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British Journal of Rheumatology 1997;36:1144±1150
SCIENTIFIC REVIEW
CRYPTIC T-CELL EPITOPES AND THEIR ROLE IN THE
PATHOGENESIS OF AUTOIMMUNE DISEASES
M. G. WARNOCK and J. A. GOODACRE
Rheumatology Laboratory, The Medical School, University of Newcastle upon Tyne, Framlington Place,
Newcastle upon Tyne NE2 4HH
SUMMARY
Immune recognition of self-proteins features prominently in the early pathogenesis of autoimmune rheumatic diseases such as
rheumatoid arthritis (RA), SjoÈgren's syndrome (SS), systemic lupus erythematosus (SLE) and systemic sclerosis. The
mechanisms which provide lymphocytes with access to such autoantigens are therefore fundamental in creating the
opportunity for autoimmune responses to develop. It has long been thought that the tissue or cellular location of some selfproteins may determine that they are normally `hidden' from immune recognition, thereby reducing their potential for
autoantigenicity. Recently, this concept has been extended to apply even to di€erent epitopes within the same protein. Many
studies, encompassing a wide variety of antigens, have shown that some epitopes are not presented for recognition by T
lymphocytes unless they are produced in unusually large concentrations or unless they are freed from the con®guration of
their native antigen. Epitopes for which this phenomenon occurs are described as cryptic. There is increasing interest in the
possibility that crypticity may be an important characteristic of epitopes which are recognized by T lymphocytes in
autoimmune pathogenesis. The evidence which has led to this theory and its signi®cance are reviewed.
KEY WORDS: T-cell epitopes, Cryptic, Autoimmunity, Rheumatic diseases.
conditions, additional epitopes can also be produced
and presented to T cells.
Epitopes which are normally hidden from T-cell
recognition are termed cryptic. One of the
mechanisms which is well known to underlie crypticity is anatomical sequestration of antigen (Fig. 2a).
This arises if antigens are located in tissues which are
relatively inaccessible to immune cells, such as the
central nervous system. More recently, however, it
has also been established that both cryptic and
dominant epitopes may co-exist within the same
antigen. Presentation of such cryptic epitopes may
depend on how the antigen is processed and on how
strongly di€erent epitopes bind to MHC molecules.
For example, some epitopes may be cryptic because
they are normally destroyed during antigen
processing (Fig. 2b) or because they have lower
anity for binding MHC molecules compared to
other epitopes produced by processing (Fig. 2c).
Examples of circumstances which may lead to
presentation of cryptic epitopes by APC are shown in
Fig. 3. The ®rst example, shown in Fig. 3a, illustrates
a model antigen containing two epitopes. Under
normal circumstances, only the epitope depicted as a
circle is presented in sucient quantities to be
recognized by T cells. However, increased concentrations of antigen in the APC may lead to the production of increased amounts of the cryptic epitope
(depicted as a triangle) during processing. As a result,
the cryptic epitope may also be displayed on the
APC surface in sucient quantity to be recognized
by speci®c T cells. This situation might arise either
from increased extracellular concentration of antigen
or from increased antigen uptake by APC, e.g.
EXTRACELLULAR antigens are taken up by antigenpresenting cells (APC) and degraded by proteases
into fragments for presentation to T lymphocytes.
This mechanism is known as antigen processing and
is a fundamental early step in the introduction of
immunity to protein antigens. Of the many fragments
produced by processing, not all are necessarily
presented to or recognized by T lymphocytes.
However, in certain situations, immune responses to
fragments which are normally `hidden' can occur.
Epitopes which are located within such fragments are
termed cryptic. There is increasing evidence that the
revelation of cryptic self-epitopes may be an important requirement for initiating autoimmune diseases.
T lymphocytes use clonally unique antigen
receptors (TCR) to recognize peptide epitopes. In
order for this to occur, extracellular antigens must
®rst be internalized by APC and degraded in lysosomes into short peptide fragments (reviewed in [1]).
