Cutting Edge: A Soluble Form of CTLA-4 in Patients with Autoimmune Thyroid Disease

Abstract

We have recently identified a novel transcript of the CTLA-4 gene that may represent a native soluble form of CTLA-4 (sCTLA-4). To determine whether sCTLA-4 was expressed in humans, we applied a sensitive enzyme immunoassay on serum from patients with autoimmune thyroid disease (ATD). Eleven of 20 patients with ATD had circulating levels of sCTLA-4 ranging from 28 to 78 ng/ml, whereas only 1 of 30 apparently healthy volunteers had a level greater than 4 ng/ml. sCTLA-4 immunoreactivity was inhibited by its binding to B7.1, suggesting that sCTLA-4 is a functional receptor. Immunoprecipitation analysis of serum from patients with ATD revealed a polypeptide consistent with the predicted size of sCTLA-4. We conclude that a native soluble form of CTLA-4 is derived from an alternate transcript of the CTLA-4 gene, and its level in plasma is elevated among a population of patients with ATD.

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

“…The human CTLA-4 gene consists of four exons: exon 1 encodes a leader peptide (of approximately 37 amino acids), exon 2 the ligand-binding domain (116 amino acids), exon 3 the transmembrane domain (37 amino acids), and exon 4 the cytoplasmic tail (34 amino acids) [20][21][22][23].…”

“…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].…”

“…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]. The spliced transcript produces a 23-kDa sCTLA-4 characterized by a cytoplasmic tail shorter than that of the full-length form of the CTLA-4 antigen.…”

“…In addition, sCTLA-4 contains the MYPPPY motif located in the extracellular domain which is critical for B7 molecule binding [23]. Therefore it maintains the ability to bind CD80/CD86 and to participate in the B7/CTLA-4/CD28 signalling pathway of T-cell regulation [10,20,53]. Soluble CTLA-4 transcripts have been detected in lymph nodes, spleen, CD4 and CD8 subsets of T cells, B lymphocytes [10], and in monocytes [8,56], but not in a wide variety of nonlymphoid tissues.…”

“…Soluble CTLA-4 transcripts have been detected in lymph nodes, spleen, CD4 and CD8 subsets of T cells, B lymphocytes [10], and in monocytes [8,56], but not in a wide variety of nonlymphoid tissues. A distribution analysis of the soluble and full-length CTLA-4 transcripts among the CD4 and CD8 subsets of T cells has demonstrated that CD4 cells express both transcripts at the same level, whereas CD8 cells appear to express nearly 2.5-fold more full-length product with respect to sCTLA-4 [10,20,53]. An analysis of the association between the sCTLA-4 mRNA level and exon 1 +49A/G and CT60A/G CTLA-4 gene polymorphisms in healthy subjects also showed that the sCTLA-4 mRNA level in unstimulated CD4 T cells is higher for allele A at position +49 and the CT60 A variant [29].…”