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Original Studies |
Department of Medicine (M.E.F., K.S., Y.S., Y.H., L.J.DeG.), Department of Pathology (E.M.P., G.A.vanS.), Department of Surgery (E.K.), and Center for Medical Genetics (C.O.), The University of Chicago, Chicago, Illinois 60637
Address all correspondence and requests for reprints to: Leslie J. DeGroot, 5841 South Maryland, MC 3090, Chicago, Illinois 60637.
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Abstract |
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The TCC were classified according to their cytokine profile into T
helper cell (Th)0 [secreting interleukin (IL)-4, IL-5, interferon
(IFN)-
], Th1 (secreting IFN-) and Th2 (secreting IL-4 and/or
IL-5). Tumor necrosis factor-ß and IL-10 were produced by all
subsets. The specific TCC were predominantly Th1-like cells in HT, and
were Th0- and Th1-like cells in GD. Fifty three percent of Th0 clones
were derived from GD patients and were reactive to TSH-R, whereas 50%
of Th1 clones were derived from HT patients and were reactive to TPO or
Tg. Most Th2 clones (82%) were reactive to TPO and were established
from peripheral blood. All these clones produced IL-5, and 64%
produced IL-4 and IL-10. Interestingly, IFN- was highly produced by
TPO- or Tg-specific clones established from HT thyroid tissue.
These results confirm at the clonal level our previous studies regarding T cell epitopes on TPO and TSH-R molecules and support the concept that immunodominant T cell epitopes are located on amino acid residues 100–119 and 625–644 of TPO in HT and amino acid residues 158–176, 207–222 and 343–362/357–376 of TSH-R in GD. Our studies also demonstrate that thyroid-specific T cells can be classified into Th0, Th1, and Th2 subsets. TPO- or Tg-specific clones with Th1 phenotype appear to be involved in the pathogenesis of HT, mediating thyroid tissue destruction, whereas TSH-R clones with Th0 phenotype may induce thyroid-stimulating autoantibodies in GD.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN-), and tumor necrosis factor-ß (TNF-ß),
mediating delayed-type hypersensitivity and macrophage activation and
opsonizing antibody production (such as IgG2a and IgG2b in mice). Th2
cells release IL-4, IL-5, IL-6, IL-10, and IL-13, stimulate IgA and IgE
and nonopsonizing antibody production, and support the development and
degranulation of eosinophils and mast cells. In addition, both Th1 and
Th2 subsets produce IL-3, TNF-
, and granulocyte-macrophage
colony-stimulating factor (1, 2). The expression of some cytokines such
as IL-2, IL-10, and IL-13 are less restricted in humans (3, 4). The
development of Th1 and Th2 cells from Th0 cells is regulated by factors
such as the nature of antigen, the type of antigen-presenting cells
(APCs), the costimulatory molecules, and the interaction of cytokines.
IL-4 promotes the differentiation of Th2 cells and, similar to IL-10,
inhibits cytokine secretion by Th1 cells. On the other hand, IFN-
and IL-12 promote the generation and proliferation of Th1 cells, and
down-regulate Th2 cell responses (except for IL-12, which stimulates
IL-10 secretion) (2, 5). A similar dichotomy exists in
CD8+cells (5, 6). The predominance of Th1 or Th2 cells varies from one disease to another, and may promote different immunopathological responses. Thus, Th1 responses appear to be involved in organ-specific autoimmunity, e.g. autoimmune thyroiditis, rheumatoid arthritis, and diabetes mellitus, as well as in contact dermatitis, whereas Th2 responses are predominant when single or multiple environmental antigens trigger allergic atopic disorders, or in certain autoimmune disorders such as bullous and chronic graft-vs.-host diseases. This Th1/Th2 polarization is not apparent in some other autoimmune diseases (4, 7, 8).
