title: A functional soluble form of CTLA-4 is present in the serum of celiac patients and correlates with mucosal injury.
abstract: Celiac disease (CD) is a multifactorial disorder influenced by environmental, genetic and immunological factors. Increasing evidence showed CTLA-4 gene as an important susceptibility locus for autoimmune disorders. A native soluble cytotoxic T-lymphocyte-associated protein-4 (sCTLA-4), lacking of transmembrane sequence, has been described in several autoimmune diseases. We aimed to evaluate the presence of increased sCTLA-4 concentration in the serum of patients with CD and the possible immunoregulatory function. Blood samples were collected from 160 CD patients; sCTLA-4 levels were evaluated by ELISA, western blot and reverse transcription-PCR. The capability of serum sCTLA-4 to modulate T-lymphocyte proliferation in vitro was evaluated by two-way mixed leukocyte reaction assay. We demonstrated high levels of sCTLA-4 in serum of untreated celiac patients. Additionally, we observed that sCTLA-4 concentrations are related to gluten intake and that a correlation between autoantibodies to tissue transglutaminase and sCTLA-4 concentration exists. Moreover, sCTLA-4 levels correlate with the degree of mucosal damage. Conversely, no correlation between sCTLA4 levels and the HLA-related risk was observed. Finally, we show that sCTLA-4 from sera of CD patients displays functional activities. These results strongly suggest a regulation of sCTLA-4 synthesis depending on the presence or absence of dietary gluten and imply a possible immunomodulatory effect on cytotoxic T lymphocyte functions. In gluten-exposed patients, serum sCTLA-4 levels might provide insight about mucosal injury.
authors.affiliation: Section of Human Anatomy, Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Simone
authors.forename: Renata
authors.initials: R
authors.lastname: Brizzolara
authors.forename: Alessandra
authors.initials: A
authors.lastname: Chiappori
authors.forename: Francesca
authors.initials: F
authors.lastname: Milintenda-Floriani
authors.forename: Clelia
authors.initials: C
authors.lastname: Natale
authors.forename: Luigi
authors.initials: L
authors.lastname: Greco
authors.forename: Mara
authors.initials: M
authors.lastname: Schiavo
authors.forename: Marcello
authors.initials: M
authors.lastname: Bagnasco
authors.forename: Giampaola
authors.initials: G
authors.lastname: Pesce
authors.forename: Daniele
authors.initials: D
authors.lastname: Saverino
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000097:blood / Q000276:immunology*; D001284:Atrophy / Q000473:pathology; D001323:Autoantibodies / Q000097:blood; D060908:CTLA-4 Antigen; D002446:Celiac Disease / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D005838:Genotype; D005983:Glutens / Q000378:metabolism; D006683:HLA-DQ Antigens / Q000235:genetics; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007223:Infant; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology*; D008875:Middle Aged; D013601:T-Lymphocytes / Q000166:cytology; D011503:Transglutaminases / Q000276:immunology
chemical_list: D015703:Antigens, CD; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006683:HLA-DQ Antigens; D007070:Immunoglobulin A; D005983:Glutens; D011503:Transglutaminases