Epidermolysis bullosa acquisita (EBA) is an acquired, autoimmune blistering disease (AIBD) clinically characterized by erosions and blisters on the skin, and the presence of IgG class autoantibodies to type VII collagen. EBA, when compared to other AIBD, has a decreased responsiveness to therapy, making it essential to investigate the role of various disease contributing factors.
Myeloperoxidase (MPO) is a peroxidase enzyme abundantly expressed by neutrophils, the main effector cells in EBA, and contributes to tissue damage and the resulting inflammation in various diseases. To provide preclinical proof for the role of MPO during the disease, a mouse model for bullous pemphigoid (BP)-like EBA was utilized. WT mice displayed clinical signs of the disease while the Mpo-/- mice were completely protected and did not develop skin lesions. Bone marrow derived PMNs from WT and Mpo-/- mice were used to study the in vitro role of MPO. Mpo-/- PMN stimulated with immune complexes (IC) indicated a complete reduction in radical oxygen species (ROS) release, NOX dependent neutrophil extracellular traps (NET) formation, and leukotriene B4 (LTB4) release when compared to their WT counterparts. PMN from WT and Mpo-/- mice stimulated with IC did not indicate differences in expression of cell surface receptors CD11b, FcgRIII, FcgRIV, and C5aR1, or in chemotaxis towards C5a and LTB4. The specific role of MPO in the inhibition of ROS and formation of NETs could be confirmed by treating PMN from WT mice, before stimulation with IC, with PF-1355, a mechanism-based inhibitor of MPO.
Taken together, our results provide evidence that MPO plays a crucial role in AIBD. The mode of action may be attributed to the inhibition of LTB4 and ROS release, and NET formation, two disease-driving actions of neutrophils, in response to IC.