Helper and/or cytotoxic T cells with Th1-like and/or Th2-like responses may be involved in autoimmune thyroid disease (AITD), but their specific pathogenic roles are unclear. AITD is an organ-specific autoimmunity, characterized by thyroid tissue destruction in both Hashimoto’s thyroiditis (HT) and atrophic thyroiditis, or by thyroid-stimulating antibodies leading to thyroid hyperfunction in Graves disease (GD). The major antigenic proteins involved in the pathogenesis of AITD include thyroid peroxidase (TPO), thyroglobulin (Tg), and TSH-receptor (TSH-R). Although TSH-R is the main antigen involved in the pathogenesis of GD, TPO is believed to be the pathogenic antigen in HT (9).
We previously reported that several immunogenic sites on TPO or TSH-R molecules are recognized by peripheral and thyroid T cells, as well as by specific T cell lines in AITD (10, 11, 12, 13). In the present study, we investigated the cytokine profile of specific T cell clones (TCC) derived from peripheral lymphocytes (PL) and thyroid lymphocytes (TL) in AITD, as well as the immunogenic T cells epitopes on TPO or TSH-R molecules recognized by these clones.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Peripheral blood mononuclear cells (PBMC) were obtained by Ficoll-Hypaque gradient centrifugation from seven patients with GD (assigned nos. 1–7), seven patients with HT (assigned nos. 8–14), and four controls [two with colloid nodular disease (CND) and two normal subjects]. Blood samples from patients with GD were collected before and/or during treatment with propylthiouracil and/or after 131I or thyroidectomy. All patients with HT were receiving T4 replacement therapy. TL were obtained at the time of thyroidectomy from four patients with GD, three patients with HT, and a patient with CND, and isolated as previously described (14). Patients with AITD, but none of the controls, were positive by hemagglutination assay for TPO and/or Tg antibodies.
Thyroid antigens
Crude TPO, Tg, and the extracellular domain (amino acid residues 19–417) of human recombinant TSH-R were obtained as previously described (11, 14, 15). A panel of TPO and TSH-R peptides was selected based on amphiphilic analysis of human TPO and TSH-R sequences, respectively, and our previous experiments (10, 11, 12, 13). The peptides were synthesized by a solid-phase peptide synthesis method (16), and were all verified by direct sequencing. The peptide amino acid residues were as follows: for TPO: 100–119, 114–126, 211–223, 261–275, 420–434, 556–575, 625–644, 708–727 and 882–901; and for TSH-R: 44–62, 145–163, 158–176, 207–222, 227–242, 237–252, 248–263, 343–362, 357–376 and 385–404. Tg peptide 2746–2765 was also included.
TCC
PBMC (2 x 106/mL) were cultured in 2 mL RPMI-1640 (Gibco, Grand Island, NY) containing heat-inactivated 5% human serum, 100 U/mL penicillin-G (Gibco), 100 mg/L streptomycin (Gibco), 50 µmol/L 2-mercaptoethanol (Sigma Chemical Co., St. Louis, MO), and 1% nonessential-amino acids (Gibco) with 10 µg/mL TPO or 5 µg/mL TSH-R. After 7 days of stimulation, new medium and 20 U/mL recombinant human IL-2 (a generous gift from Cetus Corp., Emeryville, CA) were added for an additional 3–5 days. Cycles of restimulation with antigen and irradiated autologous PBMC as APC plus IL-2 were repeated twice. After three stimulation cycles, the cells were plated in 96-well U-bottom plates (Nunc, Roskilde, Denmark) by limited dilution at 1 cell/well, plus 10 µg/mL TPO or 5 µg/mL TSH-R and in the presence of 20 U/mL IL-2 and irradiated autologous PBMC (1 x 105 cells/well). The frequency of growing cells always remained <25%. After 2–3 weeks, the clones were transferred to 24-well plates and expanded with phytohemagglutinin-P (1 µg/mL, Sigma Chemical Co.) and 20 U/mL IL-2 in the presence of irradiated allogeneic PBMC. TL were cultured with IL-2 for 5 days, and then cloned with antigen as described above.
