Plenary 4

21 Mar 2026 11:50 12:30

101

Wayne Huey-Herng SheuTaiwan Moderator

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Time	Session

11:50 12:30	Exploring the World of Autoimmune Disease: from Genetic Manipulation to Disease Reversal Huey-Kang SytwuTaiwan Speaker Exploring the World of Autoimmune Disease: from Genetic Manipulation to Disease ReversalAbstract for Asia Oceania Congress of Endocrinology 2026 Huey-Kang Sytwu1 2 1 National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Taiwan 2 Department of Microbiology and Immunology, National Defense Medical University, Taiwan TITLE: Exploring the world of autoimmune disease: From genetic manipulation to disease reversal Abstract: Insulin-dependent diabetes mellitus (IDDM) is a T cell-mediated autoimmune disease. To delineate the protective roles of some immune modulatory molecules, such as soluble decoy receptor 3 (DcR3), cytotoxic T lymphocyte antigen 4 (CTLA4), program death ligand 1 and 2 (PD-L1 and 2), heme oxygenase 1 (HO-1), and chemokine receptor D6 in the autoimmune process and to search for potential preventive and/or therapeutic targets in this disease, we have generated (a) insulin promoter (pIns)-sDcR3 transgenic non-obese diabetic (NOD) mice, (b) pIns-single chain anti-CTLA4 transgenic NOD mice, (c) pIns-single chain anti-4-1BB transgenic NOD mice, (d) pIns-PD-L1 transgenic NOD mice, (e) pIns-HO-1 transgenic NOD mice, and (f) pIns-D6 transgenic NOD mice and demonstrated their immunomodulatory potential and underlying mechanisms. Meanwhile, to explore the modulatory potential of interleukin-12, 23 and 27 on autoimmune diabetes, we have generated following transgenic, knockout and knockdown NOD mice: (1) Th1 and Th2 doubly transgenic (2) IL-12 knockout (3) IL-23 knockdown (4) IL-27 knockdown NOD mice. Our results revealed that 20% IL-12-deficient NOD mice still developed autoimmune diabetes, the diabetic incidence of IL-23 knockdown NOD mice is lower than that of control littermates, and the number and percentage of Th1 cells are dramatically decreased and Th17 cells are increased in IL-27 knockdown mice, indicating a differential role of IL-12 cytokine family in modulating Th1 and Th17 cell development during autoimmune diabetogenic process. Previously, we demonstrated that overexpression of B lymphocyte-induced maturation protein-1 (Blimp-1) in T cells decreases IL-21 expression and suppresses autoimmune diabetes, whereas, lacking Blimp-1 in T cells upregulates IL-21 and results in severe colitis and autoimmune encephalomyelitis in NOD mice. Here, we further illustrated that Blimp-1 represses IL-21 by reducing chromatin accessibility and evicting an IL-21 activator, c-Maf on its promoter. Moreover, an IL-21-accelerating autoimmune diabetogenesis in SUMO-defective c-Maf transgenic mice can be overridden by Blimp-1 overexpression-mediated reduction of permissive chromatin structures at Il21 locus. We also explored the fundamental mechanisms by which a high-salt diet (HSD) affects susceptibility to or modifies autoimmune diseases. we generated T-cell–specific STE20/SPS1-related proline/alanine–rich kinase (SPAK) knockout NOD mice and demonstrated that SPAK deficiency in T cells significantly attenuated diabetes development in NOD mice by downregulating IL-21 expression in CD4+ T cells. Furthermore, HSD-triggered diabetes acceleration was abolished in HSD-fed SPAK knockout mice when compared with HSD-fed NOD mice, suggesting an essential role of SPAK in salt-exacerbated T-cell pathogenicity. Finally, by using gain- and loss-of-function approaches, we demonstrated that T cell-specific Mgat5 overexpression-induced higher tetra-antennary N-glycans exacerbate autoimmune diabetes, whereas mutant Mgat5L188R-associated tetra-antenna deficiency completely prevents disease in a CD8+ T cell-dependent manner. Making full use of these unique mouse strains, we are quantitatively and qualitatively investigating the immunopathogenic mechanisms of autoimmune diabetes and providing valuable information for the development of novel immunotherapies. 101

