Role of bacteria in leukocyte adhesion deficiency-associated periodontitis

Abstract

Leukocyte adhesion deficiency Type I (LAD-I)-associated periodontitis is an aggressive form of inflammatory bone loss that has been historically attributed to lack of neutrophil surveillance of the periodontal infection. However, this form of periodontitis has proven unresponsive to antibiotics and/or mechanical removal of the tooth-associated biofilm. Recent studies in LAD-I patients and relevant animal models have shown that the fundamental cause of LAD-I periodontitis involves dysregulation of a granulopoietic cytokine cascade. This cascade includes interleukin IL-23 (IL-23) and IL-17 that drive inflammatory bone loss in LAD-I patients and animal models and, moreover, foster a nutritionally favorable environment for bacterial growth and development of a compositionally unique microbiome. Although the lack of neutrophil surveillance in the periodontal pockets might be expected to lead to uncontrolled bacterial invasion of the underlying connective tissue, microbiological analyses of gingival biopsies from LAD-I patients did not reveal tissue-invasive infection. However, bacterial lipopolysaccharide was shown to translocate into the lesions of LAD-I periodontitis. It is concluded that the bacteria serve as initial triggers for local immunopathology through translocation of bacterial products into the underlying tissues where they unleash the dysregulated IL-23-IL-17 axis. Subsequently, the IL-23/IL-17 inflammatory response sustains and shapes a unique local microbiome which, in turn, can further exacerbate inflammation and bone loss in the susceptible host.

Keywords: IL-17; IL-23; Inflammation; Leukocyte adhesion deficiency; Microbiota; Periodontitis.

Fig. 1. Clinical and histological profile of LAD-I periodontitis

(A) Panoramic radiograph of 11-year-old LAD-I patient with severe bone loss. Blue dotted line represents physiologic bone levels and white dotted line demonstrates current bone levels. (B) H&E staining of extracted tooth and surrounding soft tissues. Encircled soft tissue reveals dense inflammatory infiltrate in the lesion (shown in lower and higher magnification, 5×-20×). (C) Immunohistochemistry for IL-17 in LAD-I tissues. Brown staining indicates IL-17-positive cells (original magnification 5×-20×). Patients were enrolled in an IRB approved protocol and had signed informed consent.

Fig. 2. Dysregulated overproduction of IL-17 in LAD-I causes periodontal bone loss and increased microbial burden

In normal individuals (i.e., with transmigration-competent neutrophils), recruited neutrophils regulate IL-23 production by tissue phagocytes (“PHAG”; e.g., macrophages) and hence the expression of IL-17 by adaptive and innate immune cells (e.g., Th17, γδ T cells, and innate lymphoid cells [ILC]) [11]. In contrast, LAD-I, which impairs neutrophil transmigration (1) leads to dysregulation of IL-23 (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 its overgrowth (4). Microbial products translocated into the lesions (for instance, LPS [44]) persistently stimulate the disinhibited IL-23–IL-17 axis (5) amplifying the destructive response. From ref. [18]. Used by permission.

Fig. 3. Subgingival microbiome in LAD-I

(A) Gram staining (Brown and Brenn) of extracted tooth (i) and adjacent soft tissues (ii) (2×-20× original magnification). (B) Total bacterial load (quantified with real-time PCR for 16S rRNA) for LAD-I and health. Bacterial load values are expressed as log (10) of 16S rRNA gene copy number (mean+SEM shown, p<0.05) [44]. (C) Immunohistochemistry for bacterial lipopolysaccharide (LPS) on extracted LAD tooth and surrounding tissues (2×-20× original magnification). (D) Highly prevalent taxa (species) in health and LAD-I. Detection frequency shown per group. From ref. [44]. Original, not previously published images were used in this review.