GENETIC ASPECTS OF LOCALIZED AGGRESSIVE PERIODONTITIS

Comprehensive Postgraduate Theory Examination Notes

RECENT TERMINOLOGY / NOMENCLATURE CHANGES

"Localized aggressive periodontitis" is the term previously used to describe the molar-incisor pattern of periodontitis occurring in younger patients (previously known as localized aggressive or juvenile periodontitis). It is now classified under Periodontitis Stage III or IV, Grade C (rapid progression pattern) in the 2018 classification framework." (Newman & Carranza's Clinical Periodontology and Implantology, 14th ed.)

SECTION 1: INTRODUCTION - GENETIC BASIS OF LOCALIZED AGGRESSIVE PERIODONTITIS

• LAP is a multifactorial disease developing as a result of complex interactions between specific host genes and the environment.
• It is now widely accepted that differences among individuals who are at risk of the development of most diseases have a substantial inherited component.
• Factors in the environment (e.g., diet, smoking, preventive care, and exposure to pathogens) interact with each person's genetic predisposition to determine their health outcomes.
• With the exception of a handful of rare syndromes caused by mutations of single genes, evidence indicates that inherited variation in DNA has a role roughly equal to that of the environment in determining who remains periodontally healthy versus who is affected.

• Pathogenesis of LAP is related to the interplay of several factors, including: the specific microbiology of subgingival plaque, defects in cementum, hereditary factors, impaired PMN functions, and disorders of the immune system.

SECTION 2: EVIDENCE FOR A GENETIC COMPONENT IN LAP

2A. Family Aggregation (Familial Clustering)

• Aggressive periodontitis aggregates in families. Such clustering suggests - but does not prove - the disease has a genetic basis, because family members can share deleterious components of their environment as well.
• Both localized and generalized forms of AP disease frequently occur in the same family; the probability of two rare diseases occurring in the same family is exceedingly small.
• Various forms of aggressive periodontitis (e.g., prepubertal and juvenile periodontitis) have been observed in the same family and found to occur sequentially in the same individual. These findings suggest there are common genetic risk factors for the subforms of AP disease.
• There are many reports in the literature describing families with multiple affected individuals.
• The familial aggregation that is characteristic of this periodontitis with rapid progression pattern indicates that additional, as yet unidentified, genetic factors may be important in one's susceptibility.

2B. Twin Studies

• The comparison of disease occurrence or severity in identical (monozygotic) versus nonidentical (dizygotic) twins is a powerful method for distinguishing between effects caused by variation in genes versus factors in the environment.
• Twin studies have supported the theory that genetic factors significantly influence the risk for periodontitis.
• A significant portion of the variance in probing depth (PD) and clinical attachment loss measures is attributable to genetic variance.
• It has been estimated that approximately 50% of the variance in disease can be attributable to genetic variance (i.e., heritability is about 50%).
• In groups of adolescent twins, genetically related individuals were found to be more similar microbiologically than pairs of unrelated individuals.

• Additional evidence for a genetic component to AgP was provided by a study demonstrating substantial levels of heritability in quantitative parameters for periodontal disease severity of AgP patients (Diehl et al. 2005).

2C. Racial and Ethnic Differences

• Both localized and generalized forms of early-onset aggressive periodontitis occur about ten times more frequently among African Americans as compared with Caucasians.
• African Americans have more severe disease than Caucasians in U.S. studies.
• It is possible that the 10-fold higher prevalence of early-onset aggressive periodontitis in African Americans is caused by the elevated frequency of high-risk gene variants in this population.
• Clinicians have long known that susceptibility to periodontitis differs among racial and ethnic groups. In the United States, African Americans have more severe disease than Caucasians. Elsewhere, Sri Lankans and South Pacific islanders appear to be more prone to disease than other groups with similar environments.

SECTION 3: MODES OF INHERITANCE / SEGREGATION ANALYSES

• Several research groups have used segregation analyses to determine the likely mode of inheritance for AP disease.
• In most such studies, the localized and generalized forms of AP disease have been considered variants of the same disorder.

