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657
Dendritic cells in autoimmune diseases
Burkhard Ludewig, Tobias Junt, Hans Hengartner and Rolf M Zinkernagel
Subclinical autoimmune responses can be frequently detected
in healthy individuals. Sustained activation of autoreactive
lymphocytes is, however, required for the development of
autoimmune diseases associated with ongoing tissue
destruction either in single organs or generalized with multiple
manifestations. Clinical and experimental evidence suggests
that prolonged presentation of self antigens by dendritic cells
is crucial for the development of destructive autoimmune
disease. We discuss here a simplified threshold model where
the key parameters for the magnitude of the autoimmune
response are the amount of previously ignored self peptides
presented by dendritic cells and the duration of the antigen
presentation in secondary lymphoid organs. Multiple factors
influence the threshold for the conversion of an autoimmune
response to overt autoimmune disease. Frequent or persistent
viral infections of the target organ may favor autoimmune
disease by increasing the amounts of released self antigens,
generating cytokine-mediated bystander activation of selfreactive lymphocytes and/or sustaining a chronic response via
neoformation of lymphoid structures in the target organ.
Addresses
Institute of Experimental Immunology, Department of Pathology, University
of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland
Correspondence: Burkhard Ludewig;
e-mail: [email protected]
against self antigens are sustained. It is therefore important
to delineate the mechanisms leading to, and the thresholds
influencing, the initial activation of self-reactive lymphocytes and the sustenance of the autoimmune response.
Both genetic and environmental components determine the
susceptibility to autoimmune diseases. Genetic alterations
may influence the general immunoreactivity of the host.
Particularly, polymorphism in genes influencing lymphocyte
homeostasis may increase the susceptibility to autoimmune
disease. However, a large body of evidence shows that the
onset of autoimmune diseases is strongly associated with viral
or bacterial infections [1]. Epidemiological studies revealed
the link between infectious environmental factors and autoimmune diseases such as multiple sclerosis (MS) and
insulin-dependent diabetes mellitus (IDDM) [2]. Virus infections, for example, can be the initial trigger for an autoimmune
response [3] and/or contribute to the chronicity of autoimmune processes [4]. Alternatively, immune responses
against unknown or as-yet unidentified viruses may appear as
auto-immunity when the immune system targets mainly viral
antigens. It is therefore important to discriminate between
genuine autoimmune responses directed against self-antigens
and immune responses directed against persisting viral antigens that often mimic autoimmune tissue destruction, but that
are in fact virus-induced immunopathology.
Current Opinion in Immunology 2001, 13:657–662
0952-7915/01/$ — see front matter
© 2001 Elsevier Science Ltd. All rights reserved.
Abbreviations
APC
antigen-presenting cell
CTL
cytotoxic T lymphocyte
DC
dendritic cell
GP
glycoprotein
IDDM
insulin-dependent diabetes mellitus
LCMV
lymphocytic choriomeningitis virus
mOVA murine ovalbumin
RIP
rat insulin promotor
Introduction
Autoimmune responses can arise because the repertoire of
both T- and B-cell receptors, which allows recognition of
pathogens, may contain receptors recognizing self components. An important mechanism to reduce the numbers of
autoreactive lymphocytes is the elimination of self-reactive
T cells in the thymus and the deletion of B cells reacting
with self-determinants expressed on cellular surfaces in
the bone marrow. However, a great number of self-reactive
lymphocytes escape these central negative-selection
processes and form a peripheral pool of potentially autoimmune-disease-mediating lymphocytes. Destruction of self
tissue may lead to release of self antigens and subsequent
activation of transient autoimmune responses. However,
the pathological consequences of autoimmunity only
become manifest when autoimmune responses directed
Genuine autoimmune reactions are most likely to be
initiated in the course of an infection when target-tissue
inflammation is provoked either by direct cytopathic effects
or by immunopathological reactions against a persisting
microbial agent. Infection-associated inflammation, for
example, involves the release of cytokines and chemokines,
which attract antiviral effector cells and lymphocytes of
other specificities. This ‘bystander effect’ can be sufficient
to activate both lymphocytes directed against self antigens
[5] and lymphocytes directed against non-related determinants [6], leading to initiation and/or exacerbation of
autoimmune disease. A second mechanism that may lead to
the initiation of autoimmunity in the course of an infection
is the activation of T or B cells via antigenic determinants
shared between the pathogen and the host; this has been
termed ‘molecular mimicry’ [7]. Cross-reactivities between
pathogen-derived and self antigens have been described for
human autoimmune diseases such as IDDM [8], MS [9] and
Guillain−Barre syndrome [10]. In the situation of molecular
mimicry, the trigger for autoimmunity would be eliminated
when the pathogen is cleared; recurrent infections could
elicit chronic relapsing autoimmune disease.
