Transcribed by Erica Manion

10/21/2014

Diagnosis & Treatment of Oral Diseases Lecture 54 Pathogenesis of Periodontal

Disease I by Dr. Craig
[1] [Title Slide]
[Dr. Craig] Okay everyone. So, what I told you up to now is really based in the literature.
And that really is the basis of our therapy, to change the profile of the bacteria present in a
site from one associated with periodontitis to one associated with health. And that works,
you have to take my word for it, but there is an enormous amount of literature out there.
That works extremely well. Unbelievably well. The only problem is that it is sort of tedious
for us. If I never see another scaler in my life, I will be a happy man. But I know on Tuesday
Im going to see hundreds of them. Its not very efficient from a public health standpoint
because you have to have extremely well trained dental healthcare professionals. You
know, teach people to brush and floss their teeth effectively. Most people dont they have
no idea what they are doing. And you also have to go in and debride the area, debride it of
calculus, debride it of biofilm. That is grounded, really well grounded, and that is the
cornerstone of my practice. So now we go from grounded, really well documented facts,
into the pathogenesis of periodontal disease. I have to tell you right up front that there is a
lot we dont know. It is going to be your cohort of practitioners that hopefully will shed
light on the pathogenesis of periodontitis. It is the interplay, not just the bacteria, it is the
interplay between the host and bacteria and it is a very subtle dance, a very subtle
communication that results in disease. And there is a lot of targets that you could hit
therapeutically with something that would be a lot easier than teaching people how to
brush and floss and clean them up when they dont, right? So anyways, now we are going
to go into the realm of the pathogenesis of periodontal disease.
[2] [Pathogenesis of periodontal disease]
We are going to address four questions. And these are real important for you. Who is
susceptible to the disease? And we are specifically focusing on chronic adult periodontitis.
The destructive periodontal disease you are going to see in your practices all the time.
Were going to make the case that chronic periodontitis is not a simple infectious disease.
You should probably already have this idea in your mind now. But it is a polymicrobial
disease associated with several different bacterial species. And it is something called a
complex disease. It is not a simple disease, it is a complex disease, and hopefully we will
get this far into our discussion today. On Friday, we are going to talk in depth about how
chronic adult periodontitis progresses in disease susceptible individuals. And then we are
going to follow up again, like we did in the perio micro lecture, what are the implications
for periodontal therapy? Not only now, but more importantly in the future. So what Im
going to try to do here, because this is a very complex subject I always get these complex
subjects to talk about. This is a very complex area, and Im going to try to abstract stuff so I
can set you up so that you can see where I think periodontal therapy is going to go in the
future. So what are the implications for therapy?
[3] [Pathogenesis of periodontal diseases: Who are susceptible?]
So lets start. Who are susceptible to this disease?

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[4] [Development of gingivitis is plaque dependent - graph]

