Research Statement - Yang-Xin Fu, MD, PhD - Kovler Diabetes Center

Yang-Xin Fu, MD, PhD

Research Statement

Diabetes Educator FUMy clinical background and strong interest in basic immunobiology have led me to integrate basic research into more pathogenesis and treatment of diseases. The basic research in my laboratory is focused on understanding the biological consequences arising from the interaction between core molecules of the TNF superfamily, lymphotoxin (LT or TNFSF1) and LIGHT (TNFSF14), on lymphocytes, and their receptor, LT?R, on stromal cells. This research has contributed substantially to the definition of the critical role these molecules play in the development and function of lymphoid tissues. Our recent studies have defined the roles of these molecules in autoimmunity and tumor immunity in mouse models and human patients. Our research includes four major themes.

Critical role for lymphotoxin in the development and function of lymphoid tissues

The relative contributions of lymphoid tissues and non-lymphoid tissues to various immune responses had not been defined previously due to the lack of appropriate animal models and the complicated nature of the issues involved. Our pioneering studies have revealed the essential role of LT and TNF for the development and maintenance of lymphoid tissues. Using LT-deficient mice, or antibody or soluble receptor blockade, we generated unique mouse models that lack various sets of secondary lymphoid tissues to define the roles of these structures in various tissues for different types of immune responses. We have been studying the development and maintenance of complex lymphoid architecture using these models; lately, we are exploring novel LT?R-stimulated NF?B pathways shape the development and function of lymphoid tissues which are important for priming and tolerance.

Role of lymphotoxin in the remodeling or regeneration of non-lymphoid tissues

We initially noted that lymphoid-like structures outside lymphoid tissues had been implicated in a number of chronic diseases, such as autoimmune diabetes, inflammation bowel disease (IBD), autoimmune arthritis, and other chronic inflammation. However, how these lymphoid tissues are formed, and their relevance to disease pathology, had not been identified. We determined that both LT and/or LIGHT control the formation of lymphoid-like structures at sites of chronic inflammation and, subsequently, organ-specific autoimmune destruction. These observations led us to discover that agents that block LT?R ligands (LT and LIGHT) can effectively reduce ongoing, chronic, organ-specific autoimmune destruction. By such treatment, we have also uncovered new roles of LT?R signaling in autoimmune hepatitis and liver regeneration, inflammation bowel disease (IBD), asthma, chronic autoimmune diabetes, and tumor immunity. Our study has revealed the critical role of tertiary lymphoid tissues in the development of autoimmune destruction of islets.

The role of lymphotoxin receptor in central and peripheral tolerance

A central paradox in immunology is the tolerance to autoantigens that are expressed exclusively in the periphery. Recent observations indicate that a spectrum of self-antigens can be also expressed at very low levels in thymic medulla epithelial cells (mTECs) under the regulation of a newly discovered transcription factor, AIRE. These AIRE-dependent, ectopically expressed self antigens in the thymus mediate the deletion of self-reactive T cells but how AIRE is regulated is unclear. We have discovered that LT?R pathways regulate AIRE in the thymus. This has allowed us, for the first time, to dissect the LT?R signaling pathways and transcription factors involved in regulating the expression of self-antigens, and our model allows us to identify novel LT-dependent but AIRE-independent pathways. Thus our study has opened new avenues to study how autoantigens are expressed in the thymus.