Inborn errors in immunity: unique natural models to dissect oral immunity

Abstract

In recent years, the study of genetic defects arising from inborn errors in immunity has resulted in the discovery of new genes involved in the function of the immune system and in the elucidation of the roles of known genes whose importance was previously unappreciated. With the recent explosion in the field of genomics and the increasing number of genetic defects identified, the study of naturally occurring mutations has become a powerful tool for gaining mechanistic insight into the functions of the human immune system. In this concise perspective, we discuss emerging evidence that inborn errors in immunity constitute real-life models that are indispensable both for the in-depth understanding of human biology and for obtaining critical insights into common diseases, such as those affecting oral health. In the field of oral mucosal immunity, through the study of patients with select gene disruptions, the interleukin-17 (IL-17) pathway has emerged as a critical element in oral immune surveillance and susceptibility to inflammatory disease, with disruptions in the IL-17 axis now strongly linked to mucosal fungal susceptibility, whereas overactivation of the same pathways is linked to inflammatory periodontitis.

Keywords: IL-17; Th17; human oral immunity; monogenic immune defects; oral candidiasis susceptibility; periodontitis susceptibility.

Figure.

Regulation of the interleukin (IL)–17 axis is essential for oral immunity and homeostasis. (Left) Defects in the IL-17 pathway are linked to oral candidiasis. Defective generation of Th17 cells in patients with STAT3 mutations, gain-of-function STAT1 mutations, or impaired IL-17/IL-22 signaling (caused by IL-17 receptor or ligand mutations or neutralizing autoantibodies against IL-17/IL-22) are all linked to susceptibility to mucocutaneous (including oral) candidiasis. (Right) IL-17 overproduction is linked to aggressive periodontitis. Tissue neutrophils normally regulate IL-23 production by antigen presenting cells (e.g., macrophages) and expansion of Th17 cells. In contrast, leukocyte adhesion deficiency type I (LAD-I), which causes defective neutrophil transmigration, (1) leads to dysregulation of the IL-23/Th17 axis (2) and hence overproduction of the inflammatory and bone-resorptive cytokine IL-17 (3). Inflammatory tissue breakdown products serve as nutrients for the local microbiome, thereby contributing to dysbiosis (4). Microbial by-products (including lipopolysaccharide) persistently stimulate the disinhibited IL-23/17 axis (5), further amplifying the destructive response.