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Division of Immunology and Rheumatology, University of Missouri, Columbia, MO 65212;
Harry S. Truman Memorial Veterans Hospital, Columbia, MO 65201; and
Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Also, Sm-reactive T cells produce
cytokines that are important in B cell help and differentiation,
including IFN-
, IL-2, and IL-4 (1). Finally, we have
previously shown for Sm-B (2) and recently shown for Sm-D
(3) that TCR usage by Sm-reactive T cell is highly
restricted and characteristic of an Ag-driven immune response. B cell immunity to Sm is a characteristic feature of SLE, with autoantibodies directed against Sm present in 20–30% of patients with SLE (4). The presence of anti-Sm Abs is one of the criteria proposed by the American College of Rheumatology for disease classification of SLE and is widely used in clinical practice (5). Anti-Sm Abs are frequently of the IgG isotype, which is characteristic of a T cell-dependent response (6). B cell epitope-mapping studies of Sm and other autoantigens have suggested that in autoimmunity the immune response may be directed toward self-Ags that encode domains with important biological functions (7). Other studies implicate molecular mimicry against microbial agents, such as EBV, in the initiation of the anti-Sm immune response (8). A unified model of disease pathogenesis may need to encompass all these possibilities as contributory.
Sm is a well-characterized complex Ag that consists of proteins B1, B2,
D1, D2, D3, E, F, and G. The Sm complex is highly conserved throughout
evolution and is expressed in all tissues. Sm is part of the
spliceosomal complex, whose biologic function is the splicing of
precursor mRNA to mature mRNA (9). The Sm proteins
serve an essential role in spliceosomal complex formation
(10). A unique feature of Sm proteins is the presence of
highly conserved motifs, called Sm motif 1 and Sm motif 2 (see Fig. 1
),
that are hypothesized to be involved in protein-protein interactions
(11). Detailed structural knowledge of this complex Ag
provides the opportunity to seek insight into T and B cell immune
responses against Sm.
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The goals of the present study were to characterize the T cell immune response against the Sm, including the precise Ag peptides recognized, the common features of antigenic structure recognized, and the evolution of the T cell response against Sm. We found that there was a highly restricted set of Sm self-peptides recognized by T cells, with three epitopes on Sm-B and two epitopes on Sm-D. T cell immunity against both Sm-B and Sm-D was encoded within the highly conserved Sm motif 1 and Sm motif 2. Finally, T cell immunity against these T cell epitopes appeared stable over time.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The seven patients (P1–7) selected for study met the classification criteria of SLE proposed by the American College of Rheumatology (5). Six patients were female. The University of Missouri institutional review board approved all studies involving human subjects. Sera were characterized for the presence of autoantibodies reactive with small nuclear ribonucleoprotein (snRNP) polypeptides Sm-B and Sm-D using immunoblotting and ELISA (12). All patients had autoantibodies against snRNP Ags, including Sm-B (P1–7) and Sm-D (P1 and P3). HLA typing was performed using serologic and DNA-based typing methods as described previously (13). In brief, this was done using a combination of subfamily-specific PCR and direct DNA sequencing of PCR amplified products (14, 15). The HLA-DR genotypes of the patients were: P1, HLA-DRB1*0101, 1302, DRB3*0301; P2, HLA-DRB1*0401, 1301, DRB3*0101, DRB4*0101; P3, HLA-DRB1*0401, 1301, DRB3*0101, DRB4*0101; P4, HLA-DRB1*0101, 0401, DRB4*0101; P5, HLA-DRB1*0302, 1302, DRB3*0301; P6, HLA-DRB1*0301, 0401, DRB4*0101; and P7, HLA-DRB1*0101, DRB3*0301.
One patient, P1, was analyzed with T cell cloning performed at several time points over 2 yr. Clinically, this patient had longstanding disease of 20-yr duration with an SLE disease activity index of 0–6 in the first year of the study and 4–6 in the second year of the study (16). The patient took 400 mg/day hydroxychloroquine throughout the study and took 5–15 mg/day prednisone during the second year of the study.
Recombinant Ags
Full-length cDNA for snRNP peptides Sm-B3 and Sm-D1 were subcloned into the pMAL-c2 plasmid vector (New England Biolabs, Beverly, MA) and were the gift of S. Hoch (La Jolla Institute for Experimental Medicine, La Jolla, CA) (1). When expressed, these constructs resulted in a fusion protein consisting of an snRNP peptide linked to a fragment of the maltose binding protein. Ags were analyzed by PAGE and immunoblotting for purity and antigenic activity. The protein concentration of each Ag was determined; the Ags were aliquoted and stored at -80°C before use.
