Regulation of autoantibody activity by the IL-23–TH17 axis determines the onset of autoimmune disease

Abstract

The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the T17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, T17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-T17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotolerance.

Estrogens regulate glycosylation of IgG in women and men

“…Each glycan can assume over 30 different forms (Figure 1), a diversity that affords the opportunity to fine-tune humoral immunity. For example, in patients with HIV, a shift toward proinflammatory IgG glycans correlates with more effective antiviral defense, while in rheumatoid arthritis glycan changes may contribute to the ability of IgG to trigger pathogenic inflammation (2)(3)(4)(5)(6). Glycoforms lacking terminal galactose (termed G0, denoting zero galactoses, see Figure 1) are particularly proinflammatory because they confer an enhanced ability to fix complement and to engage the activating IgG receptor FcγRIIIa while simultaneously blocking antiinflammatory mechanisms mediated through sialylated and/or bigalactosylated (G2) glycans (2,4,7,8).…”

Serum Concentrations of Th17-Associated Interleukins and Autoimmune Phenomena are Associated with the Degree of Liver Damage in Alcoholic Liver Disease

“…We can hypothesize that IL-22 signalling might be involved in alcohol-induced liver injury followed by increased α-SMA synthesis by activated HSCs and exposure of adducts between F-actin and AA/MA to immune cells with the production of anti-F-actin-Abs as a consequence of the immune stimulation. Additionally, the recently published work of Pfeifle et al in rheumatoid arthritis has demonstrated that Th17-derived cytokines, IL-22 and IL-21 triggered a shift toward a proinflammatory autoantibodies production [34]. This research gives us an insight into the potential mechanism of autoantibodies formation in alcoholic hepatitis.…”

Fra1 Controls Rheumatoid Factor Autoantibody Production by Bone Marrow Plasma Cells and the Development of Autoimmune Bone Loss

“…Purification of mouse IgG and Fc‐glycosylation analysis were performed as previously described . Briefly, mouse serum IgG was purified using Protein G‐Sepharose Fast Flow (GE Healthcare, Piscataway, NJ, USA) and digested with trypsin (sequencing grade; Promega, San Luis Obispo, CA, USA).…”