On the Pathogenesis of Autoimmune Thyroid Disease: A Unifying Hypothesis

Stelios Fountoulakis; Agathocles Tsatsoulis

Disclosures

Clin Endocrinol. 2004;60(4) 

In This Article

An Overview of the Immune Regulation

Immune cell Activation

The major role of the immune system is to discriminate between self- and foreign antigens. Under physiological conditions, self-antigens are tolerated and immune response is aimed at foreign antigens. On antigenic stimulation, CD4+ T helper precursor cells differentiate into two distinct subpopulations, Th1 and Th2. Th1 cells secrete IL-2, IFN-γ and TNF-α, which regulate the cell-mediated immune response and the induction of tissue damage through activation of cytolytic cells or other cytotoxic mechanisms (Mosmann & Sad, 1996; Blüher et al., 1999). Th2 cells on the other hand, mainly secrete IL-4, IL-5, IL-6 and IL-10 and are activated to provide help to B lymphocytes for specific immunoglobulin production (Mosmann & Sad, 1996; Blüher et al., 1999).

T lymphocytes recognize antigenic molecules, presented to them by major histocompatibility complex (MHC) bearing APCs (dendritic cells and macrophage subtypes). Activation of T lymphocytes, through the interaction with APCs, requires two distinct signals. The first is provided by the T lymphocyte receptor (TCR) binding with its antigen presented on MHC and provides specificity. The additional or co-stimulatory signal is provided by cell-surface molecules expressed on APCs. Of the known co-stimulatory molecules, the family of proteins termed B7 appears to be the most potent (Matsuoka et al., 1996). At least two B7 proteins exist, B7·1 (CD80) and B7·2 (CD70). B7·1 co-stimulates and induces Th1 cell production, while B7·2 co-stimulates and induces Th2 cell production (Kuchroo et al., 1995; Battifora et al., 1998; Salmaso et al., 2002). B7·1 and B7·2 interact with their counter receptors CD28 and cytolytic T lymphocyte associated antigen-4 (CTLA-4; Azuma et al., 1993; Freeman et al., 1993). Interaction of B7·1 or B7·2 with CD28 molecules expressed on resting T lymphocytes delivers positive signals activating these cells. CTLA-4 expressed on activated T lymphocytes competes with CD28 for the co-stimulatory receptors B7·1 and B7·2. Preferential binding of B7 molecules to CTLA-4 conveys negative regulation, inducing anergy (Fig. 1; Krummel & Allison, 1995; Weetman, 2003).

Figure 1.

Alternative outcome after antigen presentation depending on co-stimulatory molecules: (a) B7·1 ligation with CD28 induces Th1 lymphocyte stimulation; (b) B7·2 ligation with CD28 induces Th2 lymphocyte stimulation; (c) CTLA-4 interaction with either B7·1 or B7·2 inhibits T lymphocyte stimulation leading to anergy.

A native soluble form of CTLA-4 (sCTLA-4), resulting from alternative gene splicing, was found to be present in human serum (Oaks et al., 2000). There is evidence suggesting that this truncated receptor is capable of binding B7 family molecules yet its functional role remains unknown.

Two newly identified pairs of ligand-receptors have also been implicated in the delivery of the stimulatory signal. The positive regulatory co-receptor inducible co-stimulator (ICOS) binds B7RP-1 and transmits stimulatory signals (Hutloff et al., 1999; Guo et al., 2001), whereas the negative regulatory co-stimulator programmed death-1 (PD-1) binds its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2) and appears to be critical for the regulation of peripheral tolerance and autoimmunity (Freeman et al., 2000; Brown et al., 2003) PD-1 is expressed on activated T and B lymphocytes while the expression of its ligands on normal cells remains controversial (Bennett et al., 2003).

