(Journal of Leukocyte Biology. 2005;77:854-861.)
© 2005
by Society for Leukocyte Biology
Autoantigens act as tissue-specific chemoattractants
Joost J. Oppenheim*,1,
Hui Fang Dong
,
Paul Plotz
,
Rachel R. Caspi
,
Michelle Dykstra¶,
Susan Pierce¶,
Roland Martin||,
Casey Carlos**,
Olivera Finn**,
Omanand Koul and
O. M. Zack Howard*
* National Cancer Institute-Frederick, Center for Cancer Research, Laboratory of Molecular Immunoregulation, and
Science Applications International Corporation-Frederick, Maryland;
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases,
National Eye Institute, Laboratory of Immunology, and
|| National Institute of Neurological Disorders and Stroke, Bethesda, Maryland;
¶ National Institute of Allergy and Infectious Diseases, Laboratory of Immunogenetics, Rockville, Maryland;
** Department of Immunology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pennsylvania; and
Shriver Center/University of Massachusetts Medical School, Waltham
1Correspondence: Laboratory of Molecular Immunoregulation, Building 560, Room 21-89A, National Cancer Institute, Frederick, MD 21702-1201. E-mail: Oppenhei{at}ncifcrf.gov
ABSTRACT
We have investigated the chemoattractant properties of self-antigens
associated with autoimmune diseases and solid tumors. Many autoantigens
induced leukocyte migration, especially by immature dendritic
cells (iDC) by interacting with various chemoattractant Gi-protein-coupled
receptors (GiPCR). Our initial observation that myositis-associated
autoantigens, histidyl-tRNA synthetase and asparaginyl-tRNA
synthetase, were chemotactic for CC chemokine receptor 5 (CCR5)-
and CCR3-expressing leukocytes, while other nonautoantigenic
aminoacyl-tRNA synthesases were not, suggested that only self-antigens
capable of interacting with receptors on antigen-presenting
cells were immunogenic. We next determined that self-antigens
associated with autoimmune diseases, e.g., multiple sclerosis
or experimental autoimmune encephalomyelitis, type I diabetes,
scleroderma, systemic lupus erythematosus, autoimmune uveitis,
or experimental autoimmune uveitis (EAU), were chemotactic for
GiPCR expressed by iDC. The majority of autoantigens were DC
chemoattractants at 10–100 ng/ml, but did not induce DC
maturation until they reached 1000-fold higher concentrations.
Interphotoreceptor retinoid-binding protein and retinal arrestin
(S-antigen) are targets of autoantibodies in human uveitis and
are chemotactic for CXC chemokine receptor 5 (CXCR5)- and/or
CXCR3-expressing iDC. However, although S-antigen does not induce
EAU in wild-type mice, it is nevertheless a chemoattractant
for murine iDC. These unexpected observations suggested that
the chemotactic activity of these tissue-specific self-antigens
could be involved in promotion of tissue repair and restoration.
Thus, the primary role of autoantigens may be to alert the immune
system to danger signals from invaded and damaged tissues to
facilitate repair, and autoimmune responses subsequently develop
only in subjects with impaired immunoregulatory function.
Key Words: chemokines • tumor antigens • chemotaxis • migrations • dendritic cells
INTRODUCTION
Autoimmune diseases arise as a consequence of the breakdown
in tolerance to self-antigens, and the diagnosis may be confirmed
based on the detection of characteristic autoantibodies [
1
].