Then, fusion with other intracellular vesicles provides
the opportunity for some of the processed peptides to
bind to newly synthesized major histocompatibility
complex (MHC) class II molecules. Peptide + class
II complexes are subsequently transported to APC
surfaces where they are displayed for recognition by
speci®c T cells (Fig. 1). When accompanied by appropriate co-stimulatory signals, antigen recognition
leads to T-cell activation involving cytokine release
and proliferation. T-cell responses are often focused
on a limited selection of immunodominant epitopes
in any given antigen. However, under certain
Submitted 11 April 1997; revised version accepted 2 May 1997.
Correspondence to: J. A. Goodacre.
# 1997 British Society for Rheumatology
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WARNOCK AND GOODACRE: CRYPTIC T-CELL EPITOPES
1145
FIG. 1.ÐAntigen uptake, processing and presentation. An antigenpresenting cell (APC) takes up antigen (a) and degrades it in
endosome/lysosomes (b). Fusion of these vesicles with others
(c) containing newly synthesized MHC class II molecules (d) made
in the endoplasmic reticulum (e) provides the opportunity for
peptide antigens to bind to MHC class II molecules. The MHC
class II + peptide complex is then transported to the APC surface
(f ) where it is presented for recognition by antigen-speci®c T-cell
receptors (g).
following APC activation. Another factor which may
in¯uence the presentation of cryptic epitopes is
binding of antibody to antigen prior to uptake by
APC. The site on the antigen to which antibody
binds can determine how the antigen is taken up and
FIG. 2.Ð Why some epitopes may be cryptic. (a) The antigen is
sequestered in tissues not accessible to immune cells. Therefore,
APC do not have the opportunity to take up and process the antigen. (b) Following antigen uptake, the epitope is normally
destroyed during processing and is therefore unavailable for
binding to MHC class II molecules. (c) The epitope is produced
during processing, but because it binds with relatively low anity
to MHC class II molecules, it is presented less well than other
epitopes in the same antigen.
FIG. 3.Ð How previously cryptic epitopes may be revealed for Tcell recognition. (a) Increase in antigen concentration. (b) Antibody
binding leads to altered processing. (c) Antibody binding facilitates
receptor-mediated antigen uptake, e.g. by Fc receptors. (d)
Extracellular proteases degrade antigen prior to uptake by APC.
(e) Altered intracellular processing due to APC activation state.
(f ) Di€erent APC types may di€er in their processing capacity.
processed, resulting either in decreased presentation
of dominant epitopes or enhanced presentation of
cryptic epitopes (Fig. 3b). Such e€ects may also be
determined by mechanisms of receptor-mediated antigen uptake, e.g. via surface Fc receptors (Fig. 3c).
Other extracellular conditions may also in¯uence
antigen uptake and intracellular processing. These
may include the extent to which antigens are
degraded by extracellular proteases. Antigen
fragments which are produced by extracellular
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BRITISH JOURNAL OF RHEUMATOLOGY VOL. 36 NO. 11
degradation may be taken up and processed
di€erently compared to the intact form of the antigen, leading to the presentation of a di€erent pro®le
of epitopes (Fig. 3d). In some circumstances, this
could lead to enhanced presentation of cryptic
epitopes. In addition to these possibilities, the
increased production and display of cryptic epitopes
may arise primarily from changes in intracellular protease activity. This can occur following APC activation (Fig. 3e) and may result in either increased
production of cryptic epitopes or destruction of
dominant epitopes. The e€ects of protease may not
necessarily be through their direct action on the
epitopes themselves, since altered degradation of
¯anking residues adjacent to epitopes may change the
anity with which epitopes bind to MHC molecules.
Furthermore, di€erent APC types (e.g. macrophages,
dendritic cells, B lymphocytes) may di€er in their
antigen-processing capacity. Therefore, it is possible
that, for some antigens, whether or not a cryptic
epitope is presented depends on which APC type is
involved (Fig. 3f ).