Peptide design and synthesis
Peptides were synthesized using F-moc chemistry on an Applied Biosystems model 432A peptide synthesizer (Foster City, CA) or were purchased (Research Genetics, Huntsville, AL) (2). Peptides were analyzed for purity and sequence fidelity using HPLC and mass spectrometry. The peptides used were required to have at least 90% purity and unambiguous sequence fidelity.
Generation of human T cell clones
The T cell clones used in these studies were generated as described previously (17). In brief, cells were obtained by apheresis and then subjected to density gradient centrifugation using Histopaque (Sigma, St. Louis, MO). Patient PBMC were used immediately or were cryopreserved for use as APC to restimulate clones. Cells (5 x 106) were cultured in RPMI 1640 (Life Technologies, Gaithersburg, MD) with 20 µg/ml gentamicin, 2 mM L-glutamine, 15% AB-positive human serum, and pooled peptides at a final concentration of 1 µg/ml. As Ags, a series of synthetic peptides, 25 residues in length, was used. Each peptide spanned the previous peptide in the series beginning at residue 13. The entire series of peptides were designed to span either Sm-B2 (including the sequence for the shorter splice variant Sm-B1, which lacks nine residues present on the carboxyl terminus of Sm-B2), or Sm-D1. The Sm-B2 Ag consisted of a pool of 19 peptides, whereas the Sm-D1 Ag consisted of a pool of nine peptides. Cells in a final volume of 5 ml were placed in a 25-cm2 flask and incubated in 5% CO2 at 37°C. Cells were restimulated with 5 x 106 autologous APC irradiated with 30 Gy and Ag in fresh medium on day 7. On day 14, T cell blasts were separated by centrifugation on a density gradient (Percoll; Pharmacia Fine Chemical, Piscataway, NJ) and cloned by limiting dilution in the presence of pooled peptides, fresh irradiated autologous APC and 10 U/ml IL-2 (R&D Systems, Minneapolis, MN) as described previously (1, 2, 17).
Proliferation assay
T cells (2 x 104) in complete medium were cultured for 48 h in 96-well flat-bottom tissue culture plates and then pulsed for 18 h with 1 µCi/well TdR. Cells were harvested, and TdR incorporation was detected by liquid scintillation counting.
Homozygous cell lines and Ab blocking of Ag-induced proliferation
To determine the MHC restriction element(s) used by T cell clones, Ag-induced proliferation was performed in the presence of blocking concentrations of mAbs specific for HLA-DR, HLA-DQ, HLA-DP, or HLA class I framework determinants or for clones derived from P1 using a series of well-characterized homozygous lymphoblastoid cell lines of known HLA genotypes (American Society for Histocompatibility and Immunogenetics, Lenexa, KS) as APC (17, 18).
Searches for similarity with known DNA and protein sequences
Searches for similarities between T cell epitopes identified in the present study and all DNA and protein sequences in the GenBank database were performed using BLAST (National Center for Biotechnology Information, Bethesda, MD). BLAST is an alignment search tool that allows rapid comparison of a query sequence to both DNA and protein databases. BLAST scores have a well-defined statistical interpretation, and BLAST uses a heuristic algorithm that is able to detect relationships between the query sequence and those in the databases that may share only isolated regions of similarity.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of 54 Sm-B reactive human T cell clones were generated
from seven patients (P1–7). These are shown in Table I. Thirty clones were generated from P1,
one from P2, three from P3, seven from P4, four from P5, one from P6,
and eight from P7.
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An iterative process was used to define the regions of the Sm-B2
protein recognized by human T cell clones. Clones were initially
analyzed for proliferation against pools of 19 peptides, which together
span Sm-B2. Clones were subsequently tested against smaller pools of
peptides and eventually against individual peptides, 15 residues in
length. Three regions were identified by Sm-specific T cell clones on
the Sm-B protein. These epitopes are shown in Fig. 1
and are labeled Sm-B-E1, Sm-B-E2, and
Sm-B-E3. Sm-B-E1 spans residues 16–33, Sm-B-E2 spans residues 64–81,
and Sm-B-E3 spans residues 136–153 of the full-length Sm-B2 protein. T
cell clones were successfully generated from seven of seven patients.
Clones were identified from five patients that reacted with Sm-B-E1
(P1–5). Additionally, clones were identified from six patients that
reacted with Sm-B-E2 (P1 and P3–7), and finally clones were identified
from three patients that reacted with Sm-B-E3 (P1, P4–P7; Table I).
