Project Details
Projekt
Cutaneous complement C3 as key driver of pemphigoid disease pathogenesis
Subject Area
Dermatology
Term
from 2015 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 269234613
Activation of the complement system is a key pathway in pemphigoid diseases (PD), evidenced by presence of complement deposits in the skin of PD patients and the resistance of mice with specific complement deficiencies to experimental PD. Experimental studies confirmed a strong contribution of complement anaphylatoxin C5a and its receptor C5aR1 in PD. On the other hand, the contribution of many non-anaphylatoxin complement cleavage products remains largely elusive. For instance, even though the C3 activation product C3b and its breakdown fragments iC3b and C3d(g) deposit at the dermal-epidermal junction (DEJ) in PD patients, their detection even serving as important diagnostic hallmark, little is known about the actual contribution of these C3 opsonins to the disease. There are several compelling reasons to address the role of C3 opsonins in PD in greater detail: first, various antibody classes, including autoantibodies arising during PD, activate complement and can promote opsonization of (auto)antigens with C3 activation products, forming highly proinflammatory and immunogenic “immune complexes” (IC). Second, our preliminary data show how such IC, consisting of C3 opsonized IgG-bound PD autoantigens, provoke an enhanced inflammatory response of granulocytes, key skin-infiltrating cellular mediators in PD. Third, in a condition-worsening feedback loop, ongoing cutaneous inflammatory responses can further increase local C3 production in the skin. Finally, we identified that local (non-systemic) sources of complement C3 are indispensable for the generation of IgG responses to skin-localized (auto)antigens. Collectively, these observations are consistent with the idea that C3 opsonins play a central role not only in PD diagnosis, but actually directly contribute to its development and to the perpetuation of PD, fueling a deleterious vicious cycle of inflammation, local C3 expression, opsonization and autoantibody production. Importantly, since this vicious cycle revolves around local presence and production of C3 opsonins in the skin, we anticipate that cutaneous C3 sources present potent, possibly topically amenable, therapeutic targets. In P7, we will therefore (i) pinpoint relevant local cutaneous C3 sources in PD, (ii) dissect their impact on skin inflammation and vice versa, (iii) determine the impact of local C3 production on the humoral immune response towards PD antigens, (iv) explore the therapeutic potential of compounds that downregulate C3 sources or inhibit dermal activation and deposition of C3 opsonins in preclinical PD model systems. To achieve these goals, this project pairs expertise in clinical PD and its model systems (Ludwig) with in-depth background on complement C3 and its diverse immune-regulatory functions (Verschoor). With the advent of C3-targeting compounds, receiving orphan drug status and their development approaching phase II clinical trials, we anticipate that C3-modulation will present a powerful mode to address PD.
DFG Programme
Clinical Research Units
