The role of leukotriene B4 and its receptor BLT1 in the pathogenesis of the prototypical organ-specific autoimmune disease epidermolysis bullosa acquisita

• Applicant: Professor Dr. Christian David Sadik
• Subject Area: Dermatology ; Immunology ; Pharmacology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 238897420

Sequential lipid-cytokine-chemokine cascades orchestrating the recruitment of immune cells to inflammatory sites are a hallmark of the effector phase of the immune response. Herein, leukotriene B4 (LTB4) is often the lipid mediator initiating these cascades. Accordingly, inhibition of LTB4 or its receptor BLT1 protects from inflammation in diverse models of autoimmune disease. This role of LTB4/BLT1 was elaborated in most detail for autoantibody-induced arthritis. In this mouse model, LTB4 is required to act as chemoattractant initiating neutrophil recruitment.Epidermolysis bullosa acquisita (EBA) is a prototypical bullous autoimmune disease of the skin caused by autoantibodies against type VII collagen, present in the anchoring fibrils at the dermal-epidermal junction. In 2005 a research group at the Department of Dermatology in Lübeck described a mouse model of EBA, in which the formation of immune complexes at the dermal-epidermal junction initiates the recruitment of neutrophils to the skin, which in turn induce dermal-epidermal separation, the signature lesion of EBA, by radical oxygen species (ROS) release. The mechanisms inducing the release of ROS from neutrophils in this model, however, are still unknown. Recent in vitro experiments of the applicant suggest that LTB4 may be required. Although high levels of LTB4 can be found in blister fluid of bullous pemphigoid patients, another autoimmune disease similar to EBA, the role of LTB4/BLT1 in autoimmune skin diseases has not been addressed. The first-time applicant of this proposal was instrumental in elucidating the role and regulation of LTB4 in neutrophil recruitment in arthritis and in contriving the paradigm of lipid-cytokine-chemokine cascades as drivers of inflammation, which was spearheaded by Prof. Lusters lab at the Massachusetts General Hospital in Boston, where the applicant was working for 3.5 years. In the last 6 months, the applicant, funded by the DFG, learned to conduct the EBA mouse model in Prof. Zillikens lab in Lübeck. He has generated preliminary data indicating a major role of leukotrienes in the pathogenesis of EBA. The major hypothesis of the present proposal is that LTB4 is required for EBA, and that neutrophils are both its major source, and its major cellular target. Furthermore, it is hypothesized that in EBA, LTB4 acts in a bimodal way of action and mediates two pivotal effects on neutrophils by first acting as a chemoattractant initiating the recruitment of the first neutrophils into the dermis, and later by activating neutrophils in the dermis to release ROS and induce dermal-epidermal separation.In this project the overall requirement for LTB4/BLT1 in the EBA mouse model will be determined and the essential cellular sources and targets of LTB4 will be identified. Additionally, the molecular mechanisms LTB4 engages to drive skin inflammation will be precisely defined. These data will clarify the role of LTB4 in autoimmune bullous diseases of the skin.

• DFG Programme: Research Grants
• Participating Persons: Professor Dr. Ralf Joachim Ludwig; Professor Dr. Detlef Zillikens (†)