In some autoimmune diseases, autoantibodies and autoimmune T
cell responses develop against unique antigens typical of the
involved tissues and organs, e.g., insulin in type I diabetes,
interphotoreceptor retinoic-binding protein (IRBP) in autoimmune
uveitis, and myelin basic protein (MBP) or proteolipid protein
(PLP) in multiple sclerosis (MS). In contrast, some autoimmune
patients develop autoantibodies directed against proteins and
nucleotides present in every nucleated cell in the body, such
as single-stranded DNA (ssDNA) in systemic lupus erythematosus
(SLE), histidyl-tRNA synthetase (HisRS) in myositis, and topoisomerase
I in scleroderma. Nevertheless, the repertoire of the targets
of autoantibodies is surprisingly restricted, and often, they
are characteristic of only one autoimmune state. These observations
raised several questions: Why are these particular tissue antigens,
which represent probably less than 1000 of our 30,000 antigens,
more likely to break tolerance to self? As serum autoantibodies
and autoimmune T cell responses frequently appear only with
disease progression, do they play a passive or active role in
disease initiation? Why are certain tissues characterized by
the restricted development of autoantibodies and autoimmune
T cell responses to widely dispersed autoantigens? Many immunologists
have confronted these issues, and this brief review will certainly
not resolve them, but our observations that many autoantigens
are chemotactic for mononuclear leukocytes may provide some
clues that lead to new perspectives. The chemotactic capacity
of autoantigens not only can result in their attracting immune
cell subsets to a given tissue but also indicates that they
are interacting with cell membrane receptors. We propose that
this receptor interaction also promotes the internalization,
processing, and presentation of the autoantigens, thus enhancing
their immunogenic capabilities.
Over 40 chemokines have been identified as major traffic directors of leukocytes engaged in innate and adaptive immune responses [2
]. The subset of leukocytes responding to particular chemokines is based on their interaction with selected Gi protein-coupled receptors (GiPCR) [3
]. This interaction can be blocked by pertussis toxin (PTX), which is known to inhibit G
iPCR-mediated signal transduction [4
]. It was therefore surprising to learn that proteolytic cleavage of tyrosyl-tRNA synthetase (TyrRS) yielded an NH2-terminal domain, composed of amino acids 1–364, which was chemotactic for neutrophils [5
]. The chemotactic effect of TyrRS was inhibited by PTX. TyrRS interacts with a CXC chemokine receptor (CXCR1) on human neutrophils, despite the fact that it has no sequence homology with the chemokine cysteine motif of interleukin-8 (IL-8; CXC chemokine ligand 8), a known ligand for CXCR1 [5
]. This observation suggested that other aminoacyl-tRNA synthesases (aaRS) might possess chemotactic activity.
AUTOANTIGENS ARE CHEMOTACTIC FOR MONONUCLEAR CELLS
We therefore investigated the possibility that other aaRS might
be chemotactic for leukocytes. Unlike TyrRS, HisRS and asparaginyl-tRNA
synthetase (AsnRS) are known to be targets of autoantibodies
that are detected in up to 25% of patients with autoimmune myositis.
These aaRS did not induce intracellular calcium flux but do
activate extracellular signal-regulated kinase-2, and they had
chemotactic effects that were inhibited by PTX. We showed that
intact HisRS and a 1–48 amino acid peptide were chemotactic
for human CD4+ and CD8+ lymphocytes, and IL-2 activated monocytes
that express CC chemokine receptor 5 (CCR5) but not for neutrophils
or unstimulated monocytes that do not express CCR5 [
6
]. AsnRS
similarly was chemotactic for CCR3-expressing mononuclear cells
[
6
]. Although, these aaRS stimulated cells to migrate only
two- to fourfold over background and were therefore not as efficacious
as chemokines, they were potent, requiring only low (subnanomolar)
concentrations to induce migration in in vitro Boyden chamber
assays. Their chemotactic activity was also readily inhibited
(desensitized) by prior exposure of cells to the appropriate
chemokine ligands, and conversely, HisRS partially desensitized
the chemotactic response to regulated on activation, normal
T expressed and secreted [RANTES; CC chemokine ligand 5 (CCL5)].
The structural relationship between HisRS and CCL5 was studied. There is no amino acid homology among HisRS, AsnRS, and chemokines. The NH2 terminal (1–48 HisRS) domain of HisRS, containing the principal antigenic site of HisRS, was chemotactic for mononuclear cells, and a deletion mutant lacking this domain (M-HisRS) was not. Neutralizing antibodies directed against the second extracellular loop (third extracellular domain) of CCR5 blocked HisRS as well as CCL4- and CCL5-induced chemotaxis. Conversely, CCL5 and HisRS interfered with the binding of this antibody to CCR5. The use of chimeric receptors consisting of various portions of CCR5 and CCR2 (kindly provided by Dr. Israel Charo, University of California, San Francisco) did differentiate the chemotactic responses of HisRS and CCL5 and suggested that HisRS interacts predominantly with the third and to a lesser extent, with the fourth extracellular domain of CCR5, and CCL5 interacts with the first as well as the third. Thus, HisRS may be interacting with receptor domains distinct from those used by the chemokines.
