Jan Lindhe. Clinical Periodontology

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GENETICS IN RELATION TO PERIODONTITIS • 393

higher levels in the inflamed periodontal tissues

compared to healthy periodontal tissues.

Genetically determined, interindividual differences

have been observed for the IL-1 and TNF-a

production by peripheral blood mononuclear cells

or oral leukocytes, isolated from individuals with

and without periodontitis. It is conceivable that

these differences in IL-1 and TNF-a production and

secretion play a role as susceptibility and/or sever

ity factors.

Some IL-1 and TNF-a alleles have been suggested

as potential genetic markers for disease. For exam-

ple, IL-1 polymorphisms have been associated with

inflammatory bowel disease, Sjogren syndrome

and

psoriasis. TNF-a gene polymorphisms have been

associated with (chronic) inflammatory and

infectious disease processes, including leishmani-

asis, alopecia areata, meningococcal disease, lep-

rosy and cerebral malaria.

IL-1 gene polymorphisms

The genes encoding IL-1a and IL1-(3 are located in

close proximity in the IL-1 gene cluster on chromo-

some 2 (Fig. 17-4). The first study that reported poly-

morphisms for the IL-1 genes in relation to periodon-

titis was presented by Kornman et al. (1997). The

combined presence of the R-allele of the IL-1a gene at

nucleotide position -889 (IL-1a

889T

)

and the R-allele

IL-10 gene at nucleotide position +3953 (IL-1

p+3953T

)

was associated with

severity

of periodontitis in non-

smoking Caucasian patients. The combined carriage

rate of the R-alleles

IL-la

889T

and

ILAP

+3953T

desig-

nated the

IL-1

composite genotype

(Kornman et al. 1997).

Other investigators have reported similar findings

(

Table 17-1), also in cross-sectional studies (McDevitt

al. 2000, Papapanou et al. 2001). It is important to

note that the above studies were carried out in Cauca

sians (Table 17-1). Therefore, the IL-1 composite geno

type can be considered a putative severity factor for

periodontitis in Caucasians.

After these encouraging results, several studies

have investigated genetic polymorphisms in the IL-1a

and IL-1(3 genes in relation to

susceptibility for perio-

dontitis mostly in Caucasian populations (Table 17-1).

Diehl and co-workers suggest that aggressive perio-

dontitis is a complex but oligogenic condition, with

polymorphisms in the IL-1 gene cluster as (putative)

susceptibility factors (Diehl et al. 1999). However,

Hodge et al. (2001) failed to show an association be-

tween the IL-1 composite genotype and GJP. Lack of

association with IL-1 composite genotype was also

reported for chronic (adult) periodontitis patients in

two case control studies (Lain et al. 2001, Papapanou

et al. 2001). It has also been reported that patients with

the IL-1 composite genotype more often harbored

putative periodontal pathogens and had increased

counts of these pathogens (Socransky et al. 2000).

Interestingly, Laine et al. (2001) reported increased

frequency of the R-alleles of the IL-1a, I1-1(3 and IL-1

receptor antagonist genes in non-smoking patients in

whom

gingivalis

and

actinomycetemcomitans

could

not be detected. These latter results suggest that IL-1

gene polymorphisms play a role in the absence of

other (putative) risk factors. Similar studies in Chinese

and African-Americans have not resulted in signifi-

cant findings, because the IL-1 composite genotype

was hardly or not at all present in these ethnic popu-

lations (Armitage et al. 2000, Walker et al. 2000).

