TREC, KREC, and STELA analysis in adult PID

• Research type

  Research Study

• Full title

  Analysis and classification of a cohort of immunodeficiency patients by telomere length, T-receptor excision circle (TREC) and Kappa-deletion recombination excision circle (KREC) enumeration. New ways of risk profiling?

• IRAS ID

  217558

• Contact name

  Stephen Jolles

• Contact email

  jollessr@cardiff.ac.uk

• Sponsor organisation

  Cardiff and Vale University Health Board

• Duration of Study in the UK

  2 years, 0 months, 1 days

• Research summary

  The most frequent symptomatic primary immune deficiency in adults is common variable immunodeficiency (CVID) which has an estimated prevalence of 1 in 25,000, with diagnosis based on significantly reduced total immunoglobulin (antibody) levels, impaired response to vaccination, and the clinical sequelae of severe or recurrent infection. The cause of CVID remains unknown; single gene defects account for a minority of cases and phenotypic variation is wide. Symptoms may begin at any time of life. Long-term follow-up highlights the risks of dysregulated immunity extend beyond severe or recurrent infection, with autoimmunity and malignancy prominent. These features are closely resemble the sequelae of immune decline associated with the normal ageing process. Through examination of biomarkers for the production of new immune cells from the bone marrow and thymus and profiling the replicative history of peripheral blood lymphocytes using highly sensitive techniques, this research project aims to characterise markers of ageing of the immune system (immunosenesence) in patients with primary immunodeficiency.

  Lay Summary of Results:

  This project aimed to profile the role of immunosenescence in patients with a range of primary immunodeficiencies (PID) using an ultra-sensitive means of single telomere length analysis (STELA) and characterise a novel high-throughput equivalent (HT-STELA).

  Methods
  Following protocol optimisation and establishment of internal quality control standards for HT-STELA, telomere length (TL) of peripheral blood from adult PID (n=45) and healthy volunteers (n=44) were assessed using both methods. STELA data was combined with historical results to create a reference population of 109 healthy controls aged 0-80 years, allowing age-adjusted TL assessment of patients with genetically-confirmed tRNT1-mutations (n=8), asymptomatic heterozygous tRNT-1 carriers (n=4), and dyskeratosis congenita (DKC, n=4), and the adult PID cohort.

  Results
  Intra- and inter-batch co-efficients of variation for HT-STELA were 6.1% and 1.49-5.8%. Inter-method correlation with STELA showed excellent correlation (r2=0.755). STELA accurately identified individuals with DKC, with TL below the 1st percentile expected for age. Individuals with SIFD also showed significantly shorter TL for age. Unaffected carriers of the tRNT1 mutation and adult-PID patients showed a similar age-adjusted TL distribution to healthy controls.

  Conclusions
  This project has contribued to the development and optimisation of the novel HT-STELA assay and established a normal TL-distribution for age for STELA. This allows the first age-adjusted analysis of DKC by STELA and reveals the novel observation that SIFD patients also showed accelerated TL decay. Further studies assessing the clinical significance of this in SIFD patients and exploring other mitochondrial cytopathies, fever syndromes, and sideroblastic anaemias are suggested.
  Has the registry been updated to include summary results?: No
  If yes - please enter the URL to summary results:
  If no – why not?: N/A
  Did you follow your dissemination plan submitted in the IRAS application form (Q A51)?: Yes
  If yes, describe or provide URLs to disseminated materials: Work presented European Society for Immunodeficiency (ESID) 2018

  Submitted in partial fulfilment of the requirements for the degree of MSc Medical Immunology.

  High-throughput STELA provides a rapid test for the diagnosis of telomere biology disorders https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fpmc.ncbi.nlm.nih.gov%252Farticles%252FPMC8099822%252F%2FNBTI%2FOxG-AQ%2FAQ%2Ff71b4ccc-5b6c-4ed1-ae7d-fe0dab2931df%2F1%2FchfNNmcG2N&data=05%7C02%7Csurreyborders.rec%40hra.nhs.uk%7C1612bf5e5fbf48a98c6208ddd3272376%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638898887222397906%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=aYZKxY9SzU5DnE88rYXoFtWPr7P9GQFd57mhFVJ%2B4rU%3D&reserved=0

  Feedback in clinic to patient participants and patient group meeting
  If pending, date when dissemination is expected:
  If no, explain why you didn't follow it:
  Have participants been informed of the results of the study?: Yes
  If yes, describe and/or provide URLs to materials shared and how they were shared: Presentation / feedback at patient group meetings.
  If pending, date when feedback is expected:
  If no, explain why they haven't:
  Have you enabled sharing of study data with others?: Yes
  If yes, describe or provide URLs to how it has been shared: Collaboration with other groups in this field
  If no, explain why sharing hasn't been enabled:
  Have you enabled sharing of tissue samples and associated data with others?: No
  If yes, describe or provide a URL:
  If no, explain why: Yes - see publication High-throughput STELA provides a rapid test for the diagnosis of telomere biology disorders https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fpmc.ncbi.nlm.nih.gov%252Farticles%252FPMC8099822%252F%2FNBTI%2FOxG-AQ%2FAQ%2Ff71b4ccc-5b6c-4ed1-ae7d-fe0dab2931df%2F1%2FchfNNmcG2N&data=05%7C02%7Csurreyborders.rec%40hra.nhs.uk%7C1612bf5e5fbf48a98c6208ddd3272376%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638898887222412049%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=Wl1eHW5d11UUnFYsEDRAkczLusgjRAzZ1DZ4CGxa9E8%3D&reserved=0
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• REC name

  London - Surrey Borders Research Ethics Committee

• REC reference

  17/LO/0078

• Date of REC Opinion

  12 Jan 2017

• REC opinion

  Further Information Favourable Opinion