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Solving the puzzle of autoimmunity: Critical questions



Despite recent advances in delineating the pathogenic mechanisms of autoimmune disease, the puzzle that reveals the true picture of these diverse immunological disorders is yet to be solved. We know that the human leukocyte antigen (HLA) loci as well as many different genetic susceptibility loci with relatively small effect sizes predispose to various autoimmune diseases and that environmental factors are involved in triggering disease. Models for mechanisms of disease become increasingly complex as relationships between components of both the adaptive and innate immune systems are untangled at the molecular level. In this article, we pose some of the important questions about autoimmunity where the answers will advance our understanding of disease pathogenesis and improve the rational design of novel therapies. How is autoimmunity triggered, and what components of the immune response drive the clinical manifestations of disease? What determines whether a genetically predisposed individual will develop an autoimmune disease? Is restoring immune tolerance the secret to finding cures for autoimmune disease? Current research efforts seek answers to these big questions.
Solving the puzzle of autoimmunity: critical questions
Dawn E. Smilek
and E. William St. Clair
Immune Tolerance Network, 185 Berry Street #3515, San Francisco, CA 94107, USA;
Department of Medicine,
Division of Rheumatology and Immunology, School of Medicine, Duke University, Durham, NC 27710, USA
* Corresponding author: E. William St. Clair (
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Despite recent advances in delineating the pathogenic mechanisms of autoimmune disease, the puzzle
that reveals the true picture of these diverse immunological disorders is yet to be solved. We know that
the human leukocyte antigen (HLA) loci as well as many different genetic susceptibility loci with relatively
small effect sizes predispose to various autoimmune diseases and that environmental factors are involved
in triggering disease. Models for mechanisms of disease become increasingly complex as relationships
between components of both the adaptive and innate immune systems are untangled at the molecular
level. In this article, we pose some of the important questions about autoimmunity where the answers
will advance our understanding of disease pathogenesis and improve the rational design of novel
therapies. How is autoimmunity triggered, and what components of the immune response drive the
clinical manifestations of disease? What determines whether a genetically predisposed individual will
develop an autoimmune disease? Is restoring immune tolerance the secret to finding cures for
autoimmune disease? Current research efforts seek answers to these big questions.
Over the past several decades, much has been learned
about the pathogenesis of autoimmune diseases, a diverse
group of heterogeneous disorders that may be character-
ized by multi-org an or single-organ system involvement.
Underlying these diverse clinical phenotypes is a dysregu-
lated immune system with an enhanced capacity to
respond against self. The immune system is normally
designed to defend against foreign pathogens by using
an array of T and B lymphocytes, which bear antigen
receptors, and innate immune cells, which may be
activated by pathogen- or damage-associated molecular
patterns. These cells orchestrate a finely tuned immune
response through tightly regulated cell-cell interactions and
secretion of cytokines, chemokines, and other inflamma-
tory mediators. The bodys defense against foreign patho-
gens must occur without causing undue harm to self. To
accomplish this feat, the bulk of self-reactive T and B
lymphocytes are eliminated in the thymus and bone
marrow through a process of negative selection. However,
this process is imperfect, albeit purposely, and self-reactive
lymphocytes that escape into the periphery must be kept
under wraps by an array of peripheral tolerance mechan-
isms. When the balance of the effector and regulatory arms
of an immune response is thrown off, self-reactive T and B
cells become activated and promote autoimmunity [1].
What finally pushes the immune system out of balance is a
black box.
When speaking of autoimmune diseases, we often
consider those featuring immunity against self-antigens
and those without detectable anti-self-responses in the
same breath. Rheumatoid arthritis (RA), systemic lupus
erythematosus (SLE), multiple sclerosis, type 1 diabetes
(T1D), and celiac disease are examples of autoimmune
diseases associated with the production of autoantibodies
and, in some cases, self-reactive T cells. On the other hand,
immunity against self-antigens is not a feature of psoriasis,
inflammatory bowel disease, or ankylosing spondylitis,
although the adaptive immune system is clearly involved
in their pathogenesis [2,3]. There are some similarities in
disease mechanisms because they both respond favorably
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Published: 03 February 2015
© 2015 Faculty of 1000 Ltd
to anti-tumor necrosis factor (anti-TNF) therapy. In
contrast, the predominant genetic associations of seropo-
sitive and seronegative disease diverge in an important
way, namely their relationships with class II and class I
HLA risk alleles, respectively.
Despite a growing understanding about the pathogenesis
of autoimmune disease, untangling the complex events
that provoke autoimmunity, produce clinical disease, and
perpetuate its chronicity has been a major challenge. The
interrelationships between the causative factors of auto-
immune diseasegenetics and environmentare mostly
a mystery. In most instances, elucidation of the relative
contribution of T cells, B cells, myeloid cells, and dendritic
cells, as well as other rare cell types, to disease pathogen-
esis is a work in progress. The mechanisms of tissue
inflammation are complex and involve the interactions
between multiple immune cell types and an array of
mediators that are balanced to favor an effector response.
Arguably, much progress toward understanding di sease
mechanisms ha s been made through the discovery of
effective therapies that target specific cytokines [4].
These results have revealed vulner able nodes in the
mechanisms of disease, such as TNF in RA, psoriasis,
and inflammatory bowel disease. However, a substantial
proportion of patients with RA and these other diseases
are not responsive to TNF inhibitors, highlighting the
heter ogeneity of disease and the likely presence of
disease subtypes. It has also proven difficult to modulate
the immune system for sustained benefit. Therapy such as
TNF inhibition that weakens host defense and increases
malignancy risk must be maintained indefinitely. The
gaps in knowledge about the pathogenesis and treatment
of autoimmune disease are evident in this very compli-
cated puzzle. In this article, we discuss some of the
critical questions dogging the community of researchers
invested in better understanding autoimmunity (Table 1).
