title: Immunoregulatory soluble CTLA-4 modifies effector T-cell responses in systemic lupus erythematosus.
abstract: The 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).
  
  
  
  The 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.
  
  
  
  We 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.
  
  
  
  The 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.
authors.affiliation: Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.|Antibody and Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Lekh N
authors.initials: LN
authors.lastname: Dahal
authors.affiliation: Department of Rheumatology, Aberdeen Royal Infirmary, Aberdeen, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Basu
authors.affiliation: Department of Rheumatology, Aberdeen Royal Infirmary, Aberdeen, UK.
authors.forename: Hazem
authors.initials: H
authors.lastname: Youssef
authors.affiliation: Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
authors.forename: Rahul C
authors.initials: RC
authors.lastname: Khanolkar
authors.affiliation: Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Barker
authors.affiliation: Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.|Renal Unit, Aberdeen Royal Infirmary, Aberdeen, UK.|GSK, Experimental Medicine Unit, Immunoinflammation TA, Medicines Research Centre, Stevenage, Herts, SG1 2NY, UK.
authors.forename: Lars P
authors.initials: LP
authors.lastname: Erwig
authors.affiliation: Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. mmd475@abdn.ac.uk.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Ward
mesh_terms: D000328:Adult; D000368:Aged; D001324:Autoantigens / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human
keywords: Immune regulation; Soluble CTLA-4; Systemic lupus erythematosus