A role for autoantibodies in enhancement of pro-inflammatory cytokine responses to a self-antigen, thyroid peroxidase
Introduction
While autoantibodies have a clearly defined role in the pathogenesis of certain autoimmune diseases, including Graves' disease (GD) and Myasthenia Gravis [1], the role of antibodies in autoimmune diseases known to be T-cell mediated, e.g. Hashimoto's thyroiditis (HT), remains obscure. Nonetheless, their presence often precedes clinically overt disease [1]. Examples are antibodies to thyroglobulin (TG) and thyroid peroxidase (TPO), which are predictive of the development of autoimmune thyroid disease (AITD), comprising HT and GD. Virtually all patients with active HT are seropositive for TPO antibodies (TPOAbs), and 80% of the patients are positive for TGAbs [2], [3], and it has been a matter of controversy whether they play a direct role in the pathogenesis, or occur merely as a by-product of T-cell mediated destruction of thyroid cells [4]. TPOAbs and TGAbs are present in low concentrations in the circulation of healthy individuals [5], [6], but the presence of these autoantibodies at elevated concentrations is predictive for the development of clinically overt disease [7].
Unlike TG, TPO is expressed on the surface of thyroid cells, rendering the cells susceptible to TPOAb-mediated complement-dependent cytotoxicity (CDC) [8], [9], [10], [11], [12], [13] and antibody-dependent cellular cytotoxicity (ADCC) [13], [14], [15], [16]. The primary effector cells appear to be monocytes, triggered via binding of TPOAbs to Fcγ-receptor I (FcγRI, CD64) or FcγRIII (CD16) [13].Thus, TPOAbs of the IgG1 subclass, that bind to FcγRs (reviewed in [17]), mediate thyroid cell damage, whereas non-FcγR-binding IgG4 antibodies, with the same specificity, do not [18]. Others, however, have failed to find any correlation between the TPOAb IgG subclass and lysis of thyroid cells [19].
Despite the possible involvement of TPOAbs in thyroid cell damage, HT is thought to be caused primarily by T-cell mediated inflammatory processes that lead to the death of thyroid cells and, consequently, to hypothyroidism [20]. We have previously proposed that activation of pathogenic T cells may be promoted by autoantibodies, by virtue of the capability of the antibodies to promote uptake of self-antigen by antigen-presenting cells (APCs) via their FcγRs and, in the case of complement-containing autoantibody/autoantigen complexes, via complement receptors [5], [21]. In support of this notion, macrophages from immune guinea pigs are capable of presenting low concentrations of antigen to specific T cells, while macrophages from naïve animals are effective only at high antigen concentrations, unless incubated with sera from immunised animals [22]. Moreover, specific antibodies to hepatitis B surface antigen [23], trinitrophenyl-keyhole limpet hemocyanin [24], β-galactosidase [25] and a self-antigen, the acetylcholine receptor [26], [27], enhance T-cell responses to the respective antigens. In addition, the activity of diabetogenic OVA-reactive CD8+ T cells in transgenic mice expressing ovalbumin (OVA) as “self” in the thymus and by the β cells of the pancreas is greatly enhanced by administration of anti-OVA IgG [28]. While a role for IgE in directing the binding of TPO to B cells via the low affinity FcεR (CD23) has been demonstrated [29], it is unclear whether IgG autoantibodies, generated spontaneously in autoimmune disease or in healthy conditions, facilitate such uptake of TPO by antigen-presenting cells.
In the present study, we have examined to which extent serum TPOAbs affect the cytokine responses of normal mononuclear cells (MNCs) to stimulation with TPO. The cells were incubated with TPO in the presence of sera from HT patients, and sera from two groups of healthy, euthyroid individuals: a group with no familiar disposition to autoimmune thyroid disease (AITD), and – to allow for any influence of polymorphic serum proteins on the cytokine responses – a group of healthy monozygotic (MZ) co-twins to patients with HT. Our data indicate that IgG autoantibodies, regardless of their origin, promote cytokine responses to TPO through enhancement of TPO uptake by antigen-presenting MNCs bearing Fcγ-receptors (FcγRs).
Section snippets
Cells and serum
To assess the influence of serum on MNC responses to TPO, we collected sera from eleven HT patients (all females, median age: 43 years, range: 26–70 years), rendered euthyroid after treatment with levothyroxine, and two groups of healthy controls. The diagnosis of HT was based on biochemical evidence of primary hypothyroidism in combination with the presence of thyroid autoantibodies (TPOAbs and/or TGAbs).
The first control group, displaying no predisposition to autoimmune thyroid disease,
TPO-elicited cytokine production by MNCs
MNCs isolated from six randomly selected blood group 0 donors were stimulated with human TPO for 1 day in media containing 30% v/v autologous serum. A moderate, dose-dependent release of TNF-α and IL-6 was seen in 3 and 4 cultures, respectively (Figs. 1A and B), while all donors showed some degree of IFN-γ production (Fig. 1C). The levels of IL-4, IL-10, and IL-2 were non-detectable (< 10 pg/ml; not shown). On the basis of these experiments, an individual (represented by black circles in Fig. 1)
Discussion
We have previously suggested that antibodies to another thyroid self-antigen, TG, promote CD4+ T-cell responses to TG [5], [21], [33], and others have shown that antibodies to the acetylcholine receptor [26], [27], OVA expressed by transgenic mice [28], and a number of foreign antigens [22], [23], [24] enhance presentation of the antigens in question to T cells. The objective of the present study was to examine whether pro-inflammatory cytokine responses of MNCs to the self-antigen TPO were
Acknowledgments
This work was supported by the Novo Nordic Foundation, the A.P. Møller Foundation for the Advancement of Medical Science, and the Music Publishers Agnes and Knut Mørk's Foundation. We thank Dr. Andrzej Gardas, Medical Centre of Postgraduate Education, Warsaw, Poland, and Professor J. Paul Banga, King's College London School of Medicine, UK, for kindly providing us with the TPO necessary for this study, and for fruitful discussions. Moreover, we thank Ms Winnie Hansen for expert technical
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