The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases (original) (raw)

• Ochs, H. D. & Hitzig, W. H. History of primary immunodeficiency diseases. Curr. Opin. Allergy Clin. Immunol. 12, 577–587 (2012).
  CAS PubMed Google Scholar
• Bruton, O. C. Agammaglobulinemia. Pediatrics 9, 722–728 (1952).
  CAS PubMed Google Scholar
• Casanova, J. L. & Abel, L. Primary immunodeficiencies: a field in its infancy. Science 317, 617–619 (2007).
  Article CAS PubMed Google Scholar
• Davis, M. M. Immunology taught by humans. Sci. Transl. Med. 4, 117fs112 (2012).
  Article CAS Google Scholar
• Zhang, Q. et al. Combined immunodeficiency associated with DOCK8 mutations. N. Engl. J. Med. 361, 2046–2055 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Sanal, O. et al. Additional diverse findings expand the clinical presentation of DOCK8 deficiency. J. Clin. Immunol. 32, 698–708 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Jabara, H. H. et al. DOCK8 functions as an adaptor that links TLR–MyD88 signaling to B cell activation. Nature Immunol. 13, 612–620 (2012).
  Article CAS Google Scholar
• Picard, C. et al. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 89, 403–425 (2010).
  Article CAS PubMed Google Scholar
• Weller, S. et al. IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88-, and TIRAP- but not UNC-93B-deficient patients. Blood 120, 4992–5001 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• He, B. et al. The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nature Immunol. 11, 836–845 (2010).
  Article CAS Google Scholar
• Isnardi, I. et al. IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans. Immunity 29, 746–757 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Randall, K. L. et al. DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice. J. Exp. Med. 208, 2305–2320 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Randall, K. L., Lambe, T., Goodnow, C. C. & Cornall, R. J. The essential role of DOCK8 in humoral immunity. Dis. Markers 29, 141–150 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Mizesko, M. C. et al. Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency. J. Allergy Clin. Immunol. 131, 840–848 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Harada, Y. et al. DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. Blood 119, 4451–4461 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mueller, P. et al. Regulation of T cell survival through coronin-1-mediated generation of inositol-1,4,5-trisphosphate and calcium mobilization after T cell receptor triggering. Nature Immunol. 9, 424–431 (2008).
  Article CAS Google Scholar
• Shiow, L. R. et al. The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. Nature Immunol. 9, 1307–1315 (2008).
  Article CAS Google Scholar
• Moshous, D. et al. Whole-exome sequencing identifies coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation. J. Allergy Clin. Immunol. 131, 1594–1603.e9 (2013).
  Article CAS PubMed Google Scholar
• Pan, D. The hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Nehme, N. T. et al. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood 119, 3458–3468 (2012).
  Article CAS PubMed Google Scholar
• Abdollahpour, H. et al. The phenotype of human STK4 deficiency. Blood 119, 3450–3457 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Crequer, A. et al. Inherited MST1 deficiency underlies susceptibility to EV-HPV infections. PLoS ONE 7, e44010 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Heallen, T. et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Mou, F. et al. The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes. J. Exp. Med. 209, 741–759 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Palendira, U. et al. Molecular pathogenesis of EBV susceptibility in XLP as revealed by analysis of female carriers with heterozygous expression of SAP. PLoS Biol. 9, e1001187 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Palendira, U. et al. Expansion of somatically reverted memory CD8+ T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus. J. Exp. Med. 209, 913–924 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Li, F. Y. et al. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 475, 471–476 (2011). This study is a prime example of the discovery of a novel biological pathway. A previously unrecognized role for magnesium as a second messenger for signalling was identified through the study of a discrete population of immunodeficient patients
  Article CAS PubMed PubMed Central Google Scholar
• Niehues, T., Perez-Becker, R. & Schuetz, C. More than just SCID — the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin. Immunol. 135, 183–192 (2010).
  Article CAS PubMed Google Scholar
• Omenn, G. S. Familial reticuloendotheliosis with eosinophilia. N. Engl. J. Med. 273, 427–432 (1965).
  Article CAS PubMed Google Scholar
• Schuetz, C. et al. An immunodeficiency disease with RAG mutations and granulomas. N. Engl. J. Med. 358, 2030–2038 (2008). This is the first report to show that hypomorphic mutations in RAG genes could lead to phenotypes that are quite distinct from Omenn syndrome or SCID. These patients provide the opportunity to study the roles of RAG proteins in human V(D)J gene recombination, the affect they have on TCR repertoires and a new pathophysiological role for RAG function in granulomatous disease.
