The intrathymic expression of insulin-related genes: implications for pathophysiology and prevention of Type 1 diabetes

Abstract

Recent experimental work has challenged and shattered the old concept of a sequestration of pancreatic islet antigens from developing T-cells within the thymic environment. There is now compelling evidence that the central immunological tolerance of the whole insulin family may be induced during the process of T-cell ontogeny in the thymus. Transcripts of insulin-like growth factor II (IGF-II), IGF-I and insulin genes have been characterized in human, rat and mouse thymuses. At the peptide level, IGF-II was shown to be the dominant polypeptide of the insulin family in the thymus from different species. Data are presented which support a dual role of thymic IGF-II both in T-cell development as well as in T-cell negative selection. Using animal models of autoimmune diabetes, current research is investigating the hypothesis that a defect of thymic T-cell education to the insulin family is implicated in the pathophysiology of human Type 1 diabetes. An efficient and secure prevention of Type 1 diabetes could be designed on the basis of the strong natural tolerogenic properties of the thymus.

Presence of hormones (triiodothyronine, serotonin and histamine) in the immune cells of newborn rats

“…This could mean either that there is a difference between the foetal and neonatal GH-producing machinery, or that the specificity of the anti-GH antibody is very high. In the literature, the expression of insulin genes was demonstrated in rare cells of the thymus of adult animals (Hanahan, 1998;Throsby et al, 1999;Geenen, 1998), however we find these cells only among splenocytes in newborns. This means that, although the genes are present (Geenen, 1998), their activity in newborns is low.…”

“…The monoclonal anti-insulin used in this study crossreacts with rat insulin, but only very few cells showed insulin fluorescence. This means that, although the genes are present (Geenen, 1998), their activity in newborns is low. In the literature, the expression of insulin genes was demonstrated in rare cells of the thymus of adult animals (Hanahan, 1998;Throsby et al, 1999;Geenen, 1998), however we find these cells only among splenocytes in newborns.…”

Thymic Self-Antigen Expression for the Design of a Negative/Tolerogenic Self-Vaccine against Type 1 Diabetes

“…Igf2 transcripts were also present in the thymus from all BBDR rats, but were not detected in the thymus from more than 80% of BBDP rats, in close concordance with the incidence (86%) of autoimmune diabetes in those rats. This defect in Igf2 transcription in BBDP thymus could also explain both their lymphopenia (including CD8+ T cells and RT6+ Treg) and the absence of central self-tolerance to insulin-secreting islet β cells [41, 42]. As already mentioned, we have shown that susceptibility to autoimmune diabetes is correlated with the level of Ins2 transcription in the mouse thymus [6].…”

Characterization of the Insulin‐Like Growth Factor Axis in the Human Thymus

“…These receptors have been reported to be expressed by freshly isolated immature and mature T lymphocytes ( 29, 30), as well as by human leukemic lymphoblasts ( 32)In summary this study confirms—at the molecular level—the existence of IGF axis members in the human thymus with a predominance of IGF‐II synthesis within TEC and the expression of IGF receptors by lymphoid cells. The characterization of a complete IGF system in a lymphopoietic site adds another argument for its implication in thymic T‐cell differentiation and self‐tolerance ( 48). IGF‐II transgenic mice overexpress IGF‐II mRNA in the thymus and spleen, and their thymus shows a significant hyperplasia ( 35).…”