AUTOANTIGENS ARE CHEMOTACTIC FOR IMMATURE DENDRITIC CELLS (iDC)
As antigen-presenting DC activate adaptive immune responses,
the capacity of autoantigens to interact with DC is requisite
for the induction of T-dependent immune responses. It is known
that iDC express a wide variety of chemokine receptors, which
are lost as they mature into mature DC (mDC; as reviewed in
ref. [
7
]). Indeed, HisRS and AsnRS were chemotactic for iDC,
which express CCR5 and CCR3, but not mDC, which do not. Furthermore,
a number of nonautoantigenic synthetases, such as aspartyl and
lysyl-tRNA synthetases, were not chemotactic for mononuclear
cells including iDC. This led us to suggest that chemotactic
autoantigens may, at a minimum, be involved in recruiting mononuclear
antigen-presenting cells (APC) to sites of tissue damage and
inflammation. In addition, our recent collaborative studies
have shown that HisRS, just like chemokines, is internalized
only by CCR5-expressing cells, whereas cells that do not express
CCR5 do not bind fluorescent-tagged HisRS (
Fig. 1
and unpublished
data). Further, HisRS colocalizes in the endocytic compartment
with major histocompatibility complex (MHC) class II antigen
(
Fig. 2
and unpublished observations). This suggests that interaction
of autoantigens with GiPCR results in their localization in
antigen-processing compartments. Furthermore, the possibility
that interaction of these autoantigens with GiPCR may promote
their uptake, processing, and presentation by iDC has also been
suggested by studies showing that antigen-receptor interactions,
including those with GiPCR, markedly increase the immunogenicity
of self and nonself antigens [
8
9
10
11
]. Thus, autoantigens
interact with receptors and appear to be more than just passive
targets of autoantibodies/autoreactive T cells in autoimmune
disease and potentially, can be actively involved in breaking
tolerance to self. We therefore proceeded to test a number of
autoantigens from a variety of autoimmune states for their chemotactic
effects on iDC.
MANY AUTOANTIGENS ARE CHEMOTACTIC
We have established that most self-proteins that are not involved
in autoimmune responses are not chemotactic (
Table 1
). For
example, a number of serum proteins, HSPs, and aaRS, as discussed,
are not chemotactic. Although it could be argued that lack of
a chemotactic response to highly abundant proteins, such as
IgG and albumin, might be a result of constant desensitization
of the receptors, this is unlikely to be the case for intracellular
proteins such as ufd-2 and the lysyl and tryptophanyl-tRNA synthetases.
Furthermore, the classic chemoattractant proteins, chemokines
and anaphylatoxins, induce cell migration without inducing autoantibodies
or autoreactive T cells unless administered with an adjuvant
or structurally modified by fusion to an antigen [
12
13
14
15
].
Conversely, many self-proteins targeted by autoantibodies or
autoreactive T cells induce GiPCR-dependent chemotaxis (
Table 2 ).
We tested two intact, functional proteins associated with MS:
PLP (provided by Drs. Marjorie Lees and O. Koul, Shriver Center,
University of Massachusetts Medical School, Waltham) and MBP.
Both were chemotactic for human iDC. Furthermore, although MBP
was only chemotactic at micromolar (10,000 ng/ml) concentrations,
PLP was most effective at lower concentrations (100 ng/ml;
Fig. 3
). We further investigated several peptide domains from PLP,
MBP, and MOG, which are proteins capable of inducing EAE, and
observed that some fragments that were known to be capable of
inducing EAE were chemotactic (
Table 3
). Two nucleolar proteins,
fibrillarin (U3-RNP) and topoisomerase I [provided by Dr. Paul
Hu, National Cancer Institute (NCI), Frederick MD], which are
autoantigens associated with scleroderma, were chemoattractants
for human monocytes (data not shown). Similarly, a number of
autoantigens associated with type 1 diabetes, especially the
phosphatase IA-2 (provided by Dr. Abner Notkins, National Institute
of Dental and Craniofacial Research, Bethesda, MD) and transaldolase
(provided by Dr. Andras Perl, State University of New York at
Syracuse), were chemotactic for iDC
(Fig. 3)
. Additionally,
the retinal antigens, S-antigen and IRBP, which induce experimental
autoimmune uveitis (EAU), as well as several peptides derived
from them, were chemotactic for murine and human iDC (
Fig. 3
and ref. [
16
]).