• Despite inconsistent conclusions, segregation analyses consistently have supported the role of a major gene in the etiology of AP diseases.
• Multifactorial or polygenic models alone cannot adequately account for the patterns of disease observed in families.
• Results from these studies, however, are prone to error because of:
  • Difficulty in correctly diagnosing older individuals
  • Variable clinical appearance of disease
  • Likely etiologic and genetic heterogeneity of these diseases

The Schenkein Model (Key Examiner Topic)

Schenkein proposed a model of inheritance that distinguishes between the etiologies of localized and generalized aggressive periodontitis and allows for family clustering. He theorized that:

• AP disease and immunoglobulin G2 (IgG2) responsiveness to bacterial lipopolysaccharide (LPS) segregate independently as dominant and codominant traits, respectively.
• Subjects with one AP disease allele and two copies of the high-IgG2-response allele would develop only localized disease.
• Subjects who carry the AP disease allele and only one copy of the IgG2 allele would develop more widespread disease because their IgG2 response to LPS would be less robust.

SECTION 4: FLOWCHART - ECOGENETIC INTERACTIONS LEADING TO LAP AND GAP

INHERITANCE OF AgP
        |
        v
GENETIC PREDISPOSITION
[Gene of major effect - Autosomal dominant inheritance]
        |
        v
ENVIRONMENTAL EXPOSURE (Necessary step)
[Microbial exposure and infection: A. actinomycetemcomitans]
        |
        v
HOST INABILITY to effectively deal with bacterial aggression
+ inability to avoid inflammatory tissue damage
        |
        v
INITIATION OF DISEASE PROCESS
        |
        |---[GENETIC MODIFYING FACTORS]---> IgG2 response against
        |   (Codominant trait)              A. actinomycetemcomitans
        |                                   (2 copies: HIGH IgG2 response)
        |                                   |
        |                                   v
        |                              LOCALIZED AgP (LAP)
        |                              [Molar-incisor pattern]
        |
        |---[ENVIRONMENTAL MODIFYING FACTORS] + [1 copy: LOW IgG2]
            Cigarette smoking                  |
            P. gingivalis and other bacteria   v
                                        GENERALIZED AgP (GAP)

SECTION 5: CHROMOSOMAL LINKAGE STUDIES

5A. Key Linkage Findings

SECTION 6: CANDIDATE GENES AND GENETIC POLYMORPHISMS IN LAP

6A. Hart (1996) Candidate Genes Table

Hart (1996) compiled a list of candidate genes associated with increased susceptibility to AgP based on current knowledge that AgP subjects have a high prevalence of PMN functional defects, that they produce high levels of inflammatory mediators in response to LPS stimulation, and that connective tissue homeostasis is relevant in periodontitis.

6B. FcγRIIA (CD32) Polymorphism - Key Examiner Point

• PMNs expressing the R131 allotype of FcγRIIa (i.e., with an Fc receptor containing an arginine instead of a histidine at amino acid 131) show decreased phagocytosis of A. actinomycetemcomitans (Wilson & Kalmar 1996).
• The H131 allele is the only FCGR2A that recognizes IgG2 efficiently, and optimal IgG2 handling occurs only in the homozygous state for H131.
• The Fcγ receptor genes (FcγRS) encode receptors for the Fc portion of immunoglobulin G, and they are involved in the removal of antigen-antibody complexes from circulation as well as other antibody-dependent responses.
• Genetic factors appear to influence serum immunoglobulin G2 (IgG2) antibody titers and the expression of FcγRII receptors on neutrophils, both of which may be significant in aggressive periodontitis.

6C. HLA Associations in LAP

• Because of their role in regulating immune responses, the human leukocyte antigens (HLA) have long been considered as candidate genetic risk markers for AP disease.
• More than 40 diseases, most of which are autoimmune in nature, have been associated with various HLA antigens.
• Genes for the class I and II antigens are located on chromosome 6 in humans. Nearby genes encode for complement fragments and the proinflammatory cytokine, tumor necrosis factor alpha (TNF-α).

