The major role of human genetic factors in the immune response to infections is now well established, particularly for viral infections. In the context of the COVID-19 pandemic, the following results have identified 1) several inborn errors of immunity (IEI) affecting the response or production of type I interferons (type I IFNs) in around 4% of adult patients with severe clinical disease, and 2) the presence of type I IFN-neutralizing autoantibodies (auto-Abs) in around 15% of severe cases, and 20% of deaths. The investigators would like to carry out a longitudinal immunological and clinical follow-up study on a prospective cohort of patients with either a genetic defect affecting the type I IFN-dependent immune response, or anti-IFN-I auto-Abs, to monitor the incidence of infectious and/or autoimmune events in these individuals, the evolution of neutralizing power, and the kinetics of auto-Abs. This should lead to a better understanding of the prevention and management of these patients. The research design is a national multicenter prospective cohort of adults with 1) anti-IFN-I auto-Abs or 2) IEI- IFN-I, with follow-up from 1 to 4 years. These individuals may be: 1) patients who have or have had clinical disease (related to COVID-19, other viral infections, autoimmune disorders); or 2) "healthy" participants (e.g. blood donors, relatives of an IEI patient). Follow-up will include: * yearly visits to the Clinical Investigation Center (CIC) or a clinical department with blood sampling; * specific visit in case of hospitalization for infectious events or adverse effects of vaccination, exacerbation or new diagnosis of auto-immune disease, new diagnosis of cancer, or SARS-CoV-2 infection whether or not patients are admitted to hospital, with blood sampling. In addition, a retrospective "passive" follow-up will be implemented through matching with the data from the SNDS (National Health Data System), in order to collect clinical events of and healthcare resource consumption. Moreover, matching with controls adults from the national CONSTANCES cohort, not carrying auto-Abs against type I IFNs nor IEI-IFN-I, will be performed. (ratio 3:1; matching on age (+/- 5 years), gender and geographic region of recruitment). Individuals under long-lasting immunosuppressive or immunomodulatory drugs will not be eligible. Follow-up of controls, which will be carried out as part of the CONSTANCES cohort, will include web-based questionnaires, every 12 months, in addition to linking with SNDS data as already done in this cohort. Inclusion visit: After signing the consent form, the following tests will be performed: * Demographic characteristics (sex, age, country of birth) * Medical history from participant and family member(s) including infectious and auto-immune diseases, cancers and vaccination status and side effects * Blood samples for: * full blood cell count; * classical autoimmune investigations (anti-nuclear, anti-ENA, native anti-DNA, anti- thyroid antibodies, rheumatoid factor); * immunophenotyping\*; * auto-Abs against type I IFNs, other cytokines\*, or other target proteins\* (dosage and neutralization activity); * Genetic explorations by whole-exome or whole-genome sequencing\*; * Biobanking (DNA, plasma/sera; cryopreserved peripheral blood mononuclear cells (PBMCs). * these biological analyses will be carried out as part of dedicated COVIFERON RHU5 workpackages. In addition, vaccination against SARS-CoV-2 and influenza will be offered to these subjects as a priority, as part of their usual care. Follow-up visits : Annual visits to the CIC : * Medical history since last visit, including infectious, auto-immune and oncologic events, vaccination status and side effects * Blood samples for: * full blood cell count; * classical autoimmune investigation (anti-nuclear, anti-ENA, native anti- DNA, anti-thyroid antibodies, rheumatoid factor); * immunophenotyping; * Auto-Abs against type I IFNs, other cytokines, or other target proteins (dosage and neutralization) * Biobanking (DNA, plasma, cryopreserved peripheral blood mononuclear cells (PBMCs)) Additional specific visit in the event of a clinical event of interest, at any time during follow-up: * In case of SARS-CoV-2 infection, whatever the severity of the disease: blood sampling for determination and neutralization of type I anti-IFN autoAbs, CBC, and biobanking (plasma and PBMC) and teleconsultation with the CIC in charge of patients, as soon as possible. * In the event of hospitalization for infectious events or exacerbation or new diagnosis of an auto-immune disease: blood sampling for determination and neutralization of anti-IFN-I autoAbs, CBC, and biobanking (plasma and PBMCs) and collection of the hospitalization report in the case report form on a dedicated page.
Study Type
OBSERVATIONAL
Enrollment
500
After signature of consent form,blood samples will be collected for full blood cell count;classical autoimmune investigations, immunophenotyping;auto-Abs against type IIFNs, other cytokines, or other target proteins ,Genetic explorations by whole-exome or whole-genome sequencing;Biobanking
Cic Lille
Lille, France
RECRUITINGLYON HCL
Lyon, France
RECRUITINGCic Montpellier
Montpellier, France
RECRUITINGCic Bichat
Paris, France
RECRUITINGCic Creteil
Paris, France
RECRUITINGCic La Salpetriere
Paris, France
RECRUITINGCic Necker
Paris, France
RECRUITINGCic St Louis
Paris, France
RECRUITINGCic Tours
Tours, France
RECRUITINGprimary endpoint n°1 : quantitative dosage of auto-Abs against type I IFNs
Method: Quantitative trait will be measured by Gyros using commercially available internal control antibodies.
Time frame: year 0, year 1, year 2 and year 3
primary endpoint n°2 : neutralization capacity evaluation of auto-Abs against type I IFNs
The neutralization capacity will be performed as previously reported using an in vitro luciferase system in HEK293 cells
Time frame: year 0, year 1, year 2 and year 3
Cumulative incidence of clinical events of interest, i.e. infectious events, autoimmune diseases or cancers
Method: annual medical visits, SNDS (PMSI, DCIR). Incidence density rate is defined as the number of newly disease individuals on the sum of time periods for all disease-free individual-at-risk
Time frame: Year 0, year 1, year 2 and year 3
Clinical and biological factors associated with clinical outcomes
the potential predictor variables will be assessed by bivariate logistic regressions where occurrence of clinical events is the variable to be explained. Factors associated with a p-value less than 0.20 will be included in the multivariate logistic model. Backward selection on pvalue will be applied. Internal validity of the final model will be estimated by cross-validation (Leave-One-Out Cross-Validation method). Discrimination will be assessed by the area under the ROC curve and its 95% confidence interval.
Time frame: Year 0, year 1, year 2 and year 3
Cumulative incidence of the same clinical events of interest, in control participants who are negative for auto-Abs, matched by age and sex followed through the large CONSTANCES cohort
Cumulative incidence of the same clinical events of interest, in control participants who are negative for auto-Abs, matched by age and sex followed through the large CONSTANCES cohort (Constances database), and its 95% confidence interval: Incidence density rate is defined as the number of newly disease individuals on the sum of time periods for all disease-free individual-at-risk.
Time frame: Year 0, year 1, year 2 and year 3
Genetic factors associated with the development of auto-Abs against type I IFNs
searching for homozygous deletions using in-house HMZDelFinder-opt method of imagine institue
Time frame: Year 0, year 1, year 2 and year 3
Genetic factors associated with the development of auto-Abs against type I IFNs
Searching for rare candidate coding variants in patients by following an optimal filtering strategy that imagine have optimized over the last 10 years based on multiple variant-level and gene-level criteria to select the candidate variants
Time frame: year 0, year 1, year 2 and year 3
Genetic factors associated with the development of auto-Abs against type I IFNs
Using gene-level criteria to select candidate variants such as the negative selection level measured by the CoNeS approach.
Time frame: year 0, year 1, year 2 and year 3
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