☆ 4.7 Article

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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2012)

期刊

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷 129, 期 1, 页码 184-U263

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MOSBY-ELSEVIER

DOI: 10.1016/j.jaci.2011.10.009

关键词

Bruton tyrosine kinase; X-linked agammaglobulinemia; Toll-like receptors; MyD88 adapter-like protein; Toll-IL-1 receptor domain-containing adapter protein

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Allergy Immunology

资金

National Institutes of Health [AI 101093, AI-467320, AI-48693]
National Institute of Allergy and Infectious Diseases [03-22]
Jeffrey Modell Foundation
David S. Gottesman Immunology Chair

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摘要

Background: 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. Objective: 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. Methods: 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. Results: Although TLR-4, TLR-7, and TLR-8 activation of nuclear factor kappa B 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-alpha, IL-6, and IL-10 than control cells. TLR-7/8-activated plasmacytoid dendritic cells produced normal amounts of IFN-alpha. 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. Conclusion: 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. (J Allergy Clin Immunol 2012; 129: 184-90.)

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Current Spectrum of Infections in Patients with X-Linked Agammaglobulinemia

Olivier Paccoud, Nizar Mahlaoui, Despina Moshous, Claire Aguilar, Benedicte Neven, Fanny Lanternier, Felipe Suarez, Capucine Picard, Alain Fischer, Stephane Blanche, Marc Lecuit, Olivier Hermine, Olivier Lortholary

Summary: The outcome of patients with X-linked agammaglobulinemia has improved with the use of IgRT therapy, despite the persistence of infection issues. Infections mainly occur in the lungs and gastrointestinal tract, even with adequate IgG trough levels. Immunosuppressive therapies and chronic inflammatory manifestations may contribute to infections in adulthood.

JOURNAL OF CLINICAL IMMUNOLOGY (2021)