ciation of HLA, Rheumatoid Arthritis and Autoantibodies

209 Pages·2015·10.78 MB·English

Cover Page

The handle http://hdl.handle.net/1887/33221 holds various files of this Leiden University
dissertation

Author: Heemst, Jurgen van
Title: Towards a molecular basis for the association of HLA, rheumatoid arthritis and
autoantibodies
Issue Date: 2015-06-17
Towards a molecular basis for the asso-
ciation of HLA, Rheumatoid Arthritis and
Autoantibodies
Jurgen van Heemst
Towards a molecular basis for the association of HLA, Rheumatoid
Arthritis and Autoantibodies.
© Jurgen van Heemst, 2015
Cover design and printing: Ridderprint
ISBN: 978-94-6299-088-3
The research described in this thesis was performed at the Department
of Rheumatology at the Leiden University Medical Center. The research
was supported by FP7 program Masterswitch, IMI program BTcure, and
an NWO VICI-grant.
Towards a molecular basis for the asso-
ciation of HLA, Rheumatoid Arthritis and
Autoantibodies
PROEFSCHRIFT
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van Rector Magnificus prof.mr. C.J.M.M. Stolker,
volgens besluit van het College voor Promoties
te verdedigen op woensdag 17 juni 2015
klokke 11:15 uur
door
Jurgen van Heemst
geboren te Voorburg
in 1986
Promotiecommissie

Promotores: Prof. dr. R.E.M. Toes
Prof. dr. T.W.J. Huizinga
Overige Leden: Prof. dr. R.R.P. de Vries
Prof. dr. F. Koning
Dr. D. van der Woude
Dr. M.H.M. Heemskerk
Dr. N. de Vries (AMC, Amsterdam)
Table of contents

Chapter 1 Introduction 7
PART I HLA CLASS II EXPRESSION AND LIGAND-PRESENTATION 23
Chapter 2 Communication between human mast cells and CD4+ T cell through 25
antigen-dependent interactions.
Chapter 3 The HLA-class II ligandome of B cells is highly conserved on N- and 43
C-terminal residues outside the peptide-binding cleft.
Chapter 4 HLA-DQA1*01:03/DQB1*06:03, an HLA-DQ molecule associated 57
with autoimmune resistance, presents a unique peptide repertoire.
PART II TOWARDS A MOLECULAR BASIS FOR THE CONNECTION BETWEEN 69
HLA, RHEUMATOID ARTHRITIS AND AUTOANTIBODIES
Chapter 5 An investigation of the value of an ACPA multiplex assay in an early 71
arthritis setting.
Chapter 6 Fine-mapping the HLA locus in rheumatoid arthritis and other rheu- 91
matic diseases: Identifying causal amino acid variants?
Chapter 7 The protective effect of HLA-DRB1*13 alleles during specific phases 101
in the development of anti-citrullinated protein antibody positve
rheumatoid arthritis.
Chapter 8 Crossreactivity to vinculin and microbes provides a molecular basis 119
for HLA-based protection against rheumatoid arthritis.
Chapter 9 The HLA-DRB1*14:02 allele predisposes indigenous North American 157
populations to rheumatoid arthritis based on a unique molecular
mechanism.
Chapter 10 Presentation of citrullinated neo-epitopes is not unique to HLA-SE 175
alleles: Arginine to citrulline conversion also enhances peptide
affinity for HLA-DQ molecules.
Chapter 11 General discussion 185
Chapter 12 Nederlandse samenvatting 197
Curriculum Vitae 204
List of publications 205
Dankwoord 206

CHAPTER 1
Introduction
Adapted from:
Genetics of rheumatoid arthritis: What have we learned?
Immunogenetics. 2011 Aug;63(8):459-466
and
HLA and rheumatoid arthritis: How do they connect?
Ann Med. 2014 Aug;46(5):304-310

Introduction 9
1
r
THE ADAPTIVE IMMUNE SYSTEM e
pt
a
h
During life, every day, we encounter many different micro-organisms including C
potentially pathogenic bacteria, viruses, fungi and parasites. The immune system is
critically important in the defence against these pathogens.
The immune system has many different components. These include a wide variety
of immune cells, but also non-cellular effector mechanisms. The immune system
can be roughly subdivided in two components: the innate and the adaptive immune
system. Upon primary infection, the innate immune system is the first to act. The
response is generally fast and unspecific. After a few days the adaptive immune
system comes into play. This response is highly potent and extremely specific. In
addition, after clearance of the pathogen, the adaptive immune system establishes
memory resulting in a highly potent and fast specific immune response upon secon-
dary infection.
The large specificity of the adaptive immune system is mainly established by two
cell typed, the B and T cells. These lymphocytes express B or T cell receptors, highly
specific receptors with a very large diversity. B and T cells differ in the way they
recognize their antigen. B cells recognize their antigen in its native form. Antigen-re-
cognition combined with different activation signals allows for B cell activation and
their differentiation in antibody secreting plasma cells. T cells can provide these
activation signals and are therefore critically important for the generation of potent
antibody responses. In addition. T cells also have other effector functions including
killing of infected cells and the production of inflammatory cytokines. In contrast
to B cells that recognize native antigens, T cells only recognize processed antigens
presented by antigen presenting molecules, predominantly by human leukocyte
antigens (HLA) [1].
Due to the potency and specificity of adaptive immune response, B and T cells have
to be strongly educated to distinguish self from non-self. Nevertheless, autoim-
mune diseases (AID), diseases characterized by a failure of the immune response
to distinguish self from non-self, are highly prevalent in the western world. In the
United States, the prevalence was estimated between 5-8% of the population [2]. B
and T cells are implicated in the development of most of these AID.
HUMAN LEUKOCYTE ANTIGENS
HLA molecules present processed antigens to T lymphocytes. In the presence
of foreign proteins, e.g. during infection, foreign peptides are presented by HLA
molecules. Recognition of such HLA-peptide complexes by T cells results in T cell
activation and its accompanying effector mechanisms. HLA molecules can be
subdivided in two subclasses: HLA class I and class II molecules. HLA class I molecules
present peptides derived from an intracellular source. T lymphocytes that are