Others may ask different questions, but it all depends on
who is touching what part of the elephant [5]. The
geneticist searches for all elic variation in the genes
regulating immune pathways that are the driving force
behind disease. The epidemiologist focuses on the inciting
events. Clinicians who must deal with sick patients
regardless of their genetic risks and disease triggers seek
biomarkers that can identify disease subtypes and predict
treatment response.
The critical questions: pathogenesis of
rheumatoid arthritis
Hypotheses related to the triggering of autoimmune disease
are generally framed as a function of t he interplay between
heredity and the environment. Two critical questions
emerge from this organizing principle: (1) Which com-
ponents of the immune system drive the clinical pheno-
type in each autoimmune disease? (2) How, when, and
where is the autoimmune response triggered? Questions
about the disease-inducing immunity have focused on the
adaptive immune response (for example, autoantibodies
and self-reactive B and T cells). How, when, and where
disease-inducing immunity is triggered pose further ques-
tions about the events leading to the breakdown in
immune tolerance and disease perpetuation.
With reference to these questions, it is useful to describe
a conceptual model of the pathogenesis of RA, which has
Table 1. Critical questions about autoimmunity
Inciting events
How, when, and where is the autoimmune response triggered?
How does an immune response triggered at one site lead to an inflammatory response at a remote anatomically distinct site?
Genetic predisposition
What factors determine whether genetically predisposed individuals develop autoimmune disease or remain healthy?
Why do some autoimmune diseases cluster in individuals and families?
Why are some autoimmune diseases rarely observed together?
Gene-environment interactions
What are the roles of environmental influences and oxidative stress in autoimmunity?
How does the microbiome contribute to the development of autoimmune disease?
Disease mechanisms
How does the human leukocyte antigen (HLA) locus contribute to the development of autoimmunity?
How do self-reactive T cells escape normal immune tolerance mechanisms and cause autoimmunity?
Which components of the immune system drive the clinical phenotype in each autoimmune disease?
Treatment mechanisms
Why doesnt an effective therapy work for everyone with the same autoimmune disease?
Why do treatments for one group of autoimmune diseases inadvertently provoke or worsen other autoimmune diseases?
Can autoimmune disease be cured by restoration of immune tolerance?
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gained increasing support and implicates triggering
immune events at extra-articular sites, such as the lung.
This breach in turn promotes immunity against citrulli-
nated proteins in the synovium, the articular cartilage and
bone, and consequently the development of chronic joint
inflammation [6]. Autoantibodies to post-translationally
modified citrullinated proteins (ACPAs) define a clinical
phenotype associated with the two major risk factors for
RA, the HLA DRB1 shared epitopes and an environmental
exposure, cigarette smoking. Together they interact to
increase the risk of developing ACPA-positive RA [7]. The
R620W allele of PTPN22, a non-HLA genetic risk factor,
has a strong effect in models that combine it with these
other two major risk factors [8]. Serum ACPAs develop
many years before the onset of clinical disease, suggesting
that immunity to citrullinated proteins first occurs outside
the joints [9]. The initiating events in RA may take place in
the lungs. Recent studies indicate that those with or at
increased risk for ACPA-positive RA have evidence of local
production of ACPA in their bronchoalveolar fluid and
lung tissue [10]. The lungs are an attractive candidate for
an initiating immune response because of their limited
barrier to environmental exposures. Periodontal mucosa
also has a limited barrier that could be the site of initiation
or amplification of autoimmunity. Bacterial species
associated with periodontal disease, such as Porphyromonas
gingivalis, have been shown to express the enzyme peptidyl
arginine deaminase, which citrullinates human peptides
correlated with autoimmunity [11].
How does immunity to citrullinated antigens triggered in
the lungs lead to synovial inflammation? Dual expression
of the primary targets of ACPAs in the lungs and joints is a
possible explanation. Although identical citrullinated
proteins are present in bronchial and synovial tissue of
patients with RA, it remains unclear how ACPA induces
disease in the joints [12]. Indeed, marked hypercitrullina-
tion is a feature of the rheumatoid joint [13]. It also
appears that the joint is a reservoir of locally produced
ACPAs because it has been shown that synovial fluid
from ACPA-positive patients contains high titers of these
antibodies [14]. In a ddition, immunoglobulin G-positive B
cells that secrete antibodies to citrullinated peptides
have been isolated from synovial fluid [15]. Once present
in the joint, how does ACPA promote joint inflammation?
Antibodies to citrullin ated vimentin, another ant igen in the
joint, have been shown to stimulate osteoclast activation,
perhaps contributing to the early stages of joint inflamma-
tion (bone marrow edema) and later joint erosions
(damage) [16,17]. Immunity to other citrullinated antigens
may augment joint inflammation by unknown mechan-
isms. Citrullinated fibrinogen, for example, may increase
the potency of the innate immune response by binding to
Toll-like receptor-4 and Fcg receptor [18]. Another study
has shown that citrullination of a chemokine, known as
ENA/CXCL5, is higher in serum and synovial fluid from
patients with RA than healthy controls and that citrulli-
nated CXCL5 may recruit mo re monocytes to the inflamed
joint than the non-citrullinated chemokine [19].
