Screening Protocol for Genetic Diseases of Lymphocyte Homeostasis and Programmed Cell Death

This study will determine the biochemical and genetic causes of inherited immune diseases affecting lymphocyte homeostasis. Lymphocytes are a type of white blood cell that fights infections. Normally, the body keeps a precise balance in which lymphocyte growth is matched by lymphocyte death. People with constantly enlarged lymph nodes or spleen, along with autoimmune disease, immunodeficiency, lymphoma, or other immune problems affecting lymphocytes may have an abnormality of the immune system in the cell growth and cell death processes that regulate lymphocyte homeostasis.

Patients who have, or are suspected of having, an inherited lymphocyte homeostasis or programmed cell death susceptibility syndrome may be eligible for this study. Relatives of patients are also included.

Participants' (patients and relatives) medical records are reviewed and blood samples are drawn for studies to identify genes involved in immune disorders. Tissues that have been removed from patients for medical reasons, such as biopsied tissues, may be examined for tissue and DNA studies. Relatives are studied to determine if some of them may have a very mild form of lymphocyte homeostasis disorder.

Patients who have an immune problem that the researchers wish to study further will be invited to donate additional blood samples at irregular intervals (at least once a year) and to provide an update of their medical records at the same time.

Study Overview

• Status: Recruiting
• Conditions: Primary Immune Deficiency

Detailed Description

This protocol is designed to screen patients with suspected or identified genetic diseases of immune cell homeostasis, reflecting abnormalities in programmed cell death, survival, development, activation, and/or proliferation. Patients determined by clinical history and initial outside evaluation by their referring physician to be of interest will be consented and enrolled into this study. Blood and other biological specimens from patients or their family members will be obtained for research studies related to understanding the genetic and biochemical bases of these diseases. Outside medical records will be obtained for chart review to correlate clinical history to research laboratory testing results. Results will be relayed to the referring physicians and, where applicable, patients will be referred to other relevant research studies at the NIH.

The study will enroll up to 5000 patients and family members over the next 10 years.

• Study Type: Observational
• Enrollment (Estimated): 5000

Contacts and Locations

• Study Contact: Name: Michael J Lenardo, M.D.; Phone Number: (301) 496-6754; Email: mlenardo@mail.nih.gov

Study Locations

• Turkey
  • Ankara, Turkey
    • Recruiting
    • Gazi University
    • Contact: Sinan Sari, MD; Phone Number: (031) 220-2414; Email: drsinansari@gmail.com
  • Ankara, Turkey
    • Recruiting
    • Hacettepe University
    • Contact: Deniz Cagdaz; Phone Number: +903123051080; Email: dcagdas@gmail.com
  • Ankara, Turkey
    • Recruiting
    • Ankara Medical University
    • Contact: Aydan Ikinciogullari, MD; Phone Number: 903123191440 Not Listed; Email: aydan@mac.com
  • Istanbul, Turkey
    • Recruiting
    • Marmara University
    • Contact: Ahmet Ozen, M.D.; Phone Number: +90216625454; Email: ahmetozen_md@yahoo.com
  • Konya, Turkey
    • Recruiting
    • Necemttin Erbakan University
    • Contact: Sevgi Keles, M.D.; Phone Number: Not Listed; Email: sevgi_keles@yahoo.com
• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0624
      • Recruiting
      • University of Michigan
      • Contact: Kelly Walkovich, M.D.; Phone Number: 215-590-2204; Email: kwalkovi@med.umich.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients referred by physician with a suspected inherited immune deficiency and their unaffected relatives.

Description

• INCLUSION CRITERIA:

Patients known to have or suspected of having an inherited immune cell homeostasis, programmed cell death susceptibility syndrome, lymphocyte developmental block, or defective immune cell effector functions will be eligible for enrollment. We will enroll

patients with suspected disease if the investigator agrees that there is a high index of suspicion. Blood relatives of enrolled patients will be eligible for enrollment. There will be no limit as to age, sex, race or disability.

