PNAS & Nature Insights into Lupus Pathogenesis Save

Two prominent medical journals this week published new insights into the pathogenesis of systemic lupus erythematosus (SLE), with both inidicating promient roles for T cells in what is a classically viewed as a humoral (B cell) disorder. 

The the Proceedings of the National Academy of Sciences of the United States of America (PNAS), published a report on  ETV5, a specific transcription factor expressed in T cells, that promotes the differentiation of T cells into T follicular helper (TFH) cells, promoting B cells in generating antibodies. However, an overabundance of TFHs can cause B cells to become overly active, resulting in SLE or other autoimmune diseases. 

Using an ETV5-deficient SLE mouse model, researchers discovered that ETV5 enhances the expression of its target protein, osteopontin (OPN) which in turn activates the AKT protein, leading to the differentiation into TFH cells. They further confirmed in human T cells, that the differentiation into TFH cells is also regulated by the levels of ETV5 and OPN expression. Aligning with the findings from the animal models, ETV5 and OPN were expressed at higher levels in SLE patient models compared to the general population. Additionally, disease activity and blood autoantibody concentrations were generally proportional to the levels of ETV5 and OPN expression.

Another report in Nature, investigators from Northwestern Medicine and Brigham and Women’s Hospital suggest a prominent role for pollutants and type I interferon in regulating follicular helper (T_FH) cells, that are characteristically in excess in SLE. Both T follicular helper (T_FH) and T peripheral helper (T_PH) cells produce high levels of CXCL13 (a B cell chemoattractant).  They note that aryl hydrocarbon receptor (AHR) inhibits CXCL13 production by human CD4⁺ T cells.  AHR which helps regulate the body’s response to bacteria or environmental pollutants. Type I interferon, a pathogenic driver of SLE, opposes AHR to promote T cell production of CXCL13. These finding suggest a pivotal role for CXCL13⁺ T_PH/T_FH cells and reveals AHR, JUN and interferon as key regulators of T_FH cells that guide B cell activity.