Gosling, K. M. et al. A mutation in a chromosome condensin II subunit, kleisinβ, specifically disrupts T cell development. Proc. Natl Acad. Sci. USA 104, 12445–12450 (2007).
This study describes the sensitivity of thymocytes to global impairments in basic cellular processes, with a partial block at the double-negative stage of thymocyte development in mice with a point mutation in the ubiquitious chromosome component kleisin-β.
Anderson, S. J. et al. Ablation of ribosomal protein L22 selectively impairs αβT cell development by activation of a p53-dependent checkpoint. Immunity 26, 759–772 (2007).
Deutschbauer, A. M. et al. Mechanisms of haploinsufficiency revealed by genome-wide profiling in yeast. Genetics 169, 1915–1925 (2005).
Giaever, G. et al. Functional profiling of the Saccharomyces cerevisiae genome. Nature 418, 387–391 (2002).
Fischer, A. et al. Naturally occurring primary deficiencies of the immune system. Annu. Rev. Immunol. 15, 93–124 (1997).
Villa, A. et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell 93, 885–896 (1998).
A seminal paper characterizing the mechanism of Omenn syndrome, revealed as an incomplete reduction of V(D)J recombination.
Ege, M. et al. Omenn syndrome due to ARTEMIS mutations. Blood 105, 4179–4186 (2005).
Gennery, A. R. et al. Omenn's syndrome occurring in patients without mutations in recombination activating genes. Clin. Immunol. 116, 246–256 (2005).
Roifman, C. M., Gu, Y. & Cohen, A. Mutations in the RNA component of RNase mitochondrial RNA processing might cause Omenn syndrome. J. Allergy Clin. Immunol. 117, 897–903 (2006).
Giliani, S. et al. Omenn syndrome in an infant with IL7RA gene mutation. J. Pediatr. 148, 272–274 (2006).
Shibata, F. et al. Skin infiltration of CD56bright CD16− natural killer cells in a case of X-SCID with Omenn syndrome-like manifestations. Eur. J. Haematol. 79, 81–85 (2007).
Santagata, S. et al. N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains. Proc. Natl Acad. Sci. USA 97, 14572–14577 (2000).
de Saint-Basile, G. et al. Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn's syndrome). J. Clin. Invest. 87, 1352–1359 (1991).
Corneo, B. et al. Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome. Blood 97, 2772–2776 (2001).
The remarkable observation that identical alleles of RAG1 or RAG2 can give rise to the profoundly different conditions of SCID (severe combined immunodeficient) or Omenn syndrome, highlighting the contribution of unknown genetic and/or environmental influences.
Ehl, S. et al. A variant of SCID with specific immune responses and predominance of γδ T cells. J. Clin. Invest. 115, 3140–3148 (2005).
de Villartay, J. P. et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J. Clin. Invest. 115, 3291–3299 (2005).
van der Burg, M. et al. A new type of radiosensitive T−B−NK+ severe combined immunodeficiency caused by a LIG4 mutation. J. Clin. Invest. 116, 137–145 (2006).
Enders, A. et al. A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. J. Immunol. 176, 5060–5068 (2006).
O'Driscoll, M. et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol. Cell 8, 1175–1185 (2001).
Puel, A., Ziegler, S. F., Buckley, R. H. & Leonard, W. J. Defective IL7R expression in T−B+NK+ severe combined immunodeficiency. Nature Genet. 20, 394–397 (1998).
Roifman, C. M., Zhang, J., Chitayat, D. & Sharfe, N. A partial deficiency of interleukin-7Rα is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood 96, 2803–2807 (2000).
Puck, J. M. et al. The interleukin-2 receptor γ chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum. Mol. Genet. 2, 1099–1104 (1993).
Noguchi, M. et al. Interleukin-2 receptor γ chain: a functional component of the interleukin-7 receptor. Science 262, 1877–1880 (1993).
Jones, A. M. et al. B-cell-negative severe combined immunodeficiency associated with a common γ chain mutation. Hum. Genet. 99, 677–680 (1997).
Kofoed, E. M. et al. Growth hormone insensitivity associated with a STAT5b mutation. N. Engl. J. Med. 349, 1139–1147 (2003).
Hwa, V. et al. Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene. Horm. Res. 68, 218–224 (2007).
Makitie, O., Kaitila, I. & Savilahti, E. Susceptibility to infections and in vitro immune functions in cartilage-hair hypoplasia. Eur. J. Pediatr. 157, 816–820 (1998).
