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S M McLachlan

Publications and source records attributed to S M McLachlan.

At least 19 recordsLinked to original sources
PubMed2005

Interactions between the mannose receptor and thyroid autoantigens.

Thyroid autoantigens require internalization and processing by antigen-presenting cells to induce immune responses. Besides pinocytosis, antigen uptake can be receptor-mediated. The mannose receptor (ManR) has a cysteine rich domain (CR) and eight carbohydrate recognition domains (CRD) that bind glycosylated proteins. The TSH receptor (TSHR), thyroid peroxidase (TPO) and thyroglobulin (Tg) are glycoproteins. To investigate a role for the ManR in thyroid autoimmunity, we tested the interaction between these autoantigens and chimeric ManRs. Plasmids encoding the CR-domain linked to IgG-Fc (CR-Fc) and CDR domains 4-7 linked to IgG-Fc (CDR4-7-Fc) were expressed and purified with Protein A. Enzyme-linked immunosorbent assay (ELISA) plates were coated with human thyroid autoantigens and CR-Fc or CRD4-7-Fc binding detected with peroxidase-conjugated anti-IgG-Fc. CRD4-7-Fc binding was highest for the TSHR, followed by Tg and was minimal for TPO. CR-Fc bound to Tg but not to TSHR or TPO. The interaction between the TSHR and CRD-Fc was calcium-dependent; it was inhibited by mannose (not galactose), and required a glycosylated TSHR A-subunit. Moreover, precomplexing the TSHR A-subunit with CRD-Fc (but not CR-Fc), or adding mannose (but not galactose), decreased in vitro responses of splenocytes from TSHR-immunized mice. Our data indicate that the ManR may participate in autoimmune responses to Tg and the TSHR but not to TPO. Most important, ManR binding of heavily glycosylated TSHR A-subunits suggests a mechanism by which the minute amounts of A-subunit protein shed from the thyroid may be captured by antigen-presenting cells located in the gland or in draining lymph nodes.

Animals↗
PubMed2004

Susceptibility rather than resistance to hyperthyroidism is dominant in a thyrotropin receptor adenovirus-induced animal model of Graves' disease as revealed by BALB/c-C57BL/6 hybrid mice.

We investigated why TSH receptor (TSHR) adenovirus immunization induces hyperthyroidism more commonly in BALB/c than in C57BL/6 mice. Recent modifications of the adenovirus model suggested that using adenovirus expressing the TSHR A subunit (A-subunit-Ad), rather than the full-length TSHR, and injecting fewer viral particles would increase the frequency of hyperthyroidism in C57BL/6 mice. This hypothesis was not fulfilled; 65% of BALB/c but only 5% of C57BL/6 mice developed hyperthyroidism. TSH binding inhibitory antibody titers were similar in each strain. Functional TSHR antibody measurements provided a better indication for this strain difference. Whereas thyroid-stimulating antibody activity was higher in C57BL/6 than BALB/c mice, TSH blocking antibody activity was more potent in hyperthyroid-resistant C57BL/6 mice. F(1) hybrids (BALB/c x C57BL/6) responded to A-subunit-Ad immunization with hyperthyroidism and TSHR antibody profiles similar to those of the hyperthyroid-susceptible parental BALB/c strain. In contrast, ELISA of TSHR antibodies revealed that the IgG subclass distribution in the F(1) mice resembled the disease-resistant C57BL/6 parental strain. Because the IgG subclass distribution is dependent on the T helper 1/T helper 2 cytokine balance, this paradigm can likely be excluded as an explanation for susceptibility to hyperthyroidism. In summary, our data for BALB/c, C57BL/6, and F(1) strains suggest that BALB/c mice carry a dominant gene(s) for susceptibility to induction of a thyroid-stimulating antibody/TSH blocking antibody balance that results in hyperthyroidism. Study of this genetic influence will provide useful information on potential candidate genes in human Graves' disease.

Adenoviridae↗
PubMed2004

Evidence that factors other than particular thyrotropin receptor T cell epitopes contribute to the development of hyperthyroidism in murine Graves' disease.

