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(Blys) on Diabetes-Related Periodontitis ORIGINAL RESEARCH Immunology Preliminary findings on the possible role of B-lymphocyte stimulator (BLyS) on diabetes-related periodontitis Marx Haddley Ferreira Abstract: The possible role of B-cell growth and differentiation- DRUMOND(a) related cytokines on the pathogenesis of diabetes-related periodontitis Luciano Eduardo PUHL(a) has not been addressed so far. The aim of this study was to evaluate Poliana Mendes DUARTE(b) the effects of diabetes mellitus (DM) on the gene expression of Tamires Szeremeske de proliferation-inducing ligand (APRIL) and B-lymphocyte stimulator MIRANDA(c) (BLyS), two major cytokines associated to survival, differentiation Juliana Trindade and maturation of B cells in biopsies from gingival tissue with CLEMENTE-NAPIMOGA(a) periodontitis. Gingival biopsies were obtained from subjects with Daiane Cristina PERUZZO(a) periodontitis (n = 17), with periodontitis and DM (n = 19) as well as Elizabeth Ferreira MARTINEZ(a) from periodontally and systemically healthy controls (n = 10). Gene Marcelo Henrique NAPIMOGA(a) expressions for APRIL, BLyS, RANKL, OPG, TRAP and DC-STAMP were evaluated using qPCR. The expressions APRIL, BLyS, RANKL, (a) Faculdade São Leopoldo Mandic, Instituto OPG, TRAP and DC-STAMP were all higher in both periodontitis de Pesquisas São Leopoldo Mandic, groups when compared to the control group (p < 0.05). Furthermore, Campinas, SP, Brazil. the expressions of BLyS, TRAP and RANKL were significantly higher (b) University of Florida, College of Dentistry, in the subjects with periodontitis and DM when compared to those Department of Periodontology, Gainesville, FL, USA. with periodontitis alone (p < 0.05). The mRNA levels of BLyS correlated positively with RANKL in the subjects with periodontitis and DM (c) Guarulhos University, Dental Research Division, Department of Periodontology, São (p < 0.05). BLyS is overexpressed in periodontitis tissues of subjects Paulo, SP, Brazil. with type 2 DM, suggesting a possible role of this cytokine on the pathogenesis DM-related periodontitis. Declaration of Interests: The authors certify that they have no commercial or Keywords: Periodontitis; Diabetes Mellitus; Inflammation; Cytokines. associative interest that represents a conflict of interest in connection with the manuscript. Introduction Corresponding Author: Marcelo Henrique Napimoga Periodontitis has long been linked to diabetes mellitus (DM).1,2 E-mail: [email protected]; [email protected] Nowadays, DM is considered a risk factor for periodontitis and has to be included as a descriptor in grading periodontitis based on the new clinical classification of periodontal diseases.3 The pathogenesis of DM is https://doi.org/10.1590/1807-3107bor-2020.vol34.0038 multifactorial, involving several metabolic and hemodynamic disorders like insulin resistance, dyslipidemia, hypertension, hyperglycemia and immune-inflammatory dysfunctions. The immune-inflammatory dysfunctions associated to DM include increase in reactive oxygen species and a shift to an overall pro-inflammatory profile.4,5 Submitted: September 14, 2019 In recent years, the role of DM in modulating mediators involved in Accepted for publication: March 23, 2020 Last revision: March 27, 2020 the pathogenesis of periodontal diseases has been studied by our research group. In brief, higher levels of pro-inflammatory T-helper (Th)1 - and Braz. Oral Res. 2020;34:e038 1 Preliminary findings on the possible role of B-lymphocyte stimulator (BLyS) on diabetes-related periodontitis Th17-cytokines have been reported in periodontitis (BLyS; also identified as B cell–activating factor from type 2 diabetic subjects when compared [BAFF], TNFSF13B, or TALL-1), have been proposed to non-diabetics.6,7,8,9 Furthermore, subjects with as essential factors to the survival, differentiation periodontitis and type 2 DM exhibited elevated ratio and maturation of B cells.21 Overexpression of of receptor activator of nuclear factor kappa-B ligand BLyS and APRIL has been linked to development (RANKL)/osteoprotegerin (OPG), a key indicator of of several autoimmune diseases, such as systemic bone resorption,10 as well as increased expression of lupus erythematosus, Sjögren syndrome, immune sclerostin and Dickkopf-1, important inhibitors of thrombocytopenic purpura, rheumatoid arthritis the Wnt/β-catenin pathway and suppressors of bone and even neoplastic lesions.22 Previous studies formation.11 Moreover, increased expression of both demonstrated that subjects with periodontitis peroxiredoxin II and superoxide dismutase II has presented higher serum levels of APRIL and BLyS been observed in sites with periodontitis in diabetic than periodontally-healthy subjects.23,24 In addition, subjects, probably as a consequence of protective