Ординатура / Офтальмология / Учебные материалы / Эндокринная офтальмопатия - мультидисциплинарный подход 2007

both the prevalence and the severity of GO are low. In a series of 83 patients, lower lid retraction was present in 38.6%, upper lid retraction in 4.8% and mild proptosis in 12%, and GO scored class 2 or less in 64% of the cases. In this series, the largest reported so far, no factor that could have predisposed to GO was identified [11].

Is Graves’ Orbitopathy Triggered by an Autoimmune Phenomenon? If so, what Is the Nature of the Auto-Antigen?

GO is an autoimmune disease, related to autoimmune thyroid diseases (AITD):

–GO is associated in nearly 100% of the cases with AITD. GO may occur even in those cases of typical full-blown GD observed within the frame of immune reconstitution following highly active antiretroviral therapy for HIV infection or after iatrogenic lymphocyte removal by anti-CD52 monoclonal antibody in multiple sclerosis [12].

–Orbital tissues are infiltrated with inflammatory and immune cells.

–There is some evidence that immunisation of mice against the TSH receptor may induce intra-orbital inflammatory changes mimicking those observed in the human disease, but a bona fide experimental model of immunological GO has yet to be secured.

The question of the antigen(s) involved in GO is still unsolved [13]. Because of the unique association of GO with AITD, it is hypothesized that the thyroid and the orbital tissues should share antigen(s):

–Thyroglobulin (Tg): Ancient literature suggests that Tg could flow from the thyroid to the orbit. Recent studies have demonstrated the presence of Tg in orbital tissues of patients with GO but in fibro-adipose tissue rather than extraocular muscle. However, because of the lack of the apparent concordance of the presence of anti-Tg antibodies and GO and also of the weak binding of Tg to orbital structures, this antigen does not appear as a good candidate to secure the hypothesis.

–The TSH receptor: The TSH receptor is predominantly involved in the pathogenesis of GD. Higher levels of expression of the transcripts of the TSH receptor have been observed in orbital tissues specimen from GO as compared to controls. Functional TSH receptor protein has also been detected in orbital tissues. In vitro, increased expression of the TSH receptor parallels the adipogenic differentiation of orbit preadipocyte fibroblasts, and IL-6 enhances both [4, 14]. However, the level of the expression of the TSH receptor in the orbit is very low even in patients with active disease, despite markedly elevated expression of inflammatory cytokines [15]. In addition, the

TSH receptor is detectable, both at the mRNA and protein levels, in several tissues unrelated to GD and GO. Recently, transfection of orbit preadipocytes with an activating mutant TSH receptor, while stimulating adipocyte differentiation, has been shown to block PPAR- -induced adipogenesis [16].

–The IGF-1 receptor: The IGF-1 receptor could be involved in GO. The presence of anti-IGF-1 receptor antibodies has been demonstrated in patients with GO. These antibodies have been considered as potentially pathogenic for the disease. More recently, antibodies able to compete with the binding of IGF-1 to orbital fibroblasts have been identified in patient with GD. Moreover, these antibodies could activate through the IGF-1 receptor expressed by the orbital fibroblasts the production of the chemokines RANTES and IL-16 in addition to that of hyaluronan [17, 18].

–Extraocular muscle antigens: Relevant auto-antigens from extraocular muscles, despite intensive work, have not been clearly identified as potentially involved in GO, yet.

Why Is the Orbit a Special Target for Thyroid Autoimmunity?

The concept of the shared antigen, i.e. restriction of an antigen expression to both thyroid and orbit, is debated. It might well be that the involvement of orbital tissues results from a combination of factors including the presence within the orbit of (a) antigenic structures recognized by auto reactive T cells involved in thyroid autoimmune diseases, and (b) specific local conditions such as the presence of fibroblasts/preadipocytes with unique functional characteristics including exaggerated responses to pro-inflammatory cytokines [19]. Other factors could contribute to the association of thyroid and orbit pathologies:

–The orbit and the thyroid share draining lymph nodes so that sensitisation to thyroid antigens could theoretically be extended to the orbit by trafficking dendritic cells originating from the thyroid [20].

–Auto-reactive B cells to the TSH receptor could act locally as antigen-present- ing cells and support the initiation or the development of local autoimmunity. Auto-reactive B cells can modulate T cell functions as shown in a different setting of a GAD65-specific human B-T cell line cognate system in vitro [21]. Interaction of antigen-presenting cells with T cells is modulated, among other factors, by CTLA-4, the gene polymorphism of which may be involved in the susceptibility to GO (see below). A clue to the role of B cells as antigen-presenting cells is provided by the unexpected favourable effect of anti-CD20 (Rituximab) monoclonal antibody on GO, an agent which deletes pre-B and B cells but not IgG-secreting plasmocytes [22, 23].

