LTB4/BLT1 gatekeeping Effector Cell Recruitment in Pemphigoid Diseases

Illuminating the orchestration of effector cell recruitment into the skin after deposition of PD autoantibodies at the dermal-epidermal junction (DEJ) is key to develop new therapeutic strategies for PD and is therefore a major goal of the CRU “Pemphigoid Diseases”. In a running DFG project (funded from 07/2013 – 06/2016), we have recently found that deficiency in LTB4/BLT1 confers dramatic resistance to PD skin inflammation with effector cell recruitment into the skin completely abrogated. These findings add LTB4/BLT1 to the list of molecular pathways absolutely critical for the recruitment of effector cells and, consequently, for the eruption of PD skin inflammation. Project 5 will follow up these intriguing findings and will detail the role of LTB4/BLT1 in pemphigoid disease. It will define the molecular mechanisms inducing LTB4 release as one of the early events indispensable to precipitate skin inflammation. Additionally, it will elucidate the temporal and spatial organization of the molecular cues guiding neutrophils from the peripheral blood to the DEJ, herein particularly highlighting the central role of LTB4 in this process. This research will be instrumental to establish a comprehensive model of the emergence of skin inflammation in the effector phase of PD.
Finally, it will also translate its findings into the human situation by contrasting the responsiveness and state of activity of the LTB4/BLT1 pathway in different stages of bullous pemphigoid to that in healthy controls. Herein, we will provide functional data to the genetic and epigenetic analyses in LTB4/BLT1 pathway genes conducted in Project 1. Our human studies aim at consolidating the role of LTB4/BLT1 in PD, evaluating the potential of this pathway as biomarker, and preparing a clinical trial on the therapeutic potential of LTB4/BLT1 inhibition.