In contrast, some autoantigens, such as periplakin, vimentin,
SRP54, -68, and -72, B32, ssDNA, and La, failed to induce leukocyte
migration at tested concentrations. We have not tested these
antigens over a wider concentration range as yet, and like MBP
and transaldolase, some of them may be chemotactic only at micromolar
concentrations. The failure of La and ssDNA to be chemotactic
was rather disappointing. The possibility they might be active
as complexes was therefore investigated. This revealed that
mixtures of femtomolar concentrations of ssDNA and nanomolar
concentrations of La were chemotactic for iDC (
Fig. 4
), and
this response was also inhibited by PTX, implicating an interaction
of the complex with GiPCR. Based on reports that immunization
of mice with tumor antigens fused to ligands for GiPCR results
in enhanced immune responses to weak tumor antigens [
15
], we
postulated that those self-antigens interacting with GiPCR are
more capable of inducing autoimmune responses. It is also entirely
possible that some autoantigens use nonchemotactic receptors
such as scavenger receptors to enter the antigen-processing
endocytic pathway [
8
,
10
]. Overall, our data support the idea
that the majority of self-antigens that are involved in autoimmune
reactions may be those that are preferentially taken up by receptors
targeting antigen-processing pathways in APC.
TUMOR AUTOANTIGENS ARE CHEMOTACTIC
It has been clearly documented that cancer patients often develop
autoantibodies to their tumor antigens [
17
]. Furthermore, certain
melanoma patients immunized with melanocyte or melanoma-derived
antigen vaccines developed autoimmune vitiligo [
18
]. We therefore
investigated the chemotactic properties of some tumor antigens.
We tested Good Manufacturing Practice preparations of gp100
and NY-ESO-1 (provided by Drs. Steven Rosenberg and Paul Robbins,
NCI) and to our surprise, consistently obtained a chemotactic
response of iDC, monocytes, and T cells to nanomolar concentrations
of gp100
(Fig. 3)
but not at all to NY-ESO-1. Perhaps this
difference is a result of the fact that NY-ESO-1 is a fetal
and testis antigen and is therefore not systemically expressed
after birth. Based on desensitization of the chemotactic response
to gp100 by monocyte chemoattractant protein-1/CCL2 and the
selective capacity of CCR2-transfected HEK293 cells to migrate
in response to gp100, we concluded that gp100 interacts with
CCR2. Furthermore, gp100 interacts with human monocytes, T lymphocytes,
and iDC, which are known to express CCR2. In addition, human
gp100 is more chemotactic for normal murine iDC than for iDC
from CCR2–/– mice (unpublished observations). Thus,
gp100 behaves like an autoantigen with respect to chemotaxis
and the participation of gp100 peptides in vaccine-induced autoimmune
vitiligo in some of the patients experiencing tumor regression
[
19
].
In collaboration with C. Carlos and O. Finn (University of Pittsburgh Medical School, PA) we have studied a more typical tumor antigen, MUC 1 [20
]. The normal counterpart of MUC 1 is heavily glycosylated and expressed on the surface of normal gastrointestinal epithelial cells, while MUC 1 derived from pancreatic and intestinal tumors is hypoglycosylated. Only the latter is chemotactic for a PTX-inhibitable GiPCR on iDC but not for mDC. Furthermore, we have also determined that CEA is chemotactic for iDC (data not shown), while PSA derived from prostate tumors is not (kindly provided by Dr. Jeffrey Schlom, NCI). Perhaps the detection of chemotactic activity can identify candidate tumor antigens for tumor vaccine therapy.