Although the story remains incomplete, the evolving
evidence suggests that a breakdown of immune tolerance
in the lungs, potentially induced by cigarette smoking or
other exposure, in a genetically predisposed individual
with distinct HLA class II alleles and non-HLA alleles, leads
to the production of antibodies to citrullinated proteins
before disease onset. This hypothe sis raises critical
questions about the regulation of adaptive immunity in
the lungs, its dynamic behavior in relation to external
stimuli, and the role of the microbiome in shaping a local
immune response. These events in the lungs are followed
by unknown events in the joint (perhaps a second hit)
that trigger inflammation. What is the time course of these
events? The immune response to citrullinated protein is
initially restricted many years before disease onset and
later expands with time to target multiple epitopes on
different citrullinated proteins near the onset of clinical
disease [20]. This feature of epitope spreading leading up
to disease onset may be a general feature of autoimmune
disease, as illustrated by the evolution of serum autoanti-
body specificity predating the onset of SLE [21]. In RA and
SLE, increased serum levels of chemokines and cytokines
also precede the development of symptoms [22,23]. Is
epitope spreading a consequence of an evolving systemic
inflammatory response prior to onset of clinical disease, or
a factor contributing t o the development of tissue
inflammation, or both?
Environmental control of autoimmunity:
epigenetics and the microbiome
What factors determine whether genetically susceptible
individuals will develop an autoimmune disease? Twin
studies show that the environment influences the devel-
opment of autoimmunity [24], and many environmental
agents have been linked to autoimmune diseases [25].
Some environmental factors may contribute to autoim-
munity by epigenetic mechanisms. Epigenetic mechanisms
are heritable changes in gene expression that are not
encoded in the DNA sequence but that are replicated each
tim e a cell divides. DNA methylati on and hi stone
modifications are epigenetic mechanisms that control
gene expression at the transcriptional level and thus are
central to lymphocyte subset development and effector
function. Epigenetic mechanisms are susceptible to
environmental i nfluenc es such as drugs, toxins, oxida-
tive stress, and hormones, which trigger or exacerbate
autoimmune diseases such as SLE in genetically predis-
posed individuals [26,27].
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DNA methylation typically represses gene expression,
and factors that inhibit methylation can promote
expression of genes which are normally silenced.
Decreased DNA methylation seconda ry to environmen-
tal exposures and oxidative stress converts T cells into a
pro-inflammatory self-reactive phenotype that causes a
lupus-like syndr ome in mice [28]. Patients with active
SLE hav e T cells with similar epigenetic changes and
overexpression of genes that are normally silenced by
DNA methylation [29]. There is evidence that drugs such
as procainamide and hydralazine cause SLE by this
mechanism in genetically susceptible individuals [28].
Decreased DNA methylation due to oxidative stress and
other environmental factors may also be relevant in SLE
occurring in the absence of known triggers [27].
The concept of environment has expanded from exogen-
ous triggers, such as infection and toxic exposures, to
endogenous triggers harbored in the microbiome. The
complex relationships between commensal bacteria and
autoimmunity are not well understood, but increasing
evidence suggests that the microbiome may play an
important role in the development of autoimmune
disease [30,31]. One unusual species, segmented filamen-
tous bacteria, induces an intestinal pro-inflammatory
subset of T lymphocytes known as T helper 17 (Th17)
cells [32], which have been implicated in a number of
autoimmune diseases [33]. This species of bacteria also
promotes autoimmune arthritis and experimental auto-
immune encephalomyelitis at sites remote from the
intestine in animal models [34,35]. A recent study in
humans examined fecal microbiota in new-onset RA by
sequencing microbial 16S ribosomal RNA genes [36]. An
impressive 75% of patients with new-onset untreated RA
had evidence of Prevotella copri colonization, compared
with only 21% of healthy control subjects and 12% of
subjects with treated chronic RA. These data raise new
questions about the relationship between gut colonization
and pathogenesis of RA as well as additional questions
about how commensal bacteria influence autoimmunity
in general.
Genetic susceptibility: human leukocyte antigen
and the role of adaptive immunity
The first known autoimmune disease-associated gene
complex was the HLA locus, which even today predomi-
nates over other genetic associations. Proteins encoded by
HLA alleles are central to the adaptive immune response
by binding antigenic peptide fragments which, in turn,
recognize T lymphocytes. How does this normal function
of HLA molecules contribute to autoimmune disease? The
working hypothesis for this striking HLA disease associa-
tion has been that allele-specific HLA molecules bind
self-peptides, or peptides that mimic self, in a unique
conformation that is recognized by self-reactive T cells.
Such self-reactive T cells might ordinarily be eliminated by
negative selection in the thymus o r controlled by
peripheral tolerance mechanisms, such as induction of
anergy or suppression by T regulatory cells [1,37]. Why do
self-reactive T cells escape normal immune tolerance
mechanisms and cause autoimmune disease? This ques-
tion remains unansw ered today and likely involves
disruption of the fine balance between effector and
regulatory immune compartments.
Some self-peptides bind to HLA molecules weakly;
preproinsulin peptides in T1D, for example, bind with
low affinity to HLA-A2 [38]. Despite weak binding of the
peptides to HLA, T cells in the peripheral blood of T1D
subjects recogni ze these low-affinity peptide-HLA com-
plexes, suggesting that low-affinity peptide-HLA interac-
tions might trigger low-affinity T cells that are less subject
to control by normal tolerance mechanisms such as
negative selection and anergy. A recent study ha s shown
that T-cell responses to a low-affinity insulin peptide are
present in T1D subjects but not normal contro ls.
Interestingly, these T cells also recognize micro bial
antigens, suggesting a mechanism by which infection
could lead to disease [39]. Such low-af finity T cells could
escape tolerance mechanisms, persist in the body, and
when unchecked cause autoimmune disease.
Some self-antigens are created in response to environ-
mental triggers in genetically susceptible individuals. A
previously cited example is the citrullination of proteins
that occurs in genetically susceptible smokers prior to the
development of RA. Environmental factors can also
trigger disease by inducing unexpected alterations of the
peptide-HLA complex recognized by T cells, as recently
dem onstrated for be ryllium-associated inflammatory
lung disease. Chronic beryllium disease has been
described as a T cell-mediated allergic hypersensitivity
illness but shares a number of features with autoimmune
diseases, including a close association with HLA. The
immune response in chronic beryllium disease involves
T-cell reactivity to self-peptide-HLA co mplexes in which
the beryllium cation is bound dee ply buried within the
complex rather than at the surface of the complex. The
beryllium cation thus does not contact the T-cell receptor
itself but rather alters the surface conformation of self-
peptide HLA comple xes such that they are recognized as
novel by T cells [40].