Several longitudinal studies on IL-1 polymor-

phisms have been performed (Table 17-1); from these

studies it may be possible to assess whether a given

genotype can be considered a true susceptibility

and/or severity factor. For example, it was reported

among periodontitis patients in maintenance over 5 to

14 years, that the IL-1 composite genotype increased

the risk of tooth loss by 2.7 times (McGuire & Nunn

1999). The IL-1 composite genotype in combination

with heavy smoking increased the risk of tooth loss by

394 - CHAPTER

Table 17-1. Summary of studies investigating the IL-1 composite genotype (Kornman et al. 1997) in relation

to periodontitis

Study

patients

controls

putative

susceptibility

putative

severity

Kornman et al. 1997

not tested

Gore et al. 1998 32 32 –

not tested

Walker et al. 2000

37 37 –

not tested

Armitage et al. 2000

300

–

McDevitt et al. 2000

not tested

Hodge et al. 2001

56 56 –

not tested

Papapanou et al. 2001

132 73 –

Laine et al. 2001

105 53 –

not tested

B. Longitudinal studies

Study

patients

susceptibility

severity

McGuire & Nunn 1999

not tested

Ehmke et al. 1999

not tested

–

De Sanctis & Zucchelli 2000

not tested

Cattabriga et al. 2001

not tested

–

Cullinan et al. 2001

295

trend

+ or – indicates whether or not the IL-1 composite genotype can be considered a (putative) susceptibility and/or (putative) severity

factor.

1 All studies included Caucasians only, unless otherwise specified

Non-smokers only

African-Americans

with

localized juvenile periodontitis (UP)

Chinese

Formally not possible to test as there is no control group; however the genotype was virtually non-existent in this population,

therefore it can be deduced that the composite genotype is not a putative susceptibility factor

A private practice study population

Early onset periodontitis (EOP)

For non-smokers > 50 years and for smokers testing positive for

gingivalis

7.7 times (McGuire & Nunn 1999). Cullman et al. mined. Among non-smoking subjects > 50 years who (

2001) presented a study in which 295 gingivitis and were IL-1 composite genotype positive, deeper prob-

moderate periodontitis subjects were followed for 5 ing depths were observed than in IL-1 composite

years

and the IL-1 composite genotype was deter- genotype negative. Furthermore, a significant interac-

GENETICS IN RELATION TO PERIODONTITIS • 395

Fig. 17-6. Antibodies (immunoglobulins (Ig)) have a Fab-region (antigen binding, hypervariable region) and an Fc-

region (constant for each of the Ig classes). For example, the antibodies recognize antigens on a microorganism

through the Fab-region. Subsequently Fc regions bind to Fc-receptors on immune cells and this process may acti-

vate the cell. A cluster of activated receptors will initiate signal transduction and dependent on the type of immune

effector cell, may induce for example phagocytosis (Van der Pol & Van de Winkel 1998a,b).

Fig. 17-7. Schematic drawing of three of the human Fc receptors for IgG. They have an extracellular part, a trans-

membrane region and a cytoplasmic tail (except FcyRIIIb, which is anchored in the outer leaflet of the cell mem

brane

via a glycosyl-phosphatidyl-inositol (GPI) molecule). The extracellular part of leukocyte Fc7R class II and III

consists of

two immunoglobulin-like domains. The + sign in the intracellular signaling motifs (cylinder) indicates

the capacity of

signaling to the cytoplasmic environment of the cell. The FcyRIIa-mediated effector functions can be

established

through the intracellular signaling motif (cylinder) within the cytoplasmic tail of the molecule. The

FcyRIIIa is

associated with a 7-chain homodimer, which serves as signaling subunit. The Fc7RIIIb-mediated effector

functions

are transmitted through the GPI. The functional genetic polymorphisms are depicted as black dots (•) in

the

extracellular Ig-like domains. For the FcyRIIa at amino acid position 131, arginine (R) or histidine (H) is present.

For

the FcyRIIIa at amino acid position 158, valine (V) or phenylalanine (F) is present. The FcyRIIIb polymorphism

caused by four amino acid substitutions at positions 18, 47, 64 and 88 and results in glycosylation differences, af-

fecting receptor affinity. The CD indication in parentheses indicates the numbering within the cluster of differentia-

tion system of immunological markers (Van der Pol & Van de Winkel 1998a,b).

tion was found between IL-1 composite genotype

positive

and age, smoking and presence of

P. gingivalis,

which

suggests that the IL-1 composite genotype

is a

contributory but non-essential susceptibility fac

tor.

