Developing connections amongst key cytokines and dysregulated germinal centers in autoimmunity

Systemic autoimmunity owing to overactivity of Tfh and dysregulated germinal centers has been described in mice and humans. Cytokines such as IL-21, IFN-γ, IL-6 and IL-17 are elevated in the plasma of mouse models of lupus, arthritis, and multiple sclerosis, and in subsets of patients with autoimmune disease. Monoclonal antibodies targeting these cytokines are entering clinical trials. While these cytokines exert pleiotropic effects on immune cells and organs, it is becoming clear that each and all of them can profoundly regulate Tfh numbers and/or function and induce or maintain the aberrant germinal center reactions that lead to pathogenic autoantibody formation. Here we review recent discoveries into the roles of IL-21, IFN-γ, IL-6, and IL-17 in germinal center responses and antibody-driven autoimmunity. These new insights used in conjunction with biomarkers of an overactive Tfh pathway may help stratify patients to rationalize the use of emerging monoclonal anti-cytokine antibody therapies.

► IL-6, IL-17, IL-21, and IFN-γ can lead to dysregulated Tfh and GC-driven autoimmunity.
► Causes include SNPs, TLR signaling, mRNA decay, commensal bacteria, and defective Tfr.
► Anti-cytokine mAbs may prove effective in patients with elevated cytokines and Tfh.