Читать книгу Graves' Orbitopathy - Группа авторов - Страница 75

Upon infiltrating the orbit, inflammatory cells, T and B lymphocytes, macrophages and mast cells interact with orbital fibroblasts through a whole array of cytokines. This interplay amplifies and perpetuates inflammatory/autoimmune reactions and activation of fibroblasts. However, as shown by the Rundle curve, evolution of GO is monophasic and appears as self-limited, and fibrosis ultimately develops, notably in the extraocular muscles.

IL-1, IL-4 and IFN-γ have been detected in orbital connective tissue of patients with GO. T cells obtained from GO orbital tissue appear to elicit a mixed Th1/Th2 pattern. While the Th1 pattern (IL-2, IFN-γ, TNF-α) predominates in recent-onset GO, the Th2 pattern (IL-4, IL-5, IL-10) might be associated with remission [47]. IL-6 is found in the majority of GO T-cell clones.

In vitro, cytokines have many stimulatory effects on orbital fibroblasts [36] (Fig. 3–5). They:

•increase the expression of HLA class 2 molecules, heat shock protein 72 and ICAM-1;

•stimulate the production of prostaglandin E₂, a modulator of the immune response;

•stimulate the production of chemoattractants (IL-16, RANTES) as well as IL-6;

•enhance the synthesis of GAGs;

•induce extracellular matrix remodelling activity through modulation of the pericellular proteolytic environment [48];

•stimulate adipocyte differentiation (TGF-β, IFN-γ and IL-1, but not IFN-α);

•stimulate adipogenesis (IFN-α is rather inhibitory) [49].

Fig. 3. The orbital fibroblast takes part in the activation and perpetuation of the inflammatory process through the expression of HLA-DR and adhesion molecules as well as the production of chemoattractants and cytokines.

Fig. 4. Exacerbation of the production of glycosaminoglycans, notably of hyaluronan, by the fibroblasts is central to the swelling of retro-orbital tissues. Since orbital fibroblasts do not express hyaluronidase, hyaluronan accumulates. Also, the turnover of the extracellular matrix is modified by the increased expression of proteinase inhibitors which leads to changes in the structure of the adipoconnective tissue.

Fig. 5. An important feature of the pathogenesis of Graves’ orbitopathy is the differentiation of preadipocyte fibroblasts into adipocytes. This evolution is under balanced control by cytokines and activation of peroxisome proliferator-activated receptor-γ (PPAR-γ). Central to the pathogenesis of the disease is the possible link between the adipogenic differentiation and the expression at the cell surface of a functional thyroid-stimulating hormone receptor (TSH-R). TRAb, antibody against TSH-R.

Moreover, orbital fibroblasts are upregulated by IFN-γ to express CD40 allowing direct interaction with activated T cells through the CD40 ligand (CD154), which results in fibroblast activation as evidenced by the induction of IL-6 and IL-8 [50]. Targeting of IL-1 (in vitro), of TNF-α and IL-6 in small preliminary open-label trials has provided evidence for a pathogenic role of these cytokines in the active phase of GO, which probably precedes adipogenesis, but further studies are needed to understand the potential therapeutic implications of such an approach [51].

In addition to the traditional Th1 (cell-mediated) or Th2 (humoral) T-cell responses, recent unexpected results in animal models of autoimmunity revealed the need for T cells secreting IL-17, accordingly labelled Th17 cells. The current view is that Th1 cells initiate the autoimmune response but Th17 cells are required for tissue damage; indeed, lesions (e.g., multiple sclerosis plaques and rheumatoid synovial cells) contain high levels of IL-17 [52]. As yet little is known about the importance of these developments in GH or GO (Fig. 6) and the majority of studies assess regulatory T cells and Th17 cells in peripheral blood, rather than the target organ. In this setting, Kahaly et al. [53] reported similar levels of regulatory T cells in GO patients and controls whilst Peng et al. [54] demonstrated increased numbers of Th17 and Th22 cells in the periphery of GD patients which correlated with thyroid-stimulating antibody levels.