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Patients | Web Exclusive
The DNA difference
One way or another, every aspect of periodontal disease comes down to genetics; from who gets it to how severe it is to whether it can ever be cured. It’s turning out to be so important that we’re going to have to change everything we thought we knew about periodontal disease, yet again. Back in the 1970’s, most everyone thought calculus and plaque caused periodontal disease. Researchers were just beginning to suspect that specific bacteria might be the actual culprits. It was another 10 years before the evidence became overwhelming and it took another 20 years to change the clinical calculus paradigm to a bacterial infection paradigm—maybe longer. Some clinicians are still in denial. Now that most of us have finally gotten used to the idea that periodontal diseases are caused by bacteria, research is finding that there’s a lot more to it than just which bacteria are present. It turns out that periodontal diseases have much more in common with auto-immune medical diseases —such as diabetes mellitus (type 1), multiple sclerosis, and rheumatoid arthritis—than a simple bacterial infection. The most striking new finding is that most of the damage to the periodontium is not caused by the bacteria! It is caused by the inflammation generated by our own immune systems. Our own white blood cells (WBC) do most of the damage to the tissue, not bacterial toxins. And what determines and governs immunological responses? Genetics. Actually, bacterial and human genetics.
Bacterial genetics matter because not all bacteria provoke an inflammatory response. Some bacteria have particular proteins on their cell walls (antigens) that trigger our immune watchdogs. So which bacteria patients harbor still matters. Of the 500 or so species that can live in the oral cavity, most are seemingly benign. A few dozen though, are capable of possessing antigens that provoke a strong immune response. When they multiply in a host (that would be us), special WBC’s called T and B lymphocytes detect the antigens on the cell walls of pathogens and initiate an immunological chain reaction that eventually stimulates cells in the long bone marrow to produce millions of additional WBC’s, mainly PMN’s (polymorphonuclear leukocytes). Their main job is to phagocytize the pathogens identified by the T cells. When the PMN’s reach the gingiva, they squeeze out through the capillary walls, which are already more porous and leaky due to another immune reaction. One in the tissue, they are supposed to start gobbling up pathogens—but they don’t. The pathogens deploy a range of their own immune counter-measures, effectively nullifying the PMN’s. Now the damage begins. PMN’s only have a three-day life span. They’re supposed to use up all their destructive enzymes killing bacteria, but if they don’t, when they die all those enzymes are dumped onto nearby gingival cells, killing them instead. Since the pathogens are still present, the T cells continue to send urgent warnings to the thymus which ramps up the immune response by increasing PMN cell production, thus further aggravating the damage. With increased production, the body needs a better way to get all those PMN’s to the infection, so the immune system starts to build a better delivery system, i.e. more capillaries. But first, it needs more room for them. It activates collagenase (to break down collagen and connective tissue) and osteoclasts (to break down bone) to provide the physical space for a denser capillary network to deliver more inflammatory cells to the site of the infection. To no avail. Breaking down tissue to deliver even more inflammatory cells that just die in three days just adds to the overall damage. That’s why periodontal diseases are so chronic.
Human genetics matter because besides orchestrating the overall immune response, small variations in the host’s genetics determine who gets periodontal disease and how chronic and severe. A surprisingly large portion of the population have tiny mutations in one or more of the genes that produce interleukin 1. IL-1 is one of the most important and potent inflammatory cytokines (a protein that acts like a hormone or neurotransmitter). It influences almost every aspect of immune cell activity. The production of IL-1 is regulated by three genes in immune cells; two are involved in the synthesis of IL-1 and the third is an antagonist gene that inhibits IL-1 production. Mutations in any of these genes typically results in a greater production of IL-1, amplifying the immune response. Paradoxically, in auto-immune diseases, increased IL-1 production make the disease worse because most of the damage is being caused by the immune system itself. In people with no genetic mutations in their IL-1 genes, IL-1 levels are normal, which isn’t any great comfort since even normal levels of IL-1 results in the immune cascade that eventually damages the periodontium. But in people with mutations, the risk is much greater. If either of the production genes have mutations (see sidebar), IL-1 levels increase as does cellular damage. If the antagonist gene has a mutation, even if the production genes are normal there are no controls on the production genes and, again, IL-1 levels increase. The worst genetic scenario is when both production and antagonist genes have mutations. These unfortunates have extremely high levels of IL-1 and pathogenic bacteria provoke a dramatic immune response.
So periodontal diseases are really auto-immune diseases revolving around genetics. The relative risk of periodontal disease depends on three genetic factors: 1. Bacterial Genetics: Some bacteria possess antigens that provoke an immune response. 2. Human Genetics: Normal human genes react to periodontal pathogens. Witness the 70-90% levels of gingivitis and periodontitis in the population. 3. Human Genetic Mutations: It’s estimated that 20% of the population have the kinds of small genetic mutations that result in abnormal (elevated) IL-1 production and thus a greater response to pathogens than those with un-mutated genes. In the future, gene therapy may offer some therapeutic opportunities for preventing and curing periodontal diseases. Right now, there’s not much we can do to modify our genetic expression. There are, however, genetic tests commercially available to detect patients with mutated IL-1 genes. Once identified, these patients can be put on more stringent home care regimens to prevent bacterial colonization and receive more frequent professional care. We can do something about bacterial genetics simply by preventing pathogenic bacteria from colonizing the sulcus. The future of home care isn’t just teaching patients how to brush and floss more. It’s going to be about teaching patients how to prevent the colonization and growth of pathogenic biofilms. In the office, antimicrobial therapy is already becoming a fundamental part of dental hygiene procedures. New tests also are available to help hygienists identify whether their patients are infected with high risk bacteria or not. Periodontal diseases are turning out to be more complicated than we thought, but our new and better understanding of the fundamental role genetics plays in the disease is also opening up new diagnostic and therapeutic options.
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