Mechanisms of Immune Deficiency

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to learn more about the changes in genes, cells and proteins that cause immune deficiency diseases. The early stages of the study will focus on two groups of patients: members of families in which several persons have symptoms or medical histories that suggest immune deficiency. Patients who have received treatments with medications or drugs that affect functions of the immune system (secondary immune deficiencies). It is hoped that studies will provide guidelines for extension of the research to other patient groups. Up to 200 patients and family members will be invited to participate.

Detailed Description
-----------------
The experiments that are proposed in this portion of the study are intended to: characterize the significance of the variant form of EZH2 identified in this family. They will characterize the degree of methylation of lysine 27 of histone H3 in subjects with the variant and members of the same family who have the wild type gene. The functional methyltransferase activity of the variant and wild type genes will be measured. characterize the current status of B-cell maturation and function in subjects with either the variant gene and the wild type gene. characterize B-cell function (antibody production) and the quality of antibody produced after immunizations in subjects with the wild type gene or the variant gene.

Official Title
-----------------
Mechanisms of Immune Deficiency

Conditions
-----------------
Immune Deficiency

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Immunodeficiency disease; or family member of individual with immunodeficiency disease Exclusion Criteria: Persons with immune deficiencies that are secondary to other diseases such as malignancies. Persons who do not have immune deficiencies, persons who are not meet eligibility criteria

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Individuals with immune deficiencies<br>aged 18 years or older and have an immune deficiency | |
| Family members<br>aged 18 years or older and are related to a person who has an immune deficiency | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of Serum immune globulin | The clinical definition of hypogamma-globulinemia is values that are 2 SD below the mean value for the testing laboratory. For this study values that are below the lower limit of abnormal will be scored as abnormal. Chi-square analysis or Fisher's exact test will compare values between subjects with the wild type gene and the variant gene. | each year for up to 20 years | 
| Antibody responses | A four-fold difference or a post-immunization titer of ≥1.3 µg/ml is scored as a true antibody response. Antibody titers and avidity indices are transformed to log2 and evaluated using the Student's T-test. | 4 weeks | 
| Measurement of NK cell function | Spearman correlation will be used to compare the relationship between expression of CD207a by NK cells that are activated with K562 cells or NK cells that are activated with PMA/iono. | one time | 
| DNA sequencing | When indicated, whole exome or whole genome sequencing will be done to identify genetic basis (if any) of the immune deficiency | one time | 
| measurement of cellular components of the immune system | Flow cytometry will be used to identify numbers of cells of various types (e.g.,subpopulations of B-cells and T-cells) to evaluate changes in various cell populations over time. This is especially important for studies of family members who carry disease-causing or disease-associated genes but are clinically health at the time of the first study | each year for up to 20 years | 
| health outcome measurements | The SF-36 form will be used serially to identify changes in health over time | each year for up to 20 years | 
| Measurement of avidity | avidity indices are transformed to log2 and evaluated using the Student's T-test | each year for up to 20 years |