Important Examiner Point: "Associations in GAP, not LAP, group. No association with DR antigens." (Shapira et al. 1994) (Carranza's Clinical Periodontology, 10th ed.)

6D. IL-1 Gene Polymorphisms

• Polymorphisms in the interleukin-1 (IL-1) gene have been studied extensively because of the prominent role IL-1 plays in the initiation and progression of the periodontal lesion.
• In humans, genes encoding IL-1 and its receptor antagonist are clustered on the long arm of chromosome 2.
• One variant, a single-nucleotide base-pair substitution in the IL-1β coding region, designated IL-1β+3954, has been associated with a fourfold increase in IL-1β production.
• The more common allele at the IL-1β+3954 site was reported in linkage disequilibrium with generalized aggressive periodontitis.
• This "high-risk" IL-1β allele, however, may be too common in African Americans—who are at higher risk than Caucasians for AP disease—to be of diagnostic value.
• Interestingly, the IL-1 composite, which has been associated with chronic disease, does NOT appear to increase one's risk for aggressive periodontitis.
• Genetic polymorphisms in IL-1 genes, resulting in increased production of IL-1β, have been associated with a significant increase in risk for severe and generalized periodontitis (less clearly for LAP specifically).

6E. Other Gene Polymorphisms Studied

1. Neutrophil function (Fu et al. 2002; Loos et al. 2003; Kaneko et al. 2004; Jordan et al. 2005; Nibali et al. 2006; de Souza & Colombo 2006)
2. Inflammation and host's ability to effectively deal with exposure to bacterial components such as endotoxin (Suzuki et al. 2004; Scapoli et al. 2005; Brett et al. 2005; Noack et al. 2006)
3. Connective tissue homeostasis (Suzuki et al. 2004; Park et al. 2006; Soedarsono et al. 2006)

• Vitamin D receptor gene polymorphisms
• IL-1 receptor antagonist gene mutations
• N-formyl-1-methionyl-1-leucyl-1-phenylalanine (FMLP) receptor gene mutations
• TNF-α polymorphisms
• GWAS finding: A glycosyltransferase gene (GLT6D1) showed a strong association with aggressive periodontitis in the one GWAS reported for periodontitis (no clear functional relationship with periodontal disease pathogenesis established)
• Lactotransferrin (LTF) - antimicrobial role; can neutralize endotoxin; inhibit NF-κβ induction
• Myeloperoxidase (MPO) - oxidative enzyme expressed in PMNs; involved in defense against periodontal bacteria
• HLA complex genes - central role in immune system by presenting extracellular peptides
• CDKN2BAS - nonprotein-coding gene, also associated with coronary heart disease

SECTION 7: PMN (NEUTROPHIL) DEFECTS - GENETIC BASIS

• Based on current knowledge that AgP subjects have a high prevalence of PMN functional defects, several loci have been proposed as genes conferring increased susceptibility to AgP.
• Approximately 75% of patients with LAP have dysfunctional neutrophils, seen as decreased chemotactic response to several chemotactic agents including:
  • Complement component C5a
  • N-formyl-methionyl-leucyl-phenylalanine (FMLP)
  • Leukotriene B4
• The defect is also associated with a 40% deficiency in glycoprotein GP110 on the neutrophil surface.
• Inherited forms of monocyte FcγRII, the receptor for human immunoglobulin G2 (IgG2) antibodies, confer distinct phagocytic capacities.

Genetic Disorders Associated with Neutrophil Defects and Aggressive Periodontitis

SECTION 8: IgG2 ANTIBODY RESPONSE - GENETIC CONTROL

• The ability to mount high titers of specific antibodies is race dependent and probably protective (Gunsolley et al. 1987, 1988).
• This has been shown to be under genetic control as a co-dominant trait, independent of the risk for AgP.
• In individuals susceptible to AgP, therefore, the ability to mount high titers of antibodies (IgG2 in particular) may be protective and prevent extension of disease to a generalized form (Schenkein 1994; Diehl et al. 2003).
• Allelic variations in the Fc receptor for IgG2 (FcγRII) may influence the IgG2 handling capacity of PMNs.
• In patients with LAP, many have significantly elevated serum antibody titers to A. actinomycetemcomitans — this represents a protective response. The localization of disease in LAP may partly be explained by the production of opsonizing antibodies against A. actinomycetemcomitans.

