Soluble CTLA-4 in autoimmune thyroid diseases: relationship with clinical status and possible role in the immune response dysregulation.
CTLA-4 molecule, expressed by activated T and B lymphocytes, transduces an inhibitory signal. Increasing evidence showed CTLA-4 gene as an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. The aim is to evaluate the augmented sCTLA-4 serum levels in different autoimmune thyroid diseases when compared with normal donors or with non-autoimmune hyperthyroidism and to investigate the functional activities and suggest the possible pathogenetic role of sCTLA-4. We demonstrate the presence of a soluble form of CTLA-4 in 59/90 sera from patients with autoimmune thyroid diseases (both Graves' disease and autoimmune thyroiditis). sCTLA-4 levels were not related to specific clinical manifestations, such as clinical thyroid status (hypo- or hyperthyroidism), circulating thyroid hormones, or other clinical features (ophthalmopathy). sCTLA-4 production does not seem to be affected by disease evolution during time. We showed that sCTLA-4 from sera of patients with thyroid autoimmunity is able to bind its physiological ligands CD80/CD86 and displays functional activities on different in vitro systems (T-cell proliferation induced by specific soluble antigens, bi-directional mixed lymphocyte reaction). In conclusion, we demonstrate an increment of sCTLA-4 in serum of patients with autoimmune thyroid diseases. Its possible pathogenetic role during autoimmune processes can be speculated: sCTLA-4 can specifically inhibit the early T-cell activation by blocking the interaction of CD80/CD86 with the co-stimulatory receptor CD28. Conversely, higher levels of sCTLA-4 could compete with membrane-bound CTLA-4 for CD80/CD86, in later T lymphocytes activation phase, causing a reduction of inhibitory signaling.
Saverino
Daniele
D
Department of Experimental Medicine-Section of Human Anatomy, University of Genova, Italy.
Brizzolara
Renata
R
Simone
Rita
R
Chiappori
Alessandra
A
Milintenda-Floriani
Francesca
F
Pesce
Giampaola
G
Bagnasco
Marcello
M
D000328:Adult; D015703:Antigens, CD / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000097:blood* / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000097:blood; D060908:CTLA-4 Antigen; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006111:Graves Disease / Q000097:blood / Q000276:immunology / Q000378:metabolism; D050031:Hashimoto Disease / Q000097:blood / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D011485:Protein Binding; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013959:Thyroid Diseases / Q000097:blood* / Q000276:immunology / Q000378:metabolism; D013971:Thyrotoxicosis / Q000097:blood; D013997:Time Factors
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human