Inflammatory Mediators of Leprosy Reactional Episodes and Dental Infections: A Systematic Review

Table 2

Articles selected for the systematic review on dental infections and the presence of inflammatory mediators in serum (a), biopsy specimens (b), and gingival crevicular fluid (GCF) (c) according to the publication year, author, type of sample, and obtained results.

Year	Authors		Significant results
(a) Dental infections and Presence of mediators in serum
2011	Kinney et al. [105]	83 (PD)	IL-1β, MMP-8, and MMP-9 were strongly correlated with PD status.
	Özçaka et al. [106]	22 (CPD), 21 (C)	Individuals with CPD had lower IL-17 levels in saliva.
	Robati et al. [51]	25 (PDagG); 25 (C)	Low levels of IL-4 were associated with PDagG, and IL-6 levels were high compared with the control group.
	Sánchez-Hernández et al. [35]	18 (CPD),; 12 (PDag),; 9 (C)	Individuals with PDag had higher IL-12 levels in gingival tissue and serum. Those with CPD had higher serum IL-18 concentrations than controls.
2010	Duarte et al. [70]	14 (PDagG); 14 (CPDg); 14 (C)	After periodontal treatment, the serum TNF-α concentration remained high in the PDagG group
	Schenkein et al. [73]	53 (PDagL),; 49 (PDagG),; 67 (C)	IL-17 was associated with the loss of clinical insertion. Individuals with PDagG or PDagL had higher serum IL-17 concentrations.
2008	Abdolsamadi et al. [107]	40 (LPC); 40 (C)	Production of IL-6 in LPC could be used as a marker of chronic apical periodontitis.
	de Queiroz et al. [108]	17 (CPD), 8 (C)	Serum levels of RANTES, MIG, and eotaxin differed between healthy individuals and those with periodontitis.
2005	Bretz et al. [42]	1131 (severe, moderate, or absent disease)	High levels of plasma TNF-α were associated with the extent of PD and number of teeth. IL-6 levels were higher in individuals with more extensive PD than in other individuals.
2003	Górska et al. [56]	25 (CPD); 25 (C)	Serum and gingival tissue biopsy specimens of individuals with CPD had higher levels of IL-1β, TNF-α, IL-2, and IFN-γ than those of the control group.
2001	Murata et al. [52]	276 individuals	The severity of PD was not associated with the average serum IL-6 concentration. Further, 54% were positive for IL-6 in serum.
(b) Dental infections and presence of inflammatory mediators in biopsy specimens
2012	Dutzan et al. [80]	10 (CPD),; 8 (C)	Individuals with CPD showed increased expression of IL-21, IL-1β, IL-6, IL-17, and IL-23p19 and decreased expression of IL-10 and TGF-β1.
2011	Dutzan et al. [109]	15 (CPD), 19 (C)	Individuals with CPD had higher IL-21 levels in gingival tissue and GCF than controls.
	Santos [57]	36 (DGC), 31 (CPD), 15 (C)	IFN-γ was present in the gingival tissue of all samples and was present at higher concentrations in more advanced stages.
2009	Dutzan et al. [58]	106 (moderate or advanced CPD), 25 active sites; 25 inactive sites	The IFN-γ level in gingival fluid was higher than at the active site. Progressive periodontal lesions in individuals with CPD had higher expression of IFN-γ and had more frequent IFN-γ expression.
	Fukada et al. [110]	20 (GP),; 10 (cysts), 8 (C)	Granulomatous tissue showed increased expression of IL-10, whereas periapical tissue with granuloma and cyst had similar expressions of IFN-γ and IL-4.
	Ohyama et al. [74]	15 (PD); 11 (C)	Individuals with PD had higher levels of IL-23 and IL-12 in periodontal lesions than the control group.
2008	Honda et al. [75]	24 (PD); 23 (G)	Expression of IL-17A mRNA was higher than that of IL-17F mRNA. The expression of IL-17A differed in gingivitis and periodontitis.
	Menezes et al. [85]	57 (GP); 38 (C)	Periapical granulomas showed higher TNF-α, IL-10, and RANKL mRNA expression than healthy periodontal tissues.
2007	Johnson and Serio [43]	59 (BP = 3 mm and SG); 73 (BP = 4–6 mm); 53 (BP > 6 mm); 58 (C)	Affected gingival tissue (3–6 mm) showed higher concentrations of IFN-γ, IL-2, IL-4, IL-6, IL-10, and IL-13 than controls. IL-6 showed a positive correlation with sulcular impairment.
	Jurisic et al. [86]	43 (CR), 15 (keratocysts)	A higher concentration of TNF-α was observed in radicular cysts.
	Kokkas et al. [44]	6 (reversible pulpitis); 6 (irreversible pulpitis), 6 (C)	The increase in TNF-α gene expression was associated with irreversible pulpitis compared with the control group. TNF-α was positively associated with the severity of clinical parameters.
	Brekalo Pršo et al. [87]	Group I: 15 (sensitive LP), Group II: 15 (insensitive LP), 15 (C)	Groups I and II had higher levels of TNF-α. Symptomatic periapical tissues had higher levels of IL-6 than asymptomatic periapical tissues and controls.