  Article CAS PubMed Google Scholar
• De Ravin, S. S. et al. Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood 116, 1263–1271 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Avila, E. M. et al. Highly variable clinical phenotypes of hypomorphic RAG1 mutations. Pediatrics 126, e1248–e1252 (2010).
  Article PubMed Google Scholar
• Kuijpers, T. W. et al. Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations. Blood 117, 5892–5896 (2011).
  Article CAS PubMed Google Scholar
• de Villartay, J. P. et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J. Clin. Invest. 115, 3291–3299 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Marrella, V. et al. A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome. J. Clin. Invest. 117, 1260–1269 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Walter, J. E. et al. Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. J. Exp. Med. 207, 1541–1554 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Cassani, B. et al. Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome. J. Exp. Med. 207, 1525–1540 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Milner, J. D., Ward, J. M., Keane-Myers, A. & Paul, W. E. Lymphopenic mice reconstituted with limited repertoire T cells develop severe, multiorgan, Th2-associated inflammatory disease. Proc. Natl Acad. Sci. USA 104, 576–581 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Rucci, F. et al. Abnormalities of thymic stroma may contribute to immune dysregulation in murine models of leaky severe combined immunodeficiency. Front. Immunol. http://dx.doi.org/10.3389/fimmu.2011.00015 (2013).
• Conley, M. E. et al. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K. J. Exp. Med. 209, 463–470 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Fruman, D. A. et al. Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85α. Nature Genet. 26, 379–382 (2000).
  Article CAS PubMed Google Scholar
• Datta, S. & Milner, J. D. Altered T-cell receptor signaling in the pathogenesis of allergic disease. J. Allergy Clin. Immunol. 127, 351–354 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Gandhi, C., Healy, C., Wanderer, A. A. & Hoffman, H. M. Familial atypical cold urticaria: description of a new hereditary disease. J. Allergy Clin. Immunol. 124, 1245–1250 (2009).
  Article PubMed PubMed Central Google Scholar
• Ombrello, M. J. et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N. Engl. J. Med. 366, 330–338 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, D. et al. Phospholipase Cγ2 is essential in the functions of B cell and several Fc receptors. Immunity 13, 25–35 (2000).
  Article PubMed Google Scholar
• Yu, P. et al. Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase Cγ2 that specifically increases external Ca2+ entry. Immunity 22, 451–465 (2005).
  Article CAS PubMed Google Scholar
• Abe, K. et al. A novel _N_-ethyl-_N_-nitrosourea-induced mutation in phospholipase Cγ2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model. Arthritis Rheum. 63, 1301–1311 (2011).
  Article CAS PubMed Google Scholar
• Freeman, A. F. et al. Coronary artery abnormalities in Hyper-IgE syndrome. J. Clin. Immunol. 31, 338–345 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Fairchild, K. D., Singh, I. S., Carter, H. C., Hester, L. & Hasday, J. D. Hypothermia enhances phosphorylation of IκB kinase and prolongs nuclear localization of NF-κB in lipopolysaccharide-activated macrophages. Am. J. Physiol. Cell Physiol. 289, C1114–C1121 (2005).
  Article CAS PubMed Google Scholar
• Zhou, Q. et al. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am. J. Hum. Genet. 91, 713–720 (2012). References 44 and 50 show the remarkable complexity and the diversity of cellular and clinical phenotypes, including allergy, immunodeficiency and autoinflammation, which emerge from two different types of gain-of-function mutations in PLCG2.
  Article CAS PubMed PubMed Central Google Scholar
• Casanova, J. L., Abel, L. & Quintana-Murci, L. Human TLRs and IL-1Rs in host defense: natural insights from evolutionary, epidemiological, and clinical genetics. Annu. Rev. Immunol. 29, 447–491 (2011).
  Article CAS PubMed Google Scholar
• Sancho-Shimizu, V. et al. Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. J. Clin. Invest. 121, 4889–4902 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Guo, Y. et al. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J. Exp. Med. 208, 2083–2098 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Perez de Diego, R. et al. Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity 33, 400–411 (2010).
  Article CAS PubMed Google Scholar
• Zhang, S. Y. et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science 317, 1522–1527 (2007).