CRYPTIC T-CELL EPITOPES IN
EXPERIMENTAL AND MICROBIAL
ANTIGENS
The existence of cryptic T-cell epitopes has been
demonstrated both in experimental and microbial
antigens. These ®ndings ®rst arose from studies in
which synthetic peptides were used to map epitopes
recognized by T cells from antigen-primed mice. For
example, analysis of T-cell responses to mycobacterial
hsp65 antigen in several mouse strains showed that
two hsp65 synthetic peptides which were predicted to
contain T-cell epitopes could be used to prime mice,
but peptide-speci®c T cells did not respond to intact
hsp65 [2]. This study also demonstrated a possible
role for MHC type in determining responsiveness to
hsp65 cryptic epitopes, as had been suggested
previously for the p102±118 epitope of equine
myoglobin which is cryptic in B10.BR (H-2k) mice,
but dominant in B10.S (H-2s) mice [3]. The most
comprehensive description and analysis of cryptic Tcell epitopes was conducted by Sercarz and colleagues
using the experimental antigen hen egg lysozyme
(HEL). They ®rst discovered the existence of cryptic
T-cell epitopes in this antigen by studying the
response of T cells from B10.A mice (H-2a) to
cyanogen bromide fragments of HEL. Intact HEL
and three fragments, encompassing the whole HEL
molecule, were used to prime mice. They noted that
although the two smaller fragments could prime and
induce a homologous recall response, the proliferative
response was much lower when intact HEL was used
as the recall antigen ( [4], reviewed in [5]).
Subsequently, cryptic epitopes have been found in
many MHC class II-restricted antigens, including (as
described below) autoantigens implicated in autoimmune pathogenesis. Cryptic epitopes have since
been found also in class I-restricted antigens. Wolpert
et al. [6] demonstrated ®ve cryptic class I-restricted
epitopes present in minor histocompatibility antigens
in B6 and BALB.B (both H-2b) mice. Class Irestricted cytotoxic T lymphocytes (CTL) could
recognize these epitopes when presented as peptides
on congenic B6 APC, but not when they were introduced as complex antigens in the form of BALB.B
spleen cells. Viral antigens have also been shown to
contain cryptic epitopes. The p41±50 epitope of the
E6 protein of human papilloma virus binds strongly
to the class I Kb molecule and is capable of stimulating a strong peptide-speci®c CTL response. In the
context of the whole protein, however, this epitope
remains cryptic [7]. An alternative form of crypticity
in viral antigens has also been seen where epitopes
are not encoded in the primary open reading frame.
Instead, these epitopes are encoded after stop codons
in alternative reading frames and in introns. A process whereby transcription of the DNA initiates
downstream of the conventional site produces the
cryptic epitopes at low levels in vivo, though high
enough to prime immune responses [8].
CRYPTIC T-CELL EPITOPES IN
AUTOANTIGENS
Evidence to support a possible role for cryptic
T-cell epitopes in autoimmune pathogenesis has been
obtained both in humans and rodents.
Studies in human autoimmune diseases
The existence of human T cells speci®c for cryptic
epitopes in autoantigens has been demonstrated
recently. T cells have been found which respond to
synthetic peptides encompassing subregions of known
autoantigens, but which do not respond when native,
intact autoantigens are used in in vitro cultures.
These ®ndings indicate that epitopes recognized by
such T cells would not be presented following normal
processing of intact autoantigen by APC, implying
that changes in these conditions (perhaps, for example, through altered antigen con®guration, altered
processing mechanisms or APC type) would be a
necessary prerequisite for these epitopes to be presented. Incidentally, these ®ndings also raise some
potential limitations of using synthetic peptides to
identify epitopes generated from natural intracellular
processing of native antigens. Autoantigens which are
implicated in autoimmune pathogenesis and which
have recently been shown to possess cryptic T-cell
epitopes include the following.
Rhesus complex polypeptides. These are important
pathogenic target antigens in autoimmune haemolytic
anaemia (AIHA). Using peripheral blood mononuclear cells (PBMC) from healthy human donors, T-cell
responses to the Cc-Ee blood group-associated rhesus
polypeptide were analysed using a series of overlapping 15-residue synthetic peptides encompassing the
whole length of the antigen [9]. Many peptides were
found to elicit responses in proliferation assays, the
patterns of peptide responsiveness varying from
donor to donor. Both the response kinetics and the
WARNOCK AND GOODACRE: CRYPTIC T-CELL EPITOPES
CD45RA+ phenotype of the responding T cells suggested strongly that they had not previously been activated in vivo. Therefore, despite the fact that this
autoantigen is systematically available, autoreactive T
cells had not been deleted from the normal T-cell
repertoire and had either not been presented with or
not responded to their peptide ligand in vivo. Since
proliferative responses to the rhesus peptides
were obtained so readily in vitro, the ®rst of these
possibilities was thought more likely.
