Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1075-1) contains supplementary material, which is available to authorized users.
Highlights
The inhibitory Cytotoxic T lymphocyte antigen 4 (CTLA-4) molecule is a crucial regulator of immune responses and a target for therapeutic intervention in both autoimmunity and cancer
We investigated the role of previously identified peptide autoantigens (H2B10-33, H391-105, H471-93, SmB136153, and U170K131-151) [3, 22, 23] by comparing peripheral blood mononuclear cell (PBMC) responses derived from lupus patients or healthy volunteer study participants to determine whether particular effector or regulatory peptide driven responses are distinctive to lupus disease and, further, whether natural soluble CTLA-4 (sCTLA-4) has a regulatory influence over those responses
Soluble CTLA-4 levels in serum and peripheral blood mononuclear cells (PBMC) cell culture supernatants of lupus patients Previous reports identified relatively high serum levels of sCTLA-4 in systemic lupus erythematosus (SLE) patients [20, 21], but that work used antibodies capable of binding either native sCTLA-4, exocytosed full-length CTLA-4, or fragments of the extracellular domain of CTLA-4 cleaved from the cell surface
Summary
The inhibitory CTLA-4 molecule is a crucial regulator of immune responses and a target for therapeutic intervention in both autoimmunity and cancer. Activated autoantigen-specific T cells that promote production of high-affinity autoantibodies specific for nucleic acids/nucleic acid binding proteins are factors in SLE [3,4,5,6] These autoreactive T cells are driven primarily by recognition of self-peptides derived primarily from the same nucleic acid binding proteins that represent the main targets of the autoimmune. Dahal et al Arthritis Research & Therapy (2016) 18:180 response in lupus, e.g. histones [7] These peptide autoantigens can drive pathological processes in lupus, interestingly they can induce tolerance by influencing increased regulatory T-cell (Treg) activity, or by stimulating production of anti-inflammatory cytokines such as IL-10. Peptides as therapeutics are very interesting because they are relatively cheap to produce and purify compared with biologics and can be more administered [10]
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