Self-antigen Expression in the Peripheral Immune System: Roles in Self-tolerance and Type 1 Diabetes Pathogenesis

Overview

Journal Curr Diab Rep

Publisher Current Science

Specialty Endocrinology

Date 2014 Jul 18

PMID 25030265

Citations 7

Authors

Rebecca Fuhlbrigge

Linda Yip

Affiliations

Soon will be listed here.

Abstract

Type 1 diabetes (T1D) may result from a breakdown in peripheral tolerance that is partially controlled by the ectopic expression of peripheral tissue antigens (PTAs) in lymph nodes. Various subsets of lymph node stromal cells and certain hematopoietic cells play a role in maintaining T cell tolerance. These specialized cells have been shown to endogenously transcribe, process, and present a range of PTAs to naive T cells and mediate the clonal deletion or inactivation of autoreactive cells. During the progression of T1D, inflammation leads to reduced PTA expression in the pancreatic lymph nodes and the production of novel islet antigens that T cells are not tolerized against. These events allow for the escape and activation of autoreactive T cells and may contribute to the pathogenesis of T1D. In this review, we discuss recent findings in this area and propose possible therapies that may help reestablish self-tolerance during T1D.

Citing Articles

The role of islet autoantigen-specific T cells in the onset and treatment of type 1 diabetes mellitus.

Yue M, He X, Min X, Yang H, Xu H, Wu W Front Immunol. 2024; 15:1462384.

PMID: 39380988 PMC: 11458421. DOI: 10.3389/fimmu.2024.1462384.

Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes.

Sun F, Yang C, Wang F, Rong S, Luo J, Lu W Cell Biosci. 2023; 13(1):156.

PMID: 37641145 PMC: 10464122. DOI: 10.1186/s13578-023-01110-7.

Identification of key genes and pathways associated with diabetes of the exocrine pancreas.

Yang Z, Li S, Liu H, Su Q, Li X, Qiu Y Medicine (Baltimore). 2022; 101(34):e29781.

PMID: 36042664 PMC: 9410602. DOI: 10.1097/MD.0000000000029781.

Tissue-Engineered Stromal Reticula to Study Lymph Node Fibroblastic Reticular Cells in Type I Diabetes.

Gonzalez Badillo F, Zisi Tegou F, Masina R, Wright S, Scully M, Harwell L Cell Mol Bioeng. 2020; 13(5):419-434.

PMID: 33184575 PMC: 7596159. DOI: 10.1007/s12195-020-00627-y.

Autoreactive T cells in type 1 diabetes.

Pugliese A J Clin Invest. 2017; 127(8):2881-2891.

PMID: 28762987 PMC: 5531393. DOI: 10.1172/JCI94549.

References

Cohen J, Tewalt E, Rouhani S, Buonomo E, Bruce A, Xu X . Tolerogenic properties of lymphatic endothelial cells are controlled by the lymph node microenvironment. PLoS One. 2014; 9(2):e87740. PMC: 3913631. DOI: 10.1371/journal.pone.0087740. View

Garcia C, Prabakar K, Diez J, Cao Z, Allende G, Zeller M . Dendritic cells in human thymus and periphery display a proinsulin epitope in a transcription-dependent, capture-independent fashion. J Immunol. 2005; 175(4):2111-22. DOI: 10.4049/jimmunol.175.4.2111. View

Steptoe R, Ritchie J, Harrison L . Transfer of hematopoietic stem cells encoding autoantigen prevents autoimmune diabetes. J Clin Invest. 2003; 111(9):1357-63. PMC: 154439. DOI: 10.1172/JCI15995. View

Gardner J, Metzger T, McMahon E, Au-Yeung B, Krawisz A, Lu W . Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4⁺ T cells. Immunity. 2013; 39(3):560-72. PMC: 3804105. DOI: 10.1016/j.immuni.2013.08.005. View