Proteolipid protein (PLP). This is abundant in the
central nervous system of humans and is one of the
known target autoantigens in multiple sclerosis (MS).
Epitope recognition by PLP-speci®c T cells from
39 MS patients and 10 controls was analysed by
generating and testing 8207 short-term T-cell lines
with puri®ed PLP or with a series of overlapping 20residue synthetic peptides encompassing the entire
PLP sequence [10]. Analysis of 971 T-cell lines generated with PLP revealed that two peptides (p30±49,
p180±199) were immunodominant for these lines.
However, several other peptides (p80±99, p90±109,
p170±189, p260±276) stimulated DR-restricted T-cell
responses in ®ve HLA DR2+ donors, and T-cell lines
generated using these peptides did not respond to
intact PLP. Results from DR binding assays, using
PLP peptides to inhibit binding of 125I-labelled
ligands to puri®ed DR molecules, indicated that each
of the cryptic peptides bound to DR2 molecules with
higher anity than either of the two immunodominant peptides, suggesting that in this system crypticity
was determined primarily by mechanisms of antigen
processing rather than by low MHC binding anity.
Muscle acetylcholine receptors (AChR). These are
target autoantigens for pathogenic IgG autoantibodies in myasthenia gravis (MG). Production of
these autoantibodies would be expected to involve
AChR-speci®c, CD4+ T lymphocytes. The a subunit
of the AChR, which is thought to contain immunodominant B- and T-cell epitopes, has been produced
both as a full-length recombinant protein and as
shorter peptide fragments expressed in Escherichia
coli for use in epitope analysis. A set of synthetic
peptides 15±65 residues long, spanning the entire
sequence of human AChR a subunit, was used to
generate CD4+ T-cell lines or clones from MG
patients and controls [11]. Three peptides generated
DR-restricted T-cell lines (p75±115, p138±167 and
p309±344), but none of these lines responded either
to intact recombinant AChR a chain or to shorter a
chain fragments. It appeared, therefore, that the
epitopes recognized by these T cells would not
normally be generated through processing of intact
AChR a chain by professional APC. Interestingly,
one of the p309±344 speci®c lines reported in this
study responded to trypsinized, but not freshly
thawed, recombinant 256±366 fragment, suggesting
that processing mechanisms have a critical in¯uence
on whether or not this epitope is produced for presentation by APC.
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Thyroid peroxidase (TPO). This is a known target
autoantigen in Graves' disease. To analyse TPOspeci®c T cells, polyclonal stimulators (anti-CD3
monoclonal antibody or phytohaemagglutinin) were
used to clone from Graves' thyroid in®ltrates in the
absence of antigen stimulation [12]. Of two clones
which recognized TPO-535±551 peptide, one
responded well to a TPO-transfected autologous
Epstein±Barr virus (EBV) cell line and to autologous
thyroid epithelial cells, but poorly to TPO-pulsed
peripheral blood mononuclear cells, whilst the other
showed the converse pattern of reactivity. Fine
epitope mapping showed that each clone recognized
distinct epitopes within the 535±551 peptide, indicating that TPO processing by cells which produce it
may lead to presentation of a di€erent repertoire of
TPO epitopes compared to exogenous TPO which is
processed following uptake by APC. The novel di€erences in the outcome of endogenous and exogenous
antigen-processing pathways described in this study
re¯ect another facet of epitope crypticity, and suggest
another possible mechanism whereby autoreactive T
cells may escape deletion or tolerance induction yet
undergo activation following presentation by professional APC.