SECTION 9: GENE-ENVIRONMENT INTERACTIONS (ECOGENETICS OF LAP)

Diagram - Text Format (Based on Lindhe 6th ed., Fig. 21-9a-c and Fig. 21-10)

GENETIC SUSCEPTIBILITY ALLELE(S)
[Gene of major effect - Autosomal dominant]
        |
        |--- ALONE --- Insufficient for disease development
        |
        + MICROBIAL EXPOSURE (A. actinomycetemcomitans with specific virulence)
        |
        v
DISEASE INITIATION
        |
        v
OUTCOME MODULATED BY:
        |
        |--- Genetic modifying factors (IgG2 against A.a - codominant)
        |       |
        |       HIGH IgG2 (2 alleles) -----> LOCALIZED form (LAP)
        |       LOW IgG2 (1 or 0 alleles) -> GENERALIZED form (GAP)
        |
        |--- Environmental modifying factors
                |
                Cigarette smoking --------> MORE extensive GAP
                (IgG2 depressed in smokers)

• Aggressive forms of periodontitis are currently considered to be multifactorial diseases developing as a result of complex interactions between specific host genes and the environment.
• Genetic susceptibility is probably insufficient for the development of disease: environmental exposure to potential pathogens endowed with specific virulence factors is also a necessary step.

SECTION 10: CHALLENGES AND LIMITATIONS IN GENETIC STUDIES OF LAP

SECTION 11: COMPARISON OF VIEWPOINTS ACROSS REFERENCES

SECTION 12: PRECISION DENTISTRY AND PHARMACOGENOMICS

• Using genetics to guide drug prescribing decisions ("pharmacogenetics") now allows the clinician to select a drug based on the genetic makeup of the patient to maximize its safety and efficacy.
• Inherited genetic variation determines treatment success - individuals who inherited different genotypes at a gene involved in a biologic pathway may respond very differently to treatment method 1 vs. treatment method 2.
• Detection of genetic variations linked to periodontal disease can potentially influence prognosis in several ways:
  1. Early detection of patients at risk because of genetic factors can lead to early implementation of preventive and treatment measures.
  2. Identification of genetic risk factors during treatment can influence treatment recommendations, such as the use of adjunctive antibiotic therapy or increased frequency of maintenance visits.
  3. Identification of young individuals who are at risk because of familial aggregation can lead to early intervention strategies.
• A test based on inherited genetic variation at the IL-1α and IL-1β cytokine genes was proposed as being able to predict the risk, progression, and severity of periodontitis. The test has been commercialized (PST, PerioPredict, and ILUSTRA). A meta-analysis suggested these IL-1 polymorphisms have a small (odds ratio ≈1.5) but significant effect on periodontitis risk.