Mechanisms of Tolerance and Tolerance Escape

Prevention of self-reactivity depends on mechanisms controlling the autoreactive T lymphocytes. Such control mechanisms include those of adaptive (central and peripheral) tolerance induction and clonal anergy (Ramsdell & Fowlkes, 1990; Schwartz, 2003). Central and peripheral adaptive tolerance induction involve a similar mechanism, but the first occurs mainly in the thymus. Immature T and B lymphocytes bind antigens in the absence of co-stimulatory molecules or in the presence of co-inhibitory molecules, resulting in T lymphocyte deletion through apoptosis (Schwartz, 1993; Weetman & McGregor, 1994). Clonal anergy on the other hand, may be achieved when mature immune cells bind antigen in the absence of co-stimulatory molecules, leading to functional inactivation or incomplete T lymphocyte activation and desensitization rather than deletion (Schwartz, 1993, 2003).

The importance of central tolerance as an autoimmunity control mechanism has been brought back into attention with the isolation of the novel AIRE gene, a transcription factor primarily expressed on thymic medullary epithelial cells and monocyte-dendritic cells in the thymus (Heino et al., 1999). Mutations of AIRE are considered responsible for the pathogenesis of autoimmune polyglandular syndrome type 1 (APS-1) or APECED syndrome (Nagamine et al., 1997; Finnish-German APECED Consortium, 1997). APS-1 is a monogenic disorder characterized by the breakdown of tolerance to several organ-specific self-antigens probably due to thymic failure to delete autoreactive T lymphocytes (Liston et al., 2003). Studies on AIRE-deficient mice have shown that AIRE may regulate autoimmunity by promoting the ectopic expression of peripheral tissue-restricted antigens in thymic medullary epithelial cells (Anderson et al., 2002). These mice show almost complete failure to delete certain organ-specific cells in the thymus suggesting a role for AIRE protein thyroglobulin in the induction and maintenance of tolerance. Because thyrogobulin has been found to be expressed in the thymic medulla, AIRE's contribution to tolerance of thyroid specific autoantigens may be important (Derbinski et al., 2001).

Peripheral tolerance could be achieved through the interaction of APCs with autoreactive CTLA-4-bearing T lymphocytes. sCTLA-4 may also regulate peripheral tolerance. Oaks et al. (2000) proposed that, on resting cells, sCTLA-4 is more prominent and may bind B7 expressed on APCs and block B7-CD28 interactions, interfering with T lymphocyte co-stimulation. On the other hand, inhibition of B7-CTLA-4 interactions by sCTLA-4 on activated T cells (where transmembrane CTLA-4 expression is induced) may block CTLA-4-mediated negative signal of T lymphocyte responses.

PD-1 could also be involved in the maintenance of peripheral tolerance. PD-L1 expression on APCs may regulate the organ-specific tolerance in normal tissue by vetoing the effects of potential autoreactive cells (Dong et al., 2002). PD-L1 and PD-L2 function to inhibit T cell activation and may further be responsible for differential contributions to cellular and humoral immune responses (Brown et al., 2003; Youngnak et al., 2003) PD-1-deficient mice are characterized by a predisposition to autoimmunity suggesting a defect in peripheral tolerance (Nishimura et al., 1999, 2001). PD-L1 and PD-L2 might also have different functions in regulating type 1 and type 2 responses. Th1 cells can upregulate PD-L1 on macrophage populations, whereas Th2 cells may enhance PD-L2 expression on inflammatory macrophages (Loke & Allison, 2003).

On the other hand, ICOS contribution to self-tolerance also needs further investigation. ICOS is expressed on activated T lymphocytes and binding to its ligand stimulates both cellular and humoral immune responses (Guo et al., 2001; Smith et al., 2003). Furthermore, it is thought that ICOS may sustain rather than initiate T lymphocyte responses. However, the exact role of these newly discovered co-stimulatory molecules in peripheral tolerance and/or activation of immune responses remains to be clarified.

If, however, one or more of the above mechanisms of immune tolerance fails, immune cells may establish a self-directed immune reaction so intense and vigorous that it damages tissues. The result of this immune system reaction is the development of autoimmune diseases.

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