Research Article The Soluble Form of CTLA-4 from Serum of Patients with Autoimmune Diseases Regulates T-Cell Responses Rita Simone, 1,2 Giampaola Pesce, 3 Princey Antola, 3 Margarita Rumbullaku, 3 Marcello Bagnasco, 3 Nicola Bizzaro, 4 and Daniele Saverino 1 1 Section of Human Anatomy, Department of Experimental Medicine, University of Genoa, Via De Toni 14, 16132 Genoa, Italy 2 Departments of Medicine and Cell Biology, North Shore University Hospital, Manhasset, NY 11030, USA 3 Autoimmunity Unit, Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy 4 Laboratory of Clinical Pathology, San Antonio Hospital, Tolmezzo, 33100 Udine, Italy Correspondence should be addressed to Daniele Saverino; daniele.saverino@unige.it Received 30 April 2013; Revised 30 October 2013; Accepted 31 October 2013; Published 29 January 2014 Academic Editor: Koji Kawakami Copyright © 2014 Rita Simone et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is a costimulatory receptor transducing a potent inhibitory signal. Increasing evidence showed that CTLA-4 gene is an important susceptibility locus for autoimmune disorders. Alternatively spliced mRNA generates a soluble form, called sCTLA-4. Whereas low levels of sCTLA-4 are detected in normal human serum, increased/high serum levels are observed in several autoimmune diseases. he biological signiicance of increased sCTLA-4 serum level is not fully clariied yet. It can be envisaged that sCTLA-4 speciically inhibits the early T-cell activation by blocking the interaction of CD80/CD86 with the costimulatory receptor CD28. On the other hand, higher levels of sCTLA-4 could contend the binding of the membrane form of CTLA-4 with CD80/CD86, in later activation phase, causing a reduction of inhibitory signalling. We showed that sCTLA-4 from sera of patients with diferent autoimmune diseases is able to display functional activities on an in vitro system acting on the proliferation capability and modulating the secretion of cytokines. We observed a dual efect of sCTLA-4: inhibiting the secretion of IFN-, IL-2, IL-7, and IL-13 and activating the secretion of TGF- and IL-10. his study underlines the role of sCTLA-4 in modulating the immune response and its relevance in autoimmune disease pathogenesis. 1. Introduction T-cell activation is a result of two phases: the irst signal is delivered by the antigenic peptide presented by major histocompatibility complex molecules, and the second one (costimulatory signal) is mediated by CD28 interaction with B7 family members on antigen presenting cells [1]. Cyto- toxic T lymphocyte associated gene-4 (CTLA-4) is a type I glycoprotein on the surface of activated T-cells [2]. CTLA- 4 is a member of the Ig gene superfamily and along with its homologue, CD28, is a B7 binding protein [3, 4]. he function of CTLA-4 is to attenuate the ongoing immune response [5, 6]. he most convincing data that supports such a role for CTLA-4 comes from experiments in which the CTLA-4 gene is inactivated by a construction of CTLA- 4 knockout mice [7, 8]. hese mice demonstrate profound polyclonal lymphoproliferative disorders that iniltrate most major organ systems and die a few weeks ater birth. he majority of animals has increased levels of IgG; this fact illustrates the role of CTLA-4 on humoral immune responses as well [9, 10]. A role for CTLA-4 in autoimmune diseases is suggested by the observation that blockade of B7/CTLA- 4 interaction via administration of anti-CTLA-4 mAb exac- erbates autoimmune diseases in animal models such as experimental autoimmune encephalomyelitis [11] and type 1 diabetes (T1D) [12, 13]. It has been demonstrated that CTLA-4 is able to generate messenger RNA (mRNA) for two known isoforms: a full- length isoform (lCTLA-4) encoded by exon 1 (leader pep- tide), exon 2 (ligand binding domain), exon 3 (transmem- brane domain), and exon 4 (cytoplasmic tail) and a soluble form (sCTLA-4), which lacks exon 3. sCTLA-4, originating from alternative splicing, results in the loss of a cysteine residue and is found in the serum as a soluble monomeric Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 215763, 9 pages http://dx.doi.org/10.1155/2014/215763