Endosome-to-cytoplasm pathway via Sec61 and proteasomal degradation as an essential component of antigen cross-presentation and the lupus tissue injury in systemic lupus erythematosus (SLE): Extension of our self-organized criticality theory

Abstract

Abstract Objective We propose that SLE can be induced upon repeated immunization with any antigens in the mice normally not prone to SLE, in which newly generated autoantibody-inducing CD4 T cell (aiCD4 T cell) helps the generation of CTL via antigen cross-presentation and induces lupus tissue injury. Here we dissect the molecular mechanism of antigen cross-presentation. Methods Bone marrow-derived dendritic cell (BMDC) or splenic DC (spDC) was cultured with OVA, and inhibitor of Sec61 Exotoxin A (Exo A) or inhibitor of proteasome MG132. Mice were repeatedly immunized with OVA to induce SLE as in PLoS ONE 4:e8382, 2009 with/without Exo A or MG132, and immunoprecipitation or immunoblotting studies were performed. Results We show that accumulated antigen in the cytoplasm up-regulates the amount of cross-presentable antigen, thereby enhancing tissue injuries of SLE, in which Sec61 is responsible for endosome-to-cytoplasm transport of antigen: in the first, the amount of endosomal Sec61 and the amount of cytoplasmic OVA were increased in spDC after repeated immunization with OVA. Second, cytoplasmic OVA was increased after co-culture with inbibitor of proteasome MG132 in BMDC, but disappeared after adding inhibitor of Sec61 Exo A. Third, the generation of CTL and the development of lupus nephritis were both inhibited in vivo after repeated immunization with OVA in the presence of Sec61 inhibitor Exo A or proteasome inhibitor MG132. Conclusion For antigen cross-presentation, antigen must be transported from endosome to cytoplasm via Sec61 and then degraded through proteasome. The increase of endosomal Sec61 facilitates antigen cross-presentation, thereby contributing to the pathology of SLE.