July 7, 2022

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Science: The cause of periodontitis is finally understood!

Science: The cause of periodontitis is finally understood!



“Science”: The cause of periodontitis is finally understood! The most comprehensive study on the mechanism of periodontitis to date shows that the deposition of pro-inflammatory factors in the oral mucosa is the culprit丨

As the saying goes, “Toothache is not a disease, it hurts really terribly”. There are many reasons for toothache in a broad sense. One of them is periodontal disease.

Red and swollen gums may be resolved, but severe periodontitis can cause tooth looseness and Falling off, this has a greater impact on the quality of life.

Although scientists already know that severe periodontitis is caused by an excessive immune response, how does this excessive immune response occur?

How does it cause damage to the gum tissue and alveolar bone? None of these questions have been answered yet.

In the recent “Science” journal, researchers from the National Institute of Dentistry and Craniofacial Research (NIDCR) published a new study [1], they found that the excessive immune response in severe periodontitis is due to fibrin deposition in the oral cavity In the mucosa, it recruits and activates neutrophils, induces the production of reactive oxygen species (ROS) and the formation of neutrophil extracellular traps (NETosis).

Inhibition of fibrin deposition or NETosis may be a key target for the treatment of severe periodontitis.

Science: The cause of periodontitis is finally understood!

Fibrin is a pro-inflammatory factor, which is related to thrombosis and inflammation.

Past studies have found that the pathological deposition of fibrin in the oral mucosa can cause serious damage to the gingival tissue and alveolar bone, resulting in the loss of the entire dentition in adolescents [2,3], and the inflammation and inflammation of the mucosa around the dentition Alveolar bone injury is a sign of periodontitis.

Fibrin deposits are eliminated by plasmin, so plasmin is usually absent in patients with pathological deposits.

Therefore, the researchers made the hypothesis that the lack of plasmin-mediated fibrinolysis may be the cause of the excessive immune response of the oral mucosa in patients with periodontitis.

To test this hypothesis, they started a series of experiments.

First, the researchers constructed mice with double deletions of protein plasminogen (PLG, the precursor of plasmin) and fibrinogen (precursor of fibrin), and a littermate of PLG deletion/partial fibrinogen deletion Compared with mice, the former has no fibrin deposition at all , and the lack of fibrinogen completely avoids the damage to the alveolar bone caused by the loss of PLG.

This indicates that the excessive immune response of the oral mucosa caused by PLG deletion is driven by fibrin deposition.

Science: The cause of periodontitis is finally understood!

PLG and fibrinogen double deletion mice (lower right) and littermate PLG deletion/fibrinogen partial deletion small fibrin deposition

In the oral mucosa (gingival) tissues of mice with PLG deficiency and fibrin deposition, the researchers found a large number of neutrophils .

Correspondingly, the genes responsible for neutrophil recruitment and granulocyte production are involved in neutrophils. Both cell and monocyte activation of gene expression are greatly increased.

The number of neutrophils not only increases significantly at every time point in the entire pathological cycle, but is also the only cell subpopulation that also increases early in the pathological stage (12 weeks).

Integrin αMβ2 is an important molecule that mediates the recruitment of neutrophils, and members of the integrin family also play an important role in mediating the adhesion between cells and between cells and the extracellular matrix.

Experiments show that αMβ2 mediates the adhesion of neutrophils and fibrin, induces the production of reactive oxygen species (ROS) and the formation of neutrophil extracellular traps (NETosis).

Science: The cause of periodontitis is finally understood!

When researchers used pharmacological or genetic means to inhibit the accumulation of extracellular DNA and NETosis in PLG-deficient mice, the damage to the alveolar bone of the mice was significantly reduced.

Similarly, the use of small interfering RNA (siRNA) to target the elimination of fibrinogen also significantly reduces the damage to the alveolar bone.

Not only the special mice lacking PLG, in the naturally aging wild-type mice, the spontaneous alveolar bone damage of the mice that cannot deposit fibrin with age is also significantly less than that of the control mice in the same litter. .

Therefore, fibrin deposition and NETosis are both important targets to prevent alveolar bone damage caused by severe periodontitis.

Researchers also found the same high levels of fibrin deposition and neutrophil infiltration in the gum tissues of patients with periodontitis, but almost none in healthy people.

Science: The cause of periodontitis is finally understood!

Comparison of fibrin (red) deposition in the gingival tissue of healthy people (left) and periodontitis patients (right)

A genome-wide association study conducted in Europe previously suggested that the downstream polymorphism of PLG (rs1247559) is associated with aggressive periodontitis [4,5].

Researchers have also verified this in their cohort of periodontitis patients. They found that they found that PLG (rs2465836) is associated with severe periodontitis and a periodontitis-related pathogen, accompanied by high colonization of Actinomycetes Agglomerata.

In other words, even if it does not cause severe PLG deletion, single nucleotide variations in the PLG gene are also associated with an increased risk of severe periodontitis.

This also means that the immune mechanism found in mice may also be applicable to human patients.

One of the corresponding authors of the study, Dr. Niki Moutsopoulos, said that this study shows that in some cases, fibrin causes neutrophil immunity to change from protective to destructive.

This fibrin-neutrophil interaction As one of the driving factors of periodontitis, it is expected to become a target for prevention and treatment of severe periodontitis.

It may also provide new opportunities for other inflammatory diseases characterized by fibrin deposition, such as some arthritis and multiple sclerosis. Treatment ideas.

references:

[1]https://www.science.org/doi/10.1126/science.abl5450

[2] Waschulewski I K, Gökbuget A Y, Christiansen N M, et al. Immunohistochemical analysis of the gingiva with periodontitis of type I plasminogen deficiency compared to gingiva with gingivitis and periodontitis and healthy gingiva[J]. Archives of oral biology, 2016, 72: 75-86.

[3] El‐Darouti M, Zayed A A, El‐Kamah G Y, et al. Ligneous conjunctivitis with oral mucous membrane involvement and decreased plasminogen level[J]. Pediatric dermatology, 2009, 26(4): 448-451.

[4] Munz M, Richter G M, Loos B G, et al. Meta-analysis of genome-wide association studies of aggressive and chronic periodontitis identifies two novel risk loci[J]. European Journal of Human Genetics, 2019, 27(1): 102-113.

[5] Schaefer A S, Bochenek G, Jochens A, et al. Genetic evidence for PLASMINOGEN as a shared genetic risk factor of coronary artery disease and periodontitis[J]. Circulation: Cardiovascular Genetics, 2015, 8(1): 159-167.

Science: The cause of periodontitis is finally understood!

(source:internet, reference only)


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