Immunization with thyrotropin receptor (TSHR)-adenovirus is an effective approach for inducing thyroid stimulating antibodies and Graves' hyperthyroidism in BALB/c mice. In contrast, mice of the same strain vaccinated with TSHR-DNA have low or absent TSHR antibodies and their T cells recognize restricted epitopes on the TSHR. In the present study, we tested the hypothesis that immunization with TSHR-adenovirus induces a wider, or different, spectrum of TSHR T cell epitopes in BALB/c mice. Because TSHR antibody levels rose progressively from one to three TSHR-adenovirus injections, we compared T cell responses from mice immunized once or three times. Mice in the latter group were subdivided into animals that developed hyperthyroidism and those that remained euthyroid. Unexpectedly, splenocytes from mice immunized once, as well as splenocytes from hyperthyroid and euthyroid mice (three injections), all produced interferon-gamma in response to the same three synthetic peptides (amino acid residues 52-71, 67-86 and 157-176). These peptides were also the major epitopes recognized by TSHR-DNA plasmid vaccinated mice. We observed lesser responses to a wide range of additional peptides in mice injected three times with TSHR-adenovirus, but the pattern was more consistent with increased background 'noise' than with spreading from primary epitopes to dominant secondary epitopes. In conclusion, these data suggest that factors other than particular TSHR T cell epitopes (such as adenovirus-induced expression of conformationally intact TSHR protein), contribute to the generation of thyroid stimulating antibodies with consequent hyperthyroidism in TSHR-adenovirus immunized mice.

Adenoviridae↗
PubMed2004

TSH receptor-adenovirus-induced Graves' hyperthyroidism is attenuated in both interferon-gamma and interleukin-4 knockout mice; implications for the Th1/Th2 paradigm.

The role of the Th1/Th2 balance in the pathogenesis of murine Graves' hyperthyroidism is controversial. In BALB/c mice injected with adenovirus expressing TSH receptor (TSHR-adeno model), we found that suppression of TSHR-specific Th1 immune responses by exogenous interleukin-4 (IL-4), alpha-galactosylceramide or helminth (Schistosoma mansoni) infection was associated with inhibition of hyperthyroidism, indicating the critical role for Th1 cytokines. In contrast, BALB/c IL-4 knockout (KO), but not interferon-gamma (IFN-gamma) KO mice failed to develop Graves' hyperthyroidism when injected with TSHR-expressing M12 B lymphoma cells (TSHR-M12 model), suggesting the importance of Th2 cytokine IL-4. To reconcile differences in these two models, we used IL-4 KO and IFN-gamma KO BALB/c mice in the TSHR-adeno model. Unlike wild-type (wt) BALB/c mice in which 60% developed hyperthyroidism, only 13 and 7% of IL-4 KO and IFN-gamma KO mice, respectively, became hyperthyroid. Thyroid stimulating antibodies were positive in most hyperthyroid mice. TSHR antibody titres determined by TSH binding inhibition and ELISA were comparable in all three groups. IgG1 and IgG2a TSHR antibody titres were similar in IFN-gamma KO and wt mice, whereas IgG1 TSHR antibody titres and TSHR-specific splenocyte IFN-gamma secretion were lower in IL-4 KO than in IFN-gamma KO and wt mice, respectively. Our results clearly implicate both IFN-gamma and IL-4 in development of hyperthyroidism in the TSHR-adeno model. These data, together with the previous report, also indicate different cytokine requirements in these two Graves' models, with IFN-gamma being more important in the TSHR-adeno than the TSHR-M12 model. Moreover, our previous and present observations indicate a difference in the role of exogenous versus endogenous IL-4 in TSHR-adenovirus induced Graves' hyperthyroidism.

Adenoviridae↗
PubMed2003

Dendritic cells infected with adenovirus expressing the thyrotrophin receptor induce Graves' hyperthyroidism in BALB/c mice.

