Topic Overview:
Type 1 diabetes (T1D) is an autoimmune disorder in which insulin-secreting pancreatic beta cells (β-cells) are specifically targeted and destroyed by the patient’s own immune cells.  Although many genetic and environmental factors have been implicated in T1D etiology, the underlying mechanisms surrounding loss of immune system self-tolerance toward β-cells remains elusive.  Both cellular and humoral responses toward insulin, a major β-cell-specific autoantigen, are readily detected in T1D patients; and insulin autoimmunity has been shown to be a major driving force of disease initiation and progression.

Interestingly, insulin transcripts have also been found in the thymus (at a level 1,000 times lower than that of the pancreas).  Since these transcript levels appear to correlate inversely with anti-insulin autoimmunity, Fan postulated that thymi with high levels of insulin expression could deplete insulin-reactive thymocytes more effectively than those with low insulin expression.  To test the hypothesis that thymic insulin expression is essential to establish peripheral tolerance toward β-cells, the Fan team took a genetic approach to ablate insulin expression specifically in the thymus while leaving its production in pancreatic β-cells undisturbed.

Since thymic antigen presenting cells of both hematopoietic and endodermal origins had been shown to express insulin, Fan generated knockout animal models to target both cell lines, respectively:

• ID-BMC (for insulin deletion in bone marrow cells)
• ID-TEC (insulin deletion in thymic epithelial cells)

In contrast to ID-BMC mice that retained normoglycemia throughout their lifespan, the Fan team found that ID-TEC mice spontaneously developed diabetes within three weeks of birth, explicitly attributable to β-cell destruction via insulin-specific effector T cells.

Thus, the Fan study determined that the balance between autoimmunity and self-tolerance pivots on the ectopic expression of peripheral tissue antigens (PTAs) in thymic epithelial cells.  Because the normal physiological concentration of circulating insulin in pre-diabetic ID-TEC mice failed to exert any protection, Fan believes these results also demonstrate a dominant central mechanism in establishing self-tolerance.  He notes that these findings may explain the sporadic onset of T1D in very young children who express resistant human leukocyte antigen class II alleles, as well as support additional investigatory focus on thymic expression of PTAs as a potential avenue to rehabilitate adaptive immunity in T1D and other autoimmune disorders.