SECTION 13: SUMMARY FLOWCHART - GENETIC BASIS OF LAP

EVIDENCE FOR GENETIC COMPONENT IN LAP
|
|--- 1. FAMILIAL AGGREGATION
|       |--- LAP and GAP occur in same family
|       |--- Prepubertal and juvenile forms in same individual/family
|       |--- Familial clustering > chance environmental sharing
|
|--- 2. TWIN STUDIES
|       |--- Monozygotic > Dizygotic concordance
|       |--- ~50% heritability estimate
|       |--- Microbiologic similarity in genetically related twins
|
|--- 3. RACIAL PREDILECTION
|       |--- 10x higher in African Americans vs. Caucasians
|       |--- IgG2 response race-dependent (genetic control)
|       |--- Disease allele frequency higher in African Americans
|
|--- 4. SEGREGATION ANALYSES
|       |--- X-linked (Melnick) / AR (Finnish) / AD (U.S./Boughman)
|       |--- Major gene consistently supported
|       |--- Multifactorial model alone insufficient
|
|--- 5. LINKAGE STUDIES
|       |--- Chromosome 1q25: LOD score 3.48 (LAP - 4 families)
|       |--- Chromosome 4q11-13: co-segregation with DGI
|
|--- 6. ASSOCIATION STUDIES (CANDIDATE GENES)
|       |--- FCGR2A (H131/R131 FcγRIIa polymorphism)
|       |--- IgG2m allotypes
|       |--- HLA (A9, B15 - mostly GAP, NOT LAP)
|       |--- IL-1β+3954 (linked to GAP, not LAP specifically)
|       |--- FMLP receptor gene mutations
|       |--- Vitamin D receptor gene
|       |--- GLT6D1 (GWAS - AgP)
|
|--- 7. PMN FUNCTIONAL DEFECTS (GENETIC BASIS)
|       |--- 75% LAP patients have dysfunctional PMNs
|       |--- GP110 glycoprotein 40% deficiency
|       |--- FCGR2A R131 allele: decreased phagocytosis of A.a.
|
|--- 8. IgG2 ANTIBODY CONTROL (CODOMINANT TRAIT)
        |--- 2 alleles: High IgG2 -> LAP (localized)
        |--- 1 allele: Lower IgG2 -> GAP (generalized)
        |--- IgG2 response is race-dependent and protective

SECTION 14: KEY EXAMINER KEYWORDS (BOLD - MUST USE IN EXAMINATION)

• Familial aggregation
• Major gene
• Autosomal dominant inheritance (US/Boughman study)
• Autosomal recessive (Finnish/Saxen study)
• X-linked (Melnick)
• Segregation analysis
• Linkage analysis / LOD score
• Chromosome 1q25 (LAP linkage)
• Chromosome 4q11-13 (co-segregation with DGI)
• FcγRIIa (FCGR2A / CD32)
• H131 allele / R131 allele (IgG2 binding)
• IgG2 responsiveness - codominant trait
• Schenkein model (LAP vs. GAP: IgG2 codominant segregation)
• Heritability ~50% (twin studies)
• 10-fold higher prevalence in African Americans
• FMLP receptor gene mutation
• PMN functional defects (75% of LAP patients)
• GP110 glycoprotein deficiency (40%)
• Candidate genes (Hart, 1996)
• GWAS - GLT6D1
• IL-1β+3954 polymorphism
• Linkage disequilibrium
• Single nucleotide polymorphism (SNP)
• Pharmacogenetics / Precision dentistry
• Genetic heterogeneity
• Etiologic heterogeneity
• Reduced penetrance
• Multifactorial / complex disease
• Co-dominant trait (IgG2 response)
• Ecogenetic interactions

REFERENCES USED

1. Newman & Carranza's Clinical Periodontology and Implantology, 14th Edition (Chapter 9: Precision Dentistry - Genetics and Epigenetics; Chapter 41: Determination of Prognosis; Chapter 53)
2. Carranza's Clinical Periodontology, 10th Edition (Chapter 11: Genetic Factors Associated with Periodontal Disease; Chapter 8: Epidemiology of Periodontal Diseases; Chapter 3: Genetic Epidemiology)
3. Clinical Periodontology and Implant Dentistry, 6th Edition - Lindhe (Chapter 21: Aggressive Periodontitis - Table 21.4, Figs. 21-9 and 21-10)
4. Periodontics Medicine Surgery Implants (Chapter 3: Genetic Epidemiology of Chronic Periodontitis - Tables and FcγR associations)
5. Essentials of Clinical Periodontology and Periodontics - S. Reddy (Chapter 26: Aggressive Periodontitis - Pathogenesis of LAP, Immunologic factors)
6. Biomarkers in Periodontal Health and Disease (Ecological plaque hypothesis; multifactorial disease model; genetic background as a host factor)

