Identification of Autoantigens in EGPA and Severe Eosinophilic Asthma

  • STATUS
    Recruiting
  • End date
    Jun 29, 2022
  • participants needed
    120
  • sponsor
    Queen Mary University of London
Updated on 29 January 2021

Summary

In this project the investigators will look for auto-antibodies to relevant proteins both in native form and importantly in post-translationally modified forms. Potential modified auto-antigens are eosinophil proteins (analogous to the cytoplasmic neutrophil proteins identified in vasculitides such as Granulomatosis with Polyangiitis (formerly known as Wegener's granulomatosis) and alternatively structural proteins such as collagen V. As well as advancing the understanding of asthma pathology, identifying a serum auto-antibody that could then be used as a clinical blood test, analogous to anti-cyclic citrullinated peptide (CCP) antibodies in rheumatoid arthritis, may revolutionise diagnosis of severe eosinophilic asthma and Eosinophilic Granulomatosis with Polyangiitis (EGPA). There is a considerable burden of undiagnosed severe eosinophilic asthma in part due to difficulties in definitive diagnosis and a diagnostic blood test would help diagnose these patients, allowing them to receive necessary treatment.

Description

The investigators will approach the research question with parallel agnostic and targeted approaches.

In the agnostic approach the presence of auto-antibodies in patient serum and sputum to inactive and activated eosinophils, with and without post-translational modification, will be examined by indirect immunofluorescence.

In the targeted approach the investigators will examine by enzyme-linked immunoassay (ELISA) the presence/absence of antibodies to pre-selected candidate eosinophil and base membrane proteins both in native form and post-translationally modified. Proteins to examine will be chosen based on literature review (e.g. eosinophil peroxidase and collagen V) and eosinophil-specific proteins identified by FANTOM5 (Functional Annotation of the Mouse/Mammalian Genome) geneset analysis (FANTOM Consortium et al. 2014).

Both blood and sputum samples from highly-characterised patients with severe eosinophilic asthma and/or EGPA will be examined given the possibility of compartment-specific immune responses.

Once candidate auto-antigens have been identified in the selected group of patients with severe eosinophilic asthma and EGPA, the investigators will then examine their prevalence in serum samples from a wider selection of patients with eosinophilic airways diseases including mild-to-moderate asthma, severe eosinophilic asthma, EGPA, nasal polyposis and eosinophilic chronic obstructive pulmonary disease (COPD) as well as healthy controls. Length of disease, atopy, presence/absence nasal polyps, gender, age will be examined as co-variates. Correlations with highest blood eosinophil counts, requirement for oral corticosteroids and presence of other auto-antibodies, e.g. anti-MPO (myeloperoxidase) ANCA (anti-neutrophil cytoplasmic antibody), will be examined. In particular the investigators will look for the presence of novel autoantibodies in specific patient subsets: i) ANCA negative, ii) ANCA positive by immunofluorescence but negative for anti-MPO and anti-PR3 (proteinase-3) antibodies, iii) ANA (anti-nuclear antibody) positive but ANCA and extractable nuclear antigen (ENA) negative; since patients in all three groups may have novel, as yet undetermined autoantibodies. ROC (receiver operator characteristic curve) AUC (area under curve) analyses will be conducted to ascertain the predictive value of blood auto-antibodies for diagnosis of eosinophilic airways disease.

Details
Condition Pulmonary Disease, Eosinophilic esophagitis, Pulmonary Eosinophilia, Churg-Strauss Syndrome, Lung Disease
Treatment Autoantibody ELISA
Clinical Study IdentifierNCT04671446
SponsorQueen Mary University of London
Last Modified on29 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Lung Disease or Pulmonary Eosinophilia or Churg-Strauss Syndrome or Eosinophilic esophagitis or Pulmonary Disease?
Do you have any of these conditions: Lung Disease or Pulmonary Eosinophilia or Pulmonary Disease or Churg-Strauss Syndrome or Eosinophilic esophagitis?
Do you have any of these conditions: Eosinophilic esophagitis or Pulmonary Disease or Churg-Strauss Syndrome or Lung Disease or Pulmonary Eosinophilia?
Severe Eosinophilic Asthma (with multi-disciplinary diagnosis as per ERS/ATS Criteria, <20 pack year smoking history, blood eosinophils 0.3 x109/L on inhaled corticosteroids); or
EGPA (as per American College of Rheumatology (ACR) Criteria); or
Eosinophilic COPD (post-bronchodilator FEV1/FVC < 70% predicted, absence of bronchodilator reversibility, > 20 pack year smoking history, no history of asthma, blood eosinophils 0.3 x109/L); or
Eosinophilic oesophagitis (with diagnostic histology); or
Granulomatosis with Polyangiitis (GPA, formerly called Wegener's) (as per American College of Rheumatology (ACR) Criteria)

Exclusion Criteria

Known Pregnancy
Anaemia
Hepatitis B Virus, Hepatitis C Virus or HIV infection
Donation of more than 240mls blood in the last sixteen weeks (four months) to any other research study or as a donation to the National Blood Transfusion Service
Rituximab, plasmapharesis or polyclonal immunoglobulin infusion (ever)
Clear my responses

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