HLA class I and II molecules are the strongest genetic risk
factors for many autoimmune diseases. In several cases,
such as RA, disease-promoting class II HLA polymorph-
isms are located in the antigen-binding groove, implying
that altered presentation of self-peptides underlies
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disease pathogenesis [41]. HLA class I molecules present
endogenous peptides from self-proteins and intracellular
pathogens for binding by cytotoxic T cells (CTLs). The
association between HLA-B27 and the spondyloarthro-
pathies, including reactive arthritis, is the strongest genetic
risk between an HLA class I allele and a human
autoimmune disease; however, the mechanisms behind
this genetic association remain to be defined. HLA-B27-
restricted epitopes from Chalmydia trachomatis are recog-
nized by specific CTLs from patients with reactive arthritis;
these epitopes show high sequence homology with
HLA-B27 self-peptides, suggesting that molecular mimicry
is a possible mechanism by which class I HLA molecules
may be linked with the pathogenesis of disease [42].
Another possibility relates to the observation that
cytokine-induced HLA-B27 upregulation in macrophages
results in a robust induction of the unfolded protein
response (UPR) [43]. Although UPR activation has been
associated with amplification of immune and inflamma-
tory responses, direct evidence that these events act
upstream of cell signaling and contribute to human
disease pathogenesis is lacking [44].
Genetic elements and immune pathways that
contribute to autoimmune disease
Which autoimmune d isease wi ll a genetically suscep-
tible individual develop? In addition to HLA, a large
number of autoimmune-predisposing genes have been
identified [45,46]. Some gen etic v ariants lead to sev ere
autoimmune syndromes and are observed rarel y in the
population [47] . One such example is the genetic
variant encoding the autoimmune regulator AIRE, a
transcription factor required for the ectopic expression
of tissue-specific antigens in the thymus. Loss-of-function
variants of AIRE defect disrupt negative selection of
self-reactive T lymphocytes, leading to autoimmunity at
various sites [48,49].
The vast majority of the genetic loci associated with
increased susceptibility to autoimmune disease are also
found in healthy individuals. Most of these suscept-
ibility genes have been identified by genome-wide
association studies and Immunochip studies, and many
are known to affect critical immune pathways [45,46].
There are also unacco unted-for genetic contributions
known as missing heritability. Some of this missing
heritability may be due to relatively common loci with
small e ffect sizes [50]. Alternatively, rare variants with
large effect sizes may escape detection in genome-wide
association studies [51]. Since risk alleles are found
mostly in both healthy and autoimmune individuals, it
is likely that the combination of many different loci
interacting with environment factors promotes auto-
immune disea se.
Autoimmunity appears to be inherited as a trait. Indivi-
duals with one autoimmune disease are at higher risk of
developing a second autoimmune disease, and multiple
autoimmune diseases cluster within families [52]. Auto-
antibody-mediated (seropositive) diseases, such as RA,
T1D, and autoimmune thyroid disease, occur in clusters.
This clustering is likely explained by susceptibility gene
variants in common among the diseases. One prominent
example is the single-nucleotide polymorphism variant
PTPN22, which is a risk allele for RA, T1D, SLE, and other
autoimmune diseases [5356]. PTPN22 encodes lympho-
cyte tyrosine phosphatase, a negative regulator of T-cell
activation. Altered T-cell receptor (TCR) signa ling has been
reported in the setting of the autoimmunity-associated
PTPN22 variant [57,58]. Lymphocyte tyrosine phospha-
tase is expressed not only in T cells but also in B cells and
myeloid cells. The variant allele of PTPN22 has been
associated with defective B-cell tolerance and abnormally
high numbers of self-reactive B cells [5961]. The PTPN22
variant of lymphocyte tyrosine phosphatase also regulates
type I interferon production following Toll-like receptor-
driven activation of myeloid cells, an observation that
suggests a possible link between infections and auto-
immune disease [62]. PTPN22-related defects in the T cell,
B cell, and innate immune compartments could in theory
contribute to disease in many different organ systems and,
depending on the presence of other gene loci, produce a
variety of clinical phenotypes [56].
Autoimmune diseases without autoantibodies (serone-
gative), such as psoriasis, inflammatory bowel disease,
and ankylosing spondylitis, also show evidence of
clustering. These seemingly unrelated diseases share an
association with spondyloarthropathy, which is charac-
terized by sacroiliitis and enthesitis (inflammation of
tendons and ligaments at insertion sites) rather than the
synovial inflammation typical of RA. Psoriasis and
inflammatory bowel disease are associated with gene
variants of the interleukin-23 (IL-23) receptor [63,64].
IL-23 is a cytokine that supports the development of
Th17 cells, which produce the pro-inflammatory cyto-
kine IL-17 as well as other IL-17-producing cell types
[65]. Notably, there is much higher correlation between
susceptibility genes for ankylosing spondylitis and
psoriasis than between genes for ankylosing spondylitis
and RA [45].
Unifying diseases into a single diagnostic category ma y
not be particularly useful, since the molecular pat hways
contributing to disease pathogenesis are likely related in
some cases but highly distinct in others. This concept has
major implications for drug development and re-
purposing of approved medications for new indications
[66]. Discordant sets of genetic susceptibility genes may
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also explain why therapy for one autoimmune disease can
inadvertently trigger another autoimmune disease. One
example is a variant of the TNF receptor that is associated
with an increased risk for multiple sclerosis but which is
protective against developing ankylosing spondylitis [67].
