George S. Eisenbarth: insulin and type 1 diabetes - PubMed (original) (raw)

George S. Eisenbarth: insulin and type 1 diabetes

Alberto Pugliese et al. Diabetes Care. 2013 Jun.

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An evocative rendering of the late George S. Eisenbarth. A pancreatic islet under immune attack against the backdrop of his model of the multiple stages in the natural history of T1D symbolizes the disease process he wanted to defeat.

Figure 1

Figure 1

The trimolecular complex—a key target for prevention. The fundamental work of Dr. Eisenbarth is illustrated in this schematic representation of the MHC class II molecule expressed on the surface on antigen-presenting cells (APC), the insulin peptide he proved to be required for diabetes development in the NOD mouse, and a conserved TCR α chain that diabetogenic CD4 T cells use to recognize the MHC-insulin peptide complex. The figure illustrates the concept that the peptide can bind to the MHC in multiple registers. Out of at least four registers, one is considered diabetogenic (middle panel) because it results in recognition of the peptide by insulin-specific autoreactive T cells expressing a conserved TCR α chain, and this is followed by their activation. In this register, peptide binding to the MHC is actually weak, and this is believed to impair the thymic deletion of the autoreactive cells when they first encounter this peptide in the thymus. The left panel models nondiabetogenic binding registers, which fail to result in the presentation of the insulin peptide and T-cell activation. The right panel shows that the use of small molecules could block this interaction and abolish the autoimmune response, with therapeutic benefit in the NOD mouse.

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References

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