Toll-like receptor 4–, 7–, and 8–activated myeloid cells from patients with X-linked agammaglobulinemia produce enhanced inflammatory cytokines

• Published in: Journal of allergy and clinical immunology Vol. 129; no. 1; pp. 184 - 190.e4
• Main Authors: Marron, Thomas U., Martinez-Gallo, Monica, Yu, Joyce E., Cunningham-Rundles, Charlotte
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.01.2012; Elsevier; Elsevier Limited
• Subjects: Adolescent; Adult; Agammaglobulinemia - immunology; agonists; Allergy and Immunology; Amides - pharmacology; animal models; Bacterial infections; Biological and medical sciences; Bruton tyrosine kinase; Child; Child, Preschool; cultured cells; Cytokines; Cytokines - biosynthesis; dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Flow cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genetic Diseases, X-Linked - immunology; Human subjects; Humans; Immune system; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infant; Infections; Inflammation Mediators - metabolism; interferon-alpha; interleukin-6; Kinases; Ligands; Male; Medical sciences; Membrane Glycoproteins - metabolism; mice; mitogen-activated protein kinase; Mitogen-Activated Protein Kinases - metabolism; monocytes; Monocytes - immunology; Monocytes - metabolism; MyD88 adapter-like protein; Myeloid Cells - immunology; NF-kappa B - metabolism; Nitriles - pharmacology; patients; Phosphorylation; protein degradation; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Proteins; Receptors, Interleukin-1 - metabolism; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Signal Transduction; Studies; Toll-like receptor 4; Toll-Like Receptor 4 - metabolism; Toll-Like Receptor 7 - metabolism; Toll-Like Receptor 8 - metabolism; Toll-like receptors; Toll-Like Receptors - metabolism; Toll–IL-1 receptor domain–containing adapter protein; transcription factor NF-kappa B; tumor necrosis factor-alpha; tyrosine; X-linked agammaglobulinemia; Young Adult; JNK; X-linked agammaglobulinemia; MAPK; XLA; mDC; MyD88 adapter-like protein; pDC; TIRAP; CVID; IRAK; NF-κB; Bruton tyrosine kinase; Toll-like receptors; BTK; Toll–IL-1 receptor domain–containing adapter protein; TLR; ERK; Common variable immunodeficiency; Plasmacytoid dendritic cell; IL-1 receptor–associated kinase; Monocytoid dendritic cell; Toll-like receptor; Nuclear factor κB; c-Jun N-terminal kinase; Extracellular signal-regulated kinase; Mitogen-activated protein kinase; Toll–IL-1 receptor domain–containing adaptor protein; Human; Toll like receptor 7; MyD88 adaptor protein; Immunopathology; Toll like receptor 4; Toll-IL-1 receptor domain―containing adapter protein; Cytokine; Toll like receptor; Inflammation; Adaptor protein; Myeloid cell; Genetic disease; Immunology; Immunoglobulinopathy; Infantile sex linked agammaglobulinemia; Interleukin 1; Biological receptor
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2011.10.009

Bruton tyrosine kinase (BTK) is a component of signaling pathways downstream from Toll-like receptors (TLRs) 2, 4, 7, 8, and 9. Previous work in BTK-deficient mice, cell lines, and cultured cells from patients with X-linked agammaglobulinemia (XLA) suggested defective TLR-driven cytokine production. We sought to compare TLR-4–, TLR-7–, and TLR-8–induced cytokine production of primary cells from patients with XLA with that seen in control cells. PBMCs from patients with XLA, freshly isolated plasmacytoid dendritic cells, monocytes, and monocytoid dendritic cells were activated with TLR-4, TLR-7, and TLR-8 agonists. Signaling intermediates and intracellular and secreted cytokine levels were compared with those seen in control cells. Although TLR-4, TLR-7, and TLR-8 activation of nuclear factor κB and mitogen-activated protein kinase pathways in cells from patients with XLA and control cells were comparable, TLR-activated freshly isolated monocytes and monocytoid dendritic cells from patients with XLA produced significantly more TNF-α, IL-6, and IL-10 than control cells. TLR-7/8–activated plasmacytoid dendritic cells produced normal amounts of IFN-α. In murine models BTK regulates the degradation of Toll–IL-1 receptor domain–containing adaptor protein, terminating TLR-4–induced cytokine production. Although this might explain the heightened TLR-4–driven cytokine production we observed, Toll–IL-1 receptor domain–containing adaptor protein degradation is intact in cells from patients with XLA, excluding this explanation. In contrast to previous studies with BTK-deficient mice, cell lines, and cultured cells from patients with XLA suggesting impaired TLR-driven cytokine production, these data suggest that BTK inhibits TLR-induced cytokine production in primary human cells.