THE CHEMOTACTIC AND PATHOGENIC ACTIVITIES OF AUTOANTIGENS ARE DISSOCIABLE
We explored several EAU autoantigens, namely S-Ag arrestin and
IRBP, in greater detail, as they are not only putative targets
of autoantibodies/autoreactive T cells in human autoimmune uveitis
but they are capable of inducing EAU in rodents [
16
]. Rodent,
bovine, and human uveitic autoantigens are evolutionarily conserved
and are interchangeable. We determined that S-Ag and IRBP are
chemotactic for normal human iDCs and lymphocytes but not phagocytic
cells. Cross-desensitization studies and evaluation of the chemotactic
responses of cells transfected to express only one of the chemokine
receptors revealed that IRBP interacts with CXCR5 and CXCR3,
and the chemotactic response of S-Ag required only the CXCR3
chemokine receptor.
The availability of a good mouse model for EAU enabled us to compare resistant mouse strains with those sensitive to the induction of EAU. This revealed that iDC from resistant and sensitive mice exhibited equal chemotactic responses to both the autoantigens. Furthermore, unlike IRBP, S-Ag is not able to induce uveitis in wild-type mice [16
, 21
]. This suggested that the chemotactic effect of these autoantigens could be dissociated from their capacity to induce EAU.
This issue was investigated further by using 20 amino acid-overlapping, synthetic human peptide epitopes from IRBP with well-established uveitogenic (pathogenic) and antigenic (lymphoproliferative) capabilities. This revealed that some of the peptides were chemotactic, similar to the intact IRBP for normal human lymphocytes. However, some of the smaller IRBP peptides, which were reported to be uveitogenic in mice, were not chemotactic for human iDC. Conversely, the chemotactic activity of peptides could be dissociated from their ability to induce lymphocytes from patients with uveitis to proliferate. These data also suggested that the chemotactic effect of autoantigens is not necessarily related directly to the capacity to induce autoimmune processes. This was reinforced by studies of peptides associated with EAE. As shown in Table 3 , several of the peptides that were not chemotactic for human monocyte-derived iDC did induce EAE in various animal models. Additionally, most of the peptides that induced human PBMC to proliferate did not induce EAE. Taken together, our observations suggest that although recruitment of iDC by self-antigens may contribute to the development of immune tolerance or autoimmune disease, it is not the only mechanism.
AUTOANTIGENS FAIL TO INDUCE MATURATION OF DC
The fact that an autoantigen or tumor antigen is chemotactic
does not necessarily enable it to also serve as an immunogenic
stimulant. This is borne out by the observations that the gp100
melanoma tumor antigen, which is capable of interactions with
a GiPCR, even when used in vaccines together with DC, induced
little or no tumor immunity. For example, it was recently reported
that gp100 administered alone was not immunogenic and was not
capable of inducing T cell-mediated killing of melanoma in clinical
studies [
22
]. Only in the presence of multiple proinflammatory
signals that induce B7/CD40-costimulant molecules on DC can
autoantigens overcome tolerogenic/suppressive signals and generate
autoimmune reactions, which result in effective tumor immunity.
Thus, the process of autoimmunity and tumor immunity is closely
related, but although autoimmunity results in undesirable and
destructive cellular immune reactions to self-antigens, this
is often not the case in cancer patients, who instead, unfortunately,
develop no response or tolerogenic responses to their "self"
tumor antigens.
As two signals, namely antigens and costimulants, are required to induce immune responses, we have carefully evaluated the capacity of chemotactic auto and tumor antigens to induce the maturation of iDC into mDC. To be fully functional, mDC need to express costimulatory molecules such as MHC II antigens and CD83 or CD86. They also need to produce immunostimulating cytokines such as IL-12p70. Further, DC need to express CCR7 receptors to enable them to migrate to draining lymph nodes, where the processed antigen can be presented, resulting in an immune response.