Examiner's Note: The most frequently examined and clinically significant genetic aspects of LAP are: (1) familial aggregation supporting a major gene; (2) the Schenkein model of LAP vs. GAP through IgG2 codominant inheritance; (3) the FcγRIIa H131/R131 polymorphism affecting IgG2-dependent phagocytosis of A. actinomycetemcomitans; (4) chromosome 1q25 linkage in LAP families; and (5) the 10-fold higher prevalence in African Americans with race-dependent IgG2 control. The 2018 World Workshop eliminated the term "aggressive periodontitis" as a formal diagnostic category, reclassifying such patients under Periodontitis Stage III/IV, Grade C.

SHORT NOTE: ETIOLOGY OF AGGRESSIVE PERIODONTITIS

MDS University Theory Examination

TERMINOLOGY NOTE

The term "Aggressive Periodontitis" (AgP) was used in the 1999 classification. In the 2018 World Workshop classification, aggressive periodontitis is reclassified as Periodontitis Stage III/IV, Grade C (rapid progression pattern). The earlier terms "Localized Juvenile Periodontitis" and "Generalized Juvenile Periodontitis" were replaced by Localized Aggressive Periodontitis (LAP) and Generalized Aggressive Periodontitis (GAP) respectively in the 1999 classification.

INTRODUCTION

ETIOLOGY - OVERVIEW (Risk Factors)

ETIOLOGY OF AGGRESSIVE PERIODONTITIS
|
|--- A. MICROBIOLOGIC FACTORS
|--- B. IMMUNOLOGIC FACTORS
|--- C. GENETIC FACTORS
|--- D. ENVIRONMENTAL FACTORS (e.g., Cigarette Smoking)

A. MICROBIOLOGIC FACTORS

Acceptance of Bacterial Etiology

• The clinical presentation frequently shows little visible plaque accumulation
• Proximal caries, another dental disease of bacterial origin affecting younger individuals, seems much less prevalent in LAP patients than in age-, gender-, and race-matched controls (Fine et al. 1984)

Primary Pathogen: Aggregatibacter actinomycetemcomitans (formerly Actinobacillus actinomycetemcomitans)

Virulence Factors of A. actinomycetemcomitans

The JP2 Clone - Key Examiner Point

• Colonized exclusively by JP2 clones: relative risk = 18.0 (95% CI 7.8-41.2)
• Colonized by both JP2 and non-JP2 clones: relative risk = 12.4 (95% CI 5.2-29.9)
• Colonized exclusively by non-JP2 clones: relative risk = 3.0 (95% CI 1.3-7.1)

Other Organisms in LAP

• Capnocytophaga spp.
• Eikenella corrodens
• Prevotella intermedia (saccharolytic Bacteroides-like organisms)
• Campylobacter rectus (motile anaerobic rods)
• Gram-positive isolates: mostly streptococci, actinomycetes, and peptostreptococci

Organisms in GAP

• Porphyromonas gingivalis
• Tannerella forsythia
• A. actinomycetemcomitans

Important Caveat

Mechanisms of Bacterial Damage

1. Direct action of the microorganisms or their products on the host tissues
2. Tissue-damaging inflammatory responses elicited by bacteria

B. IMMUNOLOGIC FACTORS

• The chemotactic attraction of PMNs to the site of infection, OR
• Their ability to phagocytose and kill microorganisms

C. GENETIC FACTORS

• Results from several studies support the concept that all individuals are not equally susceptible to aggressive periodontitis.
• Several authors have described a familial pattern of alveolar bone loss and have implicated genetic factors.
• Segregation and linkage analyses of families with a genetic predisposition for LAP suggest that a major gene plays a role in LAP, which is transmitted through an autosomal dominant mode of inheritance in U.S. populations (Marazita et al. 1994).
• Data support the concept that a gene of major effect exists for aggressive periodontitis.
• The antibody response to periodontal pathogens (particularly A. actinomycetemcomitans) is under genetic control, and the ability to mount high titers of specific, protective antibody (primarily IgG2) may be race dependent.
• LAP linked to chromosome 1q25 (close to the COX-2 gene) (Li et al. 2004)
• Linkage to Vitamin D-binding locus on chromosome 4 in Brandywine population (Boughman et al. 1986) - not confirmed in other populations