Patient P1 selected for longitudinal cloning and analysis
One patient (P1) was selected for longitudinal cloning and
analysis to further characterize the Sm-B-E1 epitope, which was
recognized by the majority of patients. Clones generated at different
points in the patient’s illness were examined to determine the
stability of T cell epitopes recognized over time. As illustrated by
representative clones in Fig. 2, a series
of peptides, 15 residues in length (overlapping the previous peptide in
the series by 12 residues), was used to more finely map the T cell
epitope recognized by the panel of T cell clones. Only two peptides
were significantly stimulatory, and these shared the core 12 residues,
CILQDGRIFIGT. In longitudinal studies of P1, reactivity with the T cell
epitope Sm-B-E1 remained unchanged over the 2 yr of study (data not
shown).
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To determine the minimal region within the Sm-B-E1 epitope
required for T cell recognition, truncated variants of the CILQDGRIFIGT
peptide were synthesized and tested. Four representative Sm-B-reactive
clones are described in Fig. 3.
Stimulation of the clones was observed only when the truncated peptides
contained the core sequence ILQDGRIFI (contained in the full-length
Sm-B protein at positions 20–28).
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The MHC restriction element used by T cell clones from P1 was determined using Ag-induced proliferation in the presence of blocking concentrations of mAbs specific for HLA-DR, HLA-DQ, HLA-DP, or HLA class I determinants or using a series of well-characterized homozygous lymphoblastoid cell lines of known HLA genotypes as APC. All clones tested from P1 recognized Ag only in the context of HLA-DRB1*1302/B3*0301 (data not shown). Because the restriction elements HLA-DRB1*1302/B3*0301 exist in strong linkage disequilibrium among all cell lines available at the time of these studies, it could not be determined whether DRB1*1302 or DRB3*0301 was the HLA restriction element used by the clones reported here.
Alanine substitution defines essential contact residues on Sm-B peptides
To define residues critical for MHC binding or T cell contact,
peptides with sequential alanine substitutions of the core peptide
sequence ILQDGRIFI were synthesized and tested for their ability to
induce proliferation of T cell clones. A representative experiment is
described in Fig. 4. It was found that
alanine substitution of residues at positions 1, 2, 4–6, and 9
abolished the stimulatory capacity of the peptide. Alanine substitution
of the native residue at position 8 also markedly reduced the
stimulatory capacity of the peptide. Substitution at positions 3 and 7
had no inhibitory influence and appeared to have an enhancing influence
on T cell stimulation.
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The core sequences identified within the Sm-B-E1, Sm-B-E2, Sm-B-E3, Sm-D-E1, and Sm-D-E2 epitopes were compared with known protein and DNA sequences in the GenBank database using BLAST. The epitope ILQDGRIFI within Sm-B-E1 shared an identical seven-residue segment with a Mycobacterium tuberculosis hypothetical protein Rv1061 (LQDGRIF) (19). The Sm-B-E2-E3 and Sm-D-E1-E2 epitopes did not have similarity with other proteins, except for related snRNP.
Sm-D-specific human T cell clones were generated from SLE patients
A total of 28 Sm-D reactive clones were successfully generated
from three of seven patients. These are shown in Table II. Nine clones were generated from P1,
three from P2, and 16 from P3.
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The same iterative process used to characterize Sm-B was used to
define the regions of the Sm-D1 protein recognized by human T cell
clones. Clones were initially analyzed for proliferation against pools
of nine peptides, which together span Sm-D1. Clones were subsequently
tested against smaller pools of peptides and eventually against
individual peptides, 15 residues in length. Two regions were identified
by Sm-specific T cell clones on the Sm-D protein. These epitopes are
illustrated in Fig. 5 and are labeled
Sm-D-E1 and Sm-D-E2. Sm-D-E1 spans residues 35–53, and Sm-B-E2 spans
residues 53–67 of the Sm-D1 protein. There were individual clones
generated from the three Sm-D-reactive patients that recognized Sm-D-E1
(P1–3) and others that recognized Sm-D-E2 (P1–3; Table II).
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P1 was again analyzed in detail to define the regions within the
Sm-D protein recognized by the majority of T cell clones. Longitudinal
studies were also performed to delineate the stability of T cell
epitopes recognized. The T cell epitopes identified in P1 were Sm-D-E1
and Sm-D-E2 (Fig. 5 and Table II). These were the regions identified
repeatedly by cloning over 2 yr of study (data not shown). These
appeared similar to results obtained in cross-sectional studies of two
additional patients from whom Sm-D-reactive clones could be generated.
Only for P3 was there a clear preponderance of reactivity to Sm-D-E1
(15 clones) compared with Sm-D-E2 (one clone; Table II).
