Inborn Errors of Immunity Associated With Type 2 Inflammation in the USIDNET Registry

Abstract

BackgroundMonogenic conditions that disrupt proper development and/or function of the immune system are termed inborn errors of immunity (IEIs), also known as primary immunodeficiencies. Patients with IEIs often suffer from other manifestations in addition to infection, and allergic inflammation is an increasingly recognized feature of these conditions.MethodsWe performed a retrospective analysis of IEIs presenting with allergic inflammation as reported in the USIDNET registry. Our inclusion criteria comprised of patients with a reported monogenic cause for IEI where reported lab eosinophil and/or IgE values were available for the patient prior to them receiving potentially curative therapy. Patients were excluded if we were unable to determine the defective gene underlying their IEI. Patients were classified as having eosinophilia or elevated IgE when their record included at least 1 eosinophil count or IgE value that was greater than the age stratified upper limit of normal. We compared the proportion of patients with eosinophilia or elevated IgE with the proportion of samples in a reference population that fall above the upper limit of normal (2.5%).ResultsThe query submitted to the USIDNET registry identified 1409 patients meeting inclusion criteria with a monogenic cause for their IEI diagnosis, of which 975 had eosinophil counts and 645 had IgE levels obtained prior to transplantation or gene therapy that were available for analysis. Overall, 18.8% (183/975) of the patients evaluated from the USIDNET registry had eosinophilia and 20.9% (135/645) had an elevated IgE. IEIs caused by defects in 32 genes were found to be significantly associated with eosinophilia and/or an elevated IgE level, spanning 7 of the 10 IEI categories according to the International Union of Immunological Societies classification.ConclusionType 2 inflammation manifesting as eosinophilia or elevated IgE is found in a broad range of IEIs in the USIDNET registry. Our findings suggest that allergic immune dysregulation may be more widespread in IEIs than previously reported.

A Next Generation Sequencing (NGS)-based approach to diagnosing Algerian patients with suspected Inborn Errors of Immunity (IEIs)

“…The rapid pace of IEI gene discovery also poses a logistical challenge for maintaining TGP content relevance. In the time between the initial design of our TGPs and the submission of this manuscript, at least 40 more monogenic IEIs have been identified in patients with clinical diagnoses of CVID [17], another 43 in conjunction with IBD phenotypes [18], and at least 20 more genes for HIES or CMC-related phenotypes [19,135,136] (Tables S3). Genes already in the IUIS nosology have also been re-classifiedmost notably, TYK2 from HIES to MSMD and DOCK8 to CID [1].…”

Inborn Errors of the Immune System Associated With Atopy

“…While the extent to which the atopic phenotypes observed in LOF mutations in the CBM complex are explained by disrupting downstream NF-κB signaling is not clear, a retrospective analysis of patients with IEI registered in the USIDNET revealed that more than half of patients with NF-κB Essential Modulator ( NEMO , also known as IKBKG ) deficiency were noted to have atopic dermatitis ( 67 ). A more recent analysis of eosinophilia and elevated IgE in the USIDNET revealed that 3 out of 3 patients with NFKB2 defects had at least one atopic manifestation and eosinophilia above the upper limit of normal in the reference population and an increased proportion of patients with IKBKG defects had both eosinophilia and elevated IgE ( 68 ).…”

Eosinophilic gastrointestinal disorders in patients with inborn errors of immunity: Data from the USIDNET registry

“…Patients with IEI may first present with signs of immune dysregulation, which can precede symptoms or lab findings indicative of immunodeficiency (5)(6)(7). These can include autoimmune or atopic manifestations.…”