title: Invariant natural killer T cells in lupus patients promote IgG and IgG autoantibody production.
abstract: IgG autoantibodies, including antibodies to double-stranded DNA (dsDNA), are pathogenic in systemic lupus erythematosus (SLE), but the mechanisms controlling their production are not understood. To assess the role of invariant natural killer T (iNKT) cells in this process, we studied 44 lupus patients. We took advantage of the propensity of PBMCs from patients with active disease to spontaneously secrete IgG in vitro. Despite the rarity of iNKT cells in lupus blood (0.002-0.05% of CD3-positive T cells), antibody blockade of the conserved iNKT TCR or its ligand, CD1d, or selective depletion of iNKT cells, inhibited spontaneous secretion of total IgG and anti-dsDNA IgG by lupus PBMCs. Addition of anti-iNKT or anti-CD1d antibody to PBMC cultures also reduced the frequency of plasma cells, suggesting that lupus iNKT cells induce B-cell maturation. Like fresh iNKT cells, expanded iNKT-cell lines from lupus patients, but not healthy subjects, induced autologous B cells to secrete antibodies, including IgG anti-dsDNA. This activity was inhibited by anti-CD40L antibody, as well as anti-CD1d antibody, confirming a role for CD40L-CD40 and TCR-CD1d interactions in lupus iNKT-cell-mediated help. These results reveal a critical role for iNKT cells in B-cell maturation and autoantibody production in patients with lupus.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Maria
authors.initials: M
authors.lastname: Caimol
authors.forename: Claudia J
authors.initials: CJ
authors.lastname: Benike
authors.forename: Eliza F
authors.initials: EF
authors.lastname: Chakravarty
authors.forename: Samuel
authors.initials: S
authors.lastname: Strober
authors.forename: Edgar G
authors.initials: EG
authors.lastname: Engleman
mesh_terms: D000328:Adult; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D002469:Cell Separation; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000473:pathology; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D061251:Primary Cell Culture; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D000974:Antibodies, Antinuclear; D057134:Antibodies, Neutralizing; D055610:Antigens, CD1d; C526877:CD1D protein, human; D007074:Immunoglobulin G; D011948:Receptors, Antigen, T-Cell; D023201:CD40 Ligand
keywords: Autoantibodies; B cells; IFN-γ; Lupus; iNKT cells