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Abstract Number: 2035

Systemic Lupus Erythematosus (SLE) Is Caused by Expanded DOCK8-Positive Autoantibody-Inducing CD4 T (aiCD4 T) Cell

Shunichi Shiozawa1, Ken Tsumiyama 1, Yumi Miyazaki 2, Keiichi Sakurai 3, Takahiko Horiuchi 4, Motohiro Oribe 5, Takashi Yamane 6, Hidetoshi Kagawa 7 and Kazuko Shiozawa 8, 1Institute for Rheumatic Diseases, Ashiya, Japan, 2Kyushu University Beppu Hospital, Tokyo, Japan, 3Rheumatology and Allergology, St. Marianna University School of Medicine, Tokyo, Japan, 4Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan, Beppu, Japan, 5Oribe Rheumatology Clinic, Oita, Japan, 6Department of Rheumatology, Kakogawa Central City Hospital, Kakogawa, Japan, 7Rheumatology, Red Cross Society Himeji Hospital, Himeji, Japan, 8Rheumatic Diseases Center, Hyogo Prefectural Kakogawa Medical Center, Ashiya, Japan

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Autoimmunity, DOCK8 and anti-dsDNA, Systemic lupus erythematosus (SLE), T cells

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Session Information

Date: Tuesday, November 12, 2019

Session Title: SLE – Etiology & Pathogenesis Poster II

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.


Disclosure: S. Shiozawa, None; K. Tsumiyama, None; Y. Miyazaki, None; K. Sakurai, None; T. Horiuchi, None; M. Oribe, None; T. Yamane, None; H. Kagawa, None; K. Shiozawa, None.

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 January 28, 2023.
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