Innovative Vaccine Composed of the BAFF Protein Containing an Unnatural Amino Acid Triggers the Production of Autoantibodies against Endogenous BAFF and Alleviates Collagen-Induced Arthritis.

B-cell-activating factor (BAFF) plays a fundamental role in B lymphocyte survival and homeostasis, and aberrant BAFF signaling is closely related to numerous autoimmune disorders. Although passive immunization strategies using monoclonal antibodies and engineered receptors have achieved success in treating autoimmune diseases, disadvantages, including the cost of continuous administration and potential immunogenicity, still exist. Here, we report an innovative active anti-BAFF vaccine that was developed through the site-specific incorporation of the unnatural amino acid p-nitrophenylalanine (pNO(2)-Phe) in soluble murine BAFF (DmBAFF). It triggered a humoral immune response against endogenous BAFF and successfully alleviated collagen-induced arthritis in a murine model. An analysis of the immune response to the pNO(2)-Phe-containing DmBAFF mutants in both DBA/1-(H2(q)) and C57BL/6 (H2(b)) mice indicated that the mutants disrupted both T cell and B-cell tolerance toward the endogenous molecule and resulted in the production of strong and distinct antibodies against the corresponding modified epitopes of WT-mBAFF. Preventive vaccination with DmBAFF containing pNO(2)-Phe at Y91 or Y139 significantly reduced the arthritis incidence and joint inflammation compared with DmBAFF but did not obviously affect T and B-cell subpopulations. Based on these data collectively, preventive vaccination with BAFF containing the site-specific incorporation of pNO(2)-Phe is an effective prophylactic intervention option for autoimmune arthritis. The therapeutic potential of this vaccine after disease onset remains to be evaluated.