Hyperimmunoglobulin E Syndrome

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DESCRIPTION

Hyperimmunoglobulin E syndrome (HIES) consists of a group of primary immunodeficiency diseases that are characterized—in part—by a triad of elevated serum immunoglobulin E (IgE), eczematous dermatitis, and infections. The best described of these disorders is autosomal dominant-HIES (AD-HIES), previously known as Job-Buckley syndrome, but several other inborn errors of immunity present with the aforementioned triad.

EPIDEMIOLOGY

  • AD-HIES may have a prevalence of 1 in 1,000,000.
  • True incidence and prevalence are currently unknown.
  • Most HIES conditions appear to equally affect males and females.

RISK FACTORS

Genetics

  • AD-HIES is caused by dominant negative mutations in STAT3, encoding for signal transducer and activator of transcription 3 (STAT3).
  • Autosomal recessive-HIES (AR-HIES) conditions also exist and include:
    • Dedicator of cytokinesis 8 (DOCK8) deficiency
    • Interleukin-6 signal transducer (IL6ST) deficiency
    • Phosphoglucomutase 3 (PGM3) deficiency
    • ZNF341 deficiency

PATHOPHYSIOLOGY

  • STAT3 is involved in multiple cytokine signaling pathways including interleukin (IL)-6, IL-11, IL-23, and tumor necrosis factor (TNF)-α
    • STAT3 is a key transcription factor in differentiation of the Th17 helper T cell subset, which is important in bacterial and fungal immunity. Defects in Th17 cells result in increased susceptibility to these types of organisms.
    • Impaired IL-11 signaling has been associated with craniosynostosis and delayed tooth eruption.
  • Other mutations that affect Th17 differentiation, such as IL6ST deficiency and ZNF341 deficiency will present similarly to AD-HIES.
  • DOCK8 is involved in actin cytoskeleton regulation of leukocyte migration and immune synapse interactions, resulting in impaired lymphocyte activation, survival, and memory responses.
  • PGM3 is involved in glycosylation pathways required for multiple immune functions.

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