Minimal T cell epitope identified from Sm-D using overlapping peptides and truncated peptides
To determine the minimal region of the Sm-D-E1 and Sm-D-E2
epitopes required for T cell recognition, truncated peptides were
designed and synthesized. Sm-D-E1 reactive clones are described in
Figs. 6A and
7A. Sm-D-E2-reactive clones
are described in Figs. 6B and 7B. As illustrated
in Fig. 6, a series of peptides, 15 residues in length, was used to
define more precisely the T cell stimulatory peptide contained within
Sm-D-E1 and Sm-D-E2. For the Sm-D-E1 epitope the core peptide
HLKAVKMTLK was identified (Figs. 6A and 7A), and
for Sm-D-E2 the core peptide SIRGNNIRY was identified (Figs. 6B and 7B). As was observed for Sm-B, reactivity
with Sm-D epitopes was similar among clones generated from P1 at
different time points.
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The MHC restriction element used by T cell clones from P1 was determined using Ag-induced proliferation in the presence of blocking concentrations of mAbs specific for HLA-DR, HLA-DQ, HLA-DP, or HLA class I determinants or using a series of well-characterized homozygous lymphoblastoid cell lines of known HLA genotypes as APC. As was found for Sm-B-reactive clones, all Sm-D Ag-reactive clones recognized Sm-D peptides only in the context of HLA-DRB1*1302/B3*0301 (data not shown).
Alanine substitution defines essential contact residues on Sm-D peptides
To define residues critical for MHC binding or T cell contact,
peptides with sequential alanine substitutions of the core peptide
sequence SIRGNNIRY were synthesized and tested for their ability to
induce proliferation of T cell clones. A representative experiment is
shown in Fig. 8. It was found that
alanine substitution of residues at positions 2 and 5–9 abolished the
stimulatory capacity of the peptide. Substitution at positions 1, 3,
and 4 had no influence on stimulation by the peptide.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 5 and Tables I and II,
among the seven SLE patients studied there were three T cell epitopes
on Sm-B and two T cell epitopes on Sm-D. Using truncated peptides for
more precise delineation of the T cell stimulatory region, a core
sequence ILQDGRIFI was identified within the epitope Sm-B-E1 (Figs. 2 and 3). For the epitope Sm-D-E1, the core sequence HLKAVKMTLK was
identified (Figs. 6A and 7A), and within Sm-D-E2
the core sequence SIRGNNIRY was identified (Figs. 6B and
7B). These findings are consistent with recent studies of
TCR CDR3 use among Sm-B- and Sm-D-reactive clones, where limited clonal
diversity of CDR3 was found (2, 3). In previous studies it
was suggested that a limited number of immunodominant peptides could be
the basis for highly selective TCR usage (2, 3). TCR CDR3
selectivity was marked, and in some cases identical CDR3 were used by T
cell clones derived from different patients recognizing the Sm Ag
(2, 3). The present study provides direct evidence that T
cell recognition of Sm is targeted to a highly restricted set of
self-peptides. Analysis of the structural features of the epitopes recognized on the Sm Ag revealed a number of interesting characteristics. The dominant T cell epitopes identified in this study are regions encoding the so-called Sm motifs, Sm motif 1 and Sm motif 2. These were first described by Hermann et al. and are 32 and 14 residues in length, respectively (11). The Sm motifs are believed to be involved in direct protein-protein interactions (10, 11, 20). Hermann et al. have demonstrated that these motifs share similarity among the different Sm core proteins B1, B2, D1, D2, D3, E, F, and G and are evolutionarily conserved. For example, the human D1 protein shares 78% homology with its putative homologue in rice and 99% homology with its homologue in the mouse. The reader is referred to Hermann et al. for a comprehensive discussion of this subject (11). The fact that the Sm motifs are encoded in all eight Sm proteins has been suggested to explain in part the immunologic cross-reactivity by monoclonal and polyclonal Abs between multiple Sm proteins (21, 22). Although we have no direct evidence demonstrating T cells cross-reactivity between Sm-B and Sm-D, the shared structural features of the Sm motif offers an intriguing structural explanation for T cell immunodominance directed against this highly restricted set of self-peptides. This will be a focus of future research.
Although additional studies of larger numbers of patients at various stages of disease are needed, another important finding of this study was that the T cell epitopes identified among a cross-sectional panel of seven patients and longitudinal analysis of one patient were similar. Future studies of patients with early disease will be of considerable interest to determine whether early T cell reactivity is directed against similar or different T cell epitopes.