Microproliferation assay
TCC (1 x 104/well) were used in a 3-day
proliferation assay. The cells were cultured with TPO (10 µg/mL), Tg
(20 µg/mL), TSH-R (5 µg/mL), TPO or TSH-R peptides (10 µg/mL),
purified protein derivative of tuberculin (5 µg/mL; Parke Davis,
Morris Plains, NJ), or tetanus toxoid (4 µg/mL; a generous gift from
Wyeth Labs., Marietta, PA) in duplicate or triplicate in 96-well
plates. Irradiated autologous PBMC (1 x 105/well)
were used as APC. These cultures were pulsed with
[3H]thymidine (1 µCi/well, SA 6.7 Ci/mmol; ICN
Radiochemicals, Irvine, CA) for 16–18 h. A proliferative response to
antigen was considered significant when the stimulation index (SI) was
3. (SI: mean counts per minute in the presence of antigen/mean counts
per minute in culture medium alone). This SI was found to clearly
segregate results from normal controls and patients with AITD in
several prior studies (11, 12, 13).
Determination of cytokine production
T cell clones (1 x 106/well) were stimulated
with immobilized anti-CD3 monoclonal antibodies (mAb) (1 µg/mL) in
the presence of irradiated JY line (Epstein-Barr virus-tranformed B
cells; 1 x 106/well), as B7-expressing accessory
cells, in 24-well plates. Supernatants were collected 48 h later
and assayed for IL-2, IL-4, IL-5, IL-10, TNF-ß, and IFN- by
sandwich enzyme-linked immunosorbent assay (ELISA) in duplicate.
Briefly, mAb pairs from Pharmingen (San Diego, CA) were used to measure
IL-4 (sensitivity 0.1 ng/mL), IL-5 (sensitivity 0.4 ng/mL), and IL-10
(sensitivity 0.4 ng/mL). Mouse mAb and polyclonal rabbit antibody pairs
were used for detection of IL-2 (sensitivity 0.4 U/mL) with capture mAb
B-G5 (Biosource, Camarillo, CA) and polyclonal rabbit-anti-recombinant
human (rh) IL-2 (Genzyme, Cambridge, MA); for TNF-ß (sensitivity 0.4
ng/mL) with capture mAb LTX-21 and polyclonal rabbit-anti-rhTNF-ß
(Endogen, Boston, MA); and for IFN- (sensitivity 0.4 ng/mL) with
capture mAb B-B1 and polyclonal rabbit-anti-rhIFN (Biosource).
Ninety-six well plates were coated with capture mAbs (1–4 ng/mL)
overnight at 4 C. On the following day, the plates were washed and
blocked with 3% BSA in PBS at room temperature for 2 h. The
plates were subsequently washed, and standards (50 µL), as well as
samples (50 µL), were added to wells and incubated overnight at 4 C.
For the Pharmingen ELISA, avidin-peroxidase (Sigma) and
2,2'azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) (Sigma) were
used to visualize cytokine detected with biotinylated secondary mAb
(1–3 ng/mL), as per the Pharmingen protocol. Goat antirabbit
Ig-alkaline phosphatase (Pierce, Rockford, IL) and p-nitrophenyl
phosphate disodium salt (Pierce) were used to visualize the cytokines
detected by the polyclonal IL-2, TNF-ß, and IFN- antibodies
(17).
Flow cytometry
Immunofluorescence analysis was performed on T cells using unlabeled mAb to CD3, CD4, and CD8 molecules and an fluorescein isothiocyanate (FITC)-labeled polyclonal goat antimouse antibody as a second step reagent. The lymphocytes were analyzed by fluorescence-activated cell sorting scan (FACS) (Becton Dickinson, Mountain View, Ca).
Statistical analysis
All results are given as mean ± SD.
Statistical analysis was performed by ANOVA, 
2
contingency tables, and Fishers’ exact probability method.
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Results |
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Three hundred clones were isolated from peripheral (PL) and/or
thyroid (TL) lymphocytes of 14 patients with AITD. Seventy four
antigen-specific clones were reactive to TPO, Tg, or TSH-R, and a
single clone was reactive to TPO and Tg. The rest were considered
nonspecific because they were either reactive to more than one peptide
or nonreactive to any thyroid antigen. Of the 43 TCC established from
HT patients (assigned nos. 1–44), 65% were reactive to TPO, and the
rest were reactive to TSH-R (16%), Tg (16%), or TPO and Tg (2%, TCC
39). Of the 32 TCC derived from GD patients (assigned nos. 1–32), 59%
were reactive to TSH-R and 41% to TPO (Fig. 1
). Clones with positive responses to
TPO, Tg, or TSH-R molecules had SI of 4.2 ± 1.9, 5.4 ± 2.9,
or 4.3 ± 1.6 (means ± SD; ranging from 3–12),
respectively. The selection of TPO and TSH-R peptides for the
microproliferation assays was based on our previous results (11, 12, 13).
