The role of IL-39 in autoimmune diseases: From general to immunopathogenesis

IL-39, a cytokine from the IL-12 family that appears to be produced primarily by B cells, consists of the IL-23p19 and Ebi3 subunits, which signal through IL-23R/gp130 to activate STAT1/STAT3. Some studies suggest elevated IL-39 levels in certain autoimmune conditions, such as relapsing-remitting multiple sclerosis (RRMS), ankylosing spondylitis (AS), and autoimmune thyroid disease (ATD), possibly indicating a link between IL-39 and autoimmunity mediated by B cells. Preliminary evidence indicates that IL-39 might stimulate NETosis in neutrophils and promote BAFF (B-cell activating factor) secretion, which theoretically, in turn, may activate IL-39 production, T-cell-independent IgA isotype switching and somatic hypermutation. Some reports have revealed correlations between IL-39 and disease-specific autoantibodies, including RF and ACPAs in rheumatoid arthritis (RA), anti-dsDNA in systemic lupus erythematosus (SLE), and anti-AQP4 antibodies in neuromyelitis optica spectrum disorder (NMOSD), although these associations require further confirmation. Theoretically, through NETosis, IL-39 could potentially expose intracellular antigens and facilitate their citrullination via peptidyl arginine deiminase (PAD), which might contribute to autoimmunity initiation. Some data suggest that in P. gingivalis-associated dysbiosis, IL-36γ may increase IL-39 secretion by epithelial cells. As dysbiosis and inflammatory bowel disease (IBD) increase gut permeability and LPS exposure-a possible stimulus for IL-39 production-the relationships among IL-39, gut dysbiosis, and autoimmunity appear to warrant further investigation. While some studies have reported conflicting results regarding the immunological activity of IL-39 in humans, these theoretical considerations suggest the need for more rigorous, standardized research, as current investigations remain limited by small sample sizes and heavy reliance on animal models or in vitro studies rather than comprehensive human studies examining the biological effects of IL-39.