Mechanisms of Immune Deficiency

1. The purpose of this study is to learn more about the changes in genes, cells and proteins that cause immune deficiency diseases.

2. The early stages of the study will focus on two groups of patients:

   1. members of families in which several persons have symptoms or medical histories that suggest immune deficiency.
   2. 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.

Study Overview

• Status: Recruiting
• Conditions: Immune Deficiency

Detailed Description

The experiments that are proposed in this portion of the study are intended to:

1. 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.
2. characterize the current status of B-cell maturation and function in subjects with either the variant gene and the wild type gene.
3. 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.

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

• Study Contact: Name: Charles Kirkpatrick; Phone Number: (303) 724-7197; Email: charles.kirkpatrick@ucdenver.edu

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80045
      • Recruiting
      • UColorado
      • Contact: Charles H Kirkpatrick, MD; Phone Number: 303-724-7197; Email: charles.kirkparick@ucdenver.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Individuals aged 18 years or older and have an immune deficiency or are related to a person who has an immune deficiency.

Description

Inclusion Criteria:

1. Immunodeficiency disease; or
2. family member of individual with immunodeficiency disease

Exclusion Criteria:

1. Persons with immune deficiencies that are secondary to other diseases such as malignancies.
2. Persons who do not have immune deficiencies, persons who are not meet eligibility criteria

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Individuals with immune deficiencies; aged 18 years or older and have an immune deficiency
Family members; 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

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Colorado Clinical & Translational Sciences Institute
• Investigators: Principal Investigator: Charles Kirkpatrick, University of Colorado, Denver

Publications and helpful links

General Publications

• Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, Keller M, Kobrynski LJ, Komarow HD, Mazer B, Nelson RP Jr, Orange JS, Routes JM, Shearer WT, Sorensen RU, Verbsky JW, Bernstein DI, Blessing-Moore J, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller D, Spector SL, Tilles S, Wallace D; Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the Joint Council of Allergy, Asthma & Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015 Nov;136(5):1186-205.e1-78. doi: 10.1016/j.jaci.2015.04.049. Epub 2015 Sep 12.
• O'Meara MM, Simon JA. Inner workings and regulatory inputs that control Polycomb repressive complex 2. Chromosoma. 2012 Jun;121(3):221-34. doi: 10.1007/s00412-012-0361-1. Epub 2012 Feb 19.
• Su IH, Basavaraj A, Krutchinsky AN, Hobert O, Ullrich A, Chait BT, Tarakhovsky A. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol. 2003 Feb;4(2):124-31. doi: 10.1038/ni876. Epub 2002 Dec 23.
• Caganova M, Carrisi C, Varano G, Mainoldi F, Zanardi F, Germain PL, George L, Alberghini F, Ferrarini L, Talukder AK, Ponzoni M, Testa G, Nojima T, Doglioni C, Kitamura D, Toellner KM, Su IH, Casola S. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest. 2013 Dec;123(12):5009-22. doi: 10.1172/JCI70626. Epub 2013 Nov 8. Erratum In: J Clin Invest. 2014 Apr 1;124(4):1869.
• Bodor C, Grossmann V, Popov N, Okosun J, O'Riain C, Tan K, Marzec J, Araf S, Wang J, Lee AM, Clear A, Montoto S, Matthews J, Iqbal S, Rajnai H, Rosenwald A, Ott G, Campo E, Rimsza LM, Smeland EB, Chan WC, Braziel RM, Staudt LM, Wright G, Lister TA, Elemento O, Hills R, Gribben JG, Chelala C, Matolcsy A, Kohlmann A, Haferlach T, Gascoyne RD, Fitzgibbon J. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood. 2013 Oct 31;122(18):3165-8. doi: 10.1182/blood-2013-04-496893. Epub 2013 Sep 19.

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2020
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: October 12, 2018
• First Submitted That Met QC Criteria: October 12, 2018
• First Posted (Actual): October 16, 2018

Study Record Updates

• Last Update Posted (Actual): April 19, 2022
• Last Update Submitted That Met QC Criteria: April 15, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Immunologic Deficiency Syndromes
• Other Study ID Numbers: 18-0337

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No