Perhaps not surprisingly then, anti-TNF therapy, though
effective for ankylosing spondylitis, has been shown to
worsen multiple sclerosis and may induce a multiple
sclerosis-like disea se as an adverse consequence of
treatment [68].
Disease heterogeneity: variable response to
therapeutic intervention
When a therapy is effective in an au toimmune disease,
why does it not work for everyone with that disease?
Within a given autoimmune disease, there is hetero-
geneity in clinical phenotypes, implying differences
among individuals in pathogenic mechanisms. Thus, it
is not surprising that individuals within a diagnostic
category vary in their response to therapy. In relapsing-
remitting multiple sclerosis, for which type I interferon
(interferon beta) is considered standard first-line therapy,
intervention. Somewhat paradoxically, in multiple
sclerosis, elevated expression of type I interferon response
genes pre-treatment correlates with the absence of a
beneficial response to type I interferontherapy [69,70]. It
has been suggested that a high-interferon response gene
signature identifies a subset of patients with multiple
sclerosis who have a distin ctly different pathogenic
mechanism driving disease [71]. Similarly, in RA, an
interferon response gene signature has been found to
predict a lack of response to rituximab therapy [7274].
Personalizing treatment of autoimmune disease on the
basis of genetic factors, biomarkers, and lifestyle choices
has the potential to dramatically improve the therapeutic
approach for many autoimmune diseases [75].
Restoration of immune tolerance as a treatment
for autoimmunity
Amelioration of clinical disease is not usually durable
without ongoing therapy and often requires frequent
switching of drugs to sustain disease control. To keep
disease at bay, combined interventions may be needed to
simultaneously check effector lymphocytes, potentiate
regulatory elements, and control the innate immune
response [76]. Even if such combinations are successful
in remediating the manifestations of autoimmune disease,
it remains to be proven whether durable immune tolerance
and a healthy state can be restored in the autoimmune
disease setting without changing genetic predisposition or
reversing the environmental damage. Prevention may yet
prove to be the optimal treatment strategy.
A com plex picture of autoimmune pathogenesis is
emerging in which genetic predisposition resides in a
large number of loci encoding key immune pathway
molecules. We now recognize that expression of these
genes is under epigenetic control, which can be influenced
by a number of environmental factors in susceptible
individuals. The microbiome resides at the boundary of
self and the environment and appears to also influence
autoimmunity by mechanisms that are not yet under-
stood. Although progress has been made in understanding
the pathogenesis of autoimmune disease, a large number
of questions remain unanswered (Table 1). Filling this gap
in knowledge will require a greater understanding of the
inciting events leading to autoimmunity and clinical
disease, the role of the environment (including the
microbiome) in triggering and perpetuating disease, the
hierarchy of aberrantly regulated immune pathways
involved in disease pathogenesis, and identification of
the most vulnerable nodes in the immune system for
therapeutic targeting. We expect too that the nosology for
autoimmune disease will slowly evolve from its current
framework of clinical and serologically defined states into
an immune pathway-based scheme of overlapping phe-
notypes and sub-phenotypes that will underpin rationally
designed therapy in the future. The pieces of the puzzle are
slowly coming together.
ACPA, a utoantibody to citrullinated proteins; CTL,
cytotoxic T cell; HLA, human leukocyte antigen; IL,
interleukin; RA, rheum atoid arthritis; SLE, systemic
lupus erythematosus; T1D, type 1 diabetes; Th17,
T helper 17; TNF, tumor necrosis factor; UPR, unfolded
protein response.
E. William St. Clair has received in-kind support from
Biogen Idec for a National Institute of Allergy and
Infectious Diseases (NIAID)-sponsored tria l of a novel
therapy for Sjögrens syndrome. He also serves as a
deputy director for the Immune Tolerance Network, an
NIAID-funded consortium dedicated to the deve lop-
ment of tolerance-inducing therapies for allergy and
asthma, autoimmune disease, and transplant. Dawn
E. Smilek is associate director of clinical development for
the Immune Tolerance Network.
The authors thank their colleagues at the Immune
Tolerance Network and their collaborators who con-
tribute in many capacities to Immune Tolerance Network
projects and perspectives.
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... The former characterization of autoinflammatory diseases, the more recent mixed form presentation (autoinflam-matory-autoimmune), and the changing contribution of underlying autoinflammatory processes to autoimmunity pathways further complicated understanding the pathophysiological processes [1]. ...
Full-text available
Autoinflammatory and autoimmune diseases are characterized by an oversensitive immune system with loss of the physiological endogenous regulation, involving multifactorial self-reactive pathological mechanisms of mono- or polygenic nature. Failure in regulatory mechanisms triggers a complex network of dynamic relationships between innate and adaptive immunity, leading to coexistent autoinflammatory and autoimmune processes. Sustained exposure to a trigger or a genetic alteration at the level of the receptors of the natural immune system may lead to abnormal activation of the innate immune system, adaptive system activation, loss of self-tolerance, and systemic inflammation. The IL-1 family members critically activate and regulate innate and adaptive immune responses’ diversity and plasticity in autoimmune and/or autoinflammatory conditions. The IL-23/IL-17 axis is key in the communication between innate immunity (IL-23-producing myeloid cells) and adaptive immunity (Th17- and IL-17-expressing CD8+ T cells). In psoriasis, these cytokines are decisive to the different clinical presentations, whether as plaque psoriasis (psoriasis vulgaris), generalized pustular psoriasis (pustular psoriasis), or mixed forms. These forms reflect a gradient between autoimmune pathophysiology with predominant adaptive immune response and autoinflammatory pathophysiology with predominant innate immune response. 1. Introduction Autoinflammatory and autoimmune diseases are characterized by immune system hyperactivity, typically featuring an against-self pathological process. They are systemic diseases and mono- or polygenic. The innate immune system directly causes tissue inflammation in autoinflammatory diseases. An adaptive immune dysregulation—against self—is found in autoimmune diseases. Both combined are present in mixed autoinflammatory-autoimmune pattern diseases (Figure 1).