TPO epitopes, 100–119 and 625–644, were recognized by 75% of clones
established from HT patients, whereas TSH-R epitopes 158–176,
207–222, and 343–362/357–376 were recognized by 85% of TCC
established from GD patients (P < 0.005; Figs. 2 and 3).
Fourteen percent of these clones were reactive to whole protein alone,
40% were reactive to native or recombinant proteins and their
respective peptides, and 46% were reactive to a peptide but not to the
whole protein. Because only 9 TPO peptides and 10 TSH-R peptides were
evaluated, some nonspecific clones and TCC reactive only to the whole
protein may actually be reactive to epitopes not included in this
analysis.
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PL and/or TL from two normal controls and two patients with CND were reactive to TPO epitopes 114–126, 211–223, 261–275, or 882–901 (data published in Ref.11). Sixty eight clones were established from these controls. Although it should in theory be possible to develop antigen-specific T cell clones reactive to TPO or TSH-R epitopes, these clones were nonspecific and showed an autologous mixed lymphocyte reaction.
T cell phenotype
The phenotypes of the TCC were CD3+, CD4+, and CD8-, except for one CD3+ CD4- and CD8+ clone.
Cytokine production
According to their cytokine profile, the TCC were classified into
Th0-like cells (secreting IL-4, IL-5, and IFN-), Th1-like cells
(secreting IFN-), and Th2-like cells (secreting IL-4 and/or IL-5).
Almost all of the 24 nonspecific TCC derived from thyroid tissue were
Th1 cells in both GD and HT. Of the 54 specific clones, 17 (32%) were
Th0, 26 (48%) were Th1, and the rest (20%) were Th2 cells. These
clones were reactive to TPO, Tg, or TSH-R and their respective
peptides, except for TCC 39, which was reactive to both TPO and Tg. The
specific TCC derived from patients with HT were preferentially Th1
(55%), whereas in GD, both Th0 (43%) and Th1 (39%) were present
(Table 1, Fig. 4).
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and TNF-ß. The majority of Th1 clones (50%) were derived from HT
patients and were reactive to TPO or Tg (P < 0.05).
All of these clones produced IFN- (Tables 1
, 2, and 3). IL-2 was detected in
only a few clones, probably because the supernatants were collected at
48 h of culture when IL-2 had been already consumed. IL-10 was
also produced by 19% of these clones. Most Th1 clones specific for TPO
or Tg and derived from HT thyroid tissue produced higher levels of
IFN- than other thyroid-specific Th1 clones (P <
0.05; Fig. 5). Eighty-two percent of Th2 clones were reactive to TPO
and were established from peripheral blood (P < 0.05).
All these clones secreted IL-5, and 64% of them produced IL-4 and
IL-10. TNF-ß was also produced by both Th1 and Th2 clones.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There are short homologous epitopes shared by TPO and Tg. For
instance TPO peptide 114–126 and Tg peptide 2746–2765, share a common
epitope, which is also present in some Escherichia coli
proteins (18). Thus it is not surprising that single clones can react
to both antigens (19). Although the presence of a shared epitope
suggests a mechanism for antigen-spreading from an environmental
antigen or another thyroid antigen, it has not been proven that these
homologies have pathogenic role in AITD. Clone 39 (from an HT patient)
with Th1 phenotype (secreting IFN-) also recognized both TPO and Tg,
but not the common epitope shared by TPO peptide 114–126 and Tg
peptide 2746–2765, or any other peptide tested. This clone may contain
more than one population, react to a different common T cell epitope,
or least likely, bear more than one T cell receptor.
