Dysregulated B cell homeostasis and the involvement of B cell-activating factor in the progression of diabetic retinopathy

Diabetic retinopathy (DR) is a major cause of vision loss and is characterized by inflammation induced microvascular damage, but the contribution of B-cell-mediated inflammation and its key factor BAFF in the DR progression remains poorly understood. In the present study, we first found that DR patients exhibited increase in frequency of B cell and a concurrent reduction in Breg frequency compared to controls, accompanied by significantly elevated BAFF concentrations in both serum and aqueous humor, with levels peaking in proliferative DR. To further elucidate the role of B cell and BAFF, we conducted in vitro and in vivo experiments. In vitro, high-glucose stimulation of BV-2 microglial cells induced upregulation of BAFF and its receptor BAFF-R, and treatment with recombinant BAFF significantly enhanced microglial activation, as evidenced by increased Iba-1 expression. In vivo, STZ-induced diabetic mice showed the similar trends of the B cell and Breg imbalances observed in patients, with alongside marked upregulation of retinal BAFF and BAFF-R expression, consistent with the clinical findings. Importantly, BAFF neutralization significantly attenuated retinal vascular leakage in STZ-diabetic mice. Collectively, these findings suggest that BAFF-driven microglial activation and B cell-mediated inflammation are critical contributors to retinal vascular disruption in DR.