Pathogens frequently enter the body via peripheral tissues
and pathogen-derived antigens may reach local secondary
lymphoid tissues after encounter with dendritic cells (DCs)
[11]. During migration to secondary lymphoid organs and
658
Autoimmunity
Figure 1
Number of DCs loaded with
antigenic peptides
Mechanisms increasing the
threshold for autoimmune disease
Autoimmune
disease
Threshold
• High regenerative capacity of
target organ
• Low T cell precursor frequency
• Low cross-presentation efficacy
• Elimination of DCs by effector
T cells
Mechanisms decreasing the
threshold for autoimmune disease
Autoimmune response
Duration of
self-antigen presention by DCs
(weeks, months)
• Infections in target organ
(bystander cytokines)
• Shared antigenic determinants
(molecular mimicry)
• Formation of lymphoid structures
in target organ
• T cells with high affinity for
self antigens
• Genetic predisposition
Schematic representation of a simplified
threshold model for the induction of
autoimmune diseases. The duration of selfantigen presentation by DCs (x) and the
number of DCs loaded with antigenic selfpeptides (y) are the key factors determining
the strength of an autoimmune response.
Presentation of previously immunologically
ignored self-antigens by DCs results generally
in an autoimmune response. Autoimmune
disease, however, develops only if selfreactive T cells are activated by sustained
presentation of self-peptides by DCs.
Thresholds for the conversion of autoimmune
responses to autoimmune disease are usually
maintained at high levels by various
mechanisms (green arrows; examples of these
mechanisms are shown), but may be lowered
dramatically (red arrows), for example by
persistent infection of the target organ.
Current Opinion in Immunology
specific homing to T cell areas, DCs upregulate their
T-cell-stimulatory properties and function as efficient
activators of naïve T cells. Thus, translocation of live
pathogens and/or pathogen-derived antigens to secondary
lymphoid organs by DCs is most likely to be a key event for
the initiation of immune responses against the pathogen
and, under certain circumstances, also for the induction of
autoimmune sequelae. Accordingly, acquisition of self
antigens by DCs and their subsequent presentation to
self-reactive lymphocytes crucially contributes to both the
initiation and the maintenance of autoimmune responses.
We will discuss here the role of DCs in the induction of
autoimmune responses and review the recent literature
addressing the function of DCs in the pathogenesis of
autoimmune diseases.
General rules for T cell mediated immune
reactivity
A number of theories have been put forward to explain
how self-reactive lymphocytes become activated and
mediate autoimmune diseases; such theories include the
involvement of the idiotypic network and suppressor
and/or regulatory cells, and cytokine imbalances. Recently,
Roncarolo et al. [12] suggested that DCs may be involved
in the counter-regulation of potential autoimmune T cell
responses. The general motif of these theories is that, once
an anti-self response is initiated, negative regulatory mechanisms are required to avoid pathogenic T cell reactions
and that autoimmunity is a deviation of normal immune
reactivity. Before discussing the specific role of DCs in
autoimmune diseases, we should therefore outline the
critical parameters for the induction of normal T cell
responses, such as the amount and localization of antigen,
the quality and duration of antigen presentation, and the
tolerance status of the lymphocytes.
T cells recognize antigenic peptides in the context of selfMHC and are activated exclusively in secondary lymphoid
organs [13]. For the initiation of T cell responses, antigen
has to reach lymphoid organs and be presented therein by
professional antigen-presenting cells (APCs). It is important that antigens are presented first in a localized fashion
before systemic spread occurs in order to avoid exhaustive
tolerizing immune responses [14,15]. Likewise, antigen
should be present in local lymphoid organs for a minimal
time period (probably 4–6 days) to obtain optimal initial
activation of T cells. Only T cells that have not been negatively selected in the thymus and are of sufficiently high
avidity possess the capacity to elicit autoimmune reactions.
These autoreactive T cells are usually directed against
immunologically ignored antigens, which are not presented in the thymus or in peripheral lymphoid tissues such as
lymph nodes or spleen. Autoreactive T cells recognizing
immunologically ignored antigens are usually only
activated if their cognate antigen reaches lymphoid organs
and is appropriately presented by professional APCs.
The repertoire of autoreactive T cells that are not
negatively selected in the thymus is extensive, as can be
easily demonstrated by administering autoantigens or
their immunogenic peptides mixed with strong adjuvants.