Graves’ IgG

T cell

CD154

IGF-1 receptor

Leukoregulin

PGE2

Th0

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.

What Kind of Immune Reaction Takes Place within the Orbit?

Inflammatory cells, T and B lymphocytes, macrophages as well as mast cells, infiltrating the orbit 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’s 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 IFNhave 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- , TNF- ) predominates in recent onset GO, Th2 pattern (IL-4, IL-5, IL-10) might be associated with remission [24]. IL-6 is found in the majority of GO T cell clones. In vitro, cytokines have many stimulatory effects on orbital fibroblasts [19] (figs. 3–5).

Graves’ IgG

IFN-

Glycosaminoglycans

hyaluran

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.

They:

–increase the expression of HLA class 2 molecules, heat shock protein 72 (HSP-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 of IL-6,

–enhance the synthesis of glycosaminoglycans,

–induce extracellular matrix remodelling activity through modulation of pericellular proteolytic environment [25],

–stimulate adipocyte differentiation: TGF- , IFNand IL-1, but not IFN- ,

–stimulate adipogenesis, a process on which IFNis rather inhibitory [26]. In addition, orbital fibroblasts are upregulated by IFNto 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 [27].

Finally, IgG from patients with GD can stimulate orbital fibroblasts to produce lymphocyte chemoattractants, an effect possibly mediated by the IGF-1 receptor.

Do Anti-TSH Receptor Antibodies (TRAb) Play a Role in the Onset or Development of Graves’ Orbitopathy?

There is an epidemiological association between GO and TRAb:

–TRAb are detectable in nearly 100% of the patients with GO.

–TRAb are present in the patients in whom GO is associated with autoimmune thyroiditis.

–There is a gross correlation between the presence, or levels, of TRAb and

severity of GO [28].

In one study, TBII and TSI levels were closely correlated with clinical activity score of GO. Also, there is a correlation, although weak, between TRAb levels and proptosis [1]. A follow-up study showed that levels and prevalence of TRAb were higher in patients with a more severe course of GO; in 50% of the patients, TRAb appeared to be a significant independent risk factor of GO, independent from age and smoking [29].

However, TRAb are not directly responsible for GO as shown by the absence of GO in hyperthyroid neonates with TRAb-driven hyperthyroidism.

Is There a Familial Predisposition to Graves’ Orbitopathy? Is There a Specific Genetic Background for Graves’ Orbitopathy?

Among the non-modifiable risk factors for GO, male gender and age are significant, although more for the severity of the disease than for its occurrence [30].

Genetic predisposition to GD is demonstrated by familial clustering and twin studies. However, as far as GO is concerned, no clear familial aggregation has been observed in 114 consecutive patients with severe GO. Only 3/114 had a family history of GO and all 3 were second-degree relatives [31].

GD appears to be inherited as a complex multigenic disorder and candidate gene studies (HLA on chromosome 6p21, CTLA4 on chromosome 2q33, LYP on chromosome 1p13 and TSHR on chromosome 14) are promising. The CTLA4 gene is associated with susceptibility to GO. The G allele at exon 1 CTLA4(49)A/G polymorphism is associated with GO (OR: 1.65). More importantly, G allele frequency is correlated with severity of GO. The T allele at intron 1 CTLA4(1822)C/T, but not the CTLA4( 318)C/T polymorphism in the promoter region, has also showed an association with GO (OR: 1.70). Moreover, exon 1 and intron 1 polymorphisms are in linkage disequilibrium with each other [32]. These findings are in line with the fact that, for several other autoimmune disorders, exon polymorphism of CTLA4 is associated with more severe forms. As to TSHR, recent work using single nucleotide polymorphisms has identified an association of the TSHR region with GD but not autoimmune thyroiditis. However, no data concerning GO have been reported in this work [33].

Smoking Increases the Risk of Graves’ Orbitopathy and

Its Severity: What Is the Mechanism for It?

Smoking is the strongest modifiable risk factor for GO [34].

Smoking increases the incidence and the severity of GO. Smoking confers a current risk: former smokers have a lower risk than current smokers to develop GO, even for comparable life-time tobacco consumption. Smoking influences the course of GO: the response to treatment is poorer and delayed in smokers. Also, smoking increases the risk of progression of GO after radioiodine treatment. GD patients who smoke have 5 times more risk to develop 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 that 20 cigarettes/day. In exsmokers, 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 smoker and non-smoker patients with GO. Finally, stopping smoking is the only GO preventive measure.