Dendritic cells (DCs) are the most potent antigen-presenting cells and a prerequisite for the initiation of primary immune response. This study was performed to investigate the contribution of DCs to the initiation of Graves' hyperthyroidism, an organ-specific autoimmune disease in which the thyrotrophin receptor (TSHR) is the major autoantigen. DCs were prepared from bone marrow precursor cells of BALB/c mice by culturing with granulocyte macrophage-colony stimulating factor and interleukin-4. Subcutaneous injections of DCs infected with recombinant adenovirus expressing the TSHR (but not beta-galactosidase) in syngeneic female mice induced Graves'-like hyperthyroidism (8 and 35% of mice after two and three injections, respectively) characterized by stimulating TSHR antibodies, elevated serum thyroxine levels and diffuse hyperplasitc goiter. TSHR antibodies determined by ELISA were of both IgG1 (Th2-type) and IgG2a (Th1-type) subclasses, and splenocytes from immunized mice secreted interferon-gamma (a Th1 cytokine), not interleukin-4 (a Th2 cytokine), in response to TSHR antigen. Surprisingly, IFN-gamma secretion, and induction of antibodies and disease were almost completely suppressed by co-administration of alum/pertussis toxin, a Th2-dominant adjuvant, whereas polyriboinosinic polyribocytidylic acid, a Th1-inducer, enhanced splenocyte secretion of IFN-gamma without changing disease incidence. These observations demonstrate that DCs efficiently present the TSHR to naive T cells to induce TSHR antibodies and Graves'-like hyperthyroidism in mice. In addition, our results challenge the previous concept of Th2 dominance in Graves' hyperthyroidism and provide support for the role of Th1 immune response in disease pathogenesis.

Adenoviridae↗
PubMed2003

Insight into antibody responses induced by plasmid or adenoviral vectors encoding thyroid peroxidase, a major thyroid autoantigen.

Plasmid and adenoviral vectors have been used to generate antibodies in mice that resemble human autoantibodies to the thyrotrophin receptor. No such studies, however, have been performed for thyroid peroxidase (TPO), the major autoantigen in human thyroiditis. We constructed plasmid and adenovirus vectors for in vivo expression of TPO. BALB/c mice were immunized directly by intramuscular injection of TPO-plasmid or TPO-adenovirus, as well as by subcutaneous injection of dendritic cells (DC) infected previously with TPO-adenovirus. Intramuscular TPO-adenovirus induced the highest, and TPO-plasmid the lowest, TPO antibody titres. Mice injected with TPO-transfected DC developed intermediate levels. Antibodies generated by all three approaches had similar affinities (Kd approximately 10(-9)M) and recognized TPO expressed on the cell-surface. Their epitopes were analysed in competition assays using monoclonal human autoantibodies that define the TPO immunodominant region (IDR) recognized by patients with thyroid autoimmune disease. Surprisingly, high titre antibodies generated using adenovirus interacted with diverse TPO epitopes largely outside the IDR, whereas low titre antibodies induced by DNA-plasmid recognized restricted epitopes in the IDR. This inverse relationship between antibody titre and restriction to the IDR is likely to be due to epitope spreading following strong antigenic stimulation provided by the adenovirus vector. However, TPO antibody epitope spreading does not occur in Hashimoto's thyroiditis, despite high autoantibody levels. Consequently, these data support the concept that in human thyroid autoimmunity, factors besides titre must play a role in shaping an autoantibody epitopic profile.

Adenoviridae↗
PubMed2003

Thyrotrophin receptor-specific memory T cell responses require normal B cells in a murine model of Graves' disease.

The role of B cells as antigen-presenting cells is being recognized increasingly in immune responses to infections and autoimmunity. We compared T cell responses in wild-type and B cell-deficient mice immunized with the thyrotrophin receptor (TSHR), the major autoantigen in Graves' disease. Three B cell-deficient mouse strains were studied: JHD (no B cells), mIgM (membrane-bound monoclonal IgM+ B cells) and (m + s)IgM (membrane-bound and secreted monoclonal IgM). Wild-type and B cell-deficient mice (BALB/c background) were studied 8 weeks after three injections of TSHR or control adenovirus. Only wild-type mice developed IgG class TSHR antibodies and hyperthyroidism. After challenge with TSHR antigen, splenocyte cultures were tested for cytokine production. Splenocytes from TSHR adenovirus injected wild-type and mIgM-mice, but not from JHD- or (m + s)IgM- mice, produced interferon (IFN)-gamma in response to TSHR protein. Concanavalin A and pokeweed mitogen induced comparable IFN-gamma secretion in all groups of mice except in the JHD strain in which responses were reduced. The absence in (m + s)IgM mice and presence in mIgM mice of an anamnestic response to TSHR antigen was unrelated to lymphoid cell types. Surprisingly, although TSHR-specific antibodies were undetectable, low levels of serum IgG were present in mIgM- but not (m + s)IgM mice. Moreover, IFN-gamma production by antigen-stimulated splenocytes correlated with IgG levels. In conclusion, T cell responses to TSHR antigen developed only in mice with IgG-secreting B cells. Consequently, in the TSHR-adenovirus model of Graves' disease, some normal B cells appear to be required for the development of memory T cells.

