TY - JOUR
T1 - The long and winding road: From mouse linkage studies to a novel human therapeutic pathway in type 1 diabetes
T2 - From mouse linkage studies to a novel human therapeutic pathway in type 1 diabetes
AU - Rojas, Manuel
AU - Heuer, Luke S.
AU - Zhang, Weici
AU - Chen, Yi Guang
AU - Ridgway, William M.
N1 - Publisher Copyright:
Copyright © 2022 Rojas, Heuer, Zhang, Chen and Ridgway.
PY - 2022/7/22
Y1 - 2022/7/22
N2 - Autoimmunity involves a loss of immune tolerance to self-proteins due to a combination of genetic susceptibility and environmental provocation, which generates autoreactive T and B cells. Genetic susceptibility affects lymphocyte autoreactivity at the level of central tolerance (e.g., defective, or incomplete MHC-mediated negative selection of self-reactive T cells) and peripheral tolerance (e.g., failure of mechanisms to control circulating self-reactive T cells). T regulatory cell (Treg) mediated suppression is essential for controlling peripheral autoreactive T cells. Understanding the genetic control of Treg development and function and Treg interaction with T effector and other immune cells is thus a key goal of autoimmunity research. Herein, we will review immunogenetic control of tolerance in one of the classic models of autoimmunity, the non-obese diabetic (NOD) mouse model of autoimmune Type 1 diabetes (T1D). We review the long (and still evolving) elucidation of how one susceptibility gene, Cd137, (identified originally via linkage studies) affects both the immune response and its regulation in a highly complex fashion. The CD137 (present in both membrane and soluble forms) and the CD137 ligand (CD137L) both signal into a variety of immune cells (bi-directional signaling). The overall outcome of these multitudinous effects (either tolerance or autoimmunity) depends upon the balance between the regulatory signals (predominantly mediated by soluble CD137 via the CD137L pathway) and the effector signals (mediated by both membrane-bound CD137 and CD137L). This immune balance/homeostasis can be decisively affected by genetic (susceptibility vs. resistant alleles) and environmental factors (stimulation of soluble CD137 production). The discovery of the homeostatic immune effect of soluble CD137 on the CD137-CD137L system makes it a promising candidate for immunotherapy to restore tolerance in autoimmune diseases.
AB - Autoimmunity involves a loss of immune tolerance to self-proteins due to a combination of genetic susceptibility and environmental provocation, which generates autoreactive T and B cells. Genetic susceptibility affects lymphocyte autoreactivity at the level of central tolerance (e.g., defective, or incomplete MHC-mediated negative selection of self-reactive T cells) and peripheral tolerance (e.g., failure of mechanisms to control circulating self-reactive T cells). T regulatory cell (Treg) mediated suppression is essential for controlling peripheral autoreactive T cells. Understanding the genetic control of Treg development and function and Treg interaction with T effector and other immune cells is thus a key goal of autoimmunity research. Herein, we will review immunogenetic control of tolerance in one of the classic models of autoimmunity, the non-obese diabetic (NOD) mouse model of autoimmune Type 1 diabetes (T1D). We review the long (and still evolving) elucidation of how one susceptibility gene, Cd137, (identified originally via linkage studies) affects both the immune response and its regulation in a highly complex fashion. The CD137 (present in both membrane and soluble forms) and the CD137 ligand (CD137L) both signal into a variety of immune cells (bi-directional signaling). The overall outcome of these multitudinous effects (either tolerance or autoimmunity) depends upon the balance between the regulatory signals (predominantly mediated by soluble CD137 via the CD137L pathway) and the effector signals (mediated by both membrane-bound CD137 and CD137L). This immune balance/homeostasis can be decisively affected by genetic (susceptibility vs. resistant alleles) and environmental factors (stimulation of soluble CD137 production). The discovery of the homeostatic immune effect of soluble CD137 on the CD137-CD137L system makes it a promising candidate for immunotherapy to restore tolerance in autoimmune diseases.
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U2 - 10.3389/fimmu.2022.918837
DO - 10.3389/fimmu.2022.918837
M3 - Review article
C2 - 35935980
AN - SCOPUS:85135448167
SN - 1664-3224
VL - 13
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 918837
ER -