Role of bacteria in leukocyte adhesion deficiency-associated periodontitis
Introduction
Periodontitis is an inflammatory disease that typically affects adults [1]. The disease causes destruction of the periodontium (i.e., tooth-supporting tissues such as gingiva and alveolar bone) and constitutes a potential risk factor for certain systemic diseases [2], [3], [4]. However, individuals with disorders affecting neutrophil recruitment to the periodontium, such as the rare condition leukocyte adhesion deficiency (LAD), rapidly develop severe periodontitis early in life affecting both the primary and permanent dentition [5], [6], [7], [8], [9], [10], [11] (Fig. 1). In addition to severe periodontal bone loss (Fig. 1A) [11], LAD-I patients display neutrophilia (increased blood neutrophil counts) and are susceptible to persistent infections (e.g., pneumonia) [6], [7], [8], [9], [12], [13]. Rare monogenic diseases represent an important medical and social issue in its own right, cumulatively affecting 25 million patients in North America alone [14]. Importantly, however, the study of rare diseases, such as LAD-I, is not only relevant to the treatment of patients with these specific disorders; these diseases constitute real-life models to understand human biology and (patho)physiological mechanisms, thereby providing critical insights into common diseases [15], [16], [17], [18].
LAD represents a group of distinct inherited disorders, which inhibit the normal extravasation of neutrophils and their recruitment to sites of infection or inflammation [6], [8], [10], [11], [19], [20]. LAD patients have defects in the expression or function of the leukocyte-restricted β2 integrins (heterodimeric molecules, each with a distinct CD11 subunit and a common CD18 subunit), or other adhesion molecules. Consequently, their circulating neutrophils cannot adhere to vascular endothelial cells, a function that is required for extravasation [21], [22], [23]. LAD type I (LAD-I) is caused by deficiency in β2 integrins, LAD-II is due to defective glycosylation of selectin ligands, and LAD-III involves dysfunction of signaling intermediates affecting integrin activation [13].
The most common type of LAD is LAD-I, an autosomal recessive immunodeficiency caused by mutations in the CD18-encoding ITGB2 gene; therefore, LAD-I patients have defective expression in all β2 integrins [8], [11], [12], [20]. The LFA-1 integrin (CD11a/CD18) plays a crucial role in firm adhesion by interacting with endothelial cell counter-receptors (e.g., intercellular adhesion molecule-1) and is thus required for extravasation of the neutrophils to peripheral tissues [21], [22], [23]. In contrast to neutrophils, other types of leukocytes use different or additional adhesion molecules (e.g., VLA-4; very late antigen-4) for firm adhesion and extravasation [24], [25], [26], [27], [28], [29]. Consistent with this, the heavy inflammatory infiltrate (Fig. 1B) in the periodontium of LAD-I patients is specifically devoid of neutrophils (which are confined in vessels), whereas lymphocytes and other cells of hematopoietic origin are found in abundance in the periodontium [11].
LAD-I–associated periodontitis (hereafter “LAD-I periodontitis”) has been historically attributed to lack of neutrophil surveillance of the periodontal infection; yet, this form of periodontitis has proven unresponsive to antibiotics and/or mechanical removal of the tooth-associated biofilm [5], [6], [7], [11], [19], [30], [31], [32]. A recent study in LAD-I patients and relevant animal models has shown that the fundamental cause of LAD-I periodontitis involves dysregulated overproduction of interleukin (IL)-23 and hence IL-17 (Fig. 1C) [11], a pro-inflammatory and pro-osteoclastogenic cytokine implicated in inflammatory bone loss in humans and animal models of arthritis or periodontitis [33], [34], [35]. The dysregulation of the IL-23/IL-17 response is consistent with the disruption of a major neutrophil homeostatic mechanism, known as the ‘neutrostat’. This mechanism senses neutrophil recruitment and clearance in peripheral tissues and regulates neutrophil production through a granulopoietic cytokine cascade involving IL-23, IL-17, and granulocyte colony-stimulating factor (G-CSF) [36]. When neutrophils cannot transmigrate to peripheral tissues, as in LAD-I, the neutrostat breaks down leading to unrestrained expression of IL-23 and downstream cytokines including IL-17 and G-CSF. Whereas the upregulation of G-CSF explains the increased granulopoiesis and blood neutrophilia in LAD-I patients, the local overproduction of IL-17 in the periodontium drives inflammation and bone loss [11]. This study [11] conferred clinical relevance to the neutrostat concept established earlier in mice [36] but also provided for the first time a human (and animal) disease correlate of this mechanism. These recent developments beg the question as to whether there is still a role for the bacteria in the pathogenesis of LAD-I periodontitis. This review aims to clarify the precise involvement of the LAD-I-associated periodontal microbiota in the pathogenesis of this aggressive form of periodontitis.
Section snippets
LAD-I periodontitis does not involve a tissue-invasive infection
Although the lack of neutrophil surveillance in the periodontal pockets might be expected to lead to uncontrolled bacterial infection and invasion of the underlying connective tissue, microbiological analyses of gingival tissue samples from LAD-I patients did not reveal any unusual tissue-invasive infection within the lesion driving tissue destruction [11]. Specifically, gram staining of extracted teeth and surrounding tissues from LAD-I patients showed microbial colonization of tooth surfaces
Bacteria are required to unleash the disinhibited IL-23–IL-17 axis
The above facts and discussion should not be interpreted to mean that the tooth-associated microbiota is not involved in the pathogenic process leading to of LAD-I periodontitis. It was recently shown that subgingival plaque bacteria associated with LAD-I periodontitis readily stimulate IL-23 expression in human macrophages and also in vivo in murine oral tissues [44]. These findings suggest that the bacteria and their products such as lipopolysaccharide (LPS) likely act as stimuli for IL-23
Characterization of the LAD-I periodontitis-associated subgingival microbiome
The subgingival microbiome of LAD-I patients has been recently characterized using a 16s rRNA gene-based microarray (HOMIM) which simultaneously detects more than 300 of the most prevalent oral bacterial species. Results of these analyses reveal that the tooth-associated microbial communities in LAD-I are distinct from those associated with health or aggressive periodontitis in the general population [44]. Unique characteristics of the LAD-I microbiome are its increased biomass (bacterial load)
Conclusion
Recent developments in the study of LAD-I periodontitis indicate that neutrophils are implicated in periodontal tissue destruction due to their absence, rather than through the usual bystander injury dogma that applies to many other neutrophil-associated inflammatory diseases including the chronic form of periodontitis [41], [54], [55], [56], [57], [58]. The implication of the dysregulated IL-23 and IL-17 response in the pathogenesis of LAD-I periodontitis can lead to innovative and effective
Acknowledgments
This research was supported in part by the Intramural Research Program of the NIH, NIDCR (N.M.M.) and by U.S. Public Health Service grants DE015254, DE021685, DE024716, and AI068730 from NIDCR and NIAID (G.H.).
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