International Immunology Advance Access originally published online on July 22, 2009
International Immunology 2009 21(9):1037-1045; doi:10.1093/intimm/dxp069
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A functional soluble form of CTLA-4 is present in the serum of celiac patients and correlates with mucosal injury
1 Section of Human Anatomy, Department of Experimental Medicine
2 Medical and Radiometabolic Therapy Unit, Department of Internal Medicine, University of Genova, Genova, Italy
3 Department of Paediatrics, University of Naples Federico II and European Laboratory of Food Induced Disease (ELFID), Napoli, Italy
4 Present address: Section of Internal Medicine, Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy
Correspondence to: M. Bagnasco; E-mail: bagnasco{at}csita.unige.it
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.
Keywords: autoimmunity, celiac disease, CTLA-4
* These authors contributed equally to this work.
Transmitting editor: L. Moretta
Received 30 March 2009, accepted 25 June 2009.