Adenoviridae↗
PubMed2001

A full biological response to autoantibodies in Graves' disease requires a disulfide-bonded loop in the thyrotropin receptor N terminus homologous to a laminin epidermal growth factor-like domain.

We observed amino acid homology between the cysteine-rich N terminus of the thyrotropin receptor (TSHR) ectodomain and epidermal growth factor-like repeats in the laminin gamma1 chain. Thyroid-stimulating autoantibodies (TSAb), the cause of Graves' disease, interact with this region of the TSHR in a manner critically dependent on antigen conformation. We studied the role of the cluster of four cysteine (Cys) residues in this region of the TSHR on the functional response to TSAb in Graves' patients' sera. As a benchmark we also studied TSH binding and action. Removal in various permutations of the four cysteines at TSHR positions 24, 29, 31, and 41 (signal peptide residues are 1-21) revealed Cys(41) to be the key residue for receptor expression. Forced pairing of Cys(41) with any one of the three upstream Cys residues was necessary for trafficking to the cell surface of a TSHR with high affinity TSH binding similar to the wild-type receptor. However, for a full biological response to TSAb, forced pairing of Cys(41) with Cys(29) or with Cys(31), but not with Cys(24), retained functional activity comparable with the wild-type TSHR. These data suggest that an N-terminal disulfide-bonded loop between Cys(41) and Cys(29) or its close neighbor Cys(31) comprises, in part, the highly conformational epitope for TSAb at the critical N terminus of the TSHR. Amino acid homology, as well as cysteine pairing similar to the laminin gamma1 chain epidermal growth factor-like repeat 11, suggests conformational similarity between the two molecules and raises the possibility of molecular mimicry in the pathogenesis of Graves' disease.

Amino Acid Sequence↗
PubMed2001

Search for the autoantibody immunodominant region on thyroid peroxidase: epitopic footprinting with a human monoclonal autoantibody locates a facet on the native antigen containing a highly conformational epitope.

Autoantibodies to thyroid peroxidase (TPO) are the hallmark of the humoral autoimmune response in human autoimmune thyroiditis (Hashimoto's thyroiditis). The majority of TPO autoantibodies in individual patients' sera interact with a restricted immunodominant region on TPO. Although this region can be mapped, previous studies have failed to localize its position on the TPO molecule. We, therefore, used a footprinting approach that can localize a highly conformational, discontinuous epitope on a very large molecule. Extensive biotinylation ( approximately 15 biotins/molecule protein) of lysine residues on the surface of purified, native TPO resulted in loss of multiple tryptic cleavage sites, as determined by analysis of tryptic polypeptide fragments on reverse-phase HPLC. TPO was then complexed with a monoclonal human autoantibody Fab (TR1.9) before biotinylation. After dissociation from TR1.9, TPO was recovered by gel filtration. A trypsin site, previously observed to be lost after TPO biotinylation, was restored when biotinylation was performed on the TPO-TR1.9 complex. The epitope-protected lysine (K) was present in a 30-aa TPO fragment that, by N-terminal sequencing, was found to be K713. Altered recognition by TR1.9 of a TPO-myeloperoxidase chimeric molecule involving this region supported the epitope protection data. In conclusion, we provide the first identification of an amino acid residue (K713) comprising part of an epitope within the TPO immunodominant region. This focal residue localizes the facet on the large, highly complex TPO molecule that contains the immunodominant region and provides the basis for rational guided mutagenesis studies to more fully characterize this region.

Amino Acid Substitution↗
PubMed2001

Insight into thyrotropin receptor cleavage by engineering the single polypeptide chain luteinizing hormone receptor into a cleaving, two subunit receptor.