It is important to note that self-reactive T cells can be
activated not only by using sequestered antigens such as
myelin basic protein (MBP) or proteolipid protein (PLP),
but also by using highly abundant proteins such as collagen type II (found in joints), cardiac myosin, thyroglobin
or melanocyte antigens. Similarly, activated autoreactive
T cells that recognize widely distributed proteins such
as rhesus polypeptides [16] or platelet glycoprotein
(GP)IIB−GPIIIa [17] can be found in patients with
autoimmune hemolytic anemia or autoimmune thrombocytopenia purpura, respectively.
Dendritic cells in autoimmune diseases Ludewig et al.
659
Taken together, the evidence is compelling that the
above-mentioned negative regulatory mechanisms — if
they exist — are easily over-ruled and that autoimmunity
can be induced when immunologically ignored autoantigens
are presented in secondary lymphoid organs above a minimal concentration for a sufficient length of time. Therefore,
it is conceivable that the default pathway of immune reactivity after loading of previously immunologically ignored
autoantigens onto DCs is activation. Accordingly, presentation of autoantigens by DCs to high-avidity self-reactive
T cells results generally in autoimmunity. The main parameters for the strength of an autoimmune response and the
conversion of an autoimmune reaction into clinically manifest autoimmune disease are the number of DCs presenting
self-antigen and the duration of self-antigen presentation by
DCs (Figure 1). Importantly, in genetically non-predisposed
individuals, the thresholds for shifting autoimmunity to
overt autoimmune disease are generally maintained at
high levels by mechanisms such as low T cell precursor
frequencies, low efficacy of cross-presentation and
elimination of DCs by effector T cells (Figure 1).
right heart and in arterial smooth-muscle cells [27]. Despite
the widespread expression of the transgene in the vascular
system, T cells ignore the peripherally expressed antigen but
immunization with DCs presenting β-galactosidase peptide
elicited cardiovascular immunopathology [28]. Repeated
application of peptide-pulsed DCs was required to induce
the most severe phenotype of this experimental disease —
with arteritis, myocarditis and dilated cardiomyopathy. A less
severe, and transient, cardiovascular inflammation was
induced when DCs pulsed with β-galactosidase peptide
were administered less frequently or in lower numbers
(B Ludewig, unpublished data). Considering that DCs have
only a short half-life in secondary lymphoid organs [29], particularly in the presence of activated T cells that recognize
peptides presented by DCs [29–31], it appears that the
continuous replenishment of the DC pool presenting a certain peptide is crucial for the maintenance of T cell activity.
In situations where T cell precursor frequencies are low, such
as in RIP−GP or SM−LacZ mice, prolonged antigen delivery
via DCs is the crucial factor for the conversion from transient
autoimmunity to manifest autoimmune disease.
Triggering autoimmunity with dendritic cells
The usually low frequency (10−5) of self-reactive T cell precursors sets high thresholds for the induction of autoimmune
disease. RIP−GP mice, for example, do not develop diabetes
after infection with LCMV-GP-recombinant vaccinia virus
[26]. However, elevation of CTL precursor frequencies in
double-transgenic mice expressing the LCMV-GP in the
pancreas and a GP-specific TCR on their CTLs (i.e. RIP−GP
x TCR mice) leads to the rapid induction of diabetes after
infection with vaccinia virus expressing recombinant LCMVGP [26]. Similarly, elevation of organ-specific T helper
cell frequencies using TCR-transgenic models converts
DC-induced autoimmune responses to severe autoimmune
disease [24,25•]. The importance of controlled proliferation
and apoptosis of self-reactive lymphocytes becomes obvious
in patients with mutations in Fas or Fas-ligand genes or in
autoimmune lymphoproliferative syndrome [32], where high
frequencies of self-reactive T cells and their activation may
be the cause of systemic autoimmune disease.
A number of studies in human autoimmune disorders have
indicated that DCs can be found in autoimmune lesions
[18,19]. In addition, animal models of spontaneous autoimmune disease have shown that DCs are amongst the first
cells to infiltrate the target tissue [20] and are capable of
presenting autoantigens to T cells in local draining lymph
nodes [21]. The potency of DCs in priming autoreactive
T cells that precipitate an autoimmune disease has been
shown in a seminal study by Knight et al. [22] using adoptive
transfer of thyroglobulin-loaded DCs into genetically
susceptible mice. Furthermore, DCs expressing endogenous
self-peptides or pulsed ex vivo with immunogenic selfpeptides can induce severe autoimmune disease [23,24,25•].
