Abstract
Epidermolysis bullosa acquisita (EBA) is an autoimmune skin blistering disease characterized by IgG autoantibodies (aAb) against type VII collagen (COL7). The mechanisms controlling the formation of such aAbs and their effector functions in the skin tissue are incompletely understood. Here, we assessed whether the inhibitory IgG Fc receptor, FcγRIIB, controls the development of autoimmune skin blistering disease in an active model of EBA. For this purpose, we immunized congenic EBA-susceptible B6.SJL-H2s (B6.s) and B6.s-Fcgr2b−/− mice with the immunodominant vWFA2 region of COL7. B6.s-Fcgr2b−/− mice developed a strong clinical phenotype with 15 ± 3.3% of affected body surface area at week 4. In contrast, the body surface area in B6.s mice was affected to a maximum of 5% at week 6 with almost no disease signs at week 4. Surprisingly, we already found strong but similar COL7-specific serum IgG1 and IgG2b aAb production at week 2. Further, aAb and C3b deposition in the skin of B6.s and B6.s-Fcgr2b−/− mice increased between weeks 2 and 6 after vWFA2 immunization. Importantly, neutrophil skin infiltration and activation was much stronger in B6s-Fcgr2b−/− than in B6.s mice and already present at week 2. Also, the early aAb response in B6.s-Fcgr2b−/− mice was more diverse than in wt B6.s mice. Reactive oxygen species (ROS) release from infiltrating neutrophils play a crucial role as mediator of skin inflammation in EBA. In line, sera from B6.s and B6.s-Fcgr2b−/− mice induced strong ROS release from bone marrow-neutrophils in vitro. In contrast to the antibody-transfer-induced EBA model, individual targeting of FcγRIII or FcγRIV decreased ROS release to 50%. Combined FcγR blocking abrogated ROS release from BM neutrophils. Also, ROS release induced by COL7-specific serum IgG aAbs was significantly higher using BM neutrophils from B6.s-Fcgr2b−/− than from B6.s mice. Together, our findings identified FcγRIIB as a suppressor of skin inflammation in the active EBA model through inhibition of early epitope spreading, protection from strong early neutrophil infiltration to and activation of neutrophils in the skin and suppression of FcγRIII activation by IgG1 aAbs which drive strong ROS release from neutrophils leading to tissue destruction at the dermal-epidermal junction.
Highlights
Confirming previous findings [21], we found that vonWillebrand-factor-A-like domain 2 (vWFA2)-specific rabbit IgG, that are used in antibody-transfer model of Epidermolysis bullosa acquisita (EBA), drive Reactive oxygen species (ROS) release through exclusive activation of FcγRIV, whereas FcγRIII does not seem to play any role (Figure 6E)
EBA is a rare autoimmune skin disease, with an incidence of 0.08–0.5 new cases per million per year, in which autoantibodies to COL7 bind to the DEJ and induce blister formation on the skin and erosions on the mucus membranes [33,34,35]
In an antibody-transfer model of EBA, using rabbit-derived antibodies against COL7, it was shown that these antibodies activate the complement system, resulting in the release of pro-inflammatory cytokines and chemokines, and neutrophil recruitment into the skin [18]
Summary
Aggregation by IgG immune complexes (IC) results in the initiation of activating or inhibitory signaling cascades. With the exception of the inhibitory FcγRIIB, all other FcγRs trigger cellular activation. FcγRs are predominantly expressed by innate immune cells. The relative distribution of activating/inhibitory FcγR expression sets the threshold of innate immune cell activation through IgG ICs [1]. FcγRs play an important role in the host defense against pathogens as receptors for pathogen phagocytosis. They promote protective immunity against pathogens [2]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
