LatY136F mice: a preclinical model for IgG4-related disease and autoimmune disorders 2328676

Abstract

Abstract Introduction Experimental preclinical models are powerful research tools to explore autoimmune diseases as well as the efficacy and mechanism of action for novel therapeutics. Mice with a loss-of-function mutation in the LAT adaptor (LatY136F) develop an autoimmune and type 2 inflammatory disorder called defective LAT signalosome pathology (DLSP). DLSP manifestations involve accumulation of Th2 effector cells, polyclonal B cell activation, IgG1/IgE hypergammaglobulinemia and systemic autoimmunity with nephritis and severe proteinuria. The pathogenic CD4+ T cells developing in LatY136F mice have been solely analyzed in bulk, precluding to determine whether the LatY136F mouse constitutes at single-cell resolution an authentic preclinical model of human IgG4-Related Disease (IgG4-RD). This study aims to validate the LatY136F mouse as a preclinical tool for investigating the pathogenesis and treatment of IgG4-RD and type 2 autoimmune diseases at the single-cell level. Methods We used single-cell omics approaches to analyze the cellular trajectory leading to pathogenic CD4 T cells responsible for the LATY136F DLSP, a mimic of IgG4-RD. Results Single cell omics results showed that CD4+ Tfh and CTL, activated B cells, and plasma cells were found in LATY136F spleen and lung. Such cell constellation entailed all the cell types causative of human IgG4-RD. Importantly, targeted therapies using monoclonal antibodies and CAR T-cells effectively reversed LATY136F disease manifestations. Conclusion Our findings elucidate the etiology of the LatY136F DLSP and qualify it as a model of IgG4-RD and of autoimmune and inflammatory disorder. Our model is a useful tool to facilitate therapeutic target discovery and the preclinical evaluation of drug candidates intending to treat IgG4-RD, type 2 immune disorders and inflammatory fibrotic conditions. Funding Source - Centre National de la Recherche Scientifique (CNRS) - Institut National de la Santé et de la Recherche Médicale (INSERM) - The European Research Council under the European Union’s Horizon 2020 research and innovation program (Grant agreement 787300 t Topic Categories Therapeutic Approaches to Autoimmunity (THER)