Oral Bacteria and Immune System Problems Involved in Gum Disease (Periodontitis)
Oral Bacteria and Immune System Problems Involved in Gum Disease (Periodontitis)
Background:

 - Gum disease is a condition in which the tissue around the tooth root becomes swollen and
 infected. This condition can cause tooth loss if it is not treated. Who gets gum disease and
 how bad it will be depends on (1) the different bacteria in the mouth and (2) how the immune
 system of an individual handles these bacteria. Researchers want to look at the oral bacteria
 and genetic immune problems of different people to learn how these affect gum disease and
 other conditions of the mouth.

 Objectives:

 - To study how immune system problems may lead to problems in the mouth, including gum
 disease.

 Eligibility:

 -  Children and adults at least 7 years of age who have genetic problems with their immune
 system.

 -  Healthy adults that have periodontal disease

 -  Health adults that do not have periodontal disease

 Design:

 -  This study will involve a screening visit and a study visit.

 -  Participants will be screened with a medical history, blood work and a full oral and
 dental exam, including dental x-rays and photos.

 -  The study visit will involve collection of blood, urine, and other samples, including
 saliva, plaque, and gum swabs. Any abnormal tissue will sampled for a biopsy. Additional
 oral and dental exams will be performed. Participants will also answer questions about
 any current medical or dental problems.
This is a cross sectional/natural history protocol designed to investigate the clinical,

 microbiologic, and immunologic consequences of genetic immune defects in the oral cavity. The
 hypothesis is that genetic immune defects will lead to alterations in the local immune
 response and microbial colonization and ultimately predispose to susceptibility to oral
 infections and inflammatory conditions.

 In the cross-sectional phase the following individuals will be enrolled, evaluated and
 screened for presence and severity of periodontitis, presence of a genetic defects and
 sampled for studies in oral immunity and microbiome: 1) individuals diagnosed with genetic
 immune defects 2) individuals with severe periodontitis of suspected genetic etiology and
 their family members 3) healthy volunteers. Subjects identified with a genetic immune defect
 and with presence of oral disease (primarily periodontitis) may enter the natural history
 phase of the study to be clinically followed at the National Institutes of Health (NIH) over
 time. This protocol aims to determine whether specific genetic immune defects will predispose
 to oral disease (primarily periodontitis) and to better understand consequences of immune
 deficiency on the oral immune response and microbiome.

 Primary Objectives

 1. Investigate the degree, scope, etiology and natural history of oral manifestations in
 patients with genetic immune defects.

 2. Characterize the immune response in the oral cavity of patients with genetic immune
 defects.

 3. Characterize the microbiome in the oral cavity of patients with genetic immune defects.

 Secondary Objectives

 1. Assay development/validation for the study of tissue immunity and microbiome
 characterization

 2. Establishment of normative values for immune mediators and microbial elements at the
 oral cavity

 Study Population (s)

 The study population will include:

 1. Subjects with genetic immune defects

 2. Subjects with severe periodontitis of suspected genetic etiology and their family
 members

 3. Healthy volunteers (with/without periodontal disease)

 Design

 This is a cross-sectional/natural history study for the evaluation of clinical, immunologic,
 and microbiologic oral manifestations (primarily periodontitis) in patients diagnosed with
 genetic immune defects or those with severe periodontitis of suspected genetic etiology and
 healthy volunteer subjects.

 Cross Sectional Phase: Three groups of subjects will be enrolled in the cross-sectional phase
 of the study 1) individuals diagnosed with genetic immune defects 2) individuals with severe
 periodontitis of suspected genetic etiology and their family members that include parents or
 siblings 3) healthy volunteers (with/without periodontal disease). All groups will be
 evaluated for oral disease (periodontitis) and sampled for oral immunity, systemic immunity
 and microbiome characterization. Individuals with severe periodontitis in the
 presence/absence of a genetic defect may be offered the option of receiving standard of care
 inflammatory control periodontal treatment at NIH without travel compensation, following the
 cross-sectional portion of the study. Family members (parents or siblings) of individuals
 with periodontal disease of suspected genetic may be asked to participate in this study.
 During the course of genetic testing, family members may be enrolled in the cross sectional
 phase of the study for phenotyping and genetic testing.

