<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02228941</url>
  </required_header>
  <id_info>
    <org_study_id>81273314</org_study_id>
    <nct_id>NCT02228941</nct_id>
  </id_info>
  <brief_title>NFIL3-induced Pathological Enhancement of IgE Class Switch Recombination in Hyper-IgE Syndrome</brief_title>
  <sponsors>
    <lead_sponsor>
      <agency>Shanghai Children's Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Shanghai Children's Medical Center</source>
  <brief_summary>
    <textblock>
      Hyper IgE syndrome (HIES) is a rare and complex primary immunodeficiency that affects&#xD;
      multiple systems. It is characterized by elevated Immunoglobulin E(IgE), recurrent skin and&#xD;
      pulmonary infections and eczematoid dermatitis.Somatic manifestations include scoliosis,&#xD;
      joint hyperextensibility, impaired shedding of deciduous teeth and facial dysmorphism.&#xD;
&#xD;
      The reason of extremely high level of serum IgE in the patients with HIES is unknown. Signal&#xD;
      transducers and activators of transcription 3(STAT3) gene mutations can cause the STAT3/Janus&#xD;
      kinase(STAT3/JAK) signal transduction pathway disorder, then can affect the B cell&#xD;
      development.&#xD;
&#xD;
      It is reported that levels of extracellular signal cytokine and the prolonged half-life of&#xD;
      IgE are not the causes of dramatically increased IgE levels in STAT3-HIES patients. According&#xD;
      to our preliminary work, we found that the slight increase of IgE-secreting plasma cells&#xD;
      could not explain the tremendously increased IgE level and that the key class switch&#xD;
      recombination enzyme (AID) was up-regulated in STAT3-HIES patients. Intriguingly, we found&#xD;
      that deregulation of immunoglobulin class switch recombination (CSR) in IgE secreting plasma&#xD;
      cells in STAT3-HIES patients might play a key role in dramatically increased IgE levels.&#xD;
&#xD;
      Nuclear factor IL-3 regulated (NFIL3) is a newly discovered transcriptional factor. During&#xD;
      STAT3-HIES IgE-secreting plasma cells differentiating, NFIL3 was significantly upregulated.&#xD;
      The CSR of IgE was down-regulated in STAT3-deficiency mice as well as NFIL3-deficiency mice,&#xD;
      however Interleukin-4（IL-4）, a STAT3-independent cytokine, promotes NFIL3 expression by&#xD;
      Signal transducers and activators of transcription 6(STAT6) dependent manner. Thus, we&#xD;
      hypothesize that NFIL3 may play a key role in dramatically increased IgE levels in STAT3-HIES&#xD;
      patients.&#xD;
&#xD;
      In-depth insight of the pathogenic role of NFIL3 within human STAT3-HIES has great&#xD;
      significance in clarifying the pathogenesis of HIES and exploiting effective targeting&#xD;
      interventions to improve clinical outcomes. Also, it can provide valuable clues for the&#xD;
      clinical treatment of IgE-related diseases, such as parasite infection and malignant&#xD;
      diseases.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>September 2014</start_date>
  <primary_completion_date type="Anticipated">September 2014</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>3 Months</target_duration>
  <primary_outcome>
    <measure>Times of Pneumonia</measure>
    <time_frame>1 year</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Times of Skin abscess</measure>
    <time_frame>1 year</time_frame>
  </primary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Job Syndrome</condition>
  <arm_group>
    <arm_group_label>gene mutation</arm_group_label>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        We divided the patients with HIES into two groups, namely Autosomal-dominant Hyper-IgE&#xD;
        Syndrome(AD-HIES) group and Autosomal-recessive Hyper-IgE Syndrome(AR-HIES) group.&#xD;
        According to the different group, we need to do a variety of detection index, for example,&#xD;
        gene mutations, B-lymphocyte subsets, protein expression et al.In addition, healthy control&#xD;
        group is needed in the experiment.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Group 1 AD-HIES patients A.Patients with extremely high serum IgE levels,&#xD;
             IgE&gt;2000IU/ml; B.Patients diagnosis referred to the NIH, and NIH score&gt;15; C.Patients&#xD;
             must be confirmed with clinical manifestations of AD-HIES, namely:skin&#xD;
             abscesses,pneumonias,distinctive facial appearance,dental abnormalities,minimal trauma&#xD;
             fractures D.Patients must be confirmed with STAT3 gene mutations;&#xD;
&#xD;
          -  Group 2 AR-HIES patients A.Patients with extremely high serum IgE levels,&#xD;
             IgE&gt;2000IU/ml; B.Patients diagnosis referred to the NIH, and NIH score&gt;15; C.Patients&#xD;
             must be confirmed with clinical manifestations of AR-HIES,&#xD;
             namely:pneumonias,eczema,Skin abscesses,mucocutaneous viral infections,malignancy&#xD;
             D.Patients must be confirmed with Dedicator of cytokinesis protein 8（DOCK8） or&#xD;
             Tyrosine Kinase 2(Tyk2) gene mutations;&#xD;
&#xD;
          -  Group 3 Healthy Control A.Healthy control aged 1-25 year at time of enrollment.&#xD;
&#xD;
        Exclusion Criteria for all groups:&#xD;
&#xD;
          -  Any subjects with serious conditions requiring treatment or hospitalization;&#xD;
&#xD;
          -  Any subjects with pregnancy;&#xD;
&#xD;
          -  Any subjects who have a history of bone marrow transplant,or have received treatment&#xD;
             with chemotherapy or radiation;&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Month</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <verification_date>August 2014</verification_date>
  <study_first_submitted>August 18, 2014</study_first_submitted>
  <study_first_submitted_qc>August 28, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 29, 2014</study_first_posted>
  <last_update_submitted>August 28, 2014</last_update_submitted>
  <last_update_submitted_qc>August 28, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 29, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Job Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02228941
org study id: 81273314
nct id: NCT02228941
lead sponsor: 
Hyper IgE syndrome (HIES) is a rare and complex primary immunodeficiency that affects
      multiple systems. It is characterized by elevated Immunoglobulin E(IgE), recurrent skin and
      pulmonary infections and eczematoid dermatitis.Somatic manifestations include scoliosis,
      joint hyperextensibility, impaired shedding of deciduous teeth and facial dysmorphism.