Barth, R. F., Vergara, G. G., Khurana, S. K., Lowman, J. T. & Beckwith, J. B. Rapidly fatal familial histiocytosis associated with eosinophilia and primary immunological deficiency. Lancet 2, 503–506 (1972).
Berthet, F. et al. Bone marrow transplantation in cartilage-hair hypoplasia: correction of the immunodeficiency but not of the chondrodysplasia. Eur. J. Pediatr. 155, 286–290 (1996).
Kuijpers, T. W. et al. Short-limbed dwarfism with bowing, combined immune deficiency, and late onset aplastic anaemia caused by novel mutations in the RMPR gene. J. Med. Genet. 40, 761–766 (2003).
Hirschhorn, R. & Candott, F. in Primary Immunodeficiency diseases, 2nd Edn (eds H. D. Ochs, C. I. E. Smith & J. Puck) 169–196 (Oxford Univ. Press, 2007).
Shovlin, C. L. et al. Adult presentation of adenosine deaminase deficiency. Lancet 341, 1471 (1993).
Hirschhorn, R., Yang, D. R., Israni, A., Huie, M. L. & Ownby, D. R. Somatic mosaicism for a newly identified splice-site mutation in a patient with adenosine deaminase-deficient immunodeficiency and spontaneous clinical recovery. Am. J. Hum. Genet. 55, 59–68 (1994).
Hirschhorn, R. et al. Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency. Nature Genet. 13, 290–295 (1996).
Toyabe, S., Watanabe, A., Harada, W., Karasawa, T. & Uchiyama, M. Specific immunoglobulin E responses in ZAP70-deficient patients are mediated by Syk-dependent T-cell receptor signalling. Immunology 103, 164–171 (2001).
Sullivan, K. E., Mullen, C. A., Blaese, R. M. & Winkelstein, J. A. A multiinstitutional survey of the Wiskott–Aldrich syndrome. J. Pediatr. 125, 876–885 (1994).
Schurman, S. H. & Candotti, F. Autoimmunity in Wiskott–Aldrich syndrome. Curr. Opin. Rheumatol. 15, 446–453 (2003).
Derry, J. M., Ochs, H. D. & Francke, U. Isolation of a novel gene mutated in Wiskott–Aldrich syndrome. Cell 78, 635–644 (1994).
This study described the first causative mutation of a clinical immunodeficiency with immune dysregulation.
Imai, K. et al. Clinical course of patients with WASP gene mutations. Blood 103, 456–464 (2004).
Villa, A. et al. X-linked thrombocytopenia and Wiskott–Aldrich syndrome are allelic diseases with mutations in the WASP gene. Nature Genet. 9, 414–417 (1995).
Vella, A. et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76, 773–779 (2005).
Brand, O. J. et al. Association of the interleukin-2 receptor α (IL-2Rα)/CD25 gene region with Graves' disease using a multilocus test and tag SNPs. Clin. Endocrinol. 66, 508–512 (2007).
Sharfe, N., Dadi, H. K., Shahar, M. & Roifman, C. M. Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor. Proc. Natl Acad. Sci. USA 94, 3168–3171 (1997).
Caudy, A. A., Reddy, S. T., Chatila, T., Atkinson, J. P. & Verbsky, J. W. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J. Allergy Clin. Immunol. 119, 482–487 (2007).
Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992).
Spanopoulou, E. et al. Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. Genes Dev. 8, 1030–1042 (1994).
Hao, Z. & Rajewsky, K. Homeostasis of peripheral B cells in the absence of B cell influx from the bone marrow. J. Exp. Med. 194, 1151–1164 (2001).
Shinkai, Y. et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867 (1992).
Arpaia, E., Shahar, M., Dadi, H., Cohen, A. & Roifman, C. M. Defective T cell receptor signaling and CD8+ thymic selection in humans lacking ZAP-70 kinase. Cell 76, 947–958 (1994).
Elder, M. E. et al. Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 264, 1596–1599 (1994).
Chan, A. C. et al. ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science 264, 1599–1601 (1994).
Wiest, D. L. et al. A spontaneously arising mutation in the DLAARN motif of murine ZAP-70 abrogates kinase activity and arrests thymocyte development. Immunity 6, 663–671 (1997).
Negishi, I. et al. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376, 435–438 (1995).
Peschon, J. J. et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J. Exp. Med. 180, 1955–1960 (1994).
Li, L. et al. Targeted disruption of the Artemis murine counterpart results in SCID and defective V(D)J recombination that is partially corrected with bone marrow transplantation. J. Immunol. 174, 2420–2428 (2005).
