Increase of endosomal Sec61 enhances antigen cross-presentation and induces immune glomerular injury: a novel ‘self-organized criticality theory’ explaining the cause of systemic lupus erythematosus (BA4P.129)

Abstract

Abstract Objective: We found that systemic lupus erythematosus (SLE) was induced by repeatedly immunizing the mice with antigen, and have proposed a novel ‘self-organized criticality theory’ explaining the cause of SLE. CTL generated via antigen cross-presentation induces lupus tissue injuries. Here we examine the molecular mechanism of antigen cross-presentation in relation to lupus nephritis. Methods: Bone marrow-derived DC (BMDC) and splenic DC (spDC) were cultured with OVA and an inhibitor of Sec61 Exotoxin A (Exo A) to examine the localization of early endosome antigen 1 (EEA1), calnexin, Sec61 and OVA. Sec61 was immunoprecipitated from DC, followed by detection of OVA. OVA in cytoplasm was also detected. Mice were repeatedly immunized with OVA and Exo A. Sec61 in endosome of spDC was detected using immunoprecipitation of EEA1. Results: In DCs, OVA was co-localized with an endosomal marker EEA1, and subsequently separated from EEA1. OVA was not co-localized with ER marker calnexin. Instead, OVA was co-localized and co-precipitated with Sec61. OVA was detected in cytoplasm of BMDC, however, Exo A abolished the detection of OVA. In spDC of mice developed glomerular injury, not only Sec61 in endosome but also OVA in cytoplasm were increased. Further, co-immunization with OVA and Exo A abrogated the development of glomerular injury. Conclusion: Increase of Sec61 in endosome promotes antigen cross-presentation and is essential for the development of glomerular injury likely of SLE.