In summary, for the global population, IL-1 gene

polymorphisms cannot be regarded as a susceptibility

or severity factor for periodontitis. However, in Cau

casian

patients with chronic periodontitis, the IL-1

composite

genotype may behave as a severity factor,

in particular in

non-smoking subjects.

396 • CHAPTER 17

ΤΝF-

gene polymorphisms

The TNF-

gene is located on chromosome 6 within

the major histocompat

bil

ty complex (MHC) gene

cluster. Several studies have investigated genetic

polymorph

sms in the TNF-a gene as putative suscep-

tibilitγ and severity factors in relation to periodontitis.

The genetic polymorph

sms are mainly G to A transi-

tions (Fig. 17-5). Craand

jk et al. (2002) found that the

frequencies of R-alleles (an A) at nucleotide positions

-376, -308, -238 and +489 of the TNF-ec gene in 90

patients were no different from those in 264 reference

controls.

TNF-ec gene polymorph

sms in relation to aggres-

sive periodontitis were also investigated, but the TNF-

304

R-allele was found not to be associated with

aggressive periodontitis (Shapira et al. 2001). Also,

another gene marker in the ΤΝF-

gene was investi-

gated in relation to susceptibility for aggressive peri-

odontitis. This concerned a marker based on a variable

number of microsatellite repeats; again no indication

was found for an association with GJP (Κ

ηαη

e et al.

1999).

Investigations into severity of periodontitis in rela-

tion to any of the ΤΝF-

gene R-alleles also did not

reveal a positive association. The carriage of a R-allele

at nucleotide positions -308 and -238 revealed no

differences in the % of teeth with ? 50% bone loss (

Craand

jk et al. 2002). Moreover, the carriage rates of

the R-alleles at nucleotide positions -376, -308, -238, a

d +489 were no different among patients with mod-

erate or severe periodontitis. Lack of association of

ΤΝF-

genetic polymorph

sms with periodontitis se-

verity was also reported by others (Kornman et al.

1997, Galbraith et al. 1998).

Based on the literature to date on TNF-ec genetics in

relation to periodontitis, there is no indication that any

of the reported gene variations are related to the sus-

ceptibility or severity of periodont

IL-10 gene polymorphisms

IL-10 is located on chromosome 1, in a cluster with

closely related interleukin genes, including 1L-19, IL-

20 and IL-24. IL-10 plays a role in the regulation of

pro-inflammatory cytok

nes such as IL-1 and TNF-a.

Functional disturbance in IL-10 due to genetic poly-

morphisms could be detrimental to host tissues and

could be linked to periodontal disease susceptibility.

IL-10 gene polymorphisms have been

nvestigated in

relation to aggressive periodontitis; 79 Caucasian pa-

tients from West Scotland with GJP were included a

matched with a control population (Kinane et al.

1999). Two microsatellite markers located in the pro-

moter region of the gene were used; these were pre-

viously implicated in systemic lupus erythematosus (

ηα

e et al. 1999). However, no significant differ-

ences in frequencies of various IL-10 alleles in com-

parison to periodont

lly healthy controls were oh-

served. Also, in Japanese pat

ents ether with GJP (n =

18) or with adult periodontitis (n = 34), as well as 52

controls, polymorph

sms in the promoter region of the

IL-10 gene were analyzed (Yamazaki et al. 2001). No

significant differences for the carr

age rates of the

various IL-10 alleles were seen between pat

ents and

controls. The carriage rates of the studied alleles in the

IL-10 promoter reg

on were different in Japanese from

those of Caucasian heritage (Yamazak

et al. 2001),

again emphasizing that allele frequencies in relation

to disease for one ethnic group may not be extrapo-

lated to another p

ορ

οη.