Rooney, S. et al. Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Mol. Cell 10, 1379–1390 (2002).
Wakamiya, M. et al. Disruption of the adenosine deaminase gene causes hepatocellular impairment and perinatal lethality in mice. Proc. Natl Acad. Sci. USA 92, 3673–3677 (1995).
Migchielsen, A. A. et al. Adenosine-deaminase-deficient mice die perinatally and exhibit liver-cell degeneration, atelectasis and small intestinal cell death. Nature Genet. 10, 279–287 (1995).
Frank, K. M. et al. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 396, 173–177 (1998).
Cao, X. et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain. Immunity 2, 223–238 (1995).
DiSanto, J. P., Muller, W., Guy-Grand, D., Fischer, A. & Rajewsky, K. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor γ chain. Proc. Natl Acad. Sci. USA 92, 377–381 (1995).
Ohbo, K. et al. Modulation of hematopoiesis in mice with a truncated mutant of the interleukin-2 receptor γ chain. Blood 87, 956–967 (1996).
Snow, J. W. et al. Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J. Immunol. 171, 5042–5050 (2003).
Wen, L. et al. Immunoglobulin synthesis and generalized autoimmunity in mice congenitally deficient in αβ+T cells. Nature 369, 654–658 (1994).
Nijnik, A. et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature 447, 686–690 (2007).
Marrella, V. et al. A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome. J. Clin. Invest. 117, 1260–1269 (2007).
Khiong, K. et al. Homeostatically proliferating CD4 T cells are involved in the pathogenesis of an Omenn syndrome murine model. J. Clin. Invest. 117, 1270–1281 (2007).
In references 66 and 67, mouse models of Omenn syndrome were generated through limited activity of RAG1 and RAG2. Both strains developed partial T-cell immunodeficiency and spontaneous immune dysregulation.
Villa, A. et al. V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood 97, 81–88 (2001).
Cavadini, P. et al. AIRE deficiency in thymus of 2 patients with Omenn syndrome. J. Clin. Invest. 115, 728–732 (2005).
Liston, A., Lesage, S., Wilson, J., Peltonen, L. & Goodnow, C. C. Aire regulates negative selection of organ-specific T cells. Nature Immunol. 4, 350–354 (2003).
Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nature Immunol. 8, 191–197 (2007).
von Freeden-Jeffry, U. et al. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519–1526 (1995).
Yao, Z. et al. Stat5a/b are essential for normal lymphoid development and differentiation. Proc. Natl Acad. Sci. USA 103, 1000–1005 (2006).
Imada, K. et al. Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. J. Exp. Med. 188, 2067–2074 (1998).
Teglund, S. et al. Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93, 841–850 (1998).
Chiang, Y. J. et al. Inactivation of c-Cbl reverses neonatal lethality and T cell developmental arrest of SLP-76-deficient mice. J. Exp. Med. 200, 25–34 (2004).
Krawczyk, C. et al. Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity 13, 463–473 (2000).
Layer, K. et al. Autoimmunity as the consequence of a spontaneous mutation in Rasgrp1. Immunity 19, 243–255 (2003).
Drappa, J. et al. Impaired T cell death and lupus-like autoimmunity in T cell-specific adapter protein-deficient mice. J. Exp. Med. 198, 809–821 (2003).
Aguado, E. et al. Induction of T helper type 2 immunity by a point mutation in the LAT adaptor. Science 296, 2036–2040 (2002).
Sommers, C. L. et al. A LAT mutation that inhibits T cell development yet induces lymphoproliferation. Science 296, 2040–2043 (2002).
References 80 and 81 independently describe the LATY136F knock-in mouse, the first demonstration of a recurrent theme that mutations in positive regulators of TCR signalling can cause immune dysregulation.
Nuñez-Cruz, S. et al. LAT regulates γδ T cell homeostasis and differentiation. Nature Immunol. 4, 999–1008 (2003).
Oh-Hora, M. et al. Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nature Immunol. 9, 432–443 (2008).
This study shows that deletion of STIM1 and STIM2 in T cells dramatically reduced their capacity for Ca2+ flux and NFAT signalling. Despite the defect in effector T cells, the mice developed lymphoproliferation, which could be corrected by the transfer of wild-type regulatory T cells.
Sakaguchi, N. et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426, 454–460 (2003).
In this study, the skg mouse was characterized, showing a hypomorphic W163C mutation in Zap70 and the spontaneous development of autoimmune arthritis.
