A humanized mouse model to study immune complex processing and clearance 2259807

Abstract

Abstract Introduction The complement system performs diverse functions spanning immune surveillance, pathogen defense, and developmental regulation. Upon antigen recognition, antigen—antibody immune complexes (ICs) activate complement and are opsonized with C3b. In humans, C3b-opsonized ICs bind to complement receptor 1 (CR1) on erythrocytes (E), a process termed immune adherence (IA), which directs IC trafficking to the liver and spleen for clearance. In contrast, in mice, ICs do not bind erythrocyte CR1 but associate with complement factor H (FH) on platelets (Plts), limiting the translational relevance of murine models for human IA biology. Another nuance increasing the complexity of these interactions is that aside from FH on platelets, in mice and humans, the liver generates FH and releases it into the plasma. Plasma FH deficiency causes diseases such as dense deposit disease. We hypothesized that expression of human CR1 on erythrocytes, combined with platelet-specific FH deletion while preserving plasma FH, would replicate the human IA pathway. Methods To achieve this goal, we generated FHfl/fl mice and crossed them with Pf4-Cre mice to selectively deplete FH in platelets, maintaining normal plasma FH. These were then bred with CR1hu mice to yield FH fl/fl Pf4-Cre CR1huTg offspring (CR1hu on erythrocytes, no FH on platelets, and intact plasma FH). Results Characterization confirmed platelet-specific FH deletion, preserved systemic complement regulation, and physiological CR1 expression on erythrocytes. Ongoing studies are assessing erythrocyte CR1hu as the IA receptor and tracking IC trafficking in vivo. Conclusion This novel humanized immune-adherence mouse model replicates the human CR1-dependent pathway for immune complex clearance, providing an essential tool to investigate complement-mediated mechanisms and develop targeted therapies for immune complex-driven diseases. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)