FCγR GENE POLYMORPHISMS

Leukocytes exhibit receptors (R) for the constant re-

gion (Fc) of immunoglobuhn (Ig) molecules. In the

case of IgG, these receptors are termed FcγR. The FcyRs

are found on leukocytes from both the myeloid a

lymphoid lineages. The FcγR links the humoral part

of the host defense with the cellular aspects of the

immune system (Fig. 17-6). Thus, IgG opsonized anti-

gens, particles, microorganisms or cells may trigger

cellular effects, including phagocytosis, antibody de-

pendent cellular cytotoxicity (ADCC), antigen presen-

tation, cytokine release, degranulation and regulation

of antibody synthesis (Van der P01 & Van de Winkel

1998a). The FcγR belong to the Ig superfamily and

exist, like 1g, in different classes and subclasses. The

genes for the FcγR are found on the long arm (q) of

chromosome 1, and encode for three main classes of

FcR: FcγRI, Fc7RIl and FcyRI11. Several subclasses ex-

ist, like FcγRΙa and b, FcγRIIa, b and c, and FcγRlIla

and b (Van der P01 & Van de W

υΡ1

kel 1998").

The FcγRIIa is the most widelγ distributed of the Ι

gG receptor molecules. It is expressed on all granulo-

cytes, on antigen presenting cells (APC), platelets,

endothelial cells ^nd a subset of Τ cells (Van der Pol &

Van de Winkel

1998α).

It has been shown that struc-

tural and functional differences in FcγRIIa are due to

genetic polymorphsms. The G to A transition poly-

morphism in the FcγRIIa gene at nucleotide position

+392 results in the substitution of histidine (H) for

arginine (R) at amino acid position 131 of the receptor

molecule (Fig. 17-7). Subjects homozygous f

r the

FcγRIIa

ΗΙ31

allele (N-allele) bind IgG2 immune com-

plexes efficiently, while individuals homozygous for

the FcγRIIa

R131

allele (R-allele) are deficient for this

interaction (Warmerdam et al. 1991). Because IgG2 is

generally elevated in patients with LJP, it has been

speculated that the FcγRIIa R-allele m

αγ

be associated

with susceptibility for aggressive periodontitis: pa-

tients with the FcγRIIa

R131

allele could be more suscep

tible for periodontitis due to a diminished capacity to

phagocytose IgG2 opson

zed A.

ctin

rnycetemc

tans

(Wilson & Kalmar 1996). However, this hypothesis

may have to be rejected since Loos et al. (2003)

recently found that the N-allele carr

age rate

GENETICS IN RELATION TO PERIODONTITIS •

397

(FcγRIΙ

ΗΙ3Ι

) is higher in aggressive periodontitis sub-

jects than in controls. Moreover, periodontitis patients

(aggress

ve and chronic periodontitis) homozygous for

the N-allele (HΗ131genotype) have more periodontal

bone loss than the other pat

ents carrying one or t

R-

alleles. Also, both the Japanese studies (obay

et al.

1997, 2001) and two studies with Caucasian subjects (

Colombo et al. 1998, Meisel et al. 2001), have not been

able to substantiate the hypothesis by Wilson &

Kalmar (1996).

The FcγRIIIa and IIIb are expressed on a limited

number of immune cell types (Van der Pot & Van de

Winkel

1998α).

FcγRIIIa is found on monocytes and

macrophages, natural killer (ΝΚ) cells and a subset of

Τ cells. The G to T trans

on polymorphism in the Fcγ

RIIIa gene at the nucleotide position +559, results in the

substitution of valine (V) for phenylalanine (F) at

amino acid position 158 (Fig. 17-7). Individuals who are

homozygous for the FcγRllΙa

v158

allele (N-allele) have

a higher affinity for IgGl and IgG3 than subjects

homozygous for the R-allele (FcyRI11

F158

). Moreover,

subjects carrying the N-allele can bind IgG4 while the

persons w

th the R-allele are unable to do so (Van der

Pot & Van de W

nkel

1998α).

The FcγRIIIa N-allele (

V158) is proposed as a putative susceptibility factor

for perodont

s, in partcular for aggressive perio-

dont1tis in a group of Dutch patients (Loos et al. 2003).

