Читать книгу Graves' Orbitopathy - Группа авторов - Страница 73

GO is an autoimmune disease which is related to autoimmune thyroid diseases:

•GO is associated in nearly 100% of the cases with autoimmune thyroid diseases. GO may occur even in those cases of typical full-blown GH occurring 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 [20].

•Orbital tissues are infiltrated with inflammatory and immune cells.

•Although immunization of mice against the TSH-R may induce TRAbs and hyperthyroidism [21], until recently a robust experimental model of immunological GO had not been developed. This has changed with the publication by Banga’s group who established a new approach of genetic immunization of the human TSH-R A-subunit leading to sustained TRAb levels and GO-like disease comprising inflammation, adipogenesis, and fibrosis [22]. The model has been successfully reproduced by other workers, although there are some differences between the 2 centres, the immunized mice recapitulated eye disease of patients with either more myopathy or enlargement of adipose tissue [23]. Moreover, mouse fibroblasts derived from diseased orbital tissue expressed TSH and IGF-1 receptors, underwent adipogenesis and produced excess HA on TSH-R and/or IGF-1R stimulation proving orbital fibroblasts as target cell type of TSH-R-directed immunity [24]. The induction of GO-like disease using TSH-R immunization is strong evidence for its role in GO, but the IGF-1R has also been proposed as a thyroid/orbit-shared antigen.

•The TSH-R is the target of stimulating TRAbs which causes GH. Higher levels of expression of the transcripts of the TSH-R have been observed in orbital tissue specimens from GO as compared to controls. Functional TSH-R protein has also been detected in orbital tissues, although the signalling cascades may differ, e.g., PI3 kinase/pAkt rather than thyroidal TSH-R activation which mainly stimulates the production of cAMP [25]. In vitro, increased expression of the TSH-R parallels the adipogenic differentiation of orbit preadipocyte fibroblasts, and IL-6 enhances both [5, 26]. However, the level of expression of TSH-R in the orbit is very low even in patients with active disease, despite a markedly elevated expression of inflammatory cytokines [27]. In addition, the TSH-R is detectable, both at mRNA and protein levels, in several tissues unrelated to GD and GO. Transduction of orbit preadipocytes with an activating mutant TSH-R, while stimulating adipocyte differentiation, has been shown to block PPAR-γ-induced adipogenesis [28].

•IGF-1R: Kohn et al. [29] reported in 1986 that TRAbs could immunoprecipitate tyrosine kinase receptors, especially the IGF-1R. In 1993, Weightman et al. [30] demonstrated that GD patient IgGs were able to displace IGF-1 from its receptor on orbital fibroblasts. More recently, Pritchard et al. [31] have provided considerable data indicating the potential importance of this receptor in GO. Immunoglobulins from GD patients were able to stimulate IGF-1R-mediated production of the chemoattractants IL-16 and RANTES from GO, but not normal orbital fibroblasts. Despite its ubiquitous expression, the IGF-1R is upregulated in fibroblasts and thyrocytes in GH/GO [32] and IgGs from GO patients stimulate GAG production in these cell types, again in an IGF-1R-dependent manner [33]. The same group has demonstrated a possible association between TSH and IGF-1 receptors in orbital fibroblasts, to produce an autoantigen unique to GO and with distinct signalling capabilities [34] and is currently conducting a clinical trial of GO using antibodies to block IGF-1R activation (Trial No. NCT01868997). This concept has been modified recently by Krieger et al. [35], who reported “cross-talk” between the signalling cascades for TSH-R and IGF-1R. A combined therapy targeting both, the TSH-R and the IGF-1R, might be an effective treatment strategy.