Abstract
Abstract Objective: Our ‘self-organized criticality theory’ explaining the cause of SLE shows that full-matured CTL generated via antigen cross-presentation induces lupus tissue injuries. Here we examine the molecular details of antigen cross-presentation to clarify how effector CTL is generated. Methods: Bone marrow-derived DC (BMDC) from BALB/c mice was cultured with fluorescent-labeled OVA. EEA1, calnexin and Sec61 were detected by using immunofluorescent staining. MG132 or primaquine (PQ) was repeatedly co-immunized with OVA to inhibit proteasomal degradation or endosomal trafficking to cell surface, respectively. Proteinuria and IFNγ-producing CD8+ T cell in spleen were examined. Results: In BMDC, OVA co-localized with EEA1, an endosomal marker. However, OVA was gradually separated from EEA1. In contrast, OVA never co-localized with calnexin, a ER marker. Sec61, a translocon, was co-localized with OVA, which indicated that OVA was transported from endosome to cytoplasm via Sec61. MG132, which inhibits proteasomal degradation, and PQ, which inhibits endosomal trafficking to cell surface, abrogated generation of CTL and development of nephritis. Conclusion: Endosomal trafficking, bypassing ER, is important not only in antigen cross-presentation but also development of lupus nephritis. Export of antigen from endosome to cytoplasm via Sec61 seems to be the first step in antigen cross-presentation, and subsequent the generation of lupus nephritis.
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