Welcome to the ESID 2022 Meeting Interactive Programme
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Introduction
Type I IFN Autoantibodies and Viral Infections
TLR8 Somatic and Germline GOF Variants
IFNG Autoantibodies and Susceptibility to Mycobacteria
IS THE PRESENCE OF CYTOKINE-AUTOANTIBODIES IN PATIENTS WITH ENDOCRINE AUTOIMMUNE DISORDERS POINTING TO AN UNDERLYING MONOGENIC ETIOLOGY?
Abstract
Background and Aims
Monogenic causes of several different disorders with simultaneous autoimmune and immune deficiency features have been identified. Apt examples are patients with mutations in AIRE, RAG1 or 2, FOXP3, CTLA-4 and IKZF2. Curiously, all these conditions are hallmarked by presence of neutralizing autoantibodies against type I Interferons and IL-22-antibodies.
We here wanted to utilize screening of antibodies against IFN-ω and IL-22 in patients with endocrine autoimmune disorders to identify individuals with monogenic etiology.
Methods
Patients in the Norwegian registry for organ-specific autoimmune disorders were screened for antibodies against IFN-ω (N ~1700) and IL-22 (N=675) using radioimmunoassay and ELISA, respectively. Sequencing of the AIRE-gene and NGS with an in house immune panel (N=312 genes) was done to identify rare genetic aberrations (MAF<0.5%) in cytokine antibody-positive individuals.
Results
Screening patients with endocrine autoimmune disorders for IFN-ω antibodies have the last years identified at least 8 patients with AIRE-mutations, i.e. autoimmune polyendocrine syndrome type I in our cohort. In addition, we have identified 24 patients with antibodies against IFN-ω and/or IL22 but without AIRE-mutations in this project. Two patients were found to harbor disease-causing mutations in CTLA4 and NFKB2, respectively, while nine rare variants in genes encoding checkpoints within the T cell pathway in six other patients were also found. The functional consequences of the identified variants need to be explored further to draw conclusion about their disease-causing potential.
Conclusions
Screening of cytokine autoantibodies in patient cohorts with autoimmune endocrine diseases could be a valuable tool to identify the molecular cause of their disease.
A HIGH-THROUGHPUT AMPLICON SCREEN FOR SOMATIC UBA1 VARIANTS IN CYTOPENIC AND GIANT CELL ARTERITIS COHORTS
Abstract
Background and Aims
Somatic mutations in UBA1 exon 3 are a known cause of VEXAS syndrome, a late-onset acquired auto-inflammatory syndrome. Differential diagnoses for patients subsequently found to have VEXAS include, relapsing polychondritis (most frequent diagnosis), Sweet’s syndrome, myelodysplastic syndrome (MDS), giant cell arteritis (GCA) and undifferentiated systemic autoinflammatory disease (uSAID). We sought to investigate the frequency of VEXAS associated mutations in patients with confirmed GCA and those with unexplained cytopenia.
Methods
A one-step, PCR-based amplicon sequencing assay was developed to screen UBA1 exon 3 in high-throughput. Using the amplicon sequencing assay, 612 males diagnosed with GCA, and 1,055 cases with an undiagnosed cytopenia were sequenced by massively paralleled sequencing.
Results
No GCA cases were found to have UBA1 mutations, however 4 different mutations in the cytopenic cohort were identified in 7 individuals (1.0% of males of males screened). We identified a female with VEXAS due to a UBA1 mutation who was subsequently found not to have Monosomy X.
Conclusions
We identified 1.0% of males with a non-diagnostic cytopenia had VEXAS syndrome. The finding of a female case adds further evidence that VEXAS should not be ruled out as a differential diagnosis in females.