Time

Session

11:50

12:30

Exploring the World of Autoimmune Disease: from Genetic Manipulation to Disease Reversal

Huey-Kang SytwuTaiwan Speaker Exploring the World of Autoimmune Disease: from Genetic Manipulation to Disease ReversalAbstract for Asia Oceania Congress of Endocrinology 2026 Huey-Kang Sytwu1 2 1 National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Taiwan 2 Department of Microbiology and Immunology, National Defense Medical University, Taiwan TITLE: Exploring the world of autoimmune disease: From genetic manipulation to disease reversal Abstract: Insulin-dependent diabetes mellitus (IDDM) is a T cell-mediated autoimmune disease. To delineate the protective roles of some immune modulatory molecules, such as soluble decoy receptor 3 (DcR3), cytotoxic T lymphocyte antigen 4 (CTLA4), program death ligand 1 and 2 (PD-L1 and 2), heme oxygenase 1 (HO-1), and chemokine receptor D6 in the autoimmune process and to search for potential preventive and/or therapeutic targets in this disease, we have generated (a) insulin promoter (pIns)-sDcR3 transgenic non-obese diabetic (NOD) mice, (b) pIns-single chain anti-CTLA4 transgenic NOD mice, (c) pIns-single chain anti-4-1BB transgenic NOD mice, (d) pIns-PD-L1 transgenic NOD mice, (e) pIns-HO-1 transgenic NOD mice, and (f) pIns-D6 transgenic NOD mice and demonstrated their immunomodulatory potential and underlying mechanisms. Meanwhile, to explore the modulatory potential of interleukin-12, 23 and 27 on autoimmune diabetes, we have generated following transgenic, knockout and knockdown NOD mice: (1) Th1 and Th2 doubly transgenic (2) IL-12 knockout (3) IL-23 knockdown (4) IL-27 knockdown NOD mice. Our results revealed that 20% IL-12-deficient NOD mice still developed autoimmune diabetes, the diabetic incidence of IL-23 knockdown NOD mice is lower than that of control littermates, and the number and percentage of Th1 cells are dramatically decreased and Th17 cells are increased in IL-27 knockdown mice, indicating a differential role of IL-12 cytokine family in modulating Th1 and Th17 cell development during autoimmune diabetogenic process. Previously, we demonstrated that overexpression of B lymphocyte-induced maturation protein-1 (Blimp-1) in T cells decreases IL-21 expression and suppresses autoimmune diabetes, whereas, lacking Blimp-1 in T cells upregulates IL-21 and results in severe colitis and autoimmune encephalomyelitis in NOD mice. Here, we further illustrated that Blimp-1 represses IL-21 by reducing chromatin accessibility and evicting an IL-21 activator, c-Maf on its promoter. Moreover, an IL-21-accelerating autoimmune diabetogenesis in SUMO-defective c-Maf transgenic mice can be overridden by Blimp-1 overexpression-mediated reduction of permissive chromatin structures at Il21 locus. We also explored the fundamental mechanisms by which a high-salt diet (HSD) affects susceptibility to or modifies autoimmune diseases. we generated T-cell–specific STE20/SPS1-related proline/alanine–rich kinase (SPAK) knockout NOD mice and demonstrated that SPAK deficiency in T cells significantly attenuated diabetes development in NOD mice by downregulating IL-21 expression in CD4+ T cells. Furthermore, HSD-triggered diabetes acceleration was abolished in HSD-fed SPAK knockout mice when compared with HSD-fed NOD mice, suggesting an essential role of SPAK in salt-exacerbated T-cell pathogenicity. Finally, by using gain- and loss-of-function approaches, we demonstrated that T cell-specific Mgat5 overexpression-induced higher tetra-antennary N-glycans exacerbate autoimmune diabetes, whereas mutant Mgat5L188R-associated tetra-antenna deficiency completely prevents disease in a CD8+ T cell-dependent manner. Making full use of these unique mouse strains, we are quantitatively and qualitatively investigating the immunopathogenic mechanisms of autoimmune diabetes and providing valuable information for the development of novel immunotherapies.

101