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.

The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

“…A comparison of these results with those obtained in 85 patients with CD in remission on a gluten-free diet showed that sCTLA-4 concentrations are related to gluten intake. A correlation between autoantibodies to tissue transglutaminase or the degree of mucosal damage and sCTLA-4 concentrations h also been found [51]. In addition, we have observed that serum sCTLA-4 is able to downregulate the proliferative ability of T lymphocytes in vitro [51].…”

“…More recently, we found an increased in sCTLA-4 levels in the serum of patients with untreated CD (in 54 out of 75 CD patients; range 0.1-96.4 ng/ml), and analysed its possible immunoregulatory function [51]. A comparison of these results with those obtained in 85 patients with CD in remission on a gluten-free diet showed that sCTLA-4 concentrations are related to gluten intake.…”

“…A sCTLA-4, namely a functional molecule with specific CD80 and CD86 binding ability, generated by alternatively spliced mRNA has been described [10,13,20,[49][50][51][52][53]. The mRNA encoding sCTLA-4 consists of three exons: exon 1 encoding the leader peptide, exon 2 the ligand-binding domain, and exon 4 the cytoplasmic tail, but it lacks exon 3 encoding the transmembrane domain [10,20,53].…”

“…Detectable levels of sCTLA-4 have been demonstrated in human serum by immunometric assays and western blot analysis [10,11,13,20,49,51,53,[55][56][57][58][59][60]. Recently, however, on the basis of mass spectrometry and biochemical evaluation, the possibility that at least some of the B7 binding material isolated from serum by means of CTLA4 antibodies is not a product of the CTLA4 gene has been considered [61].…”

“…Increased serum levels of sCTLA-4 have been reported in patients with several autoimmune diseases significantly more often than in healthy individuals [20, 33, 49-51, 60, 62]. Patients with GD [20,33,49], HT [20,49], MG [50], systemic lupus erythematosus [55], systemic sclerosis (SSc) [54], CD [51], autoimmune pancreatitis (AIP) [62] and spondyloarthropathies and RA [60] have been investigated. The first studies on sCTLA-4 serum levels in autoimmune disease were performed 10 years ago [20] in 17 patients with GD and 3 patients with HT.…”