Immunoregulatory soluble CTLA-4 modifies effector T-cell responses in systemic lupus erythematosusReport as inadecuate

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Arthritis Research and Therapy

, 18:180

First Online: 04 August 2016Received: 01 February 2016Accepted: 12 July 2016


BackgroundThe inhibitory CTLA-4 molecule is a crucial regulator of immune responses and a target for therapeutic intervention in both autoimmunity and cancer. In particular, CTLA-4 is important in controlling antigen-specific immunity, including responses to autoantigens associated with autoimmune disease. Here, we investigate cytokine responses to a range of lupus-associated autoantigens and assess whether the alternatively spliced isoform of CTLA-4, soluble CTLA-4 sCTLA-4, contributes to immune regulation of autoantigen-specific immunity in systemic lupus erythematosus SLE.

MethodsThe cell culture supernatant production of sCTLA-4 as well as the cytokines IL-10, IFN-γ, and IL-17 from peripheral blood mononuclear cells PBMC from lupus patients and age- and sex-matched healthy volunteer donors were measured in response to previously identified histone and small nuclear ribonucleoprotein snRNP autoantigen-derived peptides H391-105, H471-93, and U170K131-151 by ELISA. We also examined the functional contribution of sCTLA-4 to immune regulation in the context of these autoantigenic peptides following blockade of sCTLA-4 with a selective anti-sCTLA-4 monoclonal antibody, JMW-3B3.

ResultsWe identified responses to autoantigenic peptides, which revealed qualitative differences in cytokine IL-10, IL-17, and IFN-γ profiles between SLE patients and healthy donors. PBMC from healthy donors responded to each of the lupus peptides by secreting IFN-γ and IL-17, but PBMC from SLE patients produced IL-10. Although we did not observe differences in the levels of serum or PBMC culture supernatant sCTLA-4 in either cohort, blockade of sCTLA-4 in PBMC cultures responding to antigen enhanced the cytokine profiles associated with each group.

ConclusionThe results show that lupus autoantigen-derived peptides display varied immunogenicity in lupus versus healthy volunteer donors, while sCTLA-4 acts to regulate the T-cell activity independently of response profile.

KeywordsSoluble CTLA-4 Systemic lupus erythematosus Immune regulation Electronic supplementary materialThe online version of this article doi:10.1186-s13075-016-1075-1 contains supplementary material, which is available to authorized users.

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Author: Lekh N. Dahal - Neil Basu - Hazem Youssef - Rahul C. Khanolkar - Robert N. Barker - Lars P. Erwig - Frank J. Ward


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