So you already know from Harald Loes seminal experiment I wish I was alive. You know
how many citations this paper has gotten?? And it was so simple, it didnt cost him
anything. I dont know, just born too late. Anyways, everyone, universally, will get
gingivitis if they stop oral hygiene. Gingivitis associated with the accumulation of biofilm
mass.
[5] [Development of gingivitis is plaque dependent]
And so cessation of oral hygiene universally results in gingivitis, as we know from Harald.
Gingivitis is reversible with treatment and oral hygiene, and very few cases of gingivitis
progress to periodontitis. And that is key. So when you do these gingivitis models, I cant
think of a time when you actually start to see attachment loss. When you actually start to
see the conversion from gingivitis (gingival inflammation), to periodontitis (gingival
inflammation that results in loss of attachment). Destruction of dental cementum,
periodontal ligament, and alveolar bone. Now this is in contrast to several model systems
that we are going to talk about on Friday, where you can play with animals. You can play
with transgenic animals, you can play with a bacteria that infect them. And there has been
an incredible perspective that has arose because of these animal models. But in these
animal models, they use a ligature that they tie around the necks of the teeth. Reproducibly
that site gets periodontitis. It is not totally reflective of adult or naturally recurring
periodontitis. And of the five hundred oral bacterial species, Dr. Caufield probably says the
seven hundred fifty oral bacterial species, a lot of species, there is only a few that are
associated with periodontitis, and since weve only characterized about half, that red group
is probably going to have more bacteria associated with it.
[6] [Red group is necessary but not sufficient to develop periodontitis]
So anyways, the red group is necessary but not sufficient to develop periodontitis. So there
are people in this room who have the red group but dont have periodontitis. They might
have gingivitis, but they dont have periodontitis. Something else is necessary. Folks that
have periodontitis we feel fairly secure, at least for adult periodontitis, that they have
members of the red group, they might not have all three, but they have members of the red
group, thats why I say the red group is necessary but not sufficient. There is something
else that has to be present in order for gingivitis to progress to periodontitis.
[7] [Host susceptibility is genetically determined]
Okay, and that is genetics! So host susceptibility to periodontitis is genetically determined.
And so we are going to quickly go through, review, just a few of the papers that are
landmark papers. The early ones are almost laughable in their simplicity, but I just want to
drive home the idea that a lot of the susceptibility to this disease seems to be dependent on
host factors that are genetically determined. So there was an early paper that came out
showing that teeth lost to periodontitis are not constant throughout individuals in a
population. They seem to cluster around certain individuals. So this was an oral surgery
practice that prospectively recorded the reasons for extractions of teeth over 1800
subjects. And what they basically found and this paper is quoted over and over again
that most teeth lost to periodontitis occurred in a relatively small subset of individuals.

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10/21/2014

[8] [Host susceptibility is genetically determined]

So, in walks Harald Loe again, now he is a successful periodontal researcher, and he decides
to do something big. So at the time in the 1960s, the late 1960s, it was very fashionable for
one reason or another to look at the natural history, the natural progression of diseases.
One of which was syphilis, which is probably one of the reasons that we have human
subjects committees now. But Harald was very interested in how periodontal diseases
progressed in man, and he looked all over the world, and he found a population of folks
who lived in Sri Lanka. And they work on tea plantations. I used to be a tea drinker until I
looked to see how these people live, it is sort of barbaric. But he followed a large cohort of
Sri Lankan tea laborers. At entry into the study they were 14 to 46 years old. And he
followed the same people, he would go back there almost every year, for almost three
decades, almost 30 years! The guy is tenacious if anything. And he, these people are kind of
unusual, well maybe not that unusual, he had access to them. They received no dental care
other than emergency care, which was extractions.
[9] [Host susceptibility is genetically determined]
And there is a lot of things that fell out of these studies, the Sri Lankan epidemiology of
periodontitis or progression of periodontitis studies. But one of the most important things
for us was that he was able to identify three groups based on their patterns of attachment
loss. Even in this situation where none of them performed oral hygiene at all. I mean, they
had no idea what a toothbrush was, they had no idea what dental floss was, 11% went to
their end without any overt periodontitis. The vast majority had mild or moderate
periodontitis, and about 8% had what we would classify, well Harald classified, as severe
periodontitis. So one of the problems with perio studies, especially the studies that look at
the effect of the severity of periodontitis, is the criteria. What is the criteria for mild,
moderate, and severe? And when you look at studies up until recently, nobody came up
with agreed-upon criteria.
[10] [Host susceptibility is genetically determined: Data from NHANES 2009-2010]
So there is a recent study that came out, published in the Journal of Dental Research, and
Bob Gencos name is on this, our neighbor in Buffalo. And what they did over a period of
time, is they worked with the Center for Disease Control, and the American Academy of
Periodontology, and I can imagine, they are all sitting in these conference rooms, and they
are saying whats mild periodontitis? and you gotta have this! Nahh youre wrong!! So
there really is no scientific basis here, but they finally came up with something that they felt
was a classification of mild, moderate, and severe periodontitis. And they looked at a
survey that was conducted in the United States in 2009, 2010 of adult subjects greater than
30 years old and guess what they found? This was a paper that has been quoted so much in
the paper. Almost half of them have periodontitis. Yeah but half dont in the United
States. And of the ones that have periodontitis, about 8% have mild periodontitis, and
about 30% have moderate periodontitis, and about 8% have severe periodontitis. This is
the United States population. These people have varying degrees of dental care, probably
high dental care. So both the Sri Lankan untreated group and the United States modern and
cared for group have about the same prevalence of severe periodontitis. Or at least they
have these three levels of susceptibility.

