title: Functional Haplotypes in Interleukin 4 Gene Associated with Periodontitis.
abstract: Chronic periodontitis (CP) is an infectious inflammatory disease that affects tooth-supporting structures and in which dental plaque bacteria, immune mechanisms and genetic predisposition play important roles. Interleukin 4 (IL-4) is a key anti-inflammatory cytokine with relevant action in imbalances in inflamed periodontal tissue. Individuals carrying the TCI/CCI genotype (S-haplotype) of the IL-4 gene are 5 times more susceptible to CP, whereas the CTI/TTD genotype (P-haplotype) confers protection against CP. Compared with the S-haplotype, subjects with the P-haplotype produce higher levels of the IL-4 protein after non-surgical periodontal therapy. The present in vitro study aimed to investigate the functionality of IL-4 haplotypes in immune cells to obtain insight into the influence of these genetic variations in regulating immune responses to CP-associated bacteria. Peripheral blood was collected from 6 subjects carrying each haplotype, and their immune cells were challenged with periodontopathogens to compare responses of the different haplotypes with regard to gene expression, protein secretion and the immunophenotype of T helper responses. We found higher IL-4 mRNA and protein levels in the P-haplotype, which also presented higher levels of anti-inflammatory cytokines. In contrast, cells from S-haplotype subjects responded with higher levels of pro-inflammatory cytokines. S-haplotype individuals exhibited significantly greater polarization toward the Th1 phenotype, whereas the P-haplotype was associated with an attenuated response to periodontopathogens, with suggestive skewing toward Th2/M2 phenotypes. In conclusion, IL-4 genetic variations associated with susceptibility to or protection against chronic periodontitis are directly associated with influencing the response of immune cells to periodontopathogens.
authors.affiliation: Department of Oral Diagnosis and Surgery, School of Dentistry at Araraquara, UNESP- Univ Estadual Paulista, Araraquara, São Paulo, Brazil.|Department of Morphology, School of Dentistry at Araraquara, UNESP- Univ Estadual Paulista, Araraquara, São Paulo, Brazil.
authors.forename: Giovana
authors.initials: G
authors.lastname: Anovazzi
authors.affiliation: Department of Oral Diagnosis and Surgery, School of Dentistry at Araraquara, UNESP- Univ Estadual Paulista, Araraquara, São Paulo, Brazil.
authors.forename: Marcell Costa de
authors.initials: MC
authors.lastname: Medeiros
authors.affiliation: Department of Oral Diagnosis and Surgery, School of Dentistry at Araraquara, UNESP- Univ Estadual Paulista, Araraquara, São Paulo, Brazil.|Department of Morphology, School of Dentistry at Araraquara, UNESP- Univ Estadual Paulista, Araraquara, São Paulo, Brazil.
authors.forename: Suzane Cristina
authors.initials: SC
authors.lastname: Pigossi
authors.affiliation: Department of Oral Diagnosis and Surgery, School of Dentistry at Araraquara, UNESP- Univ Estadual Paulista, Araraquara, São Paulo, Brazil.|Department of Morphology, School of Dentistry at Araraquara, UNESP- Univ Estadual Paulista, Araraquara, São Paulo, Brazil.
authors.forename: Livia Sertori
authors.initials: LS
authors.lastname: Finoti
authors.affiliation: Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Marcia Pinto Alves
authors.initials: MP
authors.lastname: Mayer
authors.affiliation: Department of Oral Diagnosis and Surgery, School of Dentistry at Araraquara, UNESP- Univ Estadual Paulista, Araraquara, São Paulo, Brazil.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rossa
authors.affiliation: Department of Morphology, School of Dentistry at Araraquara, UNESP- Univ Estadual Paulista, Araraquara, São Paulo, Brazil.
authors.forename: Raquel Mantuaneli
authors.identifier: http://orcid.org/0000-0001-5068-0268
authors.initials: RM
authors.lastname: Scarel-Caminaga
mesh_terms: D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics*; D010518:Periodontitis / Q000235:genetics* / Q000382:microbiology; D016966:Porphyromonas gingivalis / Q000472:pathogenicity
chemical_list: D016207:Cytokines; C508598:IL4 protein, human; D015847:Interleukin-4