Xiaoxiao Wan, MD, PhD

Division

• Immunobiology

Education

• PhD (Immunology): University of Missouri, Columbia
• Postdoc (Immunology): Washington University School of Medicine
• MD, Clinical Medicine: Sichuan University

Research Lab

• Wan Lab

Clinical Interests

• Development of antigen-specific immunotherapy of type 1 diabetes
• Identification of biomarkers for indicating the onset of type 1 diabetes
• Identification of post-translational modifications that indicate islet dysfunction

Research Interests

Our laboratory focuses on examining pathogenic events responsible for initiating the development of tissue-specific autoimmune diseases. We primarily employ mouse experimental models to mechanistically dissect key factors involved in type 1 diabetes, a deteriorating autoimmune disorder that eventually destroys insulin-producing β-cells in the pancreatic islets. The research projects center on 1) Identifying antigenic targets involved in disease pathogenesis, which not only serves as a platform for activating antigen-specific autoreactive T cells but also can be used as diagnostic and therapeutic targets; 2) Examining the biological behaviors of the tissue innate immune system that finely tunes tissue homeostasis and shapes the phenotypic signatures of localized autoimmunity.

We recently identified a specific site in pancreatic β cells, the crinosomes, responsible for generating disease-relevant peptides. Crinosomes are a specific set of vesicles formed by fusion of insulin granules with lysosomes. As an enzyme-rich structure, crinosomes not only generate unique or “cryptic” epitopes from degraded protein segments but also produce neoepitopes formed by post-translational modifications. These immunogenic materials are released into circulation during β-cell degranulation and become an antigen source for sensitizing peripheral lymphoid tissues. We aim to better understand crinosome biology and apply this knowledge to diagnostic and therapeutic aspects of type 1 diabetes. Using a platform integrating mass spectrometry with immunological characterization, we are moving forward to determine disease-relevant epitopes in the islets and peripheral blood from humans with type 1 diabetes.

The pancreatic islet is a mini-organ essential for maintaining body metabolism. This tissue contains several types of endocrine cells, including the insulin-producing β cells, but only consists of one immune cell, the resident macrophages. Lineage tracing studies indicate that islet macrophages derive from definitive hematopoiesis. The islet macrophages are in intimate contact with β cells, extending long filopodia in between them. Some of these filopodia enter the blood lumen and can capture microparticles. Islet macrophages isolated from different mouse strains (NOD, NOD.Rag1–/–, B6) have a high expression of genes encoding MHC-II, costimulatory molecules, and inflammatory cytokines and chemokines. We consider such an activation state as a self-defensive mechanism for protecting the islets from pathogen infections. However, autoimmune risk can also be precipitated to foster incoming autoimmune responses. We seek to dissect the key factors expressed by the islet macrophages that not only influence β-cell biology during homeostasis but also play a role in the pathogenesis of autoimmune diabetes.

DBBS Affiliation

• Immunology Program

Selected Publications

Wan, X, Thomas, JW, Unanue, ER. Class-switched anti-insulin antibodies originate from unconventional antigen presentation in multiple lymphoid sites. J. Exp. Med 2016: 213: 967–978.

Wan, X, Zinselmeyer, BH, Zakharov, PN, Vomund, AN, Taniguchi, R, Santambrogio, L,Anderson, MS, Lichti, CF, Unanue, ER. Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides. Nature 2018: 560: 107–111.

Wan, X., Vomund, A.N., Peterson, OJ., Chervonsky, AV., Lichti, CF., Unanue, ER. The MHC-II peptidome of pancreatic islets identifies key features of autoimmune peptides. Nat. Immunol 2020: 21, 455–463.

*Vomund, AN., Lichti, CF., Peterson, O.J., Arbelaez, AM., Wan, X., Unanue, ER. Blood leukocytes recapitulate diabetogenic peptide-MHC-II complexes displayed in the pancreatic islets. J. Exp. Med 2021: 218 (6): e20202530 (co-corresponding author).

*Srivastava, N., Hu, H., Vomund, AN., Peterson, O.J., Baker, RL., Haskins, K., Teyton, L., Wan, X., Unanue, ER. Chromogranin A deficiency confers protection from autoimmune diabetes via multiple mechanisms. Diabetes 2021 (co-corresponding author).

Srivastava, N., Hu, H., Peterson, O.J., Vomund, AN., …Wan, X., CXCL16-dependent scavenging of oxidized LDL acts as a tissue-specific modifier of the exhaustion-like CD8 T cell differentiation program in diabetic autoimmunity. Immunity 2024; Jul 9;57(7):1629-1647. PMID: 38754432.

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