We present two novel insights of the role of Clec4b in autoimmune disease: (1) interaction between Clec4b-Ncf1 manifests as an additive effect on PIA clinical outcome and (2) stimulation via Clec4b induces ROS production through the Ncf1/NOX2 complex, an activation pathway shown to be of major regulatory impact on the development of the inflammatory response and arthritis. Here, NCF1 is linked to arthritic joint disease.