Walnut antigens can trigger autoantibody development in patients with pemphigus vulgaris through a “hit-and-run” mechanism

Background: Environmental factors, as well as genetic predisposition, are known to be critical for the development of autoimmunity. However, the environmental agents that trigger autoimmune responses have remained elusive. One possible explanation is the “hit-and-run” mechanism in which the inciting antigens that initiate autoimmune responses are not present at the time of overt autoimmune disease. Objective: After our previous findings that some allergens can incite autoimmune responses, we investigated the potential role of environmental allergens in triggering autoantibody development in patients with an autoimmune skin disease, pemphigus vulgaris (PV). Methods: Revertant/germline mAbs (with mutations on variable regions of heavy and light chains reverted to germline forms) of 8 anti–desmoglein (Dsg) 3 pathogenic mAbs from patients with PV were tested for reactivity against a panel of possible allergens, including insects, pollens, epithelia, fungi, and food antigens. Results: All the PV germline mAbs were reactive to antigens from walnut, including the well-known allergen Jug r 2 and an uncharacterized 85-kDa protein component. Sera from patients with PV contained significantly greater levels of anti-Dsg3 autoantibodies than walnut-specific antibodies, suggesting that the autoreactive B-cell response in patients with PV might be initially triggered by walnut antigens but is subsequently driven by Dsg3. Conclusion: Our findings suggest that walnut antigens/allergens can initiate autoantibody development in patients with PV through a “hit-and-run” mechanism. The revertant/germline mAb approach might provide a paradigm for the etiological study of other allergic and autoimmune diseases.