title: Disruption of Pathogenic Cellular Networks by IL-21 Blockade Leads to Disease Amelioration in Murine Lupus.
abstract: Systemic lupus erythematosus (lupus) is characterized by autoantibody-mediated organ injury. Follicular Th (Tfh) cells orchestrate physiological germinal center (GC) B cell responses, whereas in lupus they promote aberrant GC responses with autoreactive memory B cell development and plasma cell-derived autoantibody production. IL-21, a Tfh cell-derived cytokine, provides instructional cues for GC B cell maturation, with disruption of IL-21 signaling representing a potential therapeutic strategy for autoantibody-driven diseases such as systemic lupus erythematosus. We used blockade of IL-21 to dissect the mechanisms by which this cytokine promotes autoimmunity in murine lupus. Treatment of lupus-prone B6.Sle1.Yaamice with an anti-IL-21 blocking Ab reduced titers of autoantibodies, delayed progression of glomerulonephritis and diminished renal-infiltrating Tfh and Th1 cells, and improved overall survival. Therapy inhibited excessive accumulation of Tfh cells coexpressing IL-21 and IFN-γ, and suppressed their production of the latter cytokine, albeit while not affecting their frequency. Anti-IL-21 treatment also led to a reduction in GC B cells, CD138hiplasmablasts, IFN-γ-dependent IgG2c production, and autoantibodies, indicating that Tfh cell-derived IL-21 is critical for pathological B cell cues in lupus. Normalization of GC responses was, in part, caused by uncoupling of Tfh-B cell interactions, as evidenced by reduced expression of CD40L on Tfh cells and reduced B cell proliferation in treated mice. Our work provides mechanistic insight into the contribution of IL-21 to the pathogenesis of murine lupus, while revealing the importance of T-B cellular cross-talk in mediating autoimmunity, demonstrating that its interruption impacts both cell types leading to disease amelioration.
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Jin-Young
authors.identifier: 0000-0002-7867-2427
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Seth
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Michael
authors.identifier: 0000-0003-0362-7688
authors.initials: M
authors.lastname: Kashgarian
authors.affiliation: AbbVie Bioresearch Center, Worcester, MA 01605; and.
authors.forename: Sonia
authors.initials: S
authors.lastname: Terrillon
authors.affiliation: AbbVie Bioresearch Center, Worcester, MA 01605; and.
authors.forename: Emma
authors.initials: E
authors.lastname: Fung
authors.affiliation: AbbVie Bioresearch Center, Worcester, MA 01605; and.
authors.forename: Lili
authors.initials: L
authors.lastname: Huang
authors.affiliation: AbbVie Bioresearch Center, Worcester, MA 01605; and.
authors.forename: Li Chun
authors.initials: LC
authors.lastname: Wang
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520; joseph.craft@yale.edu.|Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Joe
authors.initials: J
authors.lastname: Craft
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D007378:Interleukins / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020239:Receptor Cross-Talk / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D000098546:Interleukin-21