2006	Honda et al. [59]	25 (CPD); 23 (G)	Individuals with periodontitis had higher levels of IL-1β, IFN-γ, RANKL, HSP60, and TGF-β1. The levels of IL-4 were slightly higher in periodontitis than in gingivitis.
2005	Johnson and Serio [45]	36 (BP = 3 mm and SG); 39 (BP 4–6 mm); 15 (BP > 6 mm); 42 (C)	Concentrations of IL-2, IL-4, IL-6, IL-10, IL-18, and IFN-γ were higher in biopsy specimens from tissue adjacent to BP of 4–6 mm than in controls. Higher concentrations of IL-6 and IL-18 were noted adjacent to sites with a probing depth >6 mm than in healthy sites.
	Rodríguez and López [46]	13 (G), 9 (CPD); 13 (C)	Individuals with gingivitis and periodontitis had higher concentrations of IL-6 in gingival tissues than in healthy tissues.
2004	Johnson et al. [47]	19 (BP = 3 mm and SG); 24 (BP 4-5 mm); 11 (BP ≥ 6 mm); 31 (C)	IL-6 concentration increased with probing depth; the IL-11 concentration was higher around BP = 3 mm, and the IL-17 concentration was higher around BP of 4-5 mm compared with the other sites.
2003	Zehnder et al. [111]	11 (severe caries, symptomatic), 13 (C)	Teeth with severe caries showed a higher expression of IL-6, IL-8, and IL-18.
2002	Pezelj-Ribaric et al. [112]	20 (irreversible pulpitis); 20 (extensive caries restoration), 20 (C)	Teeth with irreversible pulpitis showed higher concentrations of TNF-α than controls.
2001	Lappin et al. [60]	10 (PIP); 10 (CPD)	IFN-γ and IL-2 were involved in disease progression, suggesting a modulator role in the inflammatory response.
2000	Danin et al. [113]	25 (LPC)	TGF-β per mg tissue was correlated with the diameter of the lesions.
1999	Barkhordar et al. [114]	6 (pulpitis), 6 (LP); 8 (C)	Samples of the periapical and inflamed pulp tissue showed medium levels of IL-6, which were higher compared with control levels.
	Huang et al. [115]	Teeth (irreversible pulpitis and C)	Teeth with irreversible pulpitis had higher levels of IL-8 than those with healthy pulp.
1998	McGee et al. [48]	= 8; : BP ≤3 mm; : BP with 4–6 mm; : BP >6 mm	There was a higher concentration of IL-8 around BP ≤3 mm and a higher concentration of IL-6 and IL-1β around BP >6 mm.
	Shimauchi et al. [81]	29 teeth with pulp exudates (EP) (symptomatic and asymptomatic)	There was a positive correlation between IL-1ra and IL-1β, at relatively higher levels of IL-1ra when compared with IL-1β.
1997	Rauschenberger [116]	12 (irreversible pulpitis), 17 (C)	IL-2 concentrations differed significantly between inflamed pulp tissue and healthy pulp tissue.
	Roberts et al. [117]	17 (CPD)	TNF-α and IL-1ra mRNA expression were higher in CPD than in healthy gingival tissue.
	Roberts et al. [118]	34 (CPD); 5 (C)	TNF-α mRNA expression was higher in CPD than in controls. IL-1β, IL-1ra, and IL-1α were seen more often in healthy tissue.
	Tokoro et al. [89]	13 (moderate or advanced (PD), 5 (G)	Gingival tissue with periodontitis showed a predominant expression of IL-4 and IL-5. There was a predominance of IL-1α, IL-1β, and TNF-α in gingivitis.
(c) Dental infections and presence of inflammatory mediators in GCF and saliva
2013	Ertugrul et al. [90]	21 (PDagG),; 21 (CPD); 21 (G), 21 (C)	PDagG had higher total levels of IL-8 in GCF than CPD, G, and controls. Levels of IL-1β and TNF-α were higher for the group with PDagG.
	Rathnayake et al. [82]	441 (PD)	IL-1β can be used as a marker in PD. Individuals with severe periodontitis showed a higher concentration of IL-1β.
	Yue et al. [49]	40 (PDag); 40 (C)	In PDag, there were higher concentrations of IL-1β, IL-2, IL-6, IFN-γ, and TNF-α in saliva and GCF.
2012	Ay et al. [119]	20 (PDagG),; 18 (C)	The frequency of IL-11 was lower in the group with PDagG, and the concentration of IL-17 was lower than in the control group.
2011	Chaudhari et al. [95]	30 (CPD); 30 (C)	IL-1β was positively correlated with the following clinical parameters: bleeding on probing, pocket depth, periodontal disease rating, and tooth mobility.
	Garrido Flores et al. [88]	14 (PAA),; 14 (C)	Higher TNFα concentrations were noted in gingival sites of teeth with PAA than in the control group.
	Kaushik et al. [83]	28 (CPDg), (C)	Individuals with PD had a medium level of elevated IL-1β compared with the control group.