How smoking affects GO is conjectural. Several mechanisms have been discussed:

–superoxide radicals generated by smoking can induce orbital fibroblasts to proliferate,

–hypoxia also can stimulate orbital fibroblasts to proliferate and produce GAG,

–nicotine and tar can increase class II HLA molecules expression by orbital fibroblasts in the presence of IFN- , and

–total cigarette smoke extract increases in vitro GAG production by orbital

fibroblasts as well as adipogenesis [35].

The adipogenic effect of cigarette smoke extract is synergistic with that of IL-1. However, relevant compounds within cigarette smoke extract have not been identified, yet. 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 cytokine IL-1, TNF- , IFNby orbital fibroblasts.

How May the Observations Described Above and the Current Understanding of the Disease Lead to More Effective Treatment of Graves’ Orbitopathy?

Current understanding of the pathophysiology of GO sets the orbital fibroblast as the main target of the autoimmune process. On stimulation by pro-inflammatory cytokines, orbital fibroblasts are induced to interact with activated auto-reactive immune cells present within orbital tissues. As a consequence, they produce an excess of GAG, proliferate and can differentiate into adipocytes, and secrete cytokines, chemoattractants and an excess of PGE2.

Current therapeutic approaches are based on non-specific immunosuppression by glucocorticoids and orbit radiotherapy. For years, more specific immunomodulatory treatments have been considered and some tested [36, 37]. Among the classical immunosuppressants, only ciclosporine has shown some efficacy in combination with glucocorticoids. Somatostatin analogs, if assimilated to immunosuppressive agents because of the expression of somatostatin receptors by activated lymphocytes, have not proved to be of significant efficacy.

At this point, several possible therapeutic routes could theoretically be explored:

–Interfering with up-regulated functions of orbital fibroblasts: While glucocorticoids interfere with the production of both GAG and PGE, more

specific agents could be considered, for instance cyclo-oxygenase inhibitors and non-steroidal anti-inflammatory drugs. Due to its central role in adipogenesis, the use of antagonists of PPARor of selective PPARmodulators represents a logical route to be considered. However, because of the pleiotropic effects of PPARon metabolism, inflammation, fibrosis, cell cycle regulation, etc. preliminary studies using reliable experimental models of GO are mandatory.

–Inhibition of cytokine actions: GO appears as a cytokine-driven disease, therefore anti-cytokine approaches could be considered as in other autoimmune/inflammatory affections such as rheumatoid arthritis and Crohn’s disease. Anti-TNF- (etanercept, TNFreceptor ectodomain fusion protein antagonist), which neutralises the expression of other pro-inflamma- tory cytokines, has been tested in a small open-label trial in 10 patients with some improvement of CAS from moderate to marked in 60% of the patients [38]; tolerance was satisfactory. Controlled trials are obviously needed. The use of anti-IL-1 and anti-IL-6 could also be considered. A trial of pentoxifylline, a non-specific cytokine antagonist, is currently tested in a controlled trial within the EUGOGO consortium.

–Deletion or downregulation of activated autoreactive lymphocytes: Several approaches are possible. The CTLA-4 agonist (abatacept), a potent inhibitor of T cell proliferation, has been tested in psoriasis and rheumatoid arthritis. A non-mitogenic humanised anti-CD3 monoclonal antibody, the effect of which is to induce CD8 and CD4 CD25 T regulator cells, has been beneficial in 2 large controlled trials in type 1 diabetes. In GO, two reports have recently shown the potential beneficial effect of B cell depletion by anti-CD20 monoclonal antibody (rituximab) [22, 23]. As in other diseases such as rheumatoid arthritis, systemic lupus erythematosus and idiopathic thrombopenia, rituximab has proved efficient. This observation was unexpected and points out to B cell playing an important role in the pathogenesis of autoimmune diseases not only in producing antibodies but also as antigen-presenting cells, as mentioned above, and in secreting cytokines. Other B cell-depleting pathways are available through blockade

of ligands from the TNF family such as BAFF and APRIL.

However, a word of caution is necessary. Indeed, not only is the pathogenic antigenic system of GO still uncertain but it is obvious that modulation of the cytokine network as well as that of the number and functional state of T or B cells might induce deleterious consequences disproportionate with the usual morbidity of GO. The availability of in vitro or, rather, in vivo models of GO is therefore badly needed.

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