Session Type: Poster Session (Tuesday)
Session Time: 9:00AM-11:00AM
Background/Purpose: We previously found in reproducible experiments in which the mice not prone to autoimmune disease were immunized repeatedly with antigen that overstimulation of CD4 T cells led to the development of autoantibody-inducing CD4 T cell (aiCD4 T cell) which had undergone TCR revision capable of inducing varieties of autoantibody and antigen-specific CTL via antigen cross-presentation, after which they caused SLE (Tsumiyama K et al. PLoS ONE 4(12): e8382, 2009). Here we show that the aiCD4 T cell is DOCK8-positive, and this DOCK8+CD4 T cell caused SLE in the mice not prone to autoimmune disease when adoptively transferred. Further, the SLE as induced in the mice was cured by anti-DOCK8 antibody treatment. The DOCK8+CD4 T cells were found to be expanded in association with patients’ disease activity (SLEDAI).
Methods: The aiCD4 T cell was identified by transferring different CD4 T cell subsets of x12 OVA-immunized BALB/c mice into naïve mice and testing generation of autoantibodies in the recipients, where DOCK8 was identified by extraction of membrane proteins, electrophoresis, mass spectrometry of isolated subsets. The DOCK8+CD4 T cell was then transferred into naïve mice to confirm generation of classical SLE features. The number of DOCK8+CD4 T cell was measured in the PBMC of SLE patients and evaluated with reference to clinical manifestation.
Results: Transfer of DOCK8+CD4 T cells into naïve mice induced autoantibodies including anti-dsDNA and anti-Sm antibodies and organ diseases such as WHO IV/V lupus nephritis, skin liquefaction degeneration, and splenic periarteriolar fibrosis with amyloid-like deposits known as Onion-skin lesion classical to SLE. The lesion such as pericholangitis, pneumonitis, thyroiditis, perineuritis or panniculitis was also induced. Such manifestations subsided after anti-DOCK8 Ab treatment. The DOCK8+CD4 T cell was a large lymphocyte with abundant ER and mitochondria, expressing ICOS, PD1, Ly6C and LFA1 but not CXCR5. The DOCK8+CD4 T cell produced increased amounts of IFNg, IL-4, IL-6, IL-17, IL-21 and IL-22, but not IL-2. The TCR repertoire of DOCK8+CD4 T cell was significantly deviated. In the PBMC of active patients with SLE, DOCK8+CD4 T cells were significantly increased, whereas they were negligible in inactive disease, other rheumatic diseases, or healthy control.
Conclusion: We prove the self-organized criticality theory explaining that autoimmunity, i.e., SLE, arises as a natural consequence of routine but exaggerated immune response against antigen when stimulated maximally beyond immune system’s self-organized criticality, where expanded DOCK8+CD4 T cell was responsible for inducing SLE.
To cite this abstract in AMA style:Shiozawa S, Tsumiyama K, Miyazaki Y, Sakurai K, Horiuchi T, Oribe M, Yamane T, Kagawa H, Shiozawa K. Systemic Lupus Erythematosus (SLE) Is Caused by Expanded DOCK8-Positive Autoantibody-Inducing CD4 T (aiCD4 T) Cell [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/systemic-lupus-erythematosus-sle-is-caused-by-expanded-dock8-positive-autoantibody-inducing-cd4-t-aicd4-t-cell/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/systemic-lupus-erythematosus-sle-is-caused-by-expanded-dock8-positive-autoantibody-inducing-cd4-t-aicd4-t-cell/