PMID- 29276776 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210520 IS - 2380-0844 (Print) IS - 2380-0852 (Electronic) IS - 2380-0844 (Linking) VI - 3 IP - 1 DP - 2018 Jan TI - Periodontitis in Chediak-Higashi Syndrome: An Altered Immunoinflammatory Response. PG - 35-46 LID - 10.1177/2380084417724117 [doi] AB - Chediak-Higashi syndrome (CHS), a rare autosomal recessive disorder caused by mutations in the lysosomal trafficking regulator gene (LYST), is associated with aggressive periodontitis. It is suggested that LYST mutations affect the toll-like receptor (TLR)-mediated immunoinflammatory response, leading to frequent infections. This study sought to determine the periodontal status of patients with classic (severe) and atypical (milder) forms of CHS and the immunoregulatory functions of gingival fibroblasts in CHS patients. In contrast to aged-matched healthy controls, atypical (n = 4) and classic (n = 3) CHS patients presented with mild chronic periodontitis with no evidence of gingival ulceration, severe tooth mobility, or premature exfoliation of teeth. As a standard of care, all classic CHS patients had undergone bone marrow transplantation (BMT). Primary gingival fibroblasts obtained from atypical and BMT classic CHS patients displayed higher protein expression of TLR-2 (1.81-fold and 1.56-fold, respectively) and decreased expression of TLR-4 (-2.5-fold and -3.85-fold, respectively) at baseline when compared with healthy control gingival fibroblasts. When challenged with whole bacterial extract of Fusobacterium nucleatum, both atypical and classic CHS gingival fibroblasts failed to up-regulate TLR-2 and TLR-4 expression when compared with their respective untreated groups and control cells. Cytokine multiplex analysis following F. nucleatum challenge showed that atypical CHS gingival fibroblasts featured significantly increased cytokine expression (interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, IL-12, interferon-gamma, tumor necrosis factor-alpha), whereas classic CHS cells featured similar/decreased cytokine expression when compared with treated control cells. Collectively, these results suggest that LYST mutations in CHS patients affect TLR-2 and TLR-4 expression/function, leading to dysregulated immunoinflammatory response, which in turn may influence the periodontal phenotype noted in CHS patients. Furthermore, our results suggest that atypical CHS patients and classic CHS patients who undergo BMT early in life are less susceptible to aggressive periodontitis and that hematopoietic cells play a critical role in mitigating the risk of aggressive periodontitis in CHS. Knowledge Transfer Statement: Results from this study can be used to create awareness among clinicians and researchers that not all CHS patients exhibit historically reported aggressive periodontitis, especially if they have atypical CHS disease or have received bone marrow transplantation. LYST mutations in CHS patients may affect TLR-2 and TLR-4 expression/function leading to dysregulated immunoinflammatory response, which in turn may influence the periodontal phenotype noted in CHS patients. FAU - Thumbigere Math, V AU - Thumbigere Math V AD - Laboratory of Oral and Connective Tissue Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA. FAU - Reboucas, P AU - Reboucas P AD - Department of Pediatric Dentistry, State University of Campinas, Piracicaba Dental School, Piracicaba, SP, Brazil. FAU - Giovani, P A AU - Giovani PA AD - Department of Pediatric Dentistry, State University of Campinas, Piracicaba Dental School, Piracicaba, SP, Brazil. FAU - Puppin-Rontani, R M AU - Puppin-Rontani RM AD - Department of Pediatric Dentistry, State University of Campinas, Piracicaba Dental School, Piracicaba, SP, Brazil. FAU - Casarin, R AU - Casarin R AD - Department of Prosthodontics and Periodontics, State University of Campinas, Piracicaba Dental School, Piracicaba, SP, Brazil. FAU - Martins, L AU - Martins L AD - Department of Prosthodontics and Periodontics, State University of Campinas, Piracicaba Dental School, Piracicaba, SP, Brazil. FAU - Wang, L AU - Wang L AD - Laboratory of Oral and Connective Tissue Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA. FAU - Krzewski, K AU - Krzewski K AD - Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA. FAU - Introne, W J AU - Introne WJ AD - Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD, USA. FAU - Somerman, M J AU - Somerman MJ AD - Laboratory of Oral and Connective Tissue Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA. FAU - Nociti, F H Jr AU - Nociti FH Jr AD - Department of Prosthodontics and Periodontics, State University of Campinas, Piracicaba Dental School, Piracicaba, SP, Brazil. FAU - Kantovitz, K R AU - Kantovitz KR AD - Department of Pediatric Dentistry, State University of Campinas, Piracicaba Dental School, Piracicaba, SP, Brazil. AD - Department of Dental Materials, Sao Leopoldo Mandic Research Center, Dental School, Campinas, SP, Brazil. LA - eng GR - K99 DE028439/DE/NIDCR NIH HHS/United States GR - R00 DE028439/DE/NIDCR NIH HHS/United States PT - Journal Article DEP - 20170803 PL - United States TA - JDR Clin Trans Res JT - JDR clinical and translational research JID - 101684997 PMC - PMC5734460 OTO - NOTNLM OT - immunodeficiency OT - lysosomal trafficking regulator (LYST) protein OT - lysosomes OT - periodontal disease OT - phagocyte bactericidal dysfunction OT - toll-like receptors COIS- The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. EDAT- 2017/12/26 06:00 MHDA- 2017/12/26 06:01 PMCR- 2018/08/03 CRDT- 2017/12/26 06:00 PHST- 2017/12/26 06:00 [entrez] PHST- 2017/12/26 06:00 [pubmed] PHST- 2017/12/26 06:01 [medline] PHST- 2018/08/03 00:00 [pmc-release] AID - 10.1177_2380084417724117 [pii] AID - 10.1177/2380084417724117 [doi] PST - ppublish SO - JDR Clin Trans Res. 2018 Jan;3(1):35-46. doi: 10.1177/2380084417724117. Epub 2017 Aug 3.