In 2009 we started the international Spondyloarthritis Caught
Early (SPACE) cohort with centres from Netherlands, Sweden, Norway and Italy participating to
detect and treat axSpA in an early stage.
In the cohort, students are invited to help develop innovative diagnostic strategies and tests,
evaluate the burden of disease, help predict disease outcome and identify new therapeutic targets.
[14]
Title PhD project:
Studies into the effect of intracellular complement activation on immune
cell activation in Rheumatoid Arthritis
Department:
Rheumatology
Promotor:
Prof Dr R.E.M. Toes
Supervisor (PI):
Dr L.A. Trouw
Email address contact person: L.A.Trouw@lumc.nl
Description:
Until recently complement activation was considered to be a process occurring in the extracellular
space aimed at protection against pathogens. Recent evidence suggests that also intracellular
complement activation takes place. This intracellular complement activation is important for cell
viability and upon activation of the cells the intracellularly generated active complement fragments
can quickly be used for signalling with complement receptors on other surrounding cells. This
process was shown to occur in human T cells, but was also suggested to occur on other (all) cells of
the body. The role and importance of intracellular complement activation in the activation status of
immune cells is currently unknown. Our work focusses on the questions whether intracellular
complement activation also takes place in immune cells participating in the inflammation in the
joints of patients with rheumatoid arthritis and what the functional relevance is of such intracellular
complement activation.
[15]
Title PhD project:
Diagnostic and prognostic value of autoantibodies in Rheumatoid arthritis
Department:
Rheumatology
Promotor:
Prof Dr R.E.M. Toes
Supervisor (PI):
Dr D. van der Woude
Email address contact person: R.E.M.Toes@lumc.nl
Description:
Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease with features strongly
pointing towards pathogenic involvement of adaptive immunity. RA affects around 1% of the general
population, leading to erosive joint destruction followed by early disability, work loss, treatment
related complications and, consequently, considerable health care costs. Work by us and others has
shown that autoantibodies, especially anti-citrullinated protein antibodies (ACPA), are intimately
associated with RA pathogenesis. For example, we have shown that the ACPA response matures
before the manifestation of full-blown Rheumatoid arthritis, and that this goes hand in hand with a
rise in ACPA-level (see figure). Recently, we discovered that IgG-ACPA are larger than other IgG
molecules. Our data on this unique finding revealed that the increase in size is explained by
hyperglycosylation of the antigen-binding part in ACPA molecules. This is occurring in all RA-patients
analysed to date. The goal of this project is to define the nature and biological relevance of ACPA
and ACPA-hyperglycosylation and to delineate its potential for diagnostic and prognostic value.
[16]
Title PhD project:
Obesity as risk factor for Osteoarthritis: how does it work?
Department:
Rheumatology
Promotor:
Prof Dr M. Kloppenburg, Prof. R.E.M.Toes
Supervisor (PI):
Dr Andreea Ioan-Facsinay
Email address contact person: a.ioan@lumc.nl
Description:
Osteoarthritis (OA) is the most prevalent rheumatic disease, being present in more than 60% of the
old population. Age and obesity are major risk factors for development and progression of OA, and
this implies that the incidence of this disease will be dramatically increasing in the future, as life
expectancy increases and obesity expands. In our department, several translational research
projects aim at understanding the mechanisms involved in the association of obesity with OA.
Exciting research during the last decade indicates that obesity is accompanied by increased local and
systemic inflammation. Using various clinically well-defined patient cohorts, we study the
association between systemic or local inflammatory/obesity-related factors with
development/severity of OA. Moreover, we characterize the inflammation present in the obese
adipose tissue both at cellular and molecular level, using tissues obtained from OA patients. Finally,
we use experimental disease models to discover novel disease mechanisms and potential
therapeutic targets in a pre-clinical setting. We hope that the combination of these studies will lead
a better understanding of OA pathophysiology and to development of novel therapies for a disease
in which currently no disease-modifying drugs exist.
[17]