Mutations in the ELANE Gene are Associated with Development of Periodontitis in Patients with Severe Congenital Neutropenia

Abstract

BackgroundPatients with severe congenital neutropenia (SCN) often develop periodontitis despite standard medical and dental care. In light of previous findings that mutations in the neutrophil elastase gene, ELANE, are associated with more severe neutropenic phenotypes, we hypothesized an association between the genotype of SCN and development of periodontitis.MethodsFourteen Swedish patients with SCN or cyclic neutropenia harboring different genetic backgrounds were recruited for periodontal examination. Peripheral blood, gingival crevicular fluid (GCF), and subgingival bacterial samples were collected. The levels of cytokines and antibacterial peptides were determined in GCF and plasma by multiplex immunoassay and immunoblotting, respectively. Subgingival bacterial samples were analyzed using 16S rDNA pyrosequencing.ResultsELANE mutations correlated with more severe periodontal status than the HAX1 or unknown mutations in patients with SCN. The subjects with mutant ELANE had higher levels of IL-1β in GCF. Using principal coordinate analysis of the subgingival microbiota, patients with ELANE mutations and reference subjects with periodontitis tended to cluster differently from patients with HAX1 or unknown mutations and non-periodontitis reference subjects.ConclusionThis study demonstrates an association between ELANE mutations in SCN and the development of periodontitis with skewed subgingival microbiota, indicating a potential role of ELANE mutations in the pathogenesis of periodontitis.

Neutrophil Dysfunction and Host Susceptibility to Periodontal Inflammation: Current State of Knowledge

“…Congenital neutropenia (Kostman syndrome) is an inherited hematological disorder characterized by an arrest of PMN hematopoiesis at promyelocyte/myelocyte stage and absolute counts of <2000 cells/μL. Mutations in the ELANE gene coding for PMN elastase have been associated with periodontitis in patients with severe congenital neutropenia [41]. Gingivitis and severe periodontitis are common complications and despite some temporary improvement in PMN counts with granulocyte colony stimulating factor (G-CSF) treatment, patients with congenital neutropenia tend to have persistent gingivitis.…”

Untitled

“…Ullbro evaluated an oral treatment protocol, which showed that compliance of the patient had a strong impact on the bleeding surfaces and pathological periodontal pockets. In the same study, it was revealed that there was no and P. gingivalis in periodontal pockets [72].…”

“…The gene mutations seen are: ELANE gene encoding neutrophil elastase, which is more common in the dominant or sporadic forms of the disease [26], and in the recessive form the HAX1 gene, which encodes the mitochondrial antiapoptotic protein HS1-associating protein X-1 [70]. Patients with ELANE mutations seem to present more severe forms of periodontal disease compared to patients with HAX1 or unknown mutations [71,72]. It has been found that the neutrophils in these diseases can also have qualitative deficiencies, such as in the antimicrobial protein pro-LL-37 and reduced level of the human neutrophil peptide 1-3 in the granules, which means that their antimicrobial activity is reduced [73].…”

“…The diagnosis occurs in infancy and the reported oral clinical findings are: Gingival inflammation, increased probing depth and severe alveolar bone loss both in primary and in permanent dentition [6,72]. The microbiology is not quite clear yet, although there is some evidence of the presence of A. actinomycetemcomitans …”

Proteases, neutrophils, and periodontitis: the NET effect

“…Early onset periodontitis frequently complicates congenital neutropenias, including severe congenital neutropenia (SCN), which is commonly associated with mutations in the gene encoding neutrophil elastase (25). Periodontitis in SCN correlates with excess IL-1β locally as well as with the oral microflora skewing toward more pathogenic organisms (26). It is conceivable that the absence of granule serine proteases and LL-37 from the neutrophils of PLS patients not only limits the array of antimicrobial effectors, but also undermines the proteolytic degradation of proinflammatory chemokines and cytokines necessary for tissue homeostasis, resulting in excess neutrophil recruitment and unchecked local inflammation (27).…”