 Natural History Phase: Subjects identified with a genetic defect with the presence of oral
 disease may enroll in the natural history phase of the study to be followed clinically over
 time.

 Primary Outcome Measures

 1. Clinical intraoral characterization (i.e., presence and severity of periodontitis).

 2. Characterize the immune response in the oral cavity of patients with genetic immune
 defects

 3. Characterize the microbiome in the oral cavity of patients with genetic immune defects

 Secondary Outcome Measures

 1. Assay development/validation for the study of tissue immunity and microbiome
 characterization

 2. Establishment of normative values for immune mediators and microbial elements at the
 oral cavity

 Exploratory Outcome Measures

 Initial data from this study may generate new hypotheses for investigation as part of this
 study.
-  INCLUSION CRITERIA:

 Patients with Genetic Immune Defects:

 -Patients with an established monogenic immune defect will be eligible for screening
 inclusion under this protocol.

 -  Diagnosis of monogenic immune defect

 -  Greater than or equal to 7 years old

 Severe Periodontitis of Suspected Genetic Etiology and Family Members:

 -  History of severe periodontitis prior to age <30

 -  Willing to allow genetic testing

 -  Greater than or equal to 7 years old

 -  In good general health

 Healthy Volunteer Subjects:

 -  In good general health

 -  Greater than or equal to 18 years old

 -  Willing to allow genetic testing

 -  Have a minimum of 20 natural teeth

 Inclusion Criteria for Natural History phase, all subjects:

 -  Diagnosis of genetic immune defect

 -  Presence of oral manifestation (primarily periodontitis)

 Inclusion Criteria for standard of care treatment:

 -  Active untreated disease (visible signs of tissue inflammation including
 erythema/edema, generalized bleeding upon probing)

 -  Periodontal disease defined as bone loss of >5mm as measured on

 periodontal exam.

 EXCLUSION CRITERIA:

 All Subjects:

 -  History of Hepatitis B or C

 -  History of HIV

 -  Prior radiation therapy to the head or neck

 -  Have an active malignancy except localized basal or squamous cell carcinoma of the
 skin

 -  Have been treated with systemic chemotherapeutics or radiation therapy within 5 years
 of screening

 -  Pregnant or lactating

 -  If participation in the protocol would not be safe or in the subject s best interest
 in the opinion of either the PI or the primary medical team.

 Additional Exclusions for Healthy Volunteers:

 -  Diagnosis of diabetes and/or HbA1C level >6%

 -  More than 3 hospitalizations in the last 3years

 -  Have an autoimmune disorder such as Lupus, Rheumatoid arthritis, etc.

 -  In the 3 months before study enrollment, have used any of the following:

 -  Systemic (intravenous, intramuscular, or oral) antibiotics

 -  Oral, intravenous, intramuscular, intranasal, or inhaled corticosteroids or other
 immunosuppressants (e.g., cyclosporine)

 -  Cytokine therapy

 -  Methotrexate or immunosuppressive chemotherapeutic agents

 -  Large doses of commercial probiotics (greater than or equal to 10(8)
 colony-forming units or organisms per day); includes tablets, capsules, lozenges,
 chewing gum, or powders in which a probiotic is a primary component; ordinary
 dietary components such as fermented beverages/milks, yogurts, and foods do not
 apply

 -  Have used tobacco products (including e-cigarettes) within 1 year of screening

 -  Unwillingness to consent to oral biopsy

 -  NIH employees working in the Oral Immunity and Inflammation Unit and members of the
 Clinical Research Core Team will not be eligible for enrollment.

 Additional Exclusions for Healthy Volunteers with Periodontal Disease:

 -  Mild/moderate non-active disease (absence of active inflammatory lesions)

 -  Subjects with urgent/complex restorative needs (ex. severe active carious
 lesions/fractured dentition)

 -  Subjects in need for advance periodontal care (including bone/tissue grafts/implants)