Molekulare Mechanismen Granulozyten-abhängiger Gewebeschädigung durch Autoantikörper
Zusammenfassung der Projektergebnisse
The response of granulocytes cells to immune complexes, extracellular matrix proteins, cytokines, and cellular damage is regulated by a complex net of intracellular signal transduction pathways. The overall goal of the present project was to address the mechanisms of autoimmune tissue damage. In the first period of the grant support, we broadly followed two main aims, namely the development and optimization of disease models reproducing the autoantibody-induced granulocyte-dependent skin damage and mapping the pathogenically relevant underlying Fcγ-dependent pathogenic signaling events. We have directed considerable efforts at developing adequate animal models of buulous pemphigoid, a markedly clinically and histopathologically inflammatory disease characterized by dense dermal infiltrates of granulocytes. The animal models induced by the passive transfer of collagen XVII-specific antibodies show improved key features, including the induction of extensive skin blistering disease in adult mice and, importantly, the development of spontaneous lesions (i.e., not triggered by applying local trauma). While both models show an inflammatory phenotype, whitout prior immunization with rabbit IgG there is a lower disease activity and even when pre-immunizing with rabbit IgG, tissue damage is only partly dependent on granulocytes. The fact that the latter model is dependent on the preimmunization with rabbit IgG prior to the injection with collagen XVII-specific rabbit IgG significantly adds to the complexity of this model and should be taken into account when designing experiments addressing the role of molecules or pathways, which may also influence the immune response. In parallel sets of experiments, we have characterized the pathogenic potential of IgA autoantibodies from patients with IgA-associated skin diseases. In addition, the results of this project using various ex vivo and animal models show that blister-inducing autoantibodies recognize different epitopes on epidermal basement membrane collagen. Using newly developed and previously established models of autoantibody-induced granulocyte-dependent skin damage, we have investigated the pathogenic relevance of several molecules/pathways for the autoimmune tissue injury. As hypothesized, a major role for the activation of granulocytes by autoantibodies was demonstrated in the autoimmune skin models for Syk, Src-family kinases and Rac2. Based on preliminary results, therapeutic approaches involving inhibitors of Syk and Rac2 appear promising, while inhibition of ROS production using the plant flavonoid luteolin did not signficantly curb the experimental blistering disease. In conclusion, the results of this project demonstrate that deficiency of several signaling molecules rendered mice completely unresponsive to immune activation by anti-collagen antibodies by disabling pathways of FcγR-mediated signaling crucial for autoantibody-induced tissue damage.
Projektbezogene Publikationen (Auswahl)
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Cross-reactivity of autoantibodies from patients with epidermolysis bullosa acquisita with murine collagen VII. Cell Mol Life Sci, 67:1343-51, 2010
Csorba K, Sesarman A, Oswald E, Feldrihan V, Fritsch A, Sitaru C
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Ectodomain shedding generates neoepitopes on collagen XVII: role in autoimmune blistering diseases. J Immunol, 15;185:4938-47, 2010
Nishie W, Lamer S, Schlosser A, Licarete E, Franzke CW, Hofmann SC, Jackow J, Sitaru C, Bruckner-Tuderman L
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Development of an ELISA for sensitive and specific detection of IgA autoantibodies against BP180 in pemphigoid diseases. Orphanet J Rare Dis, 28;6:31, 2011
Csorba K, Schmidt S, Florea F, Ishii N, Hashimoto T, Hertl M, Kárpáti S, Brucknera a Tuderman L, Nishie W, Sitaru C
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IgA-FcαRI interactions induce severe tissue damage in chronic inflammatory diseases. J Immunol. 2012 Aug 15;189(4):1594-601
van der Steen L, Bakema JE, Tuk CW, Sesarman A, Kirtschig G, Sitaru C, van Egmond M
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Interaction of human IgG autoantibodies with murine innate immunity factors: implications for disease models using the passive transfer of IgG. Immunol Lett, 143:92-100, 2012
Sesarman A, Oswald E, Chiriac MT, Csorba K, Vuta V, Feldrihan V, Bruckner-Tuderman L, Sitaru C
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The flavonoid luteolin inhibits Fcγ-dependent respiratory burst in granulocytes, but not skin blistering in a new model of pemphigoid in adult mice. PLoS ONE, 7(2): e31066, 2012
Oswald E, Sesarman A, Franzke CW, Wölfle U, Bruckner-Tuderman L, Jakob T, Martin SF, Sitaru C
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Sheep antibodies to collagen XVII/BP180 are pathogenic in a novel model of bullous pemphigoid in adult wild-type mice. Orphanet J Rare Dis, 2013 ;8:17
Chiriac MT, Licarete E, Sas AG, Rados AM, Lupan I, Chiriac AM, Speth H, Pop-Vancia V, Domsa I, Sesarman A, Popescu O, Sitaru C
