Graves' immunoglobulins and cytokines stimulate the expression of intercellular adhesion molecule‐1 (ICAM‐1) in cultured Graves' orbital fibroblasts

Abstract. Intercellular adhesion molecule‐1 (ICAM‐1) and lymphocyte function‐asociated antigen‐1 (LFA‐1) are cell surface adhesion receptors that bind to one another and promote a variety of effector/target cell interactions in tissues affected by inflammatory or immune processes. Local infiltration of the thyroid gland and the retro‐ocular space by mononuclear cells is a hallmark of Graves' disease and Graves' ophthal‐mopathy (GO). Thus, we studied the role of these adhesion receptors in the interaction of inflammatory cells with retro‐ocular fibroblasts (OF) derived from patients undergoing transantral decompression for severe GO, and from normal individuals. Confluent OF‐monolayers were incubated with various cytokines or protein‐A affinity‐purified IgGs prepared from sera of patients with severe GO, Hashimoto's thyroiditis (HT), rheumatoid arthritis (RA) and normal individuals. As determined by immunocytochemistry and immunoprecipitation using a monoclonal anti‐ICAM‐1 antibody, interleukin‐1 ‐alpha (I L‐1a), tumour necrosis factor‐alpha (TNFa) and interferon‐gamma (IFNg) strongly enhanced surface expression of ICAM‐1 in both GO‐ and normal OF. By contrast, Graves' IgGs stimulated ICAM‐l expression only in GO‐, but not in normal OF. No effect was observed in either cell type with interleukin‐2, transforming growth factor‐beta, or IgGs from patients with HT, RA and normal individuals. Using phorbol ester‐activated, ⁵¹Cr‐labelled peripheral blood mononuclear cells (PBMCs) in a cell adhesion assay, we demonstrated potent adhesive activity of ICAM‐1 in GO‐OF pretreated with IL‐1a, TNFa, IFNg or Graves' IgGs, while all other compounds did not affect PBMC adhesion to GO‐OF. In other studies, PBMCs or GOOF were pre‐incubated (following stimulation with cytokines or Graves' IgGs) with monoclonal antibodies against ICAM‐1 or LFA‐1‐alpha. While PBMC‐adherence was only partially inhibited by anti‐ICAM‐1 antibody, anti‐LFA‐1‐alpha almost completely blocked cell attachment. In conclusion, inflammatory cytokines and Graves' IgGs are potent modulators of ICAM‐1/LFA‐1‐mediated interactions between immunocompetent cells and GO‐OF. These mechanisms likely play a role in the localization of the inflammatory infiltrate within the orbit and may affect antigen presentation and maintenance of the chronic immune process in GO.