title: Multi-therapeutic potential of autoantibodies induced by immune complexes trapped on follicular dendritic cells.
abstract: Induction of autoantibodies (autoAbs) targeting disease drivers / mediators is emerging as a potential immunotherapeutic strategy. Auto-immune complex (IC)-retaining follicular dendritic cells (FDCs) critically regulate pathogenic autoAb production in autoreactive germinal centers (GCs); however, their ability to induce potentially therapeutic autoAbs has not been explored. We hypothesized that deliberate display of clinically targeted antigens (Ags) in the form of ICs on FDC membranes induces target-specific autoreactive GCs and autoAbs that may be exploited therapeutically. To test our hypothesis, three therapeutically relevant Ags: TNF-α, HER2/neu and IgE, were investigated. Our results indicated that TNF-α-, HER2/neu- and IgE-specific autoAbs associated with strong GC reactions were induced by TNF-α-, HER2/neu- and IgE-IC retention on FDCs. Moreover, the induced anti-TNF-α autoAbs neutralized mouse and human TNF-α with half maximal Inhibitory Concentration (IC₅₀) of 7.1 and 1.6 nM respectively. In addition, we demonstrated that FDC-induced Ab production could be non-specifically inhibited by the IgG-specific Endo-S that accessed the light zones of GCs and interfered with FDC-IC retention. In conclusion, the ability of FDCs to productively present autoAgs raises the potential for a novel immunotherapeutic platform targeting mediators of autoimmune disorders, allergic diseases, and Ab responsive cancers.
authors.affiliation: Centre for Experimental Medicine and Rheumatology; William Harvey Research Institute; Barts and the London School of Medicine and Dentistry; Queen Mary University of London; London, UK.
authors.forename: Mohey Eldin
authors.initials: ME
authors.lastname: El Shikh
authors.forename: Maciej
authors.initials: M
authors.lastname: Kmieciak
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
authors.forename: Andras K
authors.initials: AK
authors.lastname: Szakal
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
authors.forename: John G
authors.initials: JG
authors.lastname: Tew
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000936:Antigen-Antibody Complex / Q000276:immunology* / Q000378:metabolism*; D001323:Autoantibodies / Q000276:immunology*; D020566:Dendritic Cells, Follicular / Q000276:immunology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008807:Mice, Inbred BALB C
chemical_list: D057134:Antibodies, Neutralizing; D000936:Antigen-Antibody Complex; D001323:Autoantibodies
keywords: autoantibodies; follicular dendritic cell; germinal centre; immune complexes; immunotherapeutic