(708) LatY136F mice: a preclinical model for IgG4-related disease and autoimmune disorders

Introduction/Rationale: 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.