EXCLUSION CRITERIA:

Severely debilitated health status or poor venous access may preclude obtaining adequate specimens for analysis. The minimum weight for infants on this protocol is 3 kg because of the limits of maximal acceptable blood draw volumes and minimum requirement for core laboratory tests would exceed the acceptable volume..

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
patients referred by physician with a suspected inherited immune deficiency

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
determination of underlying susceptibility trait(s) and elucidation of its mechanism of action	Goal of this study is to determine the molecular, genetic, biochemical basis for an immune problem.	2030

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Michael J Lenardo, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, Zhang Y, Liu Z, Fritz JM, Marsh R, Husami A, Kissell D, Nortman S, Chaturvedi V, Haines H, Young LR, Mo J, Filipovich AH, Bleesing JJ, Mustillo P, Stephens M, Rueda CM, Chougnet CA, Hoebe K, McElwee J, Hughes JD, Karakoc-Aydiner E, Matthews HF, Price S, Su HC, Rao VK, Lenardo MJ, Jordan MB. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015 Jul 24;349(6246):436-40. doi: 10.1126/science.aaa1663.
• Afzali B, Gronholm J, Vandrovcova J, O'Brien C, Sun HW, Vanderleyden I, Davis FP, Khoder A, Zhang Y, Hegazy AN, Villarino AV, Palmer IW, Kaufman J, Watts NR, Kazemian M, Kamenyeva O, Keith J, Sayed A, Kasperaviciute D, Mueller M, Hughes JD, Fuss IJ, Sadiyah MF, Montgomery-Recht K, McElwee J, Restifo NP, Strober W, Linterman MA, Wingfield PT, Uhlig HH, Roychoudhuri R, Aitman TJ, Kelleher P, Lenardo MJ, O'Shea JJ, Cooper N, Laurence ADJ. BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat Immunol. 2017 Jul;18(7):813-823. doi: 10.1038/ni.3753. Epub 2017 May 22.
• Ozen A, Comrie WA, Ardy RC, Dominguez Conde C, Dalgic B, Beser OF, Morawski AR, Karakoc-Aydiner E, Tutar E, Baris S, Ozcay F, Serwas NK, Zhang Y, Matthews HF, Pittaluga S, Folio LR, Unlusoy Aksu A, McElwee JJ, Krolo A, Kiykim A, Baris Z, Gulsan M, Ogulur I, Snapper SB, Houwen RHJ, Leavis HL, Ertem D, Kain R, Sari S, Erkan T, Su HC, Boztug K, Lenardo MJ. CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med. 2017 Jul 6;377(1):52-61. doi: 10.1056/NEJMoa1615887. Epub 2017 Jun 28.
• Comrie WA, Faruqi AJ, Price S, Zhang Y, Rao VK, Su HC, Lenardo MJ. RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias. J Allergy Clin Immunol. 2018 Apr;141(4):1507-1510.e8. doi: 10.1016/j.jaci.2017.11.036. Epub 2018 Jan 2. No abstract available.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): February 12, 2007

Study Registration Dates

• First Submitted: October 29, 2005
• First Submitted That Met QC Criteria: October 29, 2005
• First Posted (Estimated): October 30, 2005

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: February 22, 2024

More Information

Terms related to this study

• Keywords: Autoimmunity; Genetic Disease; Apoptosis; B-Cell; Lymphoproliferation; T-cell; Inherited Lymphhocyte Homeostasis
• Additional Relevant MeSH Terms: Immune System Diseases; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases; Genetic Diseases, Inborn
• Other Study ID Numbers: 060015; 06-I-0015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: .If an individual requests to have their raw sequencing data, we have asked the IRB for permission. This has happened in one case. @@@@@@@@@@@@In another case during this reporting period, a subject asked us to share raw sequencing data with an academic center for analysis. This required a DTA which was recently completed.@@@@@@@@@@@@Sequencing is done under research conditions and is not shared with a subject unless it is verified with a repeat independent sample and CLIA certified.

Drug and device information, study documents

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