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

Abstract

CTLA-4, initially described as a membranebound molecule, is a costimulatory receptor transducing a potent inhibitory signal. Increasing evidence shows the CTLA-4 gene to be an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. A soluble form of cytotoxic T-lymphocyte-associated antigen-4 (sCTLA-4) has been established and shown to possess CD80/CD86 binding activity and in vitro immunoregulatory functions. sCTLA-4 is generated by alternatively spliced mRNA. Whereas low levels of sCTLA-4 are detected in normal human serum, increased serum levels are observed in several autoimmune diseases (e.g. Graves’ disease, myasthenia gravis, systemic lupus erythematosus, type 1 diabetes, systemic sclerosis, coeliac disease, autoimmune pancreatitis and primary biliary cirrhosis). The biological significance of increased sCTLA-4 serum levels is not fully clarified yet. On the one hand, it can be envisaged that sCTLA-4 specifically inhibits 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 compete for the binding of the membrane form of CTLA-4 with CD80/CD86 in the later phases of T-lymphocyte activation, causing a reduction in inhibitory signalling. This double-edged nature of sCTLA-4 to block the binding of CD28 to CD80/CD86 may result in different outcomes during the clinical course of an autoimmune disease.

High Levels of Soluble Ctla-4 Are Present in Anti-Mitochondrial Antibody Positive, but Not in Antibody Negative Patients with Primary Biliary Cirrhosis

“…First of all, they are reminiscent of similar observations reported by a number of research groups, including our own, in other autoimmune diseases (both systemic and organ-specific) [26]–[31], [33], [34], and in other immunological or haematological disorders, such as IgE-mediated reaction to hymenoptera venom [35], or acute lymphoblastic leukemia (ALL) in paediatric patients [36]. In some of these conditions, sCTLA-4 concentrations appeared to be somehow correlated with disease activity or outcome (e.g.…”

“…Increased serum levels of sCTLA-4 have been demonstrated in several autoimmune diseases [31]. The results of the present study showed for the first time that high levels of the soluble form of CTLA-4 are detectable in sera from patients with PBC displaying positivity for AMA.…”

“…CTLA-4 has steady-state messenger RNA (mRNA) levels for two known isoforms: a full-length isoform (flCTLA-4) encoded by exon 1 (leader peptide), exon 2 (ligand-binding domain), exon 3 (transmembrane 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 protein [24]–[26]. The presence of high concentrations of sCTLA-4 was observed in sera of patients with autoimmune thyroid diseases [26], [27], as well as in patients with other autoimmune diseases, such as type-1 diabetes, diffuse cutaneous systemic sclerosis [28], systemic lupus erythematosus [29] and myasthenia gravis [30], [31].…”

Soluble cytotoxic T-lymphocyte antigen 4: a favorable predictor in malignant tumors after therapy

“…Thus, sCTLA-4 is capable to bind CD80/CD86 and participate in the B7/CTLA-4/CD28 signaling pathway of T-cell regulation. However, similar with the full-length CTLA-4, sCTLA-4 is also capable to bind CD80/CD86 and to participate in the B7/CTLA-4/CD28 signaling pathway of T-cell regulation, which would lead to its immunosuppressive function 21. In addition, sCTLA-4 lacking the transmembrane domain disabled sCTLA-4 in downregulating immune functions, thereby blocking the negative signal of CTLA-4 after interaction with CD80/CD86 in the later phases of T-cell responses.…”

Co-stimulatory and Co-inhibitory Pathways in Autoimmunity

“…For instance, increased serum concentrations of soluble CTLA4 were found in SLE patients (Saverino et al, 2010). A polymorphism at the CTLA4 promoter was also reported to be associated with SLE susceptibility in an Asian population (Taha Khalaf et al, 2011).…”