The depletion of t follicular helper cells (Tfh) in an animal model utilizing aquaporin 4 (AQP4) immunized mice led to a decreased neuromyelitis optica spectrum disorder (NMOSD) disease activity. Results suggest that Tfh cells could represent a potential therapeutic target in NOSD, according to a recently published study in JCI Insight.

NMOSD is characterized by the presence of immunoglobulin G (IgG) autoantibodies targeting AQP4, a membrane protein of astrocytes, the authors noted. However, the underlying immunological mechanisms responsible for producing these autoantibodies are still, for the most part, unknown. Research on the immunological pathways involved in the production of autoreactive B cells could lead to the discovery of new therapeutic targets for NMOSD, they added.

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Tfh cells play an important role in B cell differentiation into effector cells in germinal centers through the secretion of interleukin-21 (IL-21), interleukin 4 (IL-4), and CD40L. Several authors hypothesize that interrupting the interaction between Tfh cells and undifferentiated T cells could remove autoreactive B cells in autoimmune diseases, the researchers noted. Furthermore, several studies have found a direct correlation between Thf cell levels and NMOSD disease activity, they continued.

The authors aimed to create an animal model further to clarify the contribution of Thf cells in NMOSD physiopathology. Researchers immunized mice against AQP4 using electroporation and measured their AQP4 IgG levels as well as splenic levels of Tfh, T helper 1 (Th1), and T helper 17 (Th17) cells. Results revealed that cytokine levels increased significantly after immunization. AQP4- negative mice were used as control.

AQP4-positive immunized mice presented with motor impairment as well as pathological characteristics similar to those of NMOSD in humans, such as astrocytopathy, demyelination, and axonal loss. AQP4- negative mice had no clinical manifestations after AQP4 immunization. 

Researchers removed Tfh cells from the immunized mice using an inducible costimulator ligand. Mice with Tfh cell depletion had improved motor function, as well as less AQP4 loss in the spinal cord. 

“This model can be used in future studies to elucidate the autoimmune mechanisms underlying the production of AQP4 autoantibodies and to evaluate novel immune cell-targeted therapeutic interventions for NMOSD,” the authors concluded.


Yick L-W, Ma OK-F, et al. T follicular helper cells contribute to pathophysiology in a model of neuromyelitis optica spectrum disorders. JCI Insight. Published online January 17, 2023. doi:10.1172/jci.insight.161003