Abstract
IntroductionSpondylarthropathies (SpA) are characterized by abnormal immune responses including T cell activation. Cytotoxic T lymphocyte associated molecule-4 (CTLA-4) is involved in down-regulating immune responses. A soluble form of CTLA-4 (sCTLA-4), resulting from an alternative splicing, has been identified and was found increased in several autoimmune diseases. Here, we evaluated circulating levels of sCTLA-4 as a marker of immune dysregulation in SpA. Intracellular CTLA-4 and levels of CTLA-4 transcript expression in peripheral blood lymphocytes (PBL) were also studied.MethodsSera from 165 patients with SpA were evaluated for sCTLA-4 measurements. Results were compared with those from 71 patients with rheumatoid arthritis (RA) and 88 healthy subjects. In 32 patients with SpA, 22 patients with RA and 15 healthy controls, we analyzed the intracellular CTLA-4 expression in CD4+ T cells, CD8+ T cells, activated (HLA-DR+Foxp3-) CD4+ T cells, CD4+ regulatory (CD25+Foxp3+) T cells and in CD3 negative cells by flow cytometry. Expression of the full length (coding for membrane CTLA-4) and spliced form (coding for sCTLA-4) of CTLA-4 transcripts in PBL were analyzed by quantitative real-time polymerase chain reaction (QRT-PCR).ResultsHigh levels of sCTLA-4 were found in the SpA group compared to the RA group and healthy controls (P < 0.0001). Soluble CTLA-4 serum levels strongly correlated with clinical index of disease activity BASDAI (r = 0.42, P < 0.0001) and C-reactive protein (CRP) levels (r = 0.17, P = 0.037). In contrast to RA patients, SpA patients did not exhibit changes in intracellular CTLA-4 expression in the different PBL subsets tested. Finally, the SpA group showed a preferential expression of the spliced CTLA-4 mRNA (P = 0.0014) in PBL.ConclusionsSpA patients exhibit high levels of circulating sCTLA-4 that may result from an alternative splicing of CTLA-4 transcripts. This may influence immune activation and regulation in SpA.
Highlights
Spondylarthropathies (SpA) are characterized by abnormal immune responses including T cell activation
Soluble Cytotoxic T lymphocyte associated molecule-4 (CTLA-4) serum levels strongly correlated with clinical index of disease activity Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (r = 0.42, P < 0.0001) and Creactive protein (CRP) levels (r = 0.17, P = 0.037)
SpA patients exhibit high levels of circulating soluble form of CTLA-4 (sCTLA-4) that may result from an alternative splicing of CTLA-4 transcripts
Summary
Spondylarthropathies (SpA) are characterized by abnormal immune responses including T cell activation. ANOVA: analysis of variance; APC: antigen presenting cells; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index; CRP: C-reactive protein; CTLA-4: cytotoxic T lymphocyte antigen-4; EDTA: ethylenediaminetetraacetic acid; ELISA: enzyme-linked immunosorbent assay; ESR: erythrocyte sedimentation rate; FITC: fluorescein isothiocyanate; HAQ: Health Assessment Questionnaire; HLA: Histocompatibility Leukocyte Antigen; NSAIDs: non-steroidal anti-inflammatory drugs; PBL: peripheral blood lymphocytes; Pe-cy 7: phycoerythrin-cyanin 7; RA: rheumatoid arthritis; sCTLA-4: soluble cytotoxic T lymphocyte antigen-4; SEM: standard error of the mean; SLE: systemic lupus erythematosus; SpA: spondylarthropathies; TNF: tumor necrosis factor; Treg: regulatory T cells. A common genetic background, namely the Histocompatibility Leukocyte Antigen (HLA) Class I B27, which is strongly associated to SpA and to AS The pathophysiology of these diseases is not completely understood, but it is believed that the genetic component is directly involved as demonstrated by transgenic rats expressing human HLA-B27 [2]. CD4+T cells are required for the development of the disease in the animal model of transgenic rat for human HLA-B27
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