Yip L, Taylor C, Whiting C, Fathman C . Diminished adenosine A1 receptor expression in pancreatic α-cells may contribute to the pathology of type 1 diabetes. Diabetes. 2013; 62(12):4208-19. PMC: 3837064. DOI: 10.2337/db13-0614. View

Jensik P, Huggenvik J, Collard M . Identification of a nuclear export signal and protein interaction domains in deformed epidermal autoregulatory factor-1 (DEAF-1). J Biol Chem. 2004; 279(31):32692-9. DOI: 10.1074/jbc.M400946200. View

Modrek B, Resch A, Grasso C, Lee C . Genome-wide detection of alternative splicing in expressed sequences of human genes. Nucleic Acids Res. 2001; 29(13):2850-9. PMC: 55780. DOI: 10.1093/nar/29.13.2850. View

Marrack P, Kappler J . Do MHCII-presented neoantigens drive type 1 diabetes and other autoimmune diseases?. Cold Spring Harb Perspect Med. 2012; 2(9):a007765. PMC: 3426820. DOI: 10.1101/cshperspect.a007765. View

Stadinski B, Delong T, Reisdorph N, Reisdorph R, Powell R, Armstrong M . Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol. 2010; 11(3):225-31. PMC: 3166626. DOI: 10.1038/ni.1844. View

10.

Fletcher A, Lukacs-Kornek V, Reynoso E, Pinner S, Bellemare-Pelletier A, Curry M . Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med. 2010; 207(4):689-97. PMC: 2856033. DOI: 10.1084/jem.20092642. View

11.

Malhotra D, Fletcher A, Turley S . Stromal and hematopoietic cells in secondary lymphoid organs: partners in immunity. Immunol Rev. 2013; 251(1):160-76. PMC: 3539229. DOI: 10.1111/imr.12023. View

12.

Reynoso E, Lee J, Turley S . Peripheral tolerance induction by lymph node stroma. Adv Exp Med Biol. 2009; 633:113-27. DOI: 10.1007/978-0-387-79311-5_10. View

13.

Trigwell S, Radford P, Page S, Loweth A, James R, Morgan N . Islet glutamic acid decarboxylase modified by reactive oxygen species is recognized by antibodies from patients with type 1 diabetes mellitus. Clin Exp Immunol. 2001; 126(2):242-9. PMC: 1906190. DOI: 10.1046/j.1365-2249.2001.01653.x. View

14.

Thebault-Baumont K, Dubois-Laforgue D, Krief P, Briand J, Halbout P, Vallon-Geoffroy K . Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J Clin Invest. 2003; 111(6):851-7. PMC: 153768. DOI: 10.1172/JCI16584. View

15.

van Deutekom J, Janson A, Ginjaar I, Frankhuizen W, Aartsma-Rus A, Bremmer-Bout M . Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med. 2007; 357(26):2677-86. DOI: 10.1056/NEJMoa073108. View

16.

Giarratana N, Penna G, Adorini L . Animal models of spontaneous autoimmune disease: type 1 diabetes in the nonobese diabetic mouse. Methods Mol Biol. 2007; 380:285-311. DOI: 10.1007/978-1-59745-395-0_17. View

17.

Hutton J, Davidson H . Cytokine-induced dicing and splicing in the beta-cell and the immune response in type 1 diabetes. Diabetes. 2010; 59(2):335-6. PMC: 2809971. DOI: 10.2337/db09-1767. View

18.

Wegner N, Lundberg K, Kinloch A, Fisher B, Malmstrom V, Feldmann M . Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol Rev. 2010; 233(1):34-54. DOI: 10.1111/j.0105-2896.2009.00850.x. View

19.

Hua Y, Krainer A . Antisense-mediated exon inclusion. Methods Mol Biol. 2012; 867:307-23. PMC: 3390937. DOI: 10.1007/978-1-61779-767-5_20. View

20.

Peakman M, Stevens E, Lohmann T, Narendran P, Dromey J, Alexander A . Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4. J Clin Invest. 1999; 104(10):1449-57. PMC: 409844. DOI: 10.1172/JCI7936. View