The Role of Monocyte-derived Cells and the molecular Mechanisms of their Recruitment in the Pathogenesis of Pemphigoid Diseases

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The recruitment of effector cells into the skin is the pathogenic key process initiating and fueling skin inflammation in PDs. The spatiotemporal dynamics of effector cell recruitment from the blood vessel lumen to the dermal-epidermal junction (DEJ) as well as the molecular cues choreographing this recruitment are only poorly understood. In the 1st FP, we have set out to chart the spatiotemporal dynamics of the recruitment of different effect cell populations, including PMNs and monocytes, in emerging PD skin lesions by intravital multiphoton microscopy (IMM). We have also set out to unfold the molecular cues responsible for early effect cell recruitment, herein primarily focusing on leukotriene B4 (LTB4) and its receptor BLT1. We have uncovered that already few hours after the deposition of autoantibodies at the DEJ, significant amounts of LTB4 are generated in the skin and are indispensable to initiate the recruitment of both PMNs and monocytes into the skin and, consequently, to precipitate skin lesions. We have also deciphered that the complement fragment C5a and its receptor C5aR1 act upstream of LTB4 and presumably initiate its release. These findings have already instigated collaborations with pharmaceuticals companies. As a result, we are about to test the efficacy of novel LTB4 and C5 inhibitors in BP patients. Charting the kinetics of effector cell recruitment, we have unraveled that, unexpectedly, PMNs are not recruited in significant numbers into the skin until day 3 after antibody deposition. In contrast, monocytes are recruited into the skin and guided to the DEJ almost immediately upon antibody deposition, suggesting that monocytes may orchestrate the subsequent massive influx of PMNs into the skin. In addition, we have found evidence that in later stages of skin inflammation monocytes may act in concert with PMNs in executing dermal-epidermal cleft formation. Collectively, our findings highlight monocytes as potential, previously overseen, major contributors to PD skin inflammation. In the 2nd FP, we will therefore systematically investigate the role of monocytes in PD, focusing on their putative role as facilitators of PMN recruitment. We will also elucidate the molecular mechanisms mediating the recruitment of monocytes into the skin. We hypothesize that these molecular mechanisms depend on the C5a/C5aR1-LTB4/BLT1 axis, thus providing further evidence for the efficacy of LTB4/BLT1 or C5a/C5aR1 inhibitors in PDs. Importantly, we will also profile monocyte populations and their dynamics in BP patients to translate our findings into the human situation and evaluate monocytes as potential drug targets and biomarkers