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Published on: May 22, 2020
Genetic identification and functional validation of FcγRIV as key molecule in autoantibody-induced tissue injury
Michael Kasperkiewicz1, Falk Nimmerjahn, Sabina Wende
1Department of Dermatology, University of Lübeck, Germany. Michael.Kasperkiewicz@uk-sh.de
Abstract:
Autoantibody-mediated diseases are clinically heterogeneous and often fail conventional therapeutic strategies. Gene expression profiling has helped to identify new molecular pathways in these diseases, although their potential as treatment targets largely remains to be functionally validated. Based on weighted gene co-expression network analysis, we determined the transcriptional network in experimental epidermolysis bullosa acquisita (EBA), a paradigm of an antibody-mediated organ-specific autoimmune disease characterized by autoantibodies directed against type VII collagen. We identified 33 distinct and differentially expressed modules, including Fcγ receptor (FcγR) IV and components of the neutrophil-associated enzyme system in autoantibody transfer-induced EBA. Validation experiments, including functional analysis, demonstrated that FcγRIV expression on neutrophils crucially contributes to autoantibody-induced tissue injury in the transfer model of EBA. Mice lacking the common γ-chain of activating FcγRs, deficient in FcγRIV or treated with FcγRIV function blocking antibody, but not mice deficient in FcγRI, FcγRIIB, FcγRIII or both FcγRI and FcγRIII, were effectively protected from EBA. Skin disease was restored in γ-chain-deficient mice locally reconstituted with neutrophils from wild-type, but not from γ-chain-deficient, mice. Our findings both genetically and functionally identify a novel disease-related molecule, FcγRIV, in an autoantibody-mediated disorder, which may be of importance for the development of novel targeted therapies.
Insights
Researchers identified Fc gamma receptor IV (FcγRIV) as a key driver of tissue damage in experimental epidermolysis bullosa acquisita, an autoimmune disease. Blocking FcγRIV offers a potential new therapeutic strategy for this condition.
Area of Science:
- Immunology
- Autoimmune Diseases
- Molecular Biology
Background:
- Autoantibody-mediated diseases are complex and often resist standard treatments.
- Gene expression profiling reveals potential therapeutic targets, but functional validation is needed.
- Experimental epidermolysis bullosa acquisita (EBA) is a model for antibody-mediated autoimmune diseases targeting type VII collagen.
Purpose of the Study:
- To identify and functionally validate novel molecular targets in experimental epidermolysis bullosa acquisita (EBA).
- To investigate the role of transcriptional networks in EBA pathogenesis.
- To explore Fc gamma receptor IV (FcγRIV) as a potential therapeutic target.
Main Methods:
- Weighted gene co-expression network analysis to determine the transcriptional network in EBA.
- Functional validation experiments, including neutrophil transfer studies.
- Genetic analysis using knockout mice deficient in various Fc gamma receptors (FcγRs) and FcγRIV-blocking antibodies.
Main Results:
- Identified 33 differentially expressed gene modules in EBA, including FcγRIV and neutrophil-associated enzymes.
- FcγRIV expression on neutrophils significantly contributes to autoantibody-induced tissue injury in EBA.
- Mice lacking the common γ-chain or deficient in FcγRIV were protected from EBA; FcγRIV blockade also conferred protection.
Conclusions:
- Fc gamma receptor IV (FcγRIV) is a novel, functionally validated disease-related molecule in antibody-mediated disorders like EBA.
- FcγRIV plays a crucial role in neutrophil-mediated tissue damage in EBA.
- Targeting FcγRIV represents a promising strategy for developing novel therapies for EBA and potentially other autoantibody-mediated diseases.
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