The relationship between matrix metalloproteinases (MMP-3, -8, -9) in serum and peripheral lymphocytes (CD8 + , CD56 + ) in Down syndrome children with gingivitisby G. Tsilingaridis, T. Yucel-Lindberg, H. Concha Quezada, T. Modéer

Journal of Periodontal Research




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The relationship between matrix metalloproteinases (MMP-3, -8, -9) in serum and peripheral lymphocytes (CD8+, CD56+) in Down syndrome children with gingivitis

Tsilingaridis G, Yucel-Lindberg T, Concha Quezada H, Modeer T. The relationship between matrix metalloproteinases (MMP-3, -8, -9) in serum and peripheral lymphocytes (CD8+, CD56+) in Down syndrome children with gingivitis. J Periodont Res 2013; doi: 10.1111/jre.12157. © 2013 John Wiley &

Sons A/S. Published by John Wiley & Sons Ltd

Background and Objective: Altered immune response may be a major contributor to periodontal disease in Down syndrome. This study investigated the relationship between peripheral lymphocytes and matrix metalloproteinases (MMPs) in serum in Down syndrome children with gingivitis.

Material and Methods: Children with Down syndrome (n = 10) and healthy controls (n = 10) were clinically and radiographically examined during dental treatment under general anaesthesia. Peripheral blood and gingival crevicular fluid were collected from each subject and concentrations were determined: serum MMP-2, -3, -8 and -9; serum tissue inhibitors of metalloproteinases (TIMP) -1, -2 and -3; and gingival crevicular fluid. Leukocytes were isolated from peripheral blood and the relative amounts (%) of the various cell phenotypes were analysed using flow cytometry. In addition, peripheral blood cells were treated with Porphyromonas gingivalis lipopolysaccharide and levels of MMPs and TIMPs measured.

Results: Concentrations of MMP-3, MMP-8 and TIMP-1 in serum were significantly higher (p < 0.05) in the Down syndrome group compared to the controls.

When peripheral blood leukocytes were cultured in the presence or absence of

P. gingivalis lipopolysaccharide, MMP-8 levels were significantly (p < 0.05) higher in the Down syndrome group compared to controls. Children with Down syndrome exhibited significant positive correlations between CD8+ T cells and

MMP-8 (r = 0.630; p = 0.050), between CD8+ T cells and MMP-9 (r = 0.648; p = 0.043), and between CD56+ NK cells and MMP-3 (r = 0.828; p = 0.003) compared to controls.

Conclusions: The positive relationship of serum MMP-3, -8 and -9 with immune cells in children with Down syndrome may facilitate migration of

G. Tsilingaridis1,2, T. YucelLindberg3, H. Concha Quezada4,

T. Modeer1 1Division of Paediatric Dentistry, Department of

Dental Medicine, Karolinska Institutet,

Huddinge, Sweden, 2Department of Paediatric

Dentistry, Eastmaninstitutet, Stockholm,

Sweden, 3Division of Periodontology,

Department of Dental Medicine, Karolinska

Institutet, Huddinge, Sweden and 4Center for

Infectious Medicine, Department of Medicine,

Karolinska University Hospital, Huddinge,


Georgios Tsilingaridis, DDS, Department of

Paediatric Dentistry, Eastmaninstitutet,

Dalagatan 11, SE-113 24, Stockholm, Sweden

Tel: +46 8 123 165 40

Fax: +46 8 34 82 72 e-mail:

Key words: crevicular fluid; Down syndrome; matrix metalloproteinases; serum; T cells

Accepted for publication November 08, 2013

J Periodont Res 2013

All rights reserved © 2013 John Wiley & Sons A/S.

Published by John Wiley & Sons Ltd


CD8+ T cells and CD56+ NK cells into the periodontal tissue, which may contribute to the increased degradation of periodontal tissue in individuals with Down syndrome.

Down syndrome, caused by a chromosomal aberration in chromosome 21 (1), exhibits several functional and physical characteristics, including mental retardation, dementia, congenital heart disease, leukaemia, increased susceptibility to infection and periodontal disease (2,3). Although numerous aetiological factors such as poor oral hygiene, tongue pressure, dental calculus and periodontopathogens have been suggested to explain the higher prevalence of periodontal disease in subjects with Down syndrome, one factor that may significantly contribute to periodontal disease is an impaired host response (4). The few studies on the relationship between microorganisms and periodontal disease in Down syndrome subjects have reported increased levels of the periodontopathogens Porphyromonas gingivalis and

Actinobacillus actinomycetemcommitans in subgingival plaque (5,6).

To date, 24 matrix metalloproteinases (MMPs) have been detected, of which 23 are found in humans (7).

MMPs are classified into groups based on substrate specificity, such as collagenases (MMP-1, -8, -13), gelatinases (MMP-2, -9), stromelysins (MMP-3, -10), stromelysin-like (MMP-7, -11, -12) and membrane-type (MMP-14, -15, -16, -17) (8). Tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, -4) modulate MMP activity and partly control and stabilize MMPs, preventing tissue destruction. Almost all

MMPs can be inhibited by the four

TIMPs (7,9,10).

In subjects with Down syndrome, recent studies have shown increased levels of MMP-2, -3, -8 and -9 in gingival crevicular fluid, as well as an altered relationship between MMP-8 and TIMP-2 compared to controls (11–13). Higher immunoreactivity of

MMP-8 and -9 has also been demonstrated in the saliva of subjects with

Down syndrome when compared to healthy controls (14).

Increased susceptibility to infection is often observed in subjects with Down syndrome, probably due to an impaired host response characterized by reduced chemotactic ability, impaired phagocytosis of polymorphonuclear leukocytes, and disturbances in T- and B-cell subpopulations (15–17). In Down syndrome subjects, it has been reported that the function of the thymus is altered, with a decreased number of mature thymocytes expressing high levels of tumour necrosis factor (TNF)-a and interferon (IFN)-c (18,19). This is well compatible with our previous study reporting significantly higher levels of both TNF-a and IFN-c in gingival crevicular fluid of Down syndrome subjects (20). Circulating T and B cells have been described as abnormally low in young children with

Down syndrome (21–25), although Tcell populations in subjects with