Also, Meisel et al. (2001), in a German population,

stud

ed FcγRIIIa polymorphisms in relat

on to perio-

donttis severity; they observed more severe peri-

odontal bone destruction in homozygous FcγRIIIa N-

allele patients (V/V158). In a Japanese population it

was found that the FcγRIIIa R-allele (F158) was over-

represented in patents with periodontal dsease re-

currence (Sugita et al. 1999). In contrast, a recent Japa-

nese study showed that the FcγRIIIa N-allele was over-

represented in pat

ents with severe per

odont

s versus

subjects with the moderate form (Kobayash

et al.

2001). Again, it is apparent that comparisons between

the d

fferent studies are difficult as the prevalences of

FcγR genotypes are d

fferent among subjects of differ-

ent ethn

c background (Van der Pot & Van de W

nkel

1998α).

The FcyR1IIb is the most abundantly expressed IgG

receptor on neutrophils, and also in the FcγRΙIIb gene a

bi-allelic polymorphism exists (Van der P01 & Van de

nkel 1998a). The FcyR111b-neutrophil antigen (

NA) Ι or ΝΑ2 polymorphism is caused by four amino

acid substitutions in the Fc binding region with differ-

ent glycosylat

on patterns (Fig. 17-7). The FcΥRIIIb

allele is cons

dered the R-allele, wh

le the ΝΑΙ allele 1s

the N-allele. TheΝΑ2type receptor hinds less effic

ently with IgGl and ΙgG3

mmune complexes (Van der

Pot & Van de Winkel 1998a). In Japanese patients, the

FcγRIIlb R-allele (ΝΑ2) was associated with early onset

per

odontit

s (Kobayash

et al. 2000) and was

found more often in adult pat

ents with disease recur-

rence (Kobayashi et al. 1997). Also the combined car-

age of both the R-allele of the FcyRI1Ib gene and the

R-allele of the FcyR11Ia gene was more frequently

detected in Japanese aggressive periodontitis pat

ents

over healthy Japanese controls (Kobayashi et al. 2000).

The possibility that genes encod

ng for Fcγ recep-

tors are associated with the susceptibility and severity

of several forms of periodontitis in different ethnic

groups seems prom

ng. Further research is needed in

larger groups of subjects from different global

populations to confirm the current observations. Fur-

thermore, functional studies among subjects wth dif-

ferent FcγR genotypes need to be undertaken to inves-

tigate the correspond

ng phenotypes and unravel the r

le of the Fcγ receptors in the pathogenesis of perio-

dontitis.

CONCLUSIONS AND FUTURE

DEVELOPMENTS

An important problem related to research in the he-

redity of periodontitis 1s that, whatever the cause of

the disease, the symptoms are the same: deepening of

the per

odontal pocket, loss of attachment and bone

loss. In the majority of cases, the development of

periodont

s in an individual depends probably on the

collective presence of a number of environmental risk

factors in conjunction with a number of susceptibil

factors at a given time point during life. The more

suscept

lty factors an individual has inherited, the

greater the genet

c predisposition and the higher the

chance for early development of periodontit1s. If an

individual has inherited a major disease gene this will

also result in early development of pe

odontitis. S

nce

children of patients with chronic per

odont

s show a

relatively high prevalence of minor per

odontitis, it is

likely that some forms of early per

odont

s share a

common pathogenic path-way with that of adult

periodontitis.

th the increasing knowledge of major and modi-

fying d

sease genes it is conce

vable that a number of

genetic tests will be developed. These tests could be

used to diagnose the degree of

gene-11c

predisposit

at an early age when perodontitis has not yet devel-

oped, e.g. ch

dren of parents suffering from periodon-

titis. Depending on the degree of predisposition of a

child the appropriate preventive measures can be

taken. However, the use of

gene-11c

tests only makes

sense if enough major and modifying disease genes

have been ident

fied. In addition, before a genetic test

can be used, data of the test for the var

ous ethnic

groups /races should be available.

