Immunological Mechanisms in Hyper-IgE Syndrome

Hyper-IgE syndrome encompasses a group of inborn errors of immunity defined by markedly elevated serum IgE, eczema, recurrent staphylococcal and fungal infections, and characteristic connective‐tissue abnormalities. The autosomal dominant form arises from dominant‐negative variants in STAT3, impairing downstream signalling of interleukin-6, interleukin-21 and interleukin-23 receptors. This defect undermines differentiation of Th17 lymphocytes, diminishing mucocutaneous defence and altering B cell maturation. Autosomal recessive variants in DOCK8 disrupt cytoskeletal organisation in lymphocytes, skewing CD4+ responses towards Th2 and compromising Treg stability. Impaired cytotoxic function, reduced memory B cell formation and dysregulated cytokine milieus converge to amplify IgE synthesis and eosinophilia. Additional recessive disruptions in IL6ST and ZNF341 further attenuate JAK-STAT pathways, reinforcing vulnerability to cutaneous abscesses and pulmonary infections. Recent mechanistic insights reveal that metabolic shifts within CD4+ T cells, driven by the Akt/mTOR/S6/HIF-1α axis, modulate helper subsets and perpetuate a Th2-biased milieu. In the B cell compartment, defective somatic hypermutation and class-switch recombination contribute to dysgammaglobulinaemia, while attenuated neutrophil chemotaxis compounds susceptibility to pyogenic pathogens. Collectively, these findings underscore the interdependence of genetic lesions, intracellular signalling and immune cell metabolism in shaping the Hyper-IgE syndrome phenotype.

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Immunological Mechanisms in Hyper-IgE Syndrome publication trend

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Technical terms

STAT3: Signal transducer and activator of transcription 3, a transcription factor activated by various cytokines to regulate immune cell differentiation.

DOCK8: Dedicator of cytokinesis 8, an atypical guanine exchange factor crucial for lymphocyte cytoskeletal dynamics and immune synapse formation.

Th17 cells: A subset of CD4+ helper T cells producing interleukin-17, essential for defence against extracellular bacteria and fungi.

Th2 cells: A subset of CD4+ helper T cells producing interleukin-4 and interleukin-13, driving humoral immunity and atopic inflammation.

Regulatory T cells (Tregs): A subset of CD4+ T cells expressing FOXP3 that maintain immune tolerance and limit excessive inflammation.

JAK-STAT pathway: A signalling cascade initiated by cytokine receptors that activates gene transcription via Janus kinases and STAT proteins.

mTOR pathway: A central metabolic regulator controlling cell growth and differentiation, including the effector fate of T cells.

IL-6 receptor: The membrane-bound protein complex that binds interleukin-6 and initiates intracellular signalling via the gp130 co-receptor.

References

1. Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4+ T cells. MedComm (2024).
2. Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. Journal of Experimental Medicine (2019).
3. A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis. Journal of Experimental Medicine (2017).
4. STAT3 Hyper-IgE Syndrome—an Update and Unanswered Questions. Journal of Clinical Immunology (2021).
5. Clinical Manifestations of Hyper IgE Syndromes. Disease Markers (2010).
6. DOCK8 Immune Deficiency as a Model for Primary Cytoskeletal Dysfunction. Disease Markers (2010).
7. Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance. Journal of Experimental Medicine (2021).