Inability to resolve specific infection generates innate immunodeficiency syndrome in Xiap−/− mice

• Published in: Blood 2014-10, Vol.124 (18), p.2847-2857
• Main Authors: Hsieh, Wan-Chen, Chuang, Ya-Ting, Chiang, I-Hsuan, Hsu, Shu-Ching, Miaw, Shi-Chuen, Lai, Ming-Zong
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; B-Cell CLL-Lymphoma 10 Protein; beta-Glucans; Candida albicans - drug effects; Candida albicans - physiology; Candidiasis - immunology; Candidiasis - microbiology; Candidiasis - pathology; ErbB Receptors - metabolism; Genetic Diseases, X-Linked - immunology; Genetic Diseases, X-Linked - pathology; Humans; Imidazoles - pharmacology; Immunity, Innate - drug effects; Inhibitor of Apoptosis Proteins - deficiency; Inhibitor of Apoptosis Proteins - metabolism; Lectins, C-Type - agonists; Lectins, C-Type - metabolism; Lipopeptides - pharmacology; Lipopolysaccharides - pharmacology; Lymphoproliferative Disorders - immunology; Lymphoproliferative Disorders - pathology; Lysine - metabolism; Lysophospholipids - metabolism; Macrophages - drug effects; Macrophages - metabolism; Mice; NF-kappa B - metabolism; Phagocytosis - drug effects; Poly I-C - pharmacology; Protein Binding - drug effects; Receptors, Antigen, T-Cell - metabolism; Toll-Like Receptors - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Ubiquitination - drug effects
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-03-564609

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. •XIAP deficiency selectively diminishes BCL10-mediated innate responses and impairs the ability of the host to control specific microbes.•The selective innate immunodeficiency in the XIAP-deficient host leads to the persistent presence of specific pathogens and excess inflammation.