... Failure of self-antigens tolerance is one of the main triggers of the RA, which is characterized by constitutive stimulation of immune system leading to tissue damage [3]. Although the immunopathogenesis of RA remains elusive, the main reason seems to be the breakdown of tolerance and dysregulated lymphocyte activation [4], that can enhance progressive joint destruction and severe disability [5]. Regarding the disease complexity, genetic background and hence several genes have been suggested to play a critical role in the regulation of the immune system in RA [3]. ...
Rheumatoid arthritis (RA) is a chronic autoimmune disease that mainly affects joints and characterized by chronic joint inflammation and infiltration of various immune cells in the synovium. Forkhead box P3 (Foxp3)-expressing regulatory T cells (Tregs) play a crucial role in preventing autoimmunity and undesirable T cell responses. However, there are controversial reports regarding the defective function or frequency of these cells in various studies, which may be in part related to different polymorphisms of FoxP3 and influence of ethnicity on these differences. Therefore, the main subject of this study was to evaluate the association of Foxp3 gene polymorphism and Treg frequency in Iranian patients with RA. Accordingly, 240 RA patients diagnosed according to American college of rheumatology 2010 criteria and 240 normal subjects were recruited for this study. Genomic DNA was genotyped for -3279 C/A Foxp3 gene SNP using the PCR-RFLP. The frequency of Tregs and serum levels of interleukin (IL)-10, transforming growth factor (TGF)-β, anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) were determined by flow cytometry and ELISA methods, respectively. The results showed a significant association of Foxp3 -3279 A allele with augmented risk of RA in Iranian patients compared to wild-type allele. While the frequencies of CA and AA genotypes were significantly higher in patients, RA patients with AA genotype had a significant lower frequency of Tregs compared to patients with CC and CA genotypes. Consistently, TGF-β and IL-10 significantly diminished in patients with AA genotype compared to patients with CA and CC genotypes. Our findings indicated that the AA genotype of Foxp3 in RA patients is associated with downregulation of Tregs and susceptibility to RA in the Iranian population.
... This defence against external pathogens must occur without causing unnecessary harm to self. To achieve this delicate balance, the majority of self-reactive T and B lymphocytes are destroyed in the thymus and bone marrow through negative selection [5]. Nevertheless, this process is far from perfect, and self-reactive lymphocytes escape into the periphery. ...
Full-text available
Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role. We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with Systemic Sclerosis (SSc), 536 with Multiple Sclerosis (MS), and 93 with Myasthenia Gravis (MG) and 282 unrelated controls. We confirmed previously established associations of HLA-DRB1 * 15 (OR = 2.17) and HLA-DRB1 * 03 (OR = 1.81) alleles with MS, HLA-DRB1 * 03 with SLE (OR = 2.49), HLA-DRB1 * 01 (OR = 1.79) and HLA-DRB1 * 04 (OR = 2.81) with RA, HLA-DRB1 * 07 with Ps + PsA (OR = 1.79), HLA-DRB1 * 01 (OR = 2.28) and HLA-DRB1 * 08 (OR = 3.01) with SSc, and HLA-DRB1 * 03 with MG (OR = 2.98). We further observed a consistent negative association of HLA-DRB1 * 13 allele with SLE, Ps + PsA, RA, and SSc (18.3%, 19.3%, 16.3%, and 11.9%, resp., versus 29.8% in controls). HLA-DRB1 * 13 frequency in the AIDs group was 20.0% (OR = 0.58). Although different alleles were associated with particular AIDs, the same allele, HLA-DRB1 * 13, was underrepresented in all of the six diseases analysed. This observation suggests that this allele may confer protection for AIDs, particularly for systemic and rheumatic disease. The protective effect of HLA-DRB1 * 13 could be explained by a more proficient antigen presentation by these molecules, favouring efficient clonal deletion during thymic selection.
... But if effector and regulatory cells are imbalanced, autoreactive T and B cells are activated and promote autoimmunity [1]. A dysregulated immune system with an enhanced capacity to respond against self-antigens is a common feature of the diverse clinical phenotypes of autoimmune disorders [4]. Although their etiology is often unknown, these pathophysiological conditions seem to be initiated by the loss of immunological tolerance to autoantigens. ...
Full-text available
Functional autoantibodies are an emerging field of research that focuses on the effects of these immunoglobulins when they bind to their target molecules. Accumulating information now exists about the molecular targets and precise binding mechanisms of functional autoantibodies as well as about their downstream effects. These data raise the need to distinguish functional autoantibodies from non-functional autoantibodies with regard to their ability to stimulate or to inhibit their target protein via binding. The presence of autoantibodies has been documented in autoimmune disorders decades ago, but meanwhile, more and more autoantibodies have been identified as functional, acting as pathogenic drivers involved in the induction of organ-specific damage in systemic sclerosis as well as in other autoimmune disorders. These findings offer new opportunities for the development of novel therapeutic strategies.