To gain insight into the thyrotropin hormone (TSH) receptor (TSHR) cleavage, we sought to convert the noncleaving luteinizing hormone (LH) receptor (LHR) into a cleaved, two-subunit molecule. For this purpose, we generated a series of LHR mutants and chimeric LH-TSH receptors. Cleavage of mature, ligand binding receptors on the cell surface was determined by covalent 125I-labeled hCG crosslinking to intact, stably transfected mammalian cells. We first targeted a cluster of three N-linked glycans in the LHR (N295, N303, N317) in a region corresponding to the primary TSHR cleavage site, which has only one N-linked glycan. Elimination by mutagenesis of the most strategic N-linked glycan (LHR-N317Q) generated only a trace amount of LHR cleavage. Removal of the other N-linked glycans had no additive effect. A much greater degree of cleavage ( approximately 50%) was evident in a chimeric LH-TSHR in which the juxtamembrane segment of the LHR (domain E; amino acids 317-367) was replaced with the corresponding domain of the TSHR (residues 363-418). Similarly cleaving LHR were created using a much smaller component within this region, namely LHR-NET317-319 replaced with TSHR-GQE367-369, or by substitution of the same three amino-acid residues with AAA (LHR-NET317-319AAA). In summary, our data alter current concepts regarding TSHR cleavage by suggesting limited (not absent) amino-acid specificity in a region important for TSHR cleavage (GQE367-369). The data also support the concept of a separate and distinct downstream cleavage site 2 in the TSHR.

Amino Acid Sequence↗
PubMed2001

Reassessment of the location of the thyrotropin receptor 50 amino acid "insertion" provides evidence in favor of a second downstream cleavage site.

Cleavage of thyrotropin receptors (TSHR) on the cell surface into disulfide-linked A and B subunits involves deletion of an intervening region that corresponds approximately to a 50 amino acid "insertion" in the TSHR relative to the noncleaving luteinizing hormone/choriogonadotropin receptor (LH/CGR). The location of this insertion is imprecise because of the relatively low homology between the two receptors in this region. We tested the hypothesis that the TSHR 50 amino acid insertion was further downstream than we previously concluded, a possibility that would relocate the crucial LH/CGR glycan at N291 relative to the position of the TSHR insertion, and that would mitigate against the 50 amino acid insertion playing a role in TSHR intramolecular cleavage. Thus, we transferred the LH/CGR glycan at amino acid 291 from downstream (N367) to upstream of the 50 amino acid insertion (N317) in the TSHR, leaving this insertion intact. TSHR cleavage persisted. Moreover, deletion of amino acid residues 320-366 in addition to the upstream N291 substitution (ALN317-319NET) also did not prevent cleavage. On the other hand, deletion of three contiguous downstream residues (GQE367-369) in the TSHR 50 amino acid insertion abolished receptor cleavage into subunits. In summary, the present data are consistent with our previous location of the TSHR 50 amino acid insertion and, therefore, do not undermine evidence for the involvement of this insertion in TSHR cleavage. In addition, the data regarding TSHR residues GQE367-369 (far downstream of cleavage site 1) support the controversial possibility of a secondary cleavage site downstream of the insertion.

Amino Acid Sequence↗
PubMed2001

Human monoclonal autoantibodies to B-cell epitopes outside the thyroid peroxidase autoantibody immunodominant region.

Human autoantibodies to thyroid peroxidase (TPO) interact with a restricted or immunodominant region (IDR) on intact TPO. However, a smaller proportion of polyclonal serum TPO autoantibodies bind outside this region. To isolate monoclonal nonimmunodominant region (non-IDR) TPO autoantibodies, we screened a thyroid-derived immunoglobulin gene phage display library while "epitope masking" the TPO IDR with four human TPO monoclonal autoantibodies that define the IDR. Among 31 non-IDR autoantibodies obtained (expressed as Fab), 8 representatives were analyzed further based on their restriction digestion profiles. All are encoded by almost identical H chains (VH3 family), with extremely long D regions, paired with three different types of light chains. In contrast, IDR TPO Fab from the same patient utilize seven different heavy chains (VH1 and VH5 families) paired nonpromiscuously with different light chains. Use of VH5 genes has not been reported previously for TPO autoantibodies. Both non-IDR and IDR Fab bind specifically to TPO and not to other proteins. The non-IDR Fab affinities for TPO are moderately high (Kd 1-2 x 10(-9) M), somewhat lower than those for most IDR Fab (Kd 1-4 x 10(-10) M). The epitopes of the three types of non-IDR Fab overlap with each other, indicating a major role for their heavy chain in TPO binding. Most importantly, the epitopes of non-IDR Fab are recognized by patients' serum autoantibodies. In summary, we provide the first insight into the immunoglobulin genes, affinities and epitopes of human monoclonal autoantibodies that bind outside the TPO-immunodominant region.

Amino Acid Sequence↗
PubMed2001

Naked TSH receptor DNA vaccination: A TH1 T cell response in which interferon-gamma production, rather than antibody, dominates the immune response in mice.