Mice transgenic for the rat insulin promotor (RIP) and
lymphocytic choriomeningitis virus (LCMV) GP (i.e. the
RIP−GP model of IDDM) [26] were used to investigate the
potential of DCs to induce autoimmune diabetes. RIP−GP
mice express the transgene exclusively in pancreatic-islet
β-cells; T cells ignore the neoself-antigen until LCMV-GPspecific cytotoxic T lymphocytes (CTLs) are activated
either by LCMV infection or by immunization using DCs
presenting the immunodominant LCMV-GP epitope
endogenously (these cells are termed H8-DC) [23]. Single
immunization of RIP−GP mice with H8-DC resulted in
transient CTL activation and recruitment of islet-specific
CTLs but did not lead to diabetic disease. CTL activity
had to be maintained over a period of 10–12 days by repeated
H8−DC injections to shift the balance to a more severe
phenotype with an incidence of diabetes of >90% [23].
Similar results were obtained in the SM−LacZ model of
autoimmune arteritis and myocarditis. These transgenic
mice express the β-galactosidase antigen under the control of
a smooth-muscle-specific promotor in cardiomyocytes of the
A further factor determining the susceptibility to autoimmune
disease is the regenerational capacity of the target organ, as
demonstrated in the SM−LacZ model of DC-induced cardiovascular immunopathology. As mentioned above, repetitive
priming of SM−LacZ mice with DCs presenting β-galactosidase peptide caused acute vascular immunopathology with
strong lymphocytic infiltration in lung arteries and in the right
heart. Interestingly, cessation of chronic self-antigen delivery
by DCs to secondary lymphoid organs after 10–12 days resulted in resolution of the arterial lesions in the lung arteries with
only mild histiocytic infiltrates around the vessels, indicating
the high capacity of the arterial wall to regenerate after inflammatory injuries. However, in this chronic phase, despite
cessation of immunization with β-galactosidase-loaded DCs,
SM−LacZ mice showed a severe loss of the poorly regenerating heart tissue and showed fibrosis that eventually led to
dilated cardiomyopathy [33•]. Taken together, these results
660
Autoimmunity
show that autoimmune damage may resolve if an antigen is no
longer presented in lymphoid tissues and that the susceptibility
of an organ for autoimmune diseases critically depends on the
ability to replace damaged tissue with new functional tissue.
Antigen persistence and chronic inflammation
Previously ignored, peripheral self-antigens that are released,
for example, in the course of infection-induced inflammatory
reactions can reach secondary lymphoid organs either via
lymph transport or in association with DCs. Since DCs are
excellently equipped to process and present exogenous
antigens via MHC class II [34], induction of T helper cell
responses against self antigen is probably very efficient.
It has been suggested that DCs may also process exogenous
self antigens via MHC class I for presentation to CTLs,
leading to induction of autoimmune disease via a pathway
called cross-presentation [35]. Exogenous loading of MHC
class I molecules on DCs can be achieved using soluble [36]
or cell-associated proteins [37] and can be further enhanced
if proteins form immune complexes with antibodies [38].
However, careful titration of exogenous antigen shows that
large amounts of protein are required to achieve cross-presentation [36]. Cross-presentation can also be demonstrated
in vivo using transgenic mice expressing model antigens in
peripheral non-lymphoid tissues [39,40]. In mice transgenic
for RIP−mOVA (murine ovalbumin), for example, the widely and highly expressed ‘self’-antigen is presented via MHC
class I in draining secondary lymphoid organs by bonemarrow-derived APCs [39]. Brocker and colleagues [41•]
have shown that antigen presentation by DCs is sufficient
for cross-presentation in this model system.
However, spontaneous autoimmune disease that is mediated
by cross-presentation in ‘high expresser’ situations, such as
RIP−mOVA mice, is only elicited when central tolerance
mechanisms are bypassed by transfer of large numbers of
naïve TCR-transgenic CTLs [42]. In contrast, when self antigens are expressed at lower concentrations, and in a more
localized fashion, spontaneous autoimmune disease does not
occur, even in the presence of elevated levels of self-reactive
T cells [26,43]. Thus, self-perpetuating autoimmunity due to
cross-presentation is most likely to be a phenomenon that is
restricted to engineered transgenic models where central tolerance mechanisms can be bypassed and/or T cell frequencies
are artificially high. Furthermore, cross-presentation of cellassociated proteins in vivo appears to be a rather inefficient
process, because only a very small percentage of the CD8α–
lymphoid-DC subset cross-presented OVA, even if large
quantities of OVA protein were accessible for DCs [44•].
reduced the incidence of autoimmune diabetes [25•]. In addition, not even a minimal autoimmune response was induced
when large amounts of self-antigen in the form of apoptotic or
necrotic LCMV-GP-expressing fibroblasts were injected. Only
in the presence of high numbers of specific TCR-transgenic
T helper cells or in the presence of non-specific immunostimulatory stimuli did a mild autoimmune response develop after
injection of necrotic LCMV-GP-expressing fibroblasts [25•].