D. ENVIRONMENTAL FACTORS

Cigarette Smoking

• In a large study, cigarette smoking was shown to be a risk factor for patients with GAP (Schenkein et al. 1995).
• Smokers with GAP had more affected teeth and greater mean levels of attachment loss than patients with GAP who did not smoke.
• IgG2 serum levels and antibody levels against A. actinomycetemcomitans are significantly depressed in GAP subjects who smoke - since these antibodies are considered protective, depression of IgG2 in smokers may be associated with the observed increase in disease extent and severity.

SUMMARY FLOWCHART - ETIOLOGY OF AGGRESSIVE PERIODONTITIS

ETIOLOGY OF AGGRESSIVE PERIODONTITIS
(Multifactorial Model)

MICROBIAL CHALLENGE
     |
     |-- A. actinomycetemcomitans (LAP - primary)
     |        |-- JP2 clone: RR = 18.0 (highly leukotoxic)
     |        |-- Virulence factors: leukotoxin, endotoxin, collagenase
     |        |-- Tissue invasion across junctional epithelium
     |
     |-- P. gingivalis, T. forsythia (GAP - primary)
     |
     v
HOST RESPONSE (IMPAIRED)
     |
     |-- PMN defects (70-75% of LAP patients)
     |        |-- Decreased chemotaxis (C5a, FMLP, LTB4)
     |        |-- GP110 glycoprotein deficiency (40%)
     |        |-- FcγRIIa R131 allele: decreased IgG2 phagocytosis
     |
     |-- Monocyte hyperresponsiveness (excess PGE2)
     |
     |-- Reduced IgG2 protective antibody (GAP)
     |
     v
TISSUE DESTRUCTION
     |
     |-- MODIFYING FACTORS:
     |        |-- Genetic predisposition (major gene - AD inheritance)
     |        |-- Cigarette smoking (depresses IgG2, worsens GAP)
     |        |-- Cementum defects (hypoplastic/aplastic in LAP)
     |
     v
DISEASE EXPRESSION:
     LAP (molar-incisor pattern) or GAP (generalized)

KEY EXAMINER POINTS

• "The exact etiology of aggressive periodontitis is not known" - always state this.
• The JP2 clone of A. actinomycetemcomitans is a high-yield examiner topic - relative risk 18.0 for disease onset.
• 75% of LAP patients have PMN chemotaxis defects; GP110 glycoprotein 40% deficiency.
• FcγRIIa (CD32) H131/R131 polymorphism - R131 = decreased phagocytosis of A. actinomycetemcomitans.
• HLA-A9 and HLA-B15 consistently associated with AgP; HLA-A2 appears protective.
• Cigarette smoking is a risk factor for GAP, not specifically LAP - depresses IgG2 levels.
• Cementopathia (hypoplastic/aplastic cementum) - responsible for localization of lesions in LAP.
• A. actinomycetemcomitans may be viewed as an opportunistic pathogen or commensal as a whole - but the JP2 clone is a true pathogen in North/West African populations.
• PMN abnormalities cluster in families (Van Dyke et al. 1985) - inherited defect.

REFERENCES

1. Carranza's Clinical Periodontology, 10th Edition - Chapter 33: Aggressive Periodontitis (Risk Factors section)
2. Lindhe's Clinical Periodontology and Implant Dentistry, 6th Edition - Chapter 21: Aggressive Periodontitis (Bacterial etiology, Host response, Genetic factors)
3. Essentials of Clinical Periodontology and Periodontics - S. Reddy - Chapter 26: Aggressive Periodontitis (Pathogenesis, Virulence factors, Immunologic findings)
4. Newman & Carranza's Clinical Periodontology and Implantology, 14th Edition - Chapter 53: Antibiotic use in periodontics (LAP context)