	Shaddox et al. [50]	34 (PDagL); 9 (C)	Patients with PDag had higher levels of TNFα, IFNγ, IL1β, IL2, IL6, IL10, and IL12p40 than healthy individuals.
	Stashenko et al. [120]	103 (PIP1), 42 (PIP2); 45 (C)	Levels of IL-1β in GCF increased according to the severity of PD.
2010	Burgener et al. [121]	40 teeth (PA); 40 teeth (C)	Teeth with apical lesions had higher levels of IL-1β in the gingival fluid than the controls.
	Fitzsimmons et al. [122]	430 (moderate or severe PD), 509 (C)	PD was independently associated with higher levels of IL-1β and C-reactive protein.
	Perozini et al. [96]	12 (CPD), 12 (G); 12 (C)	IL-1β concentrations were higher in CPD than in the other groups. IL-1β levels were positively correlated with PD, the volume of gingival fluid, and pocket depth.
	Teles et al. [97]	20 (CPD); 20 (C)	Clinical parameters (PD, BOP, vol GCF, R, and Sup) were positively correlated with the levels of IL-1β and IL-8 in GCF.
	Teles et al. [98]	31 (PDagG); 25 (C)	PDagG had higher average levels of IL-1β. There was a tendency for levels of IL-2 and IL-13 to be higher in PDagG. ​
2009	Ay et al. [123]	40 (CPD): BP ≤4 mm; BP ≥5 mm; 20 (C)	The total rate and concentration of IL-11 and IL-17 were lower in the group with BP ≥5 mm.
	Bastos et al. [91]	14 (PDag); 13 (C)	TNF-α concentrations were higher in PDag than in controls.
	Fitzsimmons et al. [124]	511 (moderate or advanced PD),; 562 (C)	There were higher levels of IL-1β and PCR in individuals with PD. Clinical parameters were positively correlated with biomarker levels.
	Pradeep et al. [71]	20 (CPD), 20 (G), 20 (C), 3 individuals after treatment	IL-18 levels increased according to the severity of periodontal disease, decreasing after the treatment.
	Teles et al. [125]	74 (CPD); 44 (C)	Mean salivary levels of IL-8 were positively correlated with probing depth and the average percentage of sites with bleeding on probing.
2008	Frodge et al. [92]	35 (PD); 39 (C)	Individuals with PD had higher levels of TNF-α.
	Tóbon-Arroyave et al. [126]	30 (CPD); 18 (PDag); 18 (C)	The salivary level of IL-1β did not differ between groups with periodontitis, but it was higher than in the control group.
	Toker et al. [72]	15 (PDagG),; 15 (C)	There were higher levels of IL-1β in sites with moderate or deep initial pocket than in the shallow pockets.
	Yücel et al. [84]	12 (CPD), 14 (G); 14 (C)	IL-1β and IL-12 concentrations in GCF were higher in CPD than in the control group.
2007	Tsai et al. [69]	17 (CPD)	Nonsurgical periodontal treatment resulted in a decrease in IFN-γ and an increase in IL-4.
2006	Gürkan et al. [127]	30 (PDagG),; 32 (CPD), 15 (G); 16 (C)	The rate of TGF-β1 expression was higher in groups of individuals with PDagG and CPD than in the control group.
2003	Nicolau et al. [99]	20 (CPD); 20 (C)	Individuals with CPD showed higher concentrations of IL-1β in the gingival fluid compared with the controls.
2000	Guo et al. [128]	Chronic pulpitis; Acute pulpitis; Control	There were higher IL-8 concentrations in teeth with acute pulpitis than in those with chronic pulpitis.
1997	Ishihara et al. [94]	7 (PD); 2 (C)	IL-1β and IL-1α were associated with the severity of periodontal disease.
1996	Mathur et al. [93]	20 (PD); 20 (C)	The average rate and concentration of IL-1α in GCF were higher in individuals with PD than in controls. The site status is the major determinant of the cytokine levels in unhealthy sites.

Note  1. Analysis in serum and saliva; analysis in serum and biopsy specimens; analysis in plasma; analysis in GCF and biopsy specimens; analysis in GCF and serum. PD, periodontal disease; MMP, matrix metalloproteinases; GCF, gingival crevicular fluid; Note  2. CPD, chronic periodontitis; C, control; PDagG, generalized aggressive periodontitis; PDag, aggressive periodontitis; CPDg, generalized chronic periodontitis; PDagL, localized aggressive periodontitis; LPC, chronic apical periodontitis; RANTES, regulated on activation, normal T cell expressed and secreted; MIG, monokine induced by gamma interferon; GP, periapical granuloma; G, gingivitis; RANKL, receptor activator of nuclear factor kappa-B ligand; BP, periodontal pocket; SG, gingival bleeding; CR, radicular cyst; LP, periapical lesion; PIP, early onset periodontitis; EP, pulp exudates; BOP, bleeding on probing; R, recession; Sup, suppuration; PAA, asymptomatic apical periodontitis; PA, periapical periodontitis.