Intestinal epithelial cells constantly crosstalk with the gut microbiota and immune cells of the gut lamina propria. Enteroendocrine cells, secrete hormones, such as incretin hormones, which participate in host physiological events, such as stimulating insulin secretion, satiety, and glucose homeostasis. Interestingly, evidence suggests that the incretin pathway may influence immune cell activation. Consequently, drugs targeting the incretin hormone signaling pathway may ameliorate inflammatory diseases such as inflammatory bowel diseases, cancer, and autoimmune diseases. In this review, we discuss how these hormones may modulate two subsets of CD4+ T cells, the regulatory T cells (Treg)/Th17 axis important for gut homeostasis: thus, preventing the development and progression of inflammatory diseases. We also summarize the main experimental and clinical findings using drugs targeting the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1) signaling pathways and their great impact on conditions in which the Treg/Th17 axis is disturbed such as inflammatory diseases and cancer. Understanding the role of incretin stimulation in immune cell activation and function, might contribute to new therapeutic designs for the treatment of inflammatory diseases, autoimmunity, and tumors.
Harnessing the ability of the immune system to mount robust and effective responses in the face of pathogenic challenge or cancer development is rapidly developing into frontline treatment for these diseases. This field, called immunotherapy, relies on the activation of antibody mediated B cell and/or cellular mediated T cell responses that directly target diseased cells and tissues. One of the most challenging aspects of developing effective immunotherapeutics, however, is first identifying the target antigens that the immune system should recognize and ‘attack’. Among the many methods available today immunoproteomics is ideally suited to identify relevant target antigens. Immunoproteomics combines cutting edge proteomic methodologies to identify physiologically relevant target antigens expressed and/or produced by the diseased cells with standard immunological techniques to validate these targets. In this topic, we explore how immunoproteomics can shape the development of effective immunotherapeutics. We focus primarily on immunotherapies harnessing the cell mediated arm of the adaptive immune system and review promising clinical data on T cell-based immunotherapies in cancer, infectious diseases, and autoimmune disorders.
Full-text available
Significance The importance of antigenic peptides with low-affinity HLA binding in human autoimmune disease remains unclear. Studies in the nonobese diabetic mouse demonstrate recognition of a crucial insulin epitope presented in a weakly bound register. This work details a direct study of responses to this insulin B-chain peptide in humans. Responses were readily detected in subjects with type 1 diabetes. Furthermore, T-cell clones were shown to recognize the peptide presented in a weakly bound alternative register. These findings confirm the relevance of immune recognition of this segment of the insulin B-chain in human disease and highlight a mechanism shared by mouse and man through which T cells that recognize a weakly bound peptide can circumvent tolerance mechanisms.
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Autoimmune diseases include 80 or more complex disorders characterized by self-reactive, pathologic immune responses in which genetic susceptibility is largely insufficient to determine disease onset. In September 2010, the National Institute of Environmental Health Sciences (NIEHS) organized an expert panel workshop to evaluate the role of environmental factors in autoimmune diseases, and the state of the science regarding relevant mechanisms, animal models, and human studies. The objective of the workshop was to analyze the existing data to identify conclusions that could be drawn regarding environmental exposures and autoimmunity and to identify critical knowledge gaps and areas of uncertainty for future study. This consensus document summarizes key findings from published workshop monographs on areas in which "confident" and "likely" assessments were made, with recommendations for further research. Transcribed notes and slides were reviewed to synthesize an overview on exposure assessment and questions addressed by interdisciplinary panels. Critical advances in the field of autoimmune disease research have been made in the past decade. Collaborative translational and interdisciplinary research is needed to elucidate the role of environmental factors in autoimmune diseases. A focus on exposure assessment methodology is needed to improve the effectiveness of human studies, and more experimental studies are needed to focus on causal mechanisms underlying observed associations of environmental factors with autoimmune disease in humans.
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T-cell-mediated hypersensitivity to metal cations is common in humans. How the T cell antigen receptor (TCR) recognizes these cations bound to a major histocompatibility complex (MHC) protein and self-peptide is unknown. Individuals carrying the MHCII allele, HLA-DP2, are at risk for chronic beryllium disease (CBD), a debilitating inflammatory lung condition caused by the reaction of CD4 T cells to inhaled beryllium. Here, we show that the T cell ligand is created when a Be(2+) cation becomes buried in an HLA-DP2/peptide complex, where it is coordinated by both MHC and peptide acidic amino acids. Surprisingly, the TCR does not interact with the Be(2+) itself, but rather with surface changes induced by the firmly bound Be(2+) and an accompanying Na(+) cation. Thus, CBD, by creating a new antigen by indirectly modifying the structure of preexisting self MHC-peptide complex, lies on the border between allergic hypersensitivity and autoimmunity.
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Immunological events in the lungs might trigger production of anti-citrullinated protein antibodies during early rheumatoid arthritis (RA). We investigated the presence of shared immunological citrullinated targets in joints and lungs of patients with RA. Proteins extracted from bronchial (n=6) and synovial (n=7) biopsy specimens from patients with RA were investigated by mass spectrometry-based proteomics. One candidate peptide was synthesised and used to investigate by ELISA the presence of antibodies in patients with RA (n=393), healthy controls (n=152) and disease controls (n=236). HLA-DRB1 shared epitope (SE) alleles were detected in patients with RA. Ten citrullinated peptides belonging to seven proteins were identified, with two peptides shared between the synovial and bronchial biopsy samples. Further analysis, using accurate mass and retention time, enabled detection of eight citrullinated peptides in synovial and seven in bronchial biopsy specimens, with five peptides shared between the synovial and bronchial biopsy specimens. Two citrullinated vimentin (cit-vim) peptides were detected in the majority of synovial and lung tissues. Antibodies to a synthesised cit-vim peptide candidate (covering both cit-vim peptides identified in vivo) were present in 1.8% of healthy controls, 15% of patients with RA, and 3.4% of disease controls. Antibodies to cit-vim peptide were associated with the presence of the SE alleles in RA. Identical citrullinated peptides are present in bronchial and synovial tissues, which may be used as immunological targets for antibodies of patients with RA. The data provide further support for a link between lungs and joints in RA and identify potential targets for immunity that may mediate this link.