There is increasing evidence that autoantigens
implicated in the pathogenesis of autoimmune rheumatic diseases may also contain cryptic epitopes. For
example, the release of DNA from apoptotic cells
may be an important initial step in providing access
to nuclear autoantigens in systemic lupus erythematosus (SLE) [13, 14], whilst fragmentation of nucleolar
proteins by reactive oxygen species in the presence of
iron or copper may generate pathogenic autoantigens
in systemic sclerosis [15]. Furthermore, cartilage autoantigens implicated in RA pathogenesis (aggrecan,
type II collagen) are remarkably susceptible to degradation by extracellular proteases (reviewed in [16]). It
is, therefore, possible that degraded fragments of cartilage macromolecules might be taken up and processed di€erently than their intact forms, leading to
presentation of a di€erent array of epitopes.
Furthermore, the glycosylation status of these molecules might also in¯uence epitope recognition.
Evidence to support each of these possibilities has
been obtained by studying T-cell lines or hybridomas
from primed mice [17±20].
Studies in rodent autoimmune disease models
Rodent autoimmune disease models can be used to
test directly the concept that cryptic epitopes may
indicate pathogenesis. Data to support this concept
were obtained ®rst in the Lewis rat model of uveoretinitis [21, 22]. Uveoretinitis was induced by immunizing with bovine interphotoreceptor retinoid binding
protein (IRBP), a 1264 glycoprotein containing several dominant and cryptic epitopes. The model could
also be induced either by immunizing with cryptic
peptides or by injecting cryptic epitope-speci®c T
cells. Further analysis of T cells speci®c for one of
these epitopes (1158±1180) showed that although
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BRITISH JOURNAL OF RHEUMATOLOGY VOL. 36 NO. 11
they did not respond to intact IRBP, pre-treatment of
IRBP with certain endopeptidases produced fragments whose uptake and processing by APC led to
presentation of the cryptic epitope [23]. This indicated
that extracellular as well as intracellular antigen
degradation may in¯uence epitope presentation.
Similarly, rat experimental autoimmune thyroiditis
was induced by immunizing with the thyroglobulin
2495±2511 peptide [24], and a lupus-like syndrome
was induced in B10.BR mice by immunizing with peptides 26±40 and 56±70 containing cryptic epitopes
from the smaller nuclear ribonucleoprotein D protein
[25]. Experimental autoimmune encephalomyelitis
(EAE), which is a rodent model of human MS, was
induced in SJL/J mice by immunizing with the cryptic
104±117 peptide from myelin PLP [26], and in Lewis
rats by immunizing with cryptic peptides from rat
MBP [27]. Furthermore, myocarditis was induced in
Lewis rats by immunization with trypsin-digested, but
not untreated, porcine cardiac myosin [28]. The issue
of epitope crypticity has also been implicated in the
mechanisms of gold toxicity, since treatment of the
experimental antigen bovine ribonuclease with Au
(III) [an intermediate metabolite of Au (I)] led to presentation of cryptic ribonuclease epitopes in primed
C57BL/6J mice [29].It was postulated that this e€ect
might apply similarly to self-proteins, leading to
T-cell activation and thereby to allergic and
autoimmune side-e€ects.
Results from studies in rodents have also provided
useful insights into some of the possible mechanisms
of cryptic epitope involvement in autoimmune pathogenesis. These include further studies by Sercarz and
colleagues. Firstly, in view of the strong in¯uence of
MHC type on susceptibility to human autoimmune
diseases, it was of great interest to determine that the
mouse T-cell repertoire for mouse lysozyme (ML)
cryptic epitopes di€ered between MHC-disparate
mouse strains, as measured using primed lymph node
T-cell proliferation assays [30]. Furthermore, epitopes
which were cryptic in ML corresponded closely to
immunodominant epitopes in HEL, which shares
56% homology with ML. It was postulated that if
similar relationships apply to self-proteins homologous to common bacterial antigens, T-cell responses
to such bacterial antigens might lead, through molecular mimicry, to activation of autoimmune T cells
speci®c for self cryptic epitopes. Secondly, analysis of
T-cell responses to mouse myelin basic protein
(MBP) peptides at di€erent stages of EAE in
(SJL B10.PL)F1 mice showed that although the
Ac1±11 peptide was immunodominant during the
early stages, other more cryptic MBP epitopes were
recognized in the later stages [31, 32]. This phenomenon of epitope spreading occurred even when the
disease was induced by immunizing with peptide
Ac1±11 rather than whole MBP, but did not occur in
mice immunized with non-encephalitogenic HEL
antigen.
