AB0031 Sec61 is Essentially Required for Antigen Cross-Presentation and Induction of Lupus Kidney Disease: Proof of Concept, Self-Organized Criticality Theory Explaining the Cause of Sle. (10th June 2014)

• Record Type: Journal Article
• Authors: Tsumiyama, K.; Shiozawa, S.
• Is Part Of: Annals of the rheumatic diseases. Volume 73:Supplement 2(2014)
• Page Start: 814
• Page End: 814
• Publication Date: 2014-06-10
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2014-eular.3952
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: While antigen cross-presentation, the finding that breaks authentic theory of Zinkernagel & Doherty, has recently emerged in the field of immunology. We show here with regards to the pathogenesis of autoimmunity that an important role of antigen cross-presentation is the activation of cytotoxic T lymphocyte (CTL) by foreign antigen hence becomes the cause of immune tissue injuries. As to the cause of autoimmunity or SLE, we have proposed a novel theory, called the self-organized criticality theory, which explains that systemic autoimmunity necessarily takes place when the host's immune system is overdriven by repeated exposure to antigen, reaching levels that surpass the immune system's stability-limit, i.e., self-organized criticality (Ref 1, 2). We found a CD4 T cell subset that has passed thru TCRα but not TCRβ revision is generated at peripheral lymphoid organ spleen after heavily repeated immunization with any antigen, and we named this CD4 T cell an "autoantibody-inducing CD4 T cell" ( ai CD4 T cell). Interestingly, this ai CD4 T cell not only induced B cells to generate a large variety of autoantibodies, but also promoted final differentiation of CD8 T cells to CTL via antigen cross-presentation, and this CTL caused immune injuries such as lupus kidney disease (Ref 3). Objectives: We investigate antigen cross-presentation as a key mechanism in inducing lupus renal disease and show that Sec61 mediates antigen cross-presentation and induce lupus kidney disease. Methods: Bone marrow-derived dendritic cell (BMDC) was cultured with fluorescent-labeled OVA. Early endosome antigen 1 (EEA1), calnexin and Sec61 were detected using immunofluorescent staining. Sec61 was immunoprecipitated from OVA-pulsed BMDC lysate, followed by immunoblotting of OVA. Mice were repeatedly immunized with OVA to induce SLE. Splenic DC (spDC) was cultured with fluorescent-labeled OVA to examine localization of engulfed antigen. Further, exotoxin A was co-immunized with OVA to inhibit Sec61. Results: In BMDC, OVA was co-localized with an endosomal marker EEA1, and subsequently separated from EEA1. OVA was co-localized with Sec61, but not the ER marker calnexin. The result was similar when spDC was used. Engulfed OVA was co-precipitated with Sec61, and the amount of Sec61 in endosome was increased after repeated immunization with OVA. Instead, inhibition of Sec61 did not induce CTL nor renal injury, suggesting that OVA interacts with Sec61 hence exported from endosome to cytoplasm via Sec61. Conclusions: Increase of Sec61 in endosome and the export of antigen from endosome to cytoplasm via Sec61 are important for antigen cross-presentation and predispose to lupus kidney disease. References: 1, Shiozawa S. Joint Bone Spine 79:428, 2012. 2, Tsumiyama K et al. PLoS ONE 4(12): e8382, 2009. 3, Tsumiyama K et al. J Immunol 191:91, 2013. Disclosure of Interest: None declared DOI: 10.1136/annrheumdis-2014-eular.3952