398 • CHAPTER

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CLINICAL CONCEPTS

Examination of Patients with

Periodontal Disease

STURE NYMAN AND JAN LINDHE

Symptoms of periodontal disease

The gingiva

The periodontal ligament — the root

cementum

Assessment of pocket depth

Assessment of attachment level

Errors inherent in periodontal probing

Assessment of furcation involvement

Assessment of tooth mobility

The alveolar bone

Radiographic analysis

Sounding

Diagnosis of periodontal lesions

Oral hygiene status Conclusion

SYMPTOMS OF PERIODONTAL

DISEASE

Clinically, both aggressive and chronic forms of peri-

odontal disease are characterized by color and texture

alterations of the gingiva, e.g. redness and swelling,

as well as an increased tendency to bleeding on prob-

ing in the gingival sulcus/pocket area. In addition, the

periodontal tissues may exhibit a reduced resistance

to probing (increased depth of the clinical pocket)

and/or tissue recession (Figs. 18-1a-c). More ad-

vanced stages of the disease are also frequently asso-

ciated with increased tooth mobility as well as drifting

and crowding of teeth.

In the radiograph, periodontal disease may be rec-

ognized by moderate to advanced loss of alveolar

bone

(Fig. 18-2). If bone loss has progressed at a similar

rate

in a certain part of the dentition, the crestal con-

tour

of the remaining bone in the radiograph is even:

horizontal

bone loss. Angular bony defects are the

result of bone loss which has developed at different

rates around different teeth/tooth surfaces: "vertical"

bone loss.

In the histological section, periodontal disease is

characterized by the presence of an inflammatory cell

infiltrate (ICT, Fig. 18-3) within a 1-2 mm wide zone

of the gingival connective tissue adjacent to the

biofilm on the tooth. Within the infiltrated area there

is a pronounced loss of collagen. In more advanced

forms of periodontal disease, marked loss of connec-

tive tissue attachment to the root and apical down-

growth of dentogingival epithelium along the root are

important findings.

Results from clinical and animal research have

demonstrated that aggressive and chronic forms of

periodontal disease

affect different parts of the dentition to a varying

degree

are often progressive in character and, if left un-

treated, may result in tooth loss

can be arrested following proper therapy.

In order to arrive at a meaningful treatment plan, the

various periodontal lesions must be recognized and

their involvement in various parts of the dentition

identified.

Thus, examination of a patient with respect to peri

odontal disease must not only identify sites in the

dentition with inflammatory alterations but also the

extent of tissue breakdown in such sites. The exami-

nation should therefore include all parts of the denti-

tion and describe the periodontal conditions at all

buccal, lingual and approximal tooth surfaces. Since

periodontal disease includes inflammatory altera-

tions of the gingiva and a progressive loss of periodon

tal ligament and alveolar bone, the comprehensive

examination must include measures describing such

pathologic alterations.

CHAPTER

404 • CHAPTER 18

Fig. 18-1. (a-c) Clinical status of a patient suffering from advanced periodontal disease. Note the presence of differ

ent signs of periodontal disease such as texture alterations of the gingiva, gingival recessions (in the region of

teeth

23, 24, 31, 33, 36 and 41 ), crowding of teeth (the mandibular front teeth), pus formation (tooth 14) and

drifting of

the premolars and molars.

Fig. 18-2. Radiographic status of the patient described in Fig. 18-la-c.

Fig. 18-4a-c illustrates the clinical status of a 55-

year-old male with periodontal disease. The examina-

tion procedures used to assess the location and exten

sion of periodontal disease will be demonstrated by

using this case as an example.

THE GINGIVA

Clinical signs of gingival inflammation include

changes in color and texture of the soft marginal tissue

and an increased tendency for bleeding on probing.

Various index systems have been developed to de-

scribe gingivitis in epidemiologic and clinical re-

search. In the individual patient, refined and qualita-

tive distinctions between various forms of gingivitis,

e. initial, early and established gingival lesions (Page

Schroeder 1976), serve no meaningful purpose since

the correct diagnosis of the gingival lesion can be

made only in the histologic section. Since, however,

the symptom "bleeding on probing" to the bottom of

the gingival sulcus/pocket is associated with the pres

ence of an inflammatory cell infiltrate in this area, the

occurrence of such bleeding is an important indicator

of disease. The identification of the apical extent of the

gingival lesion is made in conjunction with

pocket

depth measurements.

In sites where "shallow" pockets