Multiple TPO and TSH-R T cell epitopes have been detected in primary lymphocyte cultures from patients with GD and HT (10, 12, 20, 21, 22, 23). We previously demonstrated that amino acid residues 100–119 and 625–644 of TPO molecule were recognized by TL and PL from patients with AITD but not by lymphocytes from normal controls (11). A similar sequence (amino acid residues 632–645 of TPO) was also reported to be recognized by clones derived from a patient with GD (24). Using lines and/or primary cultures, other studies have also demonstrated that TSH-R peptides 158–176, 207–222, and 343–362/357–376 were recognized by T cells from patients with GD and were statistically significant when compared with control groups (12, 13, 23). TSH-R-specific clones have been recently identified using autoantigen-transfected Epstein-Barr virus-transformed B cell lines, but the location of TSH-R epitopes has not been determined (25).
In this study, most clones reactive to amino acid residues 100–119 of TPO molecule were derived from HT patients. Amino acid residues 158–176 and 207–222 of TSH-R molecule were only recognized by clones derived from GD patients. TPO peptide 625–644 and TSH-R peptide 343–362/357–376 were recognized by clones derived from both GD and HT patients. Although the number of clones were limited, these results suggest that the 100–119 residue is an important TP0 epitope involved in HT, whereas amino acid residues 158–176 and 207–222 are the TSH-R epitopes involved in GD. The other three peptides to which the clones reacted may also play a pathogenic role in GD and/or HT.
The fact that a percentage of clones from AITD patients were reactive to both a peptide and whole protein, proves that some of these synthetic peptides may contain naturally formed epitopes. Another interesting point is the finding of clones that were reactive to a peptide but not to the whole protein. The underlying reason for this phenomenon is unclear. These peptides are most likely cryptic epitopes, being residues that were inefficiently processed and presented to the developing immune system, and thus remain poor tolerogens (26, 27)
One or more immunodominant determinants may be recognized in the early stage of disease. Subsequently, determinants could spread intra- and intermolecularly and lead to a diverse repertoire in the late stage of disease (26). Because GD is characterized by cycles of remission and recurrence of variable duration and HT is progressive, and because our studies involved patients with established AITD, it is possible that the epitopes we identified here represent those involved in the late stage of AITD.
There is some evidence that Th1 cells are predominant in HT, whereas T
cells with a less restricted range of cytokines are present in GD. The
results differed from one study to another depending on the techniques
used. Methods used to demonstrate these differences included
immunohistochemical staining of cytokines present in thyroid tissues
(such as IFN-), analysis of cytokine messenger RNA (mRNA) expression
in thyroid tissues or TL using in situ hybridization or
RT-PCR amplification, and isolation of T cell clones from PL and/or TL
(25, 28, 29, 30, 31, 32). In most studies, T cell clones derived from patients with
HT and/or GD were isolated with polyclonal activators, and their
antigen specificity was not evaluated (30, 31, 32). The cytokine phenotype
of these clones were not well defined, and contradictory results may
have been obtained because of their nonspecific activation.
In our experiments, the clones were isolated with specific antigens and
classified into Th0, Th1, and Th2 subsets. The predominant isolation of
Th1 clones could be related to the type of APC (mostly monocytes) or
IL-2 used for cloning, which to some extent may cause a preferential
expansion of Th1 cells (2). Our protocol for developing clones did not
include IL-4, and this might have caused a panel of TCC in which
Th2-type cells are underrepresented. Clones derived from patients with
HT preferentially had Th1 phenotype, whereas clones derived from
patients with GD were predominantly Th0 and Th1. Antigen-specific T
cells with Th0 phenotype as the major population have also been
described in other autoimmune disorders (4, 33). Thus, it is not
surprising that Th0 cells are also predominat in GD. The presence of
IL-2, IFN-, and IFN- mRNA, and the absence of IL-4 mRNA in TL
from GD patients, indicate that Th1 cells are also an important subset
in GD (28). The predominance of nonspecific clones with Th1 pattern and
the detection of a few specific TSH-R clones with Th0 and Th2 profiles
isolated from a GD thyroid tissue has also been described (25). In our
study, nonspecific clones derived from GD thyroid tissues were also
Th1, whereas TSH-R specific clones were predominantly Th0 and Th1, and
a single clone was Th2.