Our experiments clearly showed that at subnanomolar concentrations, HisRS and gp100 were chemotactic, but they did not induce maturation of iDC. Only at 20-fold greater concentrations were these autoantigens able to induce low-to-modest levels of expression of CD40, CD80, MHC II antigens, and CCR7 by iDC (unpublished observation). At the higher self-antigen concentrations, iDC were stimulated to produce low levels of some cytokines and chemokines, including IL-2, IL-12p40, and tumor necrosis factor (TNF), and somewhat higher levels of IL-6, IL-10, macrophage-derived chemokine/CCL22, and thymus and activation-regulated chemokine/CCL17. Consequently, these chemoattractants are able to induce iDC to mature only partially at "pharmacological" concentrations but not at their chemotactic concentrations.
CONCLUSIONS
What, therefore, is the relevance of the interaction between
autoantigens and chemotactic receptors? As many of these autoantigens
are intracellular moieties, they are not normally available
to cell-surface receptors but may be released in the course
of injurious insults resulting in cell death. We therefore propose
the following scenario: Injury induces the release of self-antigen,
resulting in a tissue-specific signal to cells of the host innate
and adaptive immune system to migrate to the site of injury
and eliminate pathogens and cellular debris, deliver growth
factors and other mediators that will facilitate repair, and
restore homeostasis. As Casciola-Rosen and colleagues [
23
]
have shown, selected autoantigens may be preferentially up-regulated
in inflamed tissues. As tissue injury is associated with the
in situ production of proinflammatory cytokines such as IL-1,
TNF, and chemokines, the cellular infiltration may be amplified,
macrophages may be activated, and DC may be stimulated to mature.
The mDC could deliver the preferentially processed autoantigenic
peptides to T effector cells in draining lymph nodes, thus engaging
adaptive immune responses. As the injury subsides, and cytokine
production ceases, tissue-resident DC will remain immature and
will interact with T regulatory cells to reestablish peripheral
tolerance/anergy. There are reports in the literature that support
such a scenario. Michal Schwartz and Kipnis [
24
] have shown
that prior immunization of rats with the MBP autoantigen promotes
the repair and recovery of rats from spinal cord and optic nerve
injuries. They observe increased infiltration of the sites of
injury by macrophages in rats immunized with MBP, resulting
in more effective degradation and removal of tissue debris and
facilitation of subsequent neural tissue repair. Although those
rat strains genetically proven to develop EAE go on to do so,
the resistant strains repair equally well without developing
EAE. A parallel situation involving retinal ganglion cell neuroprotection
is observed with respect to retinal antigens in mouse strains
susceptible or resistant to EAU [
25
]. Thus, the development
of autoimmune sequelae in response to the autoantigen is based
on genetic or other deficiencies, independent of their role
as harbingers of tissue damage and mobilizers of the process
of cellular repair. Presumably, genetic or acquired immune defects
can result in a failure to turn off the reparative immune response,
resulting in progressive expansion of the clone of self-reactive
T cells and consequent progression to self-destructive autoimmune
reactions.
Therefore, our current responses to the three questions posed in the introduction are as follows: Autoantigens, by interacting with receptors on leukocytes, may fulfill a primary role of alerting the innate and adaptive immune systems to danger signals from damaged tissues but induce autoimmune reactions only in the case of dysregulated, suppressive immune responses. Perhaps the reparative role in normal host defense is facilitated by the tissue specificity of many self-antigens. However, in patients with immunoregulatory defects, tissue damage as a result of injury or invasion by microorganisms may initiate immune responses that persist, despite repair of the damage, and culminates in inappropriate autoimmune, self-destructive reactions.
ACKNOWLEDGEMENTS
H. F. D. was funded in part by DHHS #NO1-CO-12400. O. K. was
partially supported by the Stanley Research Foundation. Drs.
Marjorie Lees and O. K. thank the Cooperative Human Tissue Network
(Eastern Division, University of Pennsylvania) for the human
brain samples used for isolation and purification of the proteolipid
protein used in this study. The contents of this publication
do not necessarily reflect the views or policies of the Department
of Health and Human Services nor does mention of trade names,
commercial products, or organizations imply endorsement by the
U.S. Government. The publisher or recipient acknowledges the
right of the U.S. Government to retain a nonexclusive, royalty-free
license in and to any copyright covering the article.
Received October 30, 2004;
revised February 14, 2005;
accepted February 16, 2005.
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