The Soluble Form of CTLA-4 from Serum of Patients with Autoimmune Diseases Regulates T-Cell Responses

Abstract

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. The biological significance of increased sCTLA-4 serum level is not fully clarified yet. It can be envisaged that sCTLA-4 specifically 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 different 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 effect of sCTLA-4: inhibiting the secretion of IFN-γ, IL-2, IL-7, and IL-13 and activating the secretion of TGF-β and IL-10. This study underlines the role of sCTLA-4 in modulating the immune response and its relevance in autoimmune disease pathogenesis.

Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis

“…Strikingly, 11 out of the 18 sICPs examined here were down-regulated in patients with AH. Most of the 11 sICPs, including four inhibitory ICPs (BTLA, CTLA-4, LAG-3, and PD-1) and three stimulatory ICPs (GITR, CD80, and ICOS), are generated through mRNA alternative splicing and secretion, (16,28,29) whereas sCD28, sCD160, sPD-L1 are cleaved from membrane-bound counterparts. (23)(24)(25) Consistent with their hyperactivated state, T cells from patients with AH expressed high levels of membrane-bound inhibitory ICPs, including CTLA4, LAG-3 and PD-1.…”

Correlation between systemic inflammatory response and quality of life in patients with chronic rhinosinusitis

“…Two distinct isoforms have been identified: the full‐length isomer, a transmembrane protein found primarily on T‐cells (CTLA‐4), and the soluble monomeric protein that is secreted extracellularly (sCTLA‐4). sCTLA‐4 has been linked to immune cell dysregulation with elevated levels of blood sCTLA‐4 reported in patients with thyroid disease, type I diabetes, SLE, myasthenia gravis, and celiac disease . Similarly, patients with lower airway inflammation have showed elevated levels of blood sCTLA‐4 .…”

“…sctla4 mRNA levels were also correlated with worsening objective and subjective disease severity measures (Tables and ), showing that increased expression of sctla4 is associated with increased disease severity and worse QOL. Previous research has identified sCTLA‐4 in the blood as a potential biomarker for inflammatory diseases, such as autoimmune thyroiditis (AIT), celiac disease, and prostatitis due to the positive correlation of sCTLA‐4 in the blood with clinical markers of disease . Similarly, the correlation of sctla4 with clinical measures of disease severity in CRSsNP make this gene an interesting potential biomarker for CRS.…”

Increased CTLA‐4+ T cells may contribute to impaired T helper type 1 immune responses in patients with chronic obstructive pulmonary disease

“…Polymorphisms in the gene encoding CTLA‐4 (e.g. rs231775 and rs5742909) and increased serum levels of the soluble form of CTLA‐4 have been associated with dysregulated T‐cell responses and increased susceptibility to COPD and chronic bronchitis . Furthermore, increased levels of soluble CTLA‐4 in the serum of patients with COPD paralleled decreased lung function and increased C‐reactive protein (CRP) .…”

“…rs231775 and rs5742909) and increased serum levels of the soluble form of CTLA-4 have been associated with dysregulated T-cell responses and increased susceptibility to COPD and chronic bronchitis. [17][18][19][20] Furthermore, increased levels of soluble CTLA-4 in the serum of patients with COPD paralleled decreased lung function and increased C-reactive protein (CRP). 21 Frequencies of circulating CTLA-4 + T cells and CTLA-4 + Treg cells were also higher in patients with COPD than in controls.…”