AIREing out the gut

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Science Translational Medicine  15 Jul 2015:
Vol. 7, Issue 296, pp. 296ec120
DOI: 10.1126/scitranslmed.aac8561

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal recessive disorder that results from loss of function mutations in the autoimmune regulator (AIRE ) gene. AIRE is involved in immune tolerance, and its loss prevents elimination of self-reactive T cells. Individuals with APECED have myriad symptoms related to immune dysfunction, but it’s unclear why they also suffer from gastrointestinal symptoms such as malabsorption, constipation, and diarrhea. Now, Dobeš and colleagues show that autoimmunity meets innate immunity via the α-defensins, antimicrobial peptides secreted in the gut.

In humans, paneth cells (PC) live at the base of the small intestine crypts and secrete α-defensins, which support stem cells maintenance at the base of the crypts. Serum from APECED patients displays seroreactivity against the α-defensin–containing secretory granules in PCs, raising the possibility that enteric defensins are targets in this autoimmune condition. Indeed, disruption of PC function can manifest gastrointestinal maladies.

Dobeš and colleagues demonstrated that α-defensins are expressed in normal human thymus but are absent from APECED patients, and that in affected individuals, α-defensin–producing PCs are reduced in or absent from the small intestine. After Aire–/– mice—a model for APECED—were injected with cryptidin (a mouse homolog of human α-defensin), CD8+ T cells isolated from peripheral and mesenteric lymph nodes induced apoptosis of PCs in vitro. Adoptive transfer of CD8+ T cells from cryptidin-immunized Aire–/– mice to athymic mice resulted in a significant decrease in PCs. Because defensins regulate the character of the gut microbiota, the authors inspected the gut microbial ecosystem in Aire–/– mice and detected an abnormal enrichment of filamentous bacteria.

These elegant human and rodent experiments by Dobeš and colleagues relate the essential role of AIRE in central immune tolerance to enteric α-defensins and a mechanism of PC disruption that might explain, at least in part, the clinical manifestations of this genetic disorder.

J. Dobeš et al., Gastrointestinal autoimmunity associated with loss of central tolerance to enteric α-defensins. Gastroenterology 149, 139–150 (2015). [Abstract]

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