Two approaches have been developed to induce TSH receptor antibodies in mice with properties resembling those in Graves' disease, the Shimojo model of injecting live fibroblasts coexpressing the TSH receptor and major histocompatibility complex antigen Class II, and TSH receptor-DNA vaccination. Thyroid-stimulating antibodies appear to occur less commonly after DNA vaccination, but there has been no direct comparison of these models. We performed a three-way comparison of 1) AKR/N and 2) BALB/c mice vaccinated with TSH receptor-DNA and 3) AKR/N mice injected with fibroblasts expressing the TSH receptor and the major histocompatibility complex antigen class II of AKR/N mice. TSH receptor-DNA vaccinated mice had low or undetectable levels of TSH receptor antibodies determined by ELISA or flow cytometry. Nonspecific binding precluded comparisons with sera from Shimojo mice by these assays. TSH binding inhibition and thyroid-stimulating antibody were undetectable in TSH receptor-DNA vaccinated mice. In Shimojo mice, TSH binding inhibition was positive in approximately 60%, and thyroid-stimulating antibodies were positive in hyperthyroid animals. Unlike the negative antibody data, splenocytes from TSH receptor-vaccinated (but not Shimojo) mice proliferated and produced the Th1 cytokine interferon-gamma in response to TSH receptor antigen. In conclusion, DNA vaccination is less effective at inducing TSH receptor antibodies than the Shimojo approach, but it permits the future characterization of TSH receptor-specific T cells generated without adjuvant.

Animals↗
PubMed2001

A prion-like shift between two conformational forms of a recombinant thyrotropin receptor A-subunit module: purification and stabilization using chemical chaperones of the form reactive with Graves' autoantibodies.

A secreted recombinant TSH receptor (TSHR) ectodomain variant (TSHR-289) neutralizes TSHR autoantibodies in Graves' disease, but is heterogeneous in containing both immunologically active and inactive molecules and is also unstable. We have now purified each form of TSHR-289 using sequential affinity chromatography with a mouse mAb (3BD10) specific for the inactive form, and a mAb to C-terminal His residues that recognizes both forms. The immunological difference between active and inactive TSHR-289 was unrelated to primary amino acid sequence or carbohydrate content and was, therefore, attributable to its folded state. The epitopes for Graves' autoantibodies and 3BD10 overlap, and both are destroyed by denaturation. Therefore, reciprocal binding by autoantibodies and 3BD10 to conformational determinants involving the same TSHR segment suggests a prion-like shift between two folded states of the molecule. Despite purification, immunologically active TSHR-289 remained labile, as determined by loss of autoantibody, and gain of 3BD10, recognition. However, using chemical chaperones we have, for the first time, been able to stabilize purified TSHR antigen in immunologically intact form. In summary, purification of immunologically active and stable antigen in milligram quantities provides a powerful tool for future diagnostic and therapeutic studies in Graves' disease.

Amino Acid Sequence↗
PubMed2000

Evidence for antigen presentation to sensitized T cells by thyroid peroxidase (TPO)-specific B cells in mice injected with fibroblasts co-expressing TPO and MHC class II.

Injection of AKR/N mice with fibroblasts co-expressing MHC class II and TPO in the absence of adjuvant induces IgG-class TPO antibodies that resemble spontaneously arising human thyroid autoantibodies. We have used this model to examine the effect of iodide on TPO antibody induction as well as to analyse the interaction between T and B cells. Despite its importance as a major environmental factor in thyroid autoimmunity, variable iodide intake had no detectable effects on TPO antibody levels, lymphocytic infiltration of the thyroid or thyroid hormone levels. In terms of T cell responsiveness, splenocytes from TPO fibroblast-injected mice, but not from control mice, proliferated in response to TPO. Intriguingly, B cell-depleted splenocytes (mainly T cells without reduction of macrophages) proliferated in response to TPO only when co-cultured with irradiated autologous splenocytes from TPO fibroblast-injected mice but not from control mice. These data suggest that TPO-specific B cells are involved in antigen presentation to sensitized T cells and are supported by the ability of spleen cells from TPO cell-injected (but not control) mice to secrete TPO antibodies spontaneously in culture. In conclusion, we provide the first evidence for the presence of thyroid autoantigen-specific B cells and their ability to present their autoantigen to sensitized T cells in mice induced to develop TPO antibodies resembling autoantibodies in humans.

Animals↗