title: Inability to resolve specific infection generates innate immunodeficiency syndrome in Xiap-/- mice.
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.
authors.affiliation: Graduate Institute of Life Science, National Defense Medical College, Taipei, Taiwan; Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan;
authors.forename: Wan-Chen
authors.initials: WC
authors.lastname: Hsieh
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan;
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Chuang
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan; Graduate Institute of Immunology, National Taiwan University, Taipei, Taiwan; and.
authors.forename: I-Hsuan
authors.initials: IH
authors.lastname: Chiang
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Immunology, National Taiwan University, Taipei, Taiwan; and.
authors.forename: Shi-Chuen
authors.initials: SC
authors.lastname: Miaw
authors.affiliation: Graduate Institute of Life Science, National Defense Medical College, Taipei, Taiwan; Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan; Graduate Institute of Immunology, National Taiwan University, Taipei, Taiwan; and.
authors.forename: Ming-Zong
authors.identifier: http://orcid.org/0000-0002-3237-4803
authors.initials: MZ
authors.lastname: Lai
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D002176:Candida albicans / Q000187:drug effects / Q000502:physiology; D002177:Candidiasis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism; D040181:Genetic Diseases, X-Linked / Q000276:immunology / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007113:Immunity, Innate / Q000187:drug effects; D051034:Inhibitor of Apoptosis Proteins / Q000172:deficiency* / Q000378:metabolism; D037181:Lectins, C-Type / Q000819:agonists / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D011070:Poly I-C / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects; D047071:beta-Glucans; D000099181:Dectin-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D066246:ErbB Receptors; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D037181:Lectins, C-Type; D055666:Lipopeptides; D008070:Lipopolysaccharides; D008239:Lysine; D008246:Lysophospholipids; D016328:NF-kappa B; D011070:Poly I-C; D011948:Receptors, Antigen, T-Cell; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D047071:beta-Glucans; D000099181:Dectin-1; C488088:Bcl10 protein, mouse; C107521:Birc4 protein, mouse; C508075:Pam(3)CSK(4) peptide; C038459:curdlan; C032881:lysophosphatidic acid; C402365:resiquimod