  Article CAS PubMed Google Scholar
• Casrouge, A. et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314, 308–312 (2006).
  Article CAS PubMed Google Scholar
• Herman, M. et al. Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. J. Exp. Med. 209, 1567–1582 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Lafaille, F. G. et al. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature 491, 769–773 (2012). Using induced pluripotent stem cells, this study shows that the increased susceptibility to HSV-1 encephalitis that occurs in patients with defects in TLR3 is due to intrinsic defects in innate-sensing mechanisms in central nervous system-resident cells, including neurons and oligodendrocytes.
  Article CAS PubMed PubMed Central Google Scholar
• Vinh, D. C. et al. Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood 115, 1519–1529 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Hsu, A. P. et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118, 2653–2655 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Bigley, V. et al. The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency. J. Exp. Med. 208, 227–234 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Ostergaard, P. et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nature Genet. 43, 929–931 (2011).
  Article CAS PubMed Google Scholar
• Hahn, C. N. et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nature Genet. 43, 1012–1017 (2011). References 60, 62 and 63 provide examples of multiple discrete phenotypes that arise from mutations in a single gene. These studies show how defects in a single transcription factor can lead to myeloid dysplasia and defective host defence.
  Article CAS PubMed Google Scholar
• Rodrigues, N. P. et al. Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis. Blood 106, 477–484 (2005).
  Article CAS PubMed Google Scholar
• Kumar, M. S. et al. The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell 149, 642–655 (2012).
  Article CAS PubMed Google Scholar
• Vicente, C. et al. Overexpression of GATA2 predicts an adverse prognosis for patients with acute myeloid leukemia and it is associated with distinct molecular abnormalities. Leukemia 26, 550–554 (2012).
  Article CAS PubMed Google Scholar
• Zhang, S. J. et al. Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia. Proc. Natl Acad. Sci. USA 105, 2076–2081 (2008).
  Article PubMed PubMed Central Google Scholar
• Johnson, K. D. et al. Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity. J. Clin. Invest. 122, 3692–3704 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mace, E. M. et al. Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56bright subset. Blood 121, 2669–2677 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Biron, C. A., Byron, K. S. & Sullivan, J. L. Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320, 1731–1735 (1989).
  Article CAS PubMed Google Scholar
• Kazenwadel, J. et al. Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood 119, 1283–1291 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Cuellar-Rodriguez, J. et al. Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. Blood 118, 3715–3720 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Marquis, J. F. et al. Interferon regulatory factor 8 regulates pathways for antigen presentation in myeloid cells and during tuberculosis. PLoS Genet. 7, e1002097 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Holtschke, T. et al. Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87, 307–317 (1996).
  Article CAS PubMed Google Scholar
• Hambleton, S. et al. IRF8 mutations and human dendritic-cell immunodeficiency. N. Engl. J. Med. 365, 127–138 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, Z. & O'Shea, J. J. Th17 cells: a new fate for differentiating helper T cells. Immunol. Res. 41, 87–102 (2008).
  Article CAS PubMed Google Scholar
• Milner, J. D. et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452, 773–776 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Ma, C. S. et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J. Exp. Med. 205, 1551–1557 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• de Beaucoudrey, L. et al. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J. Exp. Med. 205, 1543–1550 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Renner, E. D. et al. Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced TH17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome. J. Allergy Clin. Immunol. 122, 181–187 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Puel, A. et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65–68 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Kisand, K. et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207, 299–308 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Puel, A. et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 207, 291–297 (2010). References 81–83 were the first to highlight the remarkably limited infectious phenotype (that is, increased susceptibility to chronic mucocutaneous candidiasis) that occurs in patients with focal defects in IL-17-mediated signalling. By contrast, IL-17 has been shown to protect against a wider range of infections in mice.
  Article CAS PubMed PubMed Central Google Scholar
• Ferwerda, B. et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N. Engl. J. Med. 361, 1760–1767 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Glocker, E. O. et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N. Engl. J. Med. 361, 1727–1735 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Minegishi, Y. et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448, 1058–1062 (2007).
  Article CAS PubMed Google Scholar
• Holland, S. M. et al. STAT3 Mutations in the Hyper-IgE Syndrome. N. Engl. J. Med. 357, 1608–1619 (2007).
  Article CAS PubMed Google Scholar
• Speckmann, C. et al. Reduced memory B cells in patients with hyper IgE syndrome. Clin. Immunol. 129, 448–454 (2008).
