Self-antigen–presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs

Abstract

Recent reports indicate that genes with tissue-restricted expression, including those encoding the type 1 diabetes autoantigens insulin, glutamic acid decarboxylase (GAD), and the tyrosine-phosphatase-like protein IA-2 (or ICA512), are transcribed in the thymus. The reported modulation of diabetes susceptibility by genetically determined differences in thymic insulin levels and studies in transgenic mice provide correlative and functional evidence that thymic expression of peripheral proteins is crucial for immunological self-tolerance. However, there are no specific data about the existence, tissue distribution, phenotype, and function of those cells that express insulin and other self-antigens in the human thymus. We find that the human thymus harbors specialized cells synthesizing (pro)insulin, GAD, and IA-2, mainly localized in the medulla, and we demonstrate such cells also in peripheral lymphoid organs (spleen and lymph nodes). Phenotypic analysis qualifies these cells as antigen-presenting cells (APCs), including both dendritic cells and macrophages. These cells often appear surrounded by apoptotic lymphocytes, both in thymus and spleen, and may therefore be involved in the deletion of autoreactive lymphocytes. Our findings demonstrate the existence of, and define the tissue distribution and phenotype of, a novel subset of APCs expressing self-antigens in human lymphoid organs that appear to be involved in the regulation of self-tolerance throughout life.

Promoting tolerance to proteolipid protein-induced experimental autoimmune encephalomyelitis through targeting dendritic cells

“…Despite many studies in both rodents and humans to stimulate tolerogenic mechanisms using various protocols of antigen administration with antigens in different pharmaceutical forms (e.g., peptides or whole antigens) and testing diverse administration routes, robust data demonstrating clinical benefits are not yet available (18). Recent studies in mice have also indicated that repeated administration of free antigens can induce fatal autoimmune responses (30). In this context, the ability to target minute amounts of antigens to steady-state immature DCs in vivo has promise as an approach to obtain antigenspecific immunological tolerance.…”

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

“…Many ''tissuespecific'' molecules (55), especially of endocrine organ-related proteins including GAD and insulin (56)(57)(58), are now known to be expressed at low levels in small numbers of thymic medullary epithelial cells under the control of the AIRE gene (59). In AIRE-null mutants, T cells arising spontaneously in the thymus and specific for various self peptides escape thymic negative selection and induce organ-specific autoimmune disease in the periphery (60).…”

Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide

“…Recent studies demonstrate that a number of autoantigens, including those that were believed to be secluded from the immune system, are actually expressed in the thymus [19][20][21][22][23][24][25][26][27]. Furthermore, experiments have proven that such a promiscuous expression of autoantigen would contribute to eliminating pathogenic autoimmune T cells from the T cell repertoire [24,25].…”