Improving the Diagnosis of Common Variable Immune Deficiency

Brief Title

Improving the Diagnosis of Common Variable Immune Deficiency

Official Title

Improving the Diagnosis of Common Variable Immune Deficiency by Analysis of Innate and Adaptive Signaling Pathways

Brief Summary

      This is an observational, case-control study with a single blood draw among two cohorts,
      patients with antibody deficiency (e.g., CVID) and healthy controls. Samples will be analyzed
      by mass cytometry (CyTOF) to examine the major signaling pathways of all circulating innate
      and adaptive immune cell types, as well as whole exome sequencing. The goal is to improve our
      general understanding of the human immune response to infections and the diagnosis of CVID.
    

Detailed Description

      An increased susceptibility to bacterial and viral infections is the hallmark primary
      immunodeficiencies (PIDs). The most common PIDs requiring treatment with Ig replacement (SCIg
      or IVIg) is Common Variable Immune Deficiency (CVID), which is diagnosed by the presence of
      hypogammaglobulinemia plus defective responses to vaccine antigens. Prior to diagnosis, CVID
      patients often develop autoimmunity that requires immunosuppression or cancers that require
      chemotherapy. Unfortunately, difficulties arise in making the diagnosis of CVID in adults
      treated with immunosuppressive drugs, steroids, or chemotherapy, preventing the timely use of
      Ig replacement therapies in these patients. Furthermore, CVID is difficult to diagnose in
      young children. Exome sequencing and other genetic methods have thus far failed to identify
      clear monogenic causes for CVID. At the same time, patients with derangements of signaling
      pathways including STAT1, STAT3, NFKB, PI3K, and others, have clinical antibody deficiency,
      suggesting that by examining the signaling pathways, the investigators could find signs of
      CVID. The Investigators propose to use a broad, new screen to study the functional defects of
      human immune responses in CVID. Using time-of-flight mass cytometry (CyTOF) and
      phospho-specific antibodies, the investigators will simultaneously examine the major
      signaling pathways of all circulating innate and adaptive immune cell types at once to
      identify abnormal phosphorylation of signaling molecules in response to a variety of
      canonical stimuli. This method is innovative because it identifies signaling defects in the
      immune response while being insensitive to chemotherapy or immunosuppression, because the
      signaling responses examined are biologically upstream of immunosuppressed targets. Our
      approach generates a new "signaling fingerprint" for facilitating the diagnosis of CVID. Our
      proposal is also impactful, because knowledge gained about functional defects in CVID, when
      combined with whole exome sequencing, will improve the general understanding of the human
      immune response to infections.

      There are two major aims: 1) studying healthy control subjects across a variety of ages as
      comparisons to CVID patients, and furthermore to generate new information about how immune
      signaling responses change with age, which is currently unknown; and 2) studying CVID
      patients to identify the consistent aberrant signaling responses that will allow the
      acceleration of diagnosis and treatment.

      Design of study: The investigators propose an observational, case-control study with a single
      blood draw among two cohorts, patients with antibody deficiency (CVID) and healthy controls.
      Methods: Fifty (50) CVID patients (adult and children) will be consented in the Immunology
      Clinic at UCLA. Healthy, age- and gender-matched controls will be sought at the same time
      (100). There will be one blood draw of < 5 mL of blood to be analyzed immediately by
      phospho-CyTOF at UCLA. Genomic DNA will be prepared from samples and sequences analyzed.

      This screen examines phosphorylation of all circulating immune cell types at once (CD4 and
      CD8 T cells, B cells, NK cells, monocytes, macrophages, neutrophils, eosinophils, and DCs).
      Whole blood from subjects and from controls will be aliquotted into portions, and each
      portion will be stimulated with either cytokines, TLR agonists, anti-TCR or anti-BCR
      antibodies, PMA, or left unstimulated. Treated cells will be surface stained, fixed,
      permeabilized, and stained intracellularly for 12 signaling phospho-proteins, then analyzed
      by CyTOF, which enables measurement of over 50 parameters simultaneously.
    


Study Type

Observational


Primary Outcome

Differences in Immune Cells in CVID and healthy controls


Condition

CVI - Common Variable Immunodeficiency


Study Arms / Comparison Groups

 Antibody deficiency (CVID)
Description:  Subjects with antibody deficiency (CVID)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

150

Start Date

May 1, 2019

Completion Date

June 1, 2022

Primary Completion Date

December 31, 2021

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of antibody deficiency (CVID)

        Exclusion Criteria:

        -
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Manish J Butte, MD PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03335605

Organization ID

UCLA-IMMUNOLOGY-16-001950


Responsible Party

Principal Investigator

Study Sponsor

University of California, Los Angeles

Collaborators

 Jeffrey Modell Foundation

Study Sponsor

Manish J Butte, MD PhD, Principal Investigator, University of California, Los Angeles


Verification Date

March 2021