Background/Purpose: IgG4-related disease (IgG4RD) is an immune-mediated fibroinflammatory condition characterized by multi-organ involvement, elevated serum IgG4, and IgG4-positive plasma cell infiltrates that form tumor-like lesions and fibrosis. However, conventional mice lack the IgG4 subclass, precluding in vivo modeling of IgG4RD. We aimed to develop humanized mouse models that produce human IgG4 and replicate key features of IgG4RD.

Methods: I established four distinct human IgG4-producing xenograft models using NSG (NOD-scid IL2rγnull) and NSG-hIL6 (human IL-6 transgenic NSG) immunodeficient mice as hosts. The models included the following: 1. NSG mice injected with human peripheral blood mononuclear cells (PBMCs).2. NSG-hIL6 mice, after sublethal irradiation, engrafted with human CD34+ hematopoietic stem cells via intrahepatic injection.3. NSG-hIL6 mice intravenously injected with Epstein–Barr virus (EBV)-immortalized B cells derived from IgG4RD patients.4. NSG mice injected with a luciferase-tagged, human IgG4-secreting K562 cell line.In all models, human IgG4 in mouse serum was measured by ELISA. Spleen, kidney, and salivary gland tissues were analyzed by histology and immunohistochemistry for IgG4+ cell infiltration, inflammation, and tumefactive lesions.

Results: All four models produced human IgG4 in circulation at significantly elevated levels relative to controls (a hallmark of IgG4RD), confirming engraftment. Histopathology of the spleen, kidney, and salivary glands showed dense IgG4+ lymphoplasmacytic infiltration with associated inflammation, tissue hypertrophy, and pseudotumor-like lesions, closely mirroring human IgG4RD pathology with fibroinflammatory tissue remodeling. Notable differences among the models were observed. The EBV-immortalized B cell model exhibited the highest serum IgG4 concentrations and the most extensive IgG4+ cell infiltration. The luciferase-expressing K562 model enabled bioluminescent tracking of IgG4-secreting cells, visualizing their migration and organ colonization. Finally, the CD34+ HSC model allowed observation of IgG4 class switching, a fundamental process in IgG4RD.

Conclusion: I developed four complementary humanized mouse models that recapitulate key features of IgG4RD. These in vivo models are valuable tools for investigating IgG4RD pathogenesis and testing new therapies. Each model has unique advantages: the PBMC model provides a straightforward platform for inducing IgG4 production; the CD34+ HSC model allows analysis of IgG4 class switching; the EBV-B cell model yields high serum IgG4 levels with severe multi-organ involvement; and the IgG4-secreting K562 model enables longitudinal bioluminescent tracking of IgG4-producing cells. Together, these models form a comprehensive platform for in-depth mechanistic studies and the development of new therapies for IgG4RD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-four-distinct-human-igg4-producing-mouse-models-recapitulating-igg4-related-disease/