In addition, Ochsenbein et al. [45••] have shown recently that
cross-presentation of tumor antigens is inefficient and, if at
all feasible — in terms of antigen quantities — a very
demanding process. Thus, high threshold levels for presentation of exogenous self-antigens via MHC class I on DCs
are most likely to be a key mechanism in preventing selfperpetuating autoimmune disease and making the successful
induction of anti-tumor immunity via cross-presentation
rather the exception than the rule.
The thresholds for the development of clinically manifest
autoimmune disease can, however, be lowered if an inflammatory response in the target organ is maintained. As
mentioned above, self-antigen-induced autoimmunity, even
if the self antigen is presented by DCs, is usually self-limiting
[23,25•,33•]. Inflammatory processes associated with viral
infections, such as massive cytokine/chemokine release and
immune cell infiltration, may reactivate subclinical autoimmunity and lead to clinical disease. Indeed, expression of
inflammatory cytokines in a localized fashion in pancreatic
islet cells favored the induction of IDDM by otherwise
suboptimal stimuli [46,47]. Interestingly, repeated priming of
RIP−GP mice with DCs led to the formation of lymphoid
structures in pancreatic islets [23]. Such structures are also
seen in autoimmune diseases associated with pronounced
autoantibody responses such as Hashimoto’s thyroiditis,
Sjögren’s syndrome and rheumatoid arthritis, and usually contain B cell follicles with follicular DCs. However, chronic
inflammation of a target organ does not necessarily lead to
autoimmune disease, as shown by the pancreatic expression
of cytokines [47,48] or chemokines [49] which may even favor
the generation of organized lymphoid structures [50,51•,52•].
It is important to note that certain cytokines may also inhibit autoimmune reactions, for example via modulation of the
antigen presentation function of DCs [53••]. Thus, it appears
that both the timing and dose of self-antigen expression by
DCs and the development of lymphoid structures in the
target organs are of major importance for the development of
clinical autoimmune disease.
Conclusions
The high thresholds for induction of CTL-mediated autoimmune disease via exogenous loading of self-antigens on MHC
class I have been demonstrated in the RIP−GP model. Priming
of RIP−GP mice with H8-DC constitutively expressing the
self-peptide GP33 elicited clinical manifestation of autoimmune disease, whereas the turnover of exogenously loaded
GP33 on DCs led to detectable autoimmune responses, but
Multiple factors contribute to the pathogenesis of autoimmune diseases. Presentation of self antigens by DCs is
likely to play an important role in the initiation of autoimmunity and the progression to overt clinical autoimmune
disease. Self antigens become accessible for DCs when
the release of tissue antigens is induced, for example by
cytopathic virus infections or by physical trauma. We have
Dendritic cells in autoimmune diseases Ludewig et al.
presented evidence that the amount of self peptide loaded
on MHC molecules of DCs and the duration of their presentation in secondary lymphoid organs are the main factors
determining the magnitude of the autoimmune response. A
number of fail-safe mechanisms, however, avoid exaggerated autoimmune responses that lead to autoimmune disease;
these mechanisms include the generally very low precursor
frequency of self-reactive lymphocytes and the rather low
efficacy of exogenous loading of MHC class I molecules
with self-antigens for the activation of CTLs. The
simplified threshold model presented here may help us to
understand the relative importance of the multiple factors
involved in the conversion of relatively frequent autoimmune responses to the rather rare manifestations of
autoimmune diseases.
Update
A recent study by Kalled et al. [54] revealed the importance
of an altered DC turnover for the susceptibility to autoimmune nephritis in the (SWR × NZB)F1 mouse model of
systemic lupus erythematosus. (SWR × NZB)F1 mice are
genetically highly susceptible to autoantibody-mediated
lupus-like nephritis. Increased lymphocyte apoptosis and
particularly high apoptosis rates of DCs, leading to an
increased DC turnover, may accelerate this B-cell-driven
autoimmune disease. It will be important for future studies
on this and other autoimmune diseases to delineate how
altered DC homeostasis influences the level and/or specificity
of self-antigen presentation by DCs and other APCs.
Acknowledgements
We thank Betsy Metters for helpful discussions and critical reading of the
manuscript. This work was supported by the Swiss National Science
Foundation and the Kanton Zürich.
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