Wraith and colleagues have also used the EAE
model to address the mechanisms of cryptic epitope
involvement in autoimmune disease. T-cell responses
to mouse MBP were studied in EAE-induced PL/J
mice. The amino-terminal 20 amino acids of MBP
contain an epitope Ac1±9 which bound with relatively low anity to class II Au molecules [33]. It was
necessary to immunize with high concentrations of
MBP in strong adjuvant in order to prime T cells
speci®c for this epitope. Nevertheless, the Ac1±9 peptide was encephalitogenic. This raises the possibility
that low-anity binding of this epitope to class II
molecules may enable Ac1±9-speci®c T cells to escape
tolerance induction. Presentation of this epitope
following processing of MBP by APC in the periphery may then lead to activation of these T cells,
leading to EAE. If such a mechanism were applicable
generally, it would raise important reservations about
the validity of strategies for identifying candidate
pathogenic self-epitopes purely on the basis of their
ability to bind with high anity to disease-susceptible
class II molecules. It was shown subsequently by this
group [34] that two other MBP amino-terminal peptides (5±20, 9±20) contained cryptic epitopes which
bound to Au molecules with higher anity than
Ac1±9, but which were not presented following processing of intact MBP and were not encephalitogenic,
suggesting further that processing mechanisms have a
crucial in¯uence on the production of pathogenic
epitopes from autoantigens.
SIGNIFICANCE OF CRYPTIC T-CELL
EPITOPES FOR AUTOIMMUNE
PATHOGENESIS AND TREATMENT
As described above, the concept of cryptic antigenicity is now known to be applicable at the level of
particular epitopes within certain autoantigens.
Mechanisms of antigen degradation by intracellular
and/or extracellular proteases clearly have a very profound in¯uence on the types of epitope which are
generated for presentation to T lymphocytes. The
e€ects of antibody binding prior to antigen internalization by APC (reviewed in [35, 36]) and circumstances which cause alterations in protease activity
leading to increased display of cryptic self-epitopes
may therefore be critical in creating the fundamental
opportunity for autoimmunity to arise. If this occurs
in the appropriate context, which perhaps includes
such factors as epitope±MHC binding anity and
the functional competence of cryptic epitope-speci®c
T cells [34], autoimmune disease may develop. Other
factors which might play a role include age-related
e€ects on autoantigen turnover and con®guration,
although at present evidence to support these possibilities is only indirect. For example, the glycosylation
status of cartilage aggrecan (a candidate autoantigen
in rheumatoid arthritis) is di€erent in its fetal
compared with adult form [37], and it is therefore
intriguing that fetal, chondroitinase ABC-deglycosylated aggrecan is the most potent form of this macromolecule for inducing the BALB/c mouse arthritis
model [38, 39]. Future investigations to explore
WARNOCK AND GOODACRE: CRYPTIC T-CELL EPITOPES
further the relevance of this ®eld to autoimmune
pathogenesis are likely to include attempts to identify
cryptic epitopes in other autoantigens, to look for
evidence that they are generated and recognized by T
cells in autoimmune patients during the early stages
of disease, and to investigate their ability to induce
disease in rodent models. Also, since the approaches
used in many studies to date have relied heavily on
the use of synthetic peptides, it will be important to
try to verify that fragments represented by such peptides are produced by natural mechanisms of antigen
degradation. If future studies suggest further that
cryptic epitopes have a fundamental role in pathogenesis, their value as possible therapeutic targets
could be explored. It is dicult to envisage strategies
which could be used selectively to prevent their production, but some of the many approaches which are
currently being developed to modulate or tolerize T
cells in an antigen-speci®c manner [40, 41] may o€er
promising therapeutic possibilities.
11.
12.
13.
14.
15.
16.
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