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[11] [Host susceptibility is genetically determined: Prospective studies of LAP]

So, what are some further, so this gives you an inference that there are varying levels of
susceptibility and about maybe 8% or so of just about any human population is severely
susceptible. So there are other pieces of evidence and we can go through one example of
each. So once again, localized aggressive periodontitis. This disease that is associated with
AA serotype B from the organ slides we talked about last time. Kind of an unusual disease.
The classic disease, the classic LAP occurs on the mesial of the first molars, kind of wild,
huh? And the incisors. And it occurs right at the window of puberty. So as a boy or girl
progresses through puberty they will show this. And theres been a number of studies of
this group because attachment loss is really confined to a very discreet time window, and
theres been a lot of studies looking at what are the factors associated with this. So, this is
just one study by John Suzuki whos at Pittsburgh Perio department now. I was associated
with one of these, just a whole bunch of studies. So what you do is you identify a family that
had a sibling that had localized aggressive periodontitis and youd follow the younger
sib[ling]s as they went through that window of puberty, and youd look to see what were
the factors associated with those that got localized aggressive periodontitis and those that
didnt. And most of these studies have shown that there is about a 50% chance of a sib
going through puberty in a family that has a history of localized aggressive periodontitis of
actually getting the disease. Is this the first time you guys have actually been exposed to
localized aggressive periodontitis? Yeah, so Ill just tell you a few things so I can kind of
poison people that come after me to give a presentation. So its always fascinated people,
why it is mesials of the first molars right, and the permanent incisors that get the
attachment loss. Isnt that weird? Ok. And people in our profession have come up with very
creative ideas. One of the ideas is cemento-pathia. Well you know, during development,
Dr. Craig, theres cementum that forms there that has some defects, and thats why you get
the disease there. No one has ever shown cementum is cementum! You dont get
cementum-pathia, alright? The best suggestion I have ever come across was suggested to
me by Ken Kornman and well talk more about it. If you think about it, as teeth erupt into
the oral cavity, the succession of adult teeth after primary teeth, through that window of
puberty, its the mesial of first molars and the four incisors, upper and lower, that have
embrasures. Everywhere else, the primary teeth are lost and then you lose the embrasure,
and maybe thats the little niche that AA serotype B needs to live. But thats been kind of
the best suggestion so I just wanted to put that out there, its kind of interesting. So
anyways, 50% chance that a younger sib would also come down with the disease. Highly
suggestive of a genetic trait.
[12] [Host susceptibility is genetically determined: Twin Studies]
Twin studies, ok. Twins are a favorite medical model. Kind of follow identical twins, put
them in different environments, you know, whatever and see whatever the outcome
variable is. So there is a whole bunch of people that have done this. Perhaps the best name
is Michalowicz who is up at Minnesota. One of the papers that he reported was in a
longitudinal study of 117 identical twins, and they looked to see who had periodontitis and
who didnt. And lo and behold, there was about a 50% chance that both twins, ok, identical
twins, would exhibit moderate to severe periodontitis even if they were in different
environments. Again, highly suggestive of some kind of genetic trait or traits.

