Hyper‐IgE in the allergy clinic––when is it primary immunodeficiency?

Abstract

The 2017 International Union of Immunological Societies (IUIS) classification recognizes 3 hyper-IgE syndromes (HIES), including the prototypic Job's syndrome (autosomal dominant STAT3-loss of function) and autosomal recessive PGM3 and SPINK5 syndromes. Early diagnosis of PID can direct life-saving or transformational interventions; however, it remains challenging owing to the rarity of these conditions. This can result in diagnostic delay and worsen prognosis. Within increasing access to "clinical-exome" testing, clinicians need to be aware of the implication and rationale for genetic testing, including the benefits and limitations of current therapies. Extreme elevation of serum IgE has been associated with a growing number of PID syndromes including the novel CARD11 and ZNF341 deficiencies. Variable elevations in IgE are associated with defects in innate, humoral, cellular and combined immunodeficiency syndromes. Barrier compromise can closely phenocopy these conditions. The aim of this article was to update readers on recent developments at this important interface between allergy and immunodeficiency, highlighting key clinical scenarios which should draw attention to possible immunodeficiency associated with extreme elevation of IgE, and outline initial laboratory assessment and management.

Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

“…Such analysis of population‐based datasets can reveal novel insights to underpin therapeutic selection from an expanded range of precise biologicals . Examples are emerging from patients with inborn errors of immunity (IEI) in whom the genetically defined defect can be specifically targeted with therapeutics . The functional utility of data from the omics platforms will be further enhanced by the public release of omics datasets including Genotype‐Tissue Expression (GTEx) and Encyclopaedia of DNA Elements (ENCODE)…”

“…This allows longitudinal immunoprofiling of relevant cell subsets in individuals before and during AIT. Better dissection of mechanisms underlying allergic diseases informs better tailoring of therapies Unmet needs in precision medicine Consensus on endotypes and clinically applicable biomarkers for distinct allergic disorders Accurate targeted activity; even, widespread or specific as needed Increased availability of oral formulations: solid or liquid More favorable dosing intervals Minimization of adverse side effects (especially anaphylactic/allergic reactions, antibody induction, complement activation) Economic feasibility enhancement Determination of long‐term effects “Large dataset” protection and interpretation, including ethical considerations Development of a precision medicine‐specific nomenclature Development of treatment and diagnostic algorithms Development of precision medicine–focused guidelines …”

“…114 Examples are emerging from patients with inborn errors of immunity (IEI) in whom the genetically defined defect can be specifically targeted with therapeutics. 115,116 The functional utility of data from the omics platforms will be further enhanced by the public release of omics datasets including Genotype-Tissue Expression (GTEx) 117 and Encyclopaedia of DNA Elements (ENCODE). 118 Technological advances in immune monitoring capability are augmented by highly standardized or chimeric recombinant allergens and peptides (B-and T-cell epitope-based).…”

“…Exponential advances in microarrays, time-of-flight mass cytometry (CyTOF), basophil activation tests, next-generation gene sequencing, and RNA-seq are generating huge enabling datasets. 15,115,116,[119][120][121][122][123] The risk that small populations of highly pathogenic cells might be masked by abundant signatures of more frequent or more active cells is combated by the emergence of enhanced single B-and T-cell immunophenotyping using flow cytometry-based assays. This allows longitudinal immunoprofiling of relevant cell subsets in individuals before and during AIT.…”

“…Better dissection of mechanisms underlying allergic diseases informs better tailoring of therapies. 115,116,[119][120][121][122]124,125…”