Graves patients with high sCTLA-4 level are at risk of severe ophthalmopathy
Jacek Daroszewski1, Edyta Pawlak2, Lidia Karabon2, Marek Bolanowski1, Anna Jonkisz4 & Irena Frydecka2,3
Author affiliations
1Department of Endocrinology, Diabetology and Isotope Therapy, Medical University, Wroclaw, Poland; 2Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland; 3Department of Hematology, Blood Neoplastic Diseases and Bone Marrow Transplantation, Medical University, Wroclaw, Poland; 4Department of Forensic Medicine, Medical University, Wroclaw, Poland.
Objectives: Graves' disease (GD) is an autoimmune disease caused by combination of environmental and genetic factors. The CTLA-4 gene is a candidate gene for conferring susceptibility to thyroid autoimmunity. Increased serum level of soluble isoform of CTLA-4 molecule (sCTLA-4), resulting by alternative splicing, was found in some autoimmune diseases. The role of this molecule in the pathomechanism of autoimmunity has not been defined.
The principal aim of the study was to test clinical utility of sCTLA-4 estimation as well as to study factors influencing serum concentration of this molecule in GD accompanied by Graves ophthalmopathy (GO).
Patients and measurements: The serum sCTLA-4 concentrations were determined using specific ELISA assay in 102 GD patients and 83 controls. g.319C>T, c.49A>G, CT60G>A, Jo31G>T and g.*642AT(8_33) in CTLA-4 gene was established by minisequencing assay. GO was assessed according to the Clinical Activity Score (CAS) and to 4-stage classification of severity.
Results: Serum sCTLA-4 concentration was significantly higher in GD as compared with control (8.3 vs 2.39 ng/ml, P=0.000001). Increased level of sCTLA-4 was found in patients with severe GO as compared with controls (10.2 vs 2.39 ng/ml, P=0.000001) as well as with patients with non-severe GO (10.2 vs 7.1 ng/ml, P=0.05). Patients with Jo31G>T[G] phenotype had significantly elevated serum sCTLA-4 level as compared with [G-] (P=0.006). sCTLA-4 concentration was not related to thyroid status or thyroid hormones levels.
Conclusion: To the best of our knowledge, this is the first clinical study searching for a relationship between sCTLA-4 concentration and the clinical expression of GO and thyroid status. Our results confirm an association of sCTLA-4 with the GD. sCTLA-4 is a sensitive marker of the disease and appears to be related with the severity of eye changes and with disease-bearing Jo31G>T[G] phenotype but not to thyroid function. Increased concentration of sCTLA-4 may indicate GD patients at risk of severe GO.