Primary Immunodeficiencies with Elevated IgE

Abstract

In recent years a number of primary immunodeficiencies (PIDs) characterized by elevated Immunoglobulin E (IgE) levels have been uncovered and termed as Hyper-IgE syndrome (HIES). In addition to the elevated levels of IgE, patients with these PIDs display a spectrum of infections by staphylococci and fungi, and in some cases viruses, particularly affecting skin and lungs. Most of these PIDs also have a non-infectious phenotype, comprising musculoskeletal, vascular, and neurological abnormalities. The genetic basis for the majority of conditions with elevated IgE has now been established and includes mutations in STAT3, DOCK8, TYK2, and most recently PGM3 molecules. However, in some patients with the relevant phenotype, mutations in these molecules are not identified, suggesting additional genetic etiologies of HIES not yet discovered. As the immunological and molecular basis of HIES is being unraveled, important insights are emerging that may have implications for our understanding of basic principles of immunology and protective immunity as well as for the pathogenesis and clinical management of patients with these complex and challenging PIDs. In this review, are presented the current knowledge on the clinical presentation, infectious phenotype, and the genetic and immunological pathogenesis of hyper-IgE syndromes as well as some other PIDs with elevated levels of IgE.

Elevated total serum immunoglobulin E (>1000 IU/mL): implications?

“…Total serum IgE >1000 IU/mL is a major diagnostic criterion for ABPA, and serum IgE is also incorporated into a clinical scoring system for evaluating patients with suspected hyper‐IgE syndrome . A raised total serum IgE is a useful screening tool for patients with suspected helminthic infection, especially if there is no previous history of atopy . However, these conditions were present in only a small fraction of our cohort.…”

Who regulates whom: ZNF341 is an additional player in the STAT3/T H 17 song

“…The identification of the STAT3 mutations in humans with monogenic AD-HIES 3 , has emphasized the importance of this transcription factor in regulating Th17 cells, as well as the function of these cells in human health and disease. In humans, AD-HIES (also referred to as Job’s Syndrome) is a rare autosomal dominant genetic disorder affecting <1 in 1 million individuals.…”

“…In humans, AD-HIES (also referred to as Job’s Syndrome) is a rare autosomal dominant genetic disorder affecting <1 in 1 million individuals. Major symptoms include immunodeficiency along with elevated IgE, and patients suffer from recurrent bacterial and fungal infections, particularly candida infections in the lung, along with eczema 3 . Patients with AD-HIES also exhibit skeletal abnormalities.…”

“…Patients with AD-HIES also exhibit skeletal abnormalities. Greater than 80% of cases of AD-HIES, are a result of mutations in the gene for STAT3, a transcription factor that is a major regulator of T cell responses, particularly Th17 responses 3 . These mutations in STAT3 usually generate dominant acting negative mutants that affect the function of WT STAT3.…”

CD11b regulation of B cell receptor signaling in health and systemic lupus erythematosus.

“…In many of these diseases, such as SLE, effector IgG class antibody is the primary cause of pathogenicity. However, there are also many primary immunodeficiencies characterized by elevated levels of serum IgE, termed Hyper IgE Syndromes (277). HIES are often hallmarked by frequent and reoccurring infection of the lungs and skin by staphylococcus and fungal sources, as well as eczema and eosinophilia (278).…”