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[13] [Host susceptibility is genetically determined: About 40-50% or the variance]

So just to summarize all of that, there is strong evidence to suggest that about 40 50% of
the variance in susceptibility to periodontitis is genetic. So the question becomes, what
genes are involved, what are the genetic defects? And the answer is, we dont have the
foggiest idea. Not the foggiest idea. But this doesnt stop people from trying. Right? This
doesnt stop people from trying.
[14] [Genetic disorders associated with aggressive periodontitis: Chart]
So theres a number of genetic disorders that you will learn about in general pathology that
are also associated with severe periodontitis. And so this a leukocyte adhesion defect type
I and type II. I think Dr. McCutcheon probably touched on that. And the molecular lesion is
failure to express leukocyte functioning antigen, right? Which is the ligand for the
intercellular adhesion molecules so you can recruit polymorphoneuclear leukocytes and
other cells out of the vascular and into the extravascular site. And something called
Acatalasia, so that is a defect in the catalase enzyme, we talked about that being very
important in neutrophils. I can never pronounce, here, cyclic neutropenia, a rise and fall in
neutrophil count. The molecular lesion is unknown when you get a decrease in
neutrophils, you get an increase in periodontitis severity. Chediak-Higashi syndrome,
mutations in neutrophil lysosome trafficking. Elhers Danlos Syndrome, you dont have to
remember this, youll get it in general pathology, youll have several types. These are
defects in type III collagen. And finally, Papillion-Lefevre Syndrome, Cathepsin C. So the
take home lesson from these genetic diseases that also have severe periodontitis is that
most of these diseases tend to be associated with neutrophil recruitment, honing, or
function, so these are defects in the innate immune response. [student question: couldnt
quite hear exactly, but student asked for clarification on what from this slide we are
responsible for]. I would probably think that youre probably responsible for knowing the
take home lesson. Cause you know, you can always google, right? But you probably, you
know LAD type I and II, did Dr. McCutcheon go over that? No?!? Bad Dr. McCutcheon!!
Believe me, by the time you get out of here you will know these very well. Okay, and a host
of other syndromes.
[15] [Genes associated with chronic periodontitis by single nucleotide polymorphisms
(SNPs) analysis]
As you are aware, there can be mutations in genes in either the coding or non-coding
domain, and people like to look at where these single nucleotide polymorphisms, single
nucleotide mutations, called SNPs, are located, and to see whether they segregate with a
phenotype. So one of the first people to jump into this, is Kenneth Kornman who works for
a company called Interleukin Genetics. Hes also the editor of the Journal of Periodontology
and was a Junior Faculty Member at the University of Connecticut while I was a resident
there, so it is kind of neat to see Ken ascend over the years. And he and his company are
really interested in looking at single nucleotide polymorphisms and their associations with
human disease to try to come up with a genetic test to determine whether you are
susceptible for a disease or not. And one of the things that fell out was that since we are
dealing with inflammation and the innate immune response, why dont we look at proinflammatory cytokines and look at their genes. So here is the interleukin gene IL-1, and
interleukin gene IL-1, and low and behold. So they got DNA from a large population of
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folks and they also determined whether they had severe periodontitis at all, and if you had
these two SNPs, one in the interleukin-1 gene and one in the interleukin-1 gene at these
positions, you had a greatly increased risk of having severe periodontitis. And they have
marketed this kit to our profession, and there has been lots of studies looking at the
voracity of this analysis. As it turns out if you are a cigarette smoker the test doesnt work.
The effect of cigarette smoking on periodontitis washes away, overwhelms any effect of
these two genes. If you happen to be non-Northern European, doesnt work, alright? So
what else When this came out I was doing a collaboration with Dr. Socransky at Forsythe
and Dr. Socransky said yeah, you have to have six digits and two heads and you have to
have two heads and come from Sweden what use is it? But youll see more of these. So
other people, this company and other people have looked at other genes associated with
the innate immune response like the TNF- gene, Il-4, Il-6, Il-10, the receptor that is
expressed that binds the constant domain of IgG antibody, alright. And some people have
actually published on the vitamin D receptor (VDR) I dont know how that snuck in there,
but it did. The take home lesson is right here. Most genes are associated with the innate
immune response. Of those studied to date. The best characterized though is that
combined SNP that Ken Kornmans group came up with.
