Inability to resolve specific infection generates innate immunodeficiency syndrome in Xiap-/- mice
Journal
Blood
Journal Volume
124
Journal Issue
18
Pages
2847
Date Issued
2014-10-30
Author(s)
Abstract
Emerging evidence indicates that innate immunodeficiency syndromes are linked to mutations in innate receptors and to specific infections. X-linked lymphoproliferative syndrome type-2 (XLP-2) is associated with deficiency in X-linked inhibitor of apoptosis protein (XIAP), with poorly understood molecular mechanisms. Here we showed that XIAP deficiency selectively impaired B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-mediated innate responses to dectin-1 ligands but did not affect responses to various Toll-like receptor agonists. Consequently, Xiap(-/-) mice became highly vulnerable on Candida albicans infection. The compromised early innate responses led to the persistent presence of C albicans and inflammatory cytokines in Xiap(-/-) mice. Furthermore, priming of Xiap(-/-) mice with the dectin-1 ligand curdlan alone resulted in XLP-2-like syndromes. Restoration of dectin-1-induced Rac1 activation and phagocytosis by resolvin D1, but not up-regulation of nuclear factor-κB, rescued Xiap(-/-) mice from C albicans lethal infection. Therefore, development of XLP-2 in XIAP-deficient patients could be partly due to sustained inflammation as a consequence of defective BCL10-dependent innate immunity toward specific pathogens. Importantly, our results suggest the potential therapeutic value of resolvin D1 in the treatment of XLP-2 and innate immunodeficiency syndromes.
SDGs
Other Subjects
antiinflammatory agent; curdlan; cytokine; dectin 1; epidermal growth factor receptor; immunoglobulin enhancer binding protein; interleukin 10; interleukin 2; interleukin 6; monocyte chemotactic protein 1; protein bcl 10; Rac1 protein; resolvin D1; T lymphocyte receptor; toll like receptor agonist; tumor necrosis factor alpha; unclassified drug; X linked inhibitor of apoptosis; Bcl10 protein, mouse; beta glucan; Birc4 protein, mouse; dectin 1; epidermal growth factor receptor; imidazole derivative; immunoglobulin enhancer binding protein; inhibitor of apoptosis protein; lectin; lipopeptide; lipopolysaccharide; lymphocyte antigen receptor; lysine; lysophosphatidic acid; lysophospholipid; Pam(3)CSK(4) peptide; polyinosinic polycytidylic acid; protein binding; resiquimod; signal transducing adaptor protein; toll like receptor; tumor necrosis factor alpha; animal cell; animal experiment; animal model; Article; Candida albicans; candidiasis; controlled study; enzyme activation; female; human; human cell; immune deficiency; innate immunity; knockout mouse; lymphoproliferative disease; mouse; nonhuman; phagocytosis; protein protein interaction; ubiquitination; upregulation; X linked lymphoproliferative syndrome type 2; X linked lymphoproliferative syndrome type 2; agonists; animal; candidiasis; deficiency; drug effects; immunology; lymphoproliferative disease; macrophage; metabolism; microbiology; pathology; physiology; X chromosome linked disorder; Adaptor Proteins, Signal Transducing; Animals; beta-Glucans; Candida albicans; Candidiasis; Genetic Diseases, X-Linked; Humans; Imidazoles; Immunity, Innate; Inhibitor of Apoptosis Proteins; Lectins, C-Type; Lipopeptides; Lipopolysaccharides; Lymphoproliferative Disorders; Lysine; Lysophospholipids; Macrophages; Mice; NF-kappa B; Phagocytosis; Poly I-C; Protein Binding; Receptor, Epidermal Growth Factor; Receptors, Antigen, T-Cell; Toll-Like Receptors; Tumor Necrosis Factor-alpha; Ubiquitination
Type
journal article