      The reason of extremely high level of serum IgE in the patients with HIES is unknown. Signal
      transducers and activators of transcription 3(STAT3) gene mutations can cause the STAT3/Janus
      kinase(STAT3/JAK) signal transduction pathway disorder, then can affect the B cell
      development.

      It is reported that levels of extracellular signal cytokine and the prolonged half-life of
      IgE are not the causes of dramatically increased IgE levels in STAT3-HIES patients. According
      to our preliminary work, we found that the slight increase of IgE-secreting plasma cells
      could not explain the tremendously increased IgE level and that the key class switch
      recombination enzyme (AID) was up-regulated in STAT3-HIES patients. Intriguingly, we found
      that deregulation of immunoglobulin class switch recombination (CSR) in IgE secreting plasma
      cells in STAT3-HIES patients might play a key role in dramatically increased IgE levels.

      Nuclear factor IL-3 regulated (NFIL3) is a newly discovered transcriptional factor. During
      STAT3-HIES IgE-secreting plasma cells differentiating, NFIL3 was significantly upregulated.
      The CSR of IgE was down-regulated in STAT3-deficiency mice as well as NFIL3-deficiency mice,
      however Interleukin-4（IL-4）, a STAT3-independent cytokine, promotes NFIL3 expression by
      Signal transducers and activators of transcription 6(STAT6) dependent manner. Thus, we
      hypothesize that NFIL3 may play a key role in dramatically increased IgE levels in STAT3-HIES
      patients.

      In-depth insight of the pathogenic role of NFIL3 within human STAT3-HIES has great
      significance in clarifying the pathogenesis of HIES and exploiting effective targeting
      interventions to improve clinical outcomes. Also, it can provide valuable clues for the
      clinical treatment of IgE-related diseases, such as parasite infection and malignant
      diseases.
observational model: Cohort
time perspective: Prospective
measure: Times of Pneumonia
time frame: 1 year
measure: Times of Skin abscess
time frame: 1 year
arm group label: gene mutation
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 1 Month
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
responsible party type: Sponsor
mesh term: Job Syndrome
mesh term: Syndrome