[16] [Pathogenesis of Periodontal Diseases: Chronic periodontitis is a polymicrobial,
complex disease]
So weve discussed disease susceptibility. 50% of the variance is genetic. What is the gene?
Who knows. Thats for you guys to figure out.
Now, lets talk a little bit about how periodontitis is not your typical disease, alright? Its not
dental caries. Dr. Caufield would be very upset.
[17] [Chronic periodontitis is a polymicrobial, complex disease]
So we are going to characterize chronic periodontitis for the rest of our discussion as a
polymicrobial: its not being caused by a single, simple infection like HIV or tuberculosis.
But it is characterized by the biofilm that inhabits teeth implants from a biofilm that is sort
of in symbiosis, alright, to a biofilm thats associated with disease, and that is called a
dysbiosis. Had Dr. Saxena, Deepak Saxena talked about biofilms in the gut? Yes? In
microbiology? You dont even remember microbiology anymore do you. Ok. So, I went to
see Dr. Saxena and I said, did you talk about biofilms in the gut? and he goes yes!!!!!!
Okay, so. So we are going to build on what he presented. And as far as the complex disease
part, complex diseases have several characteristics, which chronic adult periodontitis really
fits into. And these are the characteristics. It usually presents with a mild phenotype. Most
folks dont even know they have periodontitis until it progresses to a point where they start
losing their dental papilla, the so-called black triangle disease. I used to have a beautiful
smile and now you can see through my teeth! Make it go away!! Very difficult to treat. Or,
in my practice it is usually I woke up this morning and this tooth is moving around, you
know? Make it stop moving around! Well, especially for a molar, for a molar to freely
move, visibly, you have to lose about 50% of the attachment. So already you are dealing
with someone who has severe periodontitis. So usually presents very insidiously, very
slowly, with a mild phenotype. Slow progression, more prevalent in the older population
because it takes a longer time for the pathogenesis of the disease to progress until a
clinically observable event. The pathogenesis my have several pathways, all leading to a
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common outcome. So it is not un-probable that you could have several different types of
inflammatory processes that involve the innate immune response. Several genetic defects,
all leading to chronic periodontitis. And complex diseases tend to be polygenic. So if you
have a, you know, sickle cell disease, you have one mutation, boom. And if youre
homozygous you have the disease. A simple genetic disease. Polygenic diseases may have
several genes, the contributions of all of those mutations together leads to the phenotype of
the disease. So what are the examples of complex diseases? Well, type II diabetes mellitus,
alright. Several different ways of getting type II diabetes mellitus. Usually insidious, more
prevalent in older populations, alright. Several different genes, again, can lead to type II
diabetes. Atherosclerosis, right, several different ways, we talked about in the general
pathology lecture, several different ways of getting atherosclerosis, lipidemia, systemic
inflammation, and so on. Rheumatoid arthritis, even Alzheimers disease. And as it turns
out, all of these complex diseases are associated with periodontitis. So this kind of suggests
an underlying common theme or common mechanism to all these complex diseases.
[18] [Pathogenesis of periodontal diseases: Progression of periodontitis in diseasesusceptible individuals]
So, what have we done so far? We are going to leave early today, alright!! So we talked a
little bit about disease susceptibility. Everyone gets gingivitis reproducibly, all humans.
However, a select few get chronic adult periodontitis. Chronic adult periodontitis is not a
simple infectious disease, although it is associated with a biofilm, no one has ever shown a
single bacterium or virus, people are actually looking at viruses as the cause of chronic
periodontitis, as being an etiologic agent. It more appears to be a disease that is associated
with a profile of bacteria, most of which are gram negative, anaerobic or facultative
anaerobic bacteria. And that it is a complex disease, very similar to atherosclerosis, type II
diabetes, Alzheimers disease, those sorts of things. But what we will talk about, is it
Friday? We meet back on Friday? If you dont tell me I wont be here you know? So well
talk about how this disease progresses, both at a histological and more importantly, at a
molecular biological level. And why is that important? Because how the disease progresses
is going to have a lot of bearing on how you guys treat and manage this disease in the
future. At the present time all we have is management of the biofilm and I think in the
future we are going to understand the pathogenesis from the host perspective to come up
with different kinds of strategies that perhaps may be a little easier to implement, using our
knowledge of the pathogenesis of periodontitis. See you on Friday! I think it is 10:00, 10:00
to 12:00.