Are Interleukin 4 (IL4) and Interleukin 13 (IL13) involved in the pathogenesis of Signal Transducer and Activator of Transcription 3 (STAT3) or Lymphoid-Restricted Membrane-Bound Adapter Protein (LRBA) syndromes?

IL-4 and IL-13 Involvement in STAT3 and LRBA Syndromes

IL-4 and IL-13 are directly involved in the pathophysiology of both STAT3 and LRBA syndromes through shared receptor signaling pathways, with IL-4 and IL-13 activating STAT3 phosphorylation and utilizing overlapping receptor complexes that are disrupted in these primary immunodeficiencies.

Mechanistic Connection to STAT3

Both IL-4 and IL-13 directly activate STAT3 phosphorylation through their shared receptor signaling pathways 1, 2. The evidence demonstrates that:

• IL-13 induces tyrosine phosphorylation of STAT3 in cells expressing the IL-13Rα chain, with this phosphorylation being mediated through constitutive association of the IL-13Rα cytoplasmic domain with STAT3, Tyk2, and JAK1 1
• IL-4 similarly activates STAT3, STAT5, and STAT6 proteins in normal human B cells through the shared IL-4Rα and IL-2Rγc receptor complex 2
• In cells expressing both IL-2Rγ and IL-4Rα, IL-13 mimics IL-4-induced heterodimerization and consequent marked activation of JAK3 and STAT6 3

The clinical relevance is that STAT3 deficiency (Hyper-IgE syndrome) disrupts this normal IL-4/IL-13 signaling cascade, contributing to the immune dysregulation and recurrent infections characteristic of this syndrome 4.

Connection to LRBA Deficiency

LRBA deficiency directly impacts IL-4 and IL-13 signaling through disrupted CTLA-4 trafficking and immune dysregulation 5. The pathophysiologic mechanisms include:

• LRBA deficiency causes deranged intracellular trafficking of CTLA-4, which normally regulates T-cell activation and cytokine production including IL-4 and IL-13 5
• The combined immunodeficiency in LRBA syndrome affects B-cell and T-cell populations that are primary producers and responders to IL-4 and IL-13 5
• Abatacept (CTLA-4-Ig fusion protein) is specifically recommended for LRBA deficiency because it directly addresses the pathophysiologic mechanism of disrupted IL-4/IL-13-mediated immune regulation 5

Shared Receptor Signaling Pathways

The functional overlap between IL-4 and IL-13 occurs through shared receptor subunits that are critical in both STAT3 and LRBA syndromes:

• Both cytokines utilize the IL-4Rα chain and can recruit the IL-2Rγ (common gamma chain) in cells expressing both receptors 3, 2
• IL-13 and IL-4 activate the same downstream signaling molecules (STAT6, STAT3, STAT5) despite using different Janus kinase combinations 2
• The cytoplasmic domain interaction between IL-4Rα and IL-13Rα2 (decoy receptor) regulates IL-4 signaling, adding another layer of complexity to these pathways 6

Clinical Implications for Management

Recognition of IL-4/IL-13 involvement informs therapeutic strategies for both syndromes:

• For STAT3 deficiency: Aggressive antimicrobial prophylaxis addresses the impaired IL-4/IL-13-mediated immune responses that contribute to recurrent infections 5
• For LRBA deficiency: Immunoglobulin replacement therapy (target trough IgG 600-800 mg/dL) addresses the antibody deficiency that results from disrupted IL-4/IL-13-mediated B-cell class switching 5
• Monitoring for autoimmune complications is essential in both syndromes, as dysregulated IL-4/IL-13 signaling contributes to immune dysregulation manifesting as autoimmunity 5

Important Caveats

The IL-4/IL-13 involvement differs mechanistically between the two syndromes:

• In STAT3 deficiency, the primary defect is in the transcription factor downstream of IL-4/IL-13 receptor activation 1, 7
• In LRBA deficiency, the defect is upstream in immune regulation, affecting the cellular context in which IL-4/IL-13 signaling occurs 5
• Both syndromes can present with overlapping features including recurrent infections, autoimmunity, and enteropathy, reflecting the central role of IL-4/IL-13 in immune homeostasis 4, 5