Most Th2 clones that induce nonopsonizing antibodies were isolated from peripheral blood, whereas the harmful Th1 cells, which induce opsonizing antibodies and cell-mediated responses, were predominantly recovered from thyroid (target) tissues. The predominance of Th1 cells in the thyroid tissue may be related to their thyroid-specific homing receptors (34).
Th1 clones, derived from HT thyroid tissue and reactive to TPO or Tg,
produced high levels of IFN-. This proinflammatory cytokine,
promotes activation of macrophages, production of TNF-, IL-1, IL-6,
and reactive oxygen. Thus these Th1 cells appear to be highly
inflammatory, contributing to thyroid tissue destruction. IL-1ß is
secreted by activated macrophages or thyrocytes and can induce
thyrocyte apoptosis through Fas-Fas ligand interaction. This seems to
be a major pathogenic mechanism of tissue damage in HT (35). Therefore,
Th1 cells in cooperation with macrophages and natural killer cells may
indirectly induce thyrocyte apoptosis by promoting IL-1ß production
through INF-.
IL-10, which inhibits macrophage activation and T cell proliferation,
was produced by Th0, Th1, and Th2 clones. The highest production of
IL-10 was obtained from Th2 clone supernatants (3.5 ± 2.1 ng/mL;
mean ± SD). It has been suggested that the function
of Th1 cells as proinflammatory or antiinflammatory may depend on the
ratio of IFN- or IL-2 to IL-10 (36). In our study, 19% of Th1
clones produced both IFN- and to a lesser extent IL-10. Even small
amounts of IL-10 produced by these clones could inhibit the function of
the typical Th1 cells, which produce IL-2 and IFN- but not
IL-10.
Thyrocytes are not innocent target cells. They produce TNF, TGF-ß,
IL-1, IL-6, and IL-8 and express human histocompatability leukocyte
antigen classes I and II, as well as costimulatory and adhesion
molecules such as intercellular adhesion molecule-1 and lymphocyte
function-associated molecule-3, regulated by cytokines or other
factors, which in return can induce and/or modulate the cytokine
production of T cells. Thyrocytes can function as APC, present their
own antigens, and maintain the activation of autoreactive T cells, via
aberrant expression of human histocompatability leukocyte antigen class
II molecules as a result of local production of IFN- by lymphocytes,
up-regulation of costimulatory molecules, and production of cytokines
such as IL-1 and IL-6. This may contribute to the pathogenesis and
perpetuation of AITD (9).
Our findings suggest that some of the immunodominant T cell epitopes are located on amino acid residues 100–119 and 625–644 of TPO in HT and amino acid residues 158–176, 207–222, and 343–362/357–376 of TSH-R in GD. This study further demonstrates that thyroid-specific T cells can be divided into Th0, Th1, and Th2 subsets on the basis of their cytokine profiles, and that these cytokines may be involved in the pathogenesis of AITD, leading to thyroid tissue destruction by Th1 cells in HT and stimulation of TSH-R autoantibody production by Th0 cells in GD. Based on these observations, newer therapeutic and preventative approaches may be designed to modify the cytokine profiles of autoreactive T cells to suppress, inhibit, or even reverse the autoimmune process. However, these approaches should be undertaken with certain precautions. The induction of antigen-specific immune tolerance and suppression of experimental autoimmune diseases by parenteral or oral administration of antigen can, at times, exacerbate the autoimmune process rather than suppress it. Under some conditions, the protecting Th2 cells can enhance the production of pathogenic autoantibodies and aggravate the disease (37, 38).
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Footnotes |
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Received December 5, 1996.
Revised May 6, 1997.
Revised July 2, 1997.
Accepted July 23, 1997.
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References |
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-interferon by thyroid-derived T cells clones from
patients with Hashimoto’s thyroiditis. Clin Exp Immunol. 69:323–331.[Medline]
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are clones derived from HT patients, and those by 
are clones
derived from GD patients. Most Th1 clones reactive to TPO or Tg and
established from HT thyroid tissue produced higher levels of IFN-