  Article CAS PubMed Google Scholar
• Avery, D. T. et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J. Exp. Med. 207, 155–171 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Schmitt, N. et al. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity 31, 158–169 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Ma, C. S. et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood 119, 3997–4008 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Cui, W., Liu, Y., Weinstein, J. S., Craft, J. & Kaech, S. M. An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity 35, 792–805 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Siegel, A. M. et al. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity 35, 806–818 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Kida, H. et al. GP130-STAT3 regulates epithelial cell migration and is required for repair of the bronchiolar epithelium. Am. J. Pathol. 172, 1542–1554 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kovacic, J. C. et al. Stat3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice. J. Clin. Invest. 120, 303–314 (2010).
  Article CAS PubMed Google Scholar
• Chandesris, M. O. et al. Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency. Circ. Cardiovasc. Genet. 5, 25–34 (2012).
  Article CAS PubMed Google Scholar
• Nieminen, P. et al. Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth. Am. J. Hum. Genet. 89, 67–81 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Wegrzyn, J. et al. Function of mitochondrial Stat3 in cellular respiration. Science 323, 793–797 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Gough, D. J. et al. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 324, 1713–1716 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• van der Windt, G. J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).
  Article CAS PubMed Google Scholar
• Liu, L. et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J. Exp. Med. 208, 1635–1648 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• van de Veerdonk, F. L. et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N. Engl. J. Med. 365, 54–61 (2011).
  Article CAS PubMed Google Scholar
• Boisson-Dupuis, S. et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr. Opin. Immunol. 24, 364–378 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Smeekens, S. P. et al. STAT1 hyperphosphorylation and defective IL12R/IL23R signaling underlie defective immunity in autosomal dominant chronic mucocutaneous candidiasis. PLoS ONE 6, e29248 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Sampaio, E. P. et al. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J. Allergy Clin. Immunol. 131, 1624–1634 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Uzel, G. et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J. Allergy Clin. Immunol. 131, 1611–1623.e3 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Romberg, N. et al. Gain-of-function STAT1 mutations are associated with PD-L1 overexpression and a defect in B-cell survival. J. Allergy Clin. Immunol. 131, 1691–1693 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, X. P. et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nature Immunol. 12, 247–254 (2011).
  Article CAS Google Scholar
• Yoshimura, A., Nishinakamura, H., Matsumura, Y. & Hanada, T. Negative regulation of cytokine signaling and immune responses by SOCS proteins. Arthritis Res. Ther. 7, 100–110 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Grimbacher, B. et al. Hyper-IgE syndrome with recurrent infections — an autosomal dominant multisystem disorder. N. Engl. J. Med. 340, 692–702 (1999).
  Article CAS PubMed Google Scholar
• Rezaei, N., Notarangelo, L. & Aghamohammadi, A. Primary Immunodeficiency Diseases: Definition, Diagnosis, and Management 59–64 (Springer, 2008).
  Book Google Scholar
• Lean, I. S., McDonald, V. & Pollok, R. C. The role of cytokines in the pathogenesis of Cryptosporidium infection. Curr. Opin. Infect. Dis. 15, 229–234 (2002).
  Article CAS PubMed Google Scholar
• Kotlarz, D. et al. Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome. J. Exp. Med. 210, 433–443 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Recher, M. et al. IL-21 is the primary common γ chain-binding cytokine required for human B-cell differentiation in vivo. Blood 118, 6824–6835 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• de Totero, D. et al. Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells. Blood 107, 3708–3715 (2006).
  Article CAS PubMed Google Scholar
• Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).
  Article CAS PubMed Google Scholar
• Glocker, E. O. et al. Infant colitis — it's in the genes. Lancet 376, 1272 (2010).
  Article PubMed Google Scholar
• Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Engelhardt, K. R. et al. Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J. Allergy Clin. Immunol. 131, 825–830 (2012). This study shows that colitis can be a monogenic disease and can be cured by bone marrow transplantation. It highlights the important role of IL-10 signalling in haematopoietic cells in preventing intestinal inflammation.
  Article CAS PubMed Google Scholar
• Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Sayos, J. et al.The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998).
  Article CAS PubMed Google Scholar
• Chaigne-Delalande, B. et al. Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science 341, 186–191 (2013).
  Article CAS PubMed PubMed Central Google Scholar