The recognition of a limited set of self-peptides, as observed here for Sm, has been described for T cell recognition of other autoantigens, including such autoantigens as topoisomerase I in systemic sclerosis and myelin basic protein in multiple sclerosis (23, 24). It has been proposed that a fundamental feature of autoimmunity is T cell recognition of cryptic self-Ags (25). Consistent with this hypothesis, we now provide direct evidence that T cell recognition of the Sm self-Ag is highly restricted in SLE.
An alternative concept, which has been proposed to explain the loss of self-tolerance, is molecular mimicry (26). We investigated this possibility for Sm reactivity in SLE. Similarity searches were performed between the core T cell epitopes identified in the present study and the GenBank database. Interestingly, the Sm-B-E1 core sequence has a seven-residue segment identical with an M. tuberculosis hypothetical protein RV1061 (19). Consistent with a role for Mycobacterium in initiating autoimmunity, Mycobacterium bovis has been found to induce an anti-Sm immune response in NOD mice (27). However, in preliminary studies, the seven-residue Mycobacterium peptide LQDGRIF did not cross-stimulate clones reactive with the Sm-B-E1 sequence ILQDGRIFI (nor did longer M. tuberculosis-derived peptides; data not shown). Further studies exploring cross-reactivity between Sm-B-E1 and Mycobacterium peptides are in progress.
In other work related to mimicry, Harley and James (8) found that a region of Sm-B, PPPGMRPP, that has similarity to an EBV protein is one of the early dominant B cell epitopes recognized by anti-Sm Abs. They also found that PPPGRRPP peptides could initiate SLE-like disease in animals (28). Although the PPPGMRPP B cell epitope is distant from the T cell epitopes identified in the present study, the T cell epitopes Sm-B-E1 and Sm-B-E3 contain sequences recognized by non-cross-reactive anti-Sm Abs that develop late in the evolution of anti-Sm-B Ab epitope spreading (29). Finally, it is known that T and B cell epitopes may be distinct.
Studies were performed to characterize the molecular interactions of Sm
with MHC molecules on APC. Experiments using blocking mAbs against HLA
framework determinants and cell lines homozygous for HLA demonstrated
that all clones studied were restricted in Ag presentation by
HLA-DRB1*1302/DRB3*0301. Alanine substitution studies (Figs. 4 and 8)
demonstrated that key HLA binding sites or TCR contact residues for
Sm-B-E1 were positions 1, 2, 4–6, and 9, and for Sm-D-E1 they were
positions 2 and 5–9. These results are consistent with known HLA
binding motifs for DRB1*1302/DRB3*0301 (30, 31). Future
studies directly testing HLA binding and TCR interactions using
site-directed mutagenesis of cloned TCR genes expressed in
TCR-deficient Jurkat cell lines are in progress to more precisely
define the molecular interactions among Sm self-reactive peptides, HLA,
and the TCR (32, 33).
The present study provides direct evidence that SLE is at least in part a T cell-dependent, Ag-driven immune process in which T cell immunity is directed against a highly restricted set of self-peptides, encoded within Sm motif 1 and Sm motif 2, that are shared among all Sm proteins. We provide direct evidence that this mechanism is operative. This is consistent with a broader model of etiopathogenesis in SLE in which tolerance to self-Ags is lost, perhaps through molecular mimicry and/or exposure to cryptic self-epitopes, and autoimmunity develops as an Ag-driven immune process against highly conserved self-Ags.
In summary, we found that there was a highly restricted set of Sm self-peptides recognized by T cells, with three epitopes on Sm-B and two epitopes on Sm-D. T cell immunity against both Sm-B and Sm-D was encoded within the highly conserved Sm motif 1 and Sm motif 2. These T cell epitopes appeared to be stable over time. The findings of the present study support the concept that T cell immunity to Sm Ag is an Ag-driven immune response directed against a highly restricted set of self-peptides encoded within the functional domains of Sm motif 1 and Sm motif 2, which are found on all Sm proteins.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Robert W. Hoffman, Division of Immunology and Rheumatology, MA427 HSC, University of Missouri, Columbia MO 65212. E-mail address: hoffmanr{at}health.missouri.edu
3 Abbreviations used in this paper: Sm, Smith Ag; SLE, systemic lupus erythematosus; snRNP, small nuclear ribonucleoprotein.
Received for publication January 4, 2001. Accepted for publication April 24, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain third complementarity-determining region gene usage is highly restricted among Sm-B autoantigen-specific human T cell clones derived from patients with connective tissue disease. Arthritis Rheum. 42:703.[Medline]
and chains from human T cell clones specific for small
nuclear ribonucleoprotein polypeptides Sm-D, Sm-B and U1–70kD: highly
conserved TCR complementarity determining region 3 suggest that
connective tissue diseases are antigen driven. Scand. J.
Immunol. In press.
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