Hybrid lipids, peptides, and lymphocytes: new era in type 1 diabetes research
Abdel Rahim A. Hamad, … , Mohanraj Sadasivam, Hamid Rabb
Abdel Rahim A. Hamad, … , Mohanraj Sadasivam, Hamid Rabb
Published September 3, 2019; First published August 5, 2019
Citation Information: J Clin Invest. 2019;129(9):3527-3529. https://doi.org/10.1172/JCI130313.
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Commentary

Hybrid lipids, peptides, and lymphocytes: new era in type 1 diabetes research

Abstract

Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing β cells in islets of Langerhans. Many genetic and immunological insights into autoimmune disease pathogenesis were initially uncovered in the context of T1D and facilitated by preclinical studies using the nonobese diabetic (NOD) mouse model. Recently, the study of T1D has led to the discovery of fatty acid esters of hydroxyl fatty acids (FAHFAs), which are naturally occurring hybrid peptides that modulate inflammation and diabetes pathogenesis, and a hybrid lymphocyte that expresses both B and T cell receptors. Palmitic acid esters of hydroxy stearic acids (PAHSAs) are the most extensively studied FAHFA. In this issue of the JCI, Syed et al. have shown that PAHSAs both attenuate autoimmune responses and promote β cell survival in NOD mice. Given the lack of effective T1D therapies and the paucity of known side effects of PAHSAs, this lipid may have therapeutic potential for individuals at risk for or newly diagnosed with T1D.

Authors

Abdel Rahim A. Hamad, Mohanraj Sadasivam, Hamid Rabb

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Figure 1

Key steps in the pathogenesis of T1D and sites modulated by PAHSAs.

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Key steps in the pathogenesis of T1D and sites modulated by PAHSAs. Auto...
Autoimmunity is initiated by the release of islet autoantigens (i) by pancreatic β cells that are taken up by APCs, processed, and presented in the context of MHC class molecules to autoreactive T cells (ii). Activated CD4+ T cells proliferate (iii) and release proinflammatory cytokines and then help activate cytotoxic CD8+ T cells (iv) that use different mechanisms to attack and destroy insulin-producing β cells (v). PAHSAs attenuate T cell activation and proliferation and increase Treg activity. Further, PAHSAs attenuate cytokine-mediated β cell apoptotic pathways, decrease β cell destruction, and improve β cell survival. Illustrated by Rachel Davidowitz.