and the expression of APRIL and BLyS at mRNA and adaptive mechanisms against increased levels of protein levels was locally higher in periodontitis in reactive oxidative species, as seen in a DM context.12 human and in experimental periodontitis in mice.25 Although most studies have focused on the role Despite some evidence on the possible role of of T cell-mediated immunity in the pathogenesis of APRIL and BLyS on the pathogenesis of periodontitis, periodontal diseases, pre-clinical and clinical studies the impact of DM on this mechanism has seldom been have indicated a critical contribution of B cell to explored. Therefore, the main aim of this study was to periodontal breakdown. B cell-deficient animals were evaluate the effects of DM on BLyS and APRIL mRNA protected from bacterial infection-induced alveolar expression in gingival biopsies with periodontitis. bone loss.13,14 Furthermore, the number of multiple The secondary aim was to correlate the expression subsets of B and plasma cells exceeds the number of APRIL and BLyS with genes related to osteoclast of T cells in established periodontitis in human.15,16 formation and activity, including RANKL and OPG, A possible role of B cells on osteoclastogenesis and markers of osteoclastogenesis, tartrate-resistant acid alveolar bone loss during periodontitis has therefore phosphatase (TRAP), an osteoclastic differentiation been proposed. A previous study demonstrated marker, and dendritic cell-specific transmembrane that approximately 90% of B cells express RANKL protein (DC-STAMP), an essential protein for cell in periodontitis lesions, whereas the percentage of fusion during osteoclastogenesis. RANKL-positive B cells in healthy gingiva is very low.17 Furthermore, there was a significant increase Methodology in B-cell RANKL expression in mice infected with Porphyromonas gingivalis.14 Moreover, memory B Systemically healthy subjects without periodontitis cells supported osteoclast differentiation in vitro (controls), systemically healthy subjects with in a RANKL-dependent manner, and B cells in periodontitis and type 2 diabetic subjects with the gingiva of animals submitted to experimental periodontitis were sequentially selected from the periodontitis produced RANKL and sustained population referred to the Periodontology Clinic osteoclastogenesis beyond T and other lymphocytes.18,19 of Guarulhos University (Guarulhos, Brazil) Finally, B lineage cells were an important source of between March 2014 and September 2016. Qualified secreted osteoclastogenic factor of activated T cells individuals were invited to participate in the study, (SOFAT) that induces bone resorption in a RANKL- fully informed of the nature, risks and benefits of independent manner in inflammatory states.20 the procedures and signed their informed consent. Two major cytokines belonging to the tumor During volunteer screening, medical and dental necrosis factor (TNF) superfamily, named histories were obtained. This study was approved proliferation-inducing ligand (APRIL; also identified by the Research Ethics Committee of the Guarulhos as TNFSF13 or TALL-2) and B-lymphocyte stimulator University (CAAE: 25526913.8.0000.5506). 2 Braz. Oral Res. 2020;34:e038 Drumond MHF, Puhl LE, Duarte PM, Miranda TS, Clemente-Napimoga JT, Peruzzo DC, et al. The inclusion criteria were individuals aged 30 molars, by means of a manual periodontal probe years or older, presenting a minimum of 15 teeth, (UNC15; Hu-Friedy, Chicago, USA) by the same excluding third molars. Pregnant or breastfeeding examiner (TSM), who was trained and calibrated women were excluded, as well as smokers and those using a method described elsewhere.28 with a history of subgingival periodontal therapy in the 6 months preceding the start of the study. Gingival tissue sampling Furthermore, individuals frequently using mouth In subjects with no periodontitis, the gingival rinses containing antimicrobials in the previous 2 biopsies were sampled from teeth without signs of months, systemic conditions other than DM that could clinical inflammation (BoP and/or MB), but requiring influence the pathogenesis of periodontitis and the crown lengthening procedures. All samples included expression of the studied proteins [e.g. immunological junctional and sulcular epithelia and connective disorders, bone-related diseases e complications gingival tissue. The gingival tissues were stored in (e.g., osteoporosis, ankylosing spondylitis, recent TRIizol (Thermo Fisher Scientific, Waltham, MA) at bone fractures, and rheumatoid arthritis)], use of -80°C until RNA extraction. antibiotics in the preceding 6 months, long-term use of anti-inflammatory, immunosuppressive Gene expression (e.g., glucocorticoids) and antiresorptive agents The mRNA levels corresponding to BLyS,
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