Background and objectives B cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumour necrosis factor (TNF) blocking agents. However, approximately 40–50% of rituximab (RTX) treated RA patients have a poor response. The authors investigated whether baseline gene expression levels can discriminate between clinical non-responders and responders to RTX. Materials and methods In 14 consecutive RA patients starting with RTX (test cohort), gene expression profiling on whole peripheral blood RNA was performed by Illumina HumanHT beadchip microarrays. Supervised cluster analysis (patients ranked on difference in 28 joints disease activity score (DAS28) after 6 months RTX) identified genes expressed differently at baseline in case of non-response (both ΔDAS28<1.2 and EULAR non-response). Genes of interest were measured by quantitative real-time PCR and tested for their predictive value using receiver operating characteristics (ROC) curves in an independent validation cohort (n=26). Results Genome-wide microarray analysis revealed a marked variation in the peripheral blood cells between RA patients before the start of RTX treatment. Here, the authors demonstrated that only a cluster consisting of interferon (IFN) type I network genes, represented by a set of IFN type I response genes (IRGs), that is, LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2, was associated with ΔDAS28 and EULAR response outcome (p=0.0074 and p=0.0599, respectively). Based on the 8 IRGs an IFN-score was calculated that reached an AUC of 0.82 to separate non-responders from responders in an independent validation cohort of 26 patients using ROC curves analysis according to ΔDAS28<1.2 criteria. Advanced classifier analysis yielded a 3 IRG-set that reached an AUC of 87%. Comparable findings applied to EULAR non-response criteria. Conclusions This study demonstrates clinical utility for the use of baseline IRG expression levels as predictive biomarker for non-response to RTX in RA.
Rheumatoid arthritis (RA) is a prototype for a criterion-defined inflammatory disease, for which the aetiology and initial molecular pathogenesis has been elusive for a long time. We describe in this Review how studies on the interplay between specific immunity, alongside genetic and environmental predisposing factors, provide new tools to understand the molecular basis of distinct subsets of the disease. A particular emphasis is on the possibility that pathogenic immune reactions might be initiated at other sites than the joints, and that the lungs could harbour such sites. New data strengthen this concept, showing that local immunity towards citrullinated proteins and accompanying inflammation might be present in the lungs early during disease development. This progress makes RA an interesting case for the future development of therapies that might be directed against disease-inducing immunity even before inflammation and destruction of joints has begun.
PTPN22 encodes a tyrosine phosphatase that is expressed by haematopoietic cells and functions as a key regulator of immune homeostasis by inhibiting T-cell receptor signalling and by selectively promoting type I interferon responses after activation of myeloid-cell pattern-recognition receptors. A single nucleotide polymorphism of PTPN22, 1858C>T (rs2476601), disrupts an interaction motif in the protein, and is the most important non-HLA genetic risk factor for rheumatoid arthritis and the second most important for juvenile idiopathic arthritis. PTPN22 exemplifies a shared autoimmunity gene, affecting the pathogenesis of systemic lupus erythematosus, vasculitis and other autoimmune diseases. In this Review, we explore the role of PTPN22 in autoimmune connective tissue disease, with particular emphasis on candidate-gene and genome-wide association studies and clinical variability of disease. We also propose a number of PTPN22-dependent functional models of the pathogenesis of autoimmune diseases.
Objective: To examine whether the citrullinated chemokines epithelial neutrophil-activating peptide 78 (ENA-78)/CXCL5, macrophage inflammatory protein 1α/CCL3, and monocyte chemotactic protein 1/CCL2 are detected in the biologic fluid of patients with rheumatoid arthritis (RA), and if so, to determine the biologic activities of these chemokines. Methods: Recombinant human chemokines were citrullinated by peptidylarginine deiminase. Enzyme-linked immunosorbent assays were performed to measure the concentrations of citrullinated chemokines in sera from patients with rheumatoid arthritis (RA) and normal individuals and in synovial fluid from patients with RA, patients with osteoarthritis (OA), and patients with other inflammatory rheumatic diseases. The correlation between the citrullinated chemokine levels and clinical data was analyzed. Monocyte and neutrophil chemotaxis assays were performed, and native (noncitrullinated) or citrullinated ENA-78/CXCL5 was injected into mouse knees to evaluate the biologic activities of these chemokines. Results: The concentration of citrullinated ENA-78/CXCL5 was significantly higher in RA sera and SF than in normal sera and in SF from patients with other rheumatic diseases including OA. In RA SF, a strong correlation between the amount of citrullinated ENA-78/CXCL5 and the C-reactive protein level or the erythrocyte sedimentation rate was observed. Citrullinated ENA-78/CXCL5 induced monocyte chemotaxis via CXCR1 and CXCR2, while noncitrullinated ENA-78/CXCL5 did not. In a mouse model of inflammatory arthritis, citrullinated ENA-78/CXCL5 induced more severe inflammation and recruited more monocytes than did noncitrullinated ENA-78/CXCL5. Conclusion: Citrullinated ENA-78/CXCL5 is highly correlated with RA disease activity and, unlike noncitrullinated ENA-78/CXCL5, recruits monocytes. These results indicate that citrullinated ENA-78/CXCL5 may exert previously unrecognized inflammatory properties in RA by recruiting monocytes to inflamed joint tissue.
Recent findings have highlighted the potential initiation of ACPA in sites away from the joint. Periodontitis is an example of this concept. This process in the gums appears to be independent of smoking, the main environmental risk factor for ACPA-positive RA. There is extensive literature regarding the potential role of smoking in the pathogenesis of ACPA-positive RA. As a consequence of this strong association, the lung has become the focus of research to determine whether processes within the lung are linked to the generation of ACPA. Here we outline the current body of evidence and explore the hypothesis that the lung as an organ of immune defence has a role in the pathogenesis of the autoimmune disease ACPA-positive RA.