Читать книгу Graves' Orbitopathy - Группа авторов - Страница 78

Twin studies indicate that the environment has a significant impact on determining whether an autoimmune condition develops and on the type of disease that evolves in predisposed individuals. Infection and smoking have been proposed, the latter being the strongest modifiable risk factor for GO [73].

Innate immune response to infection, driven by the interaction of microbial products (cell wall components, nucleic acids, etc.) with pattern recognition receptors on antigen-presenting cells may trigger autoimmunity. The resulting cytokine milieu directs the development of T cells and may influence the balance between regulatory T lymphocytes and the Th17 subset [74]. The mouse models of GO alluded to above were not housed in pathogen-free conditions, so the microbial flora present in 1 unit [21] might have led to tolerance (no disease) whilst the other might have produced autoreactivity [75]. These developments have led to the gut microbiome being a current focus of studies trying to identify triggers of the autoimmune response [76].

Smoking (1) increases the incidence and the severity of GO, (2) confers a current risk, with former smokers having a lower risk than current smokers of developing GO, even for comparable lifetime tobacco consumption, (3) influences the course of GO, with the response to treatment being poorer and delayed in smokers, and (4) increases the risk of progression of GO after ¹³¹I treatment. GD patients who smoke have 5 times the risk of developing GO than those who do not. The effect of smoking is dose dependent: the relative risk of diplopia or proptosis has been reported to be 1.8 at 1–10 cigarettes/day, 3.8 for 11–20 cigarettes/day and 7.0 for more than 20 cigarettes/day. In ex-smokers, the risk is no longer significant even at >20 cigarettes/day. This suggests a direct and immediate effect of smoking. Serum levels of cytokines do not differ in smoking and non-smoking GO patients. Essentially, stopping smoking is the only GO-preventive measure.

How smoking affects GO is conjectural, but several mechanisms have been discussed:

•superoxide radicals generated by smoking can induce orbital fibroblasts to proliferate;

•hypoxia can also stimulate orbital fibroblasts to proliferate and produce GAG as well as to undergo adipogenesis [46, 77];

•nicotine and tar can increase class II HLA molecule expression by orbital fibroblasts in the presence of IFN-γ;

•total cigarette smoke extract increases in vitro GAG production by orbital fibroblasts as well as adipogenesis [78]. The adipogenic effect of cigarette smoke extract is synergistic with that of IL-1. However, relevant compounds within cigarette smoke extracts have not yet been identified. It is important to note that in the absence of thyroid disease, smoking does not appear to alter orbit content. This suggests that smoking has mainly a potentiating effect. Cigarette smoke extract does not increase ICAM expression, which suggests that it does not stimulate the release of cytokines IL-1, TNF-α and IFN-γ by orbital fibroblasts.