Sommers, C. L. et al. Mutation of the phospholipase C-γ1-binding site of LAT affects both positive and negative thymocyte selection. J. Exp. Med. 201, 1125–1134 (2005).
Koonpaew, S., Shen, S., Flowers, L. & Zhang, W. LAT-mediated signaling in CD4+CD25+ regulatory T cell development. J. Exp. Med. 203, 119–129 (2006).
Siggs, O. M. et al. Opposing function of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions. Immunity 27, 912–926 (2007).
This study used ENU-induced Zap70 mutants to show that simple partial loss-of-function of ZAP70 can result in immune dysregulation when ZAP70 activity decreases to within a critical range.
Wang, Y. et al. Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells. J. Immunol. 180, 1565–1575 (2008).
Snapper, S. B. et al. Wiskott–Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Immunity 9, 81–91 (1998).
Zhang, J. et al. Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott–Aldrich syndrome protein-deficient lymphocytes. J. Exp. Med. 190, 1329–1342 (1999).
Silvin, C., Belisle, B. & Abo, A. A role for Wiskott–Aldrich syndrome protein in T-cell receptor-mediated transcriptional activation independent of actin polymerization. J. Biol. Chem. 276, 21450–21457 (2001).
Sims, T. N. et al. Opposing effects of PKCθ and WASp on symmetry breaking and relocation of the immunological synapse. Cell 129, 773–785 (2007).
Maillard, M. H. et al. The Wiskott–Aldrich syndrome protein is required for the function of CD4+CD25+Foxp3+ regulatory T cells. J. Exp. Med. 204, 381–391 (2007).
Humblet-Baron, S. et al. Wiskott–Aldrich syndrome protein is required for regulatory T cell homeostasis. J. Clin. Invest. 117, 407–418 (2007).
Marangoni, F. et al. WASP regulates suppressor activity of human and murine CD4+CD25+FOXP3+ natural regulatory T cells. J. Exp. Med. 204, 369–380 (2007).
Adriani, M. et al. Impaired in vitro regulatory T cell function associated with Wiskott–Aldrich syndrome. Clin. Immunol. 124, 41–48 (2007).
Anton, I. M. et al. WIP deficiency reveals a differential role for WIP and the actin cytoskeleton in T and B cell activation. Immunity 16, 193–204 (2002).
Curcio, C. et al. WIP null mice display a progressive immunological disorder that resembles Wiskott–Aldrich syndrome. J. Pathol. 211, 67–75 (2007).
Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).
Suzuki, H. et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science 268, 1472–1476 (1995).
Willerford, D. M. et al. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521–530 (1995).
Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nature Immunol. 6, 1142–1151 (2005).
Liston, A., Siggs, O. M. & Goodnow, C. C. Tracing the action of IL-2 in tolerance to islet-specific antigen. Immunol. Cell Biol. 85, 338–342 (2007).
Neilson, J. R., Winslow, M. M., Hur, E. M. & Crabtree, G. R. Calcineurin B1 is essential for positive but not negative selection during thymocyte development. Immunity 20, 255–266 (2004).
Gong, Q. et al. Disruption of T cell signaling networks and development by Grb2 haploid insufficiency. Nature Immunol. 2, 29–36 (2001).
McCarty, N. et al. Signaling by the kinase MINK is essential in the negative selection of autoreactive thymocytes. Nature Immunol. 6, 65–72 (2005).
Thornton, A. M. & Shevach, E. M. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J. Immunol. 164, 183–190 (2000).
Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int. Immunol. 10, 1969–1980 (1998).
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).
This study looked at the efficiency of a limited repertoire of regulatory T cells to prevent autoimmunity. They found that a numerically-equal population of regulatory T cells expanded from a limited number of precursor cells has a reduced capacity for systemic T-cell regulation.
Milner, J., Ward, J., Keane-Myers, A., Min., B. & Paul, W. E. Repertoire-dependent immunopathology. J. Autoimmun. 29, 257–261 (2007).
Lesley, R. et al. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20, 441–453 (2004).
This study showed that the deletion of autoreactive B cells varies in efficiency with population size, and that the molecular mechanism was due to competition for the B-cell survival factor BAFF (B-cell activating factor).
Venanzi, E. S., Gray, D. H., Benoist, C. & Mathis, D. Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. J. Immunol. 179, 5693–5700 (2007).
Gray, D. H. et al. Controlling the thymic microenvironment. Curr. Opin. Immunol. 17, 137–143 (2005).
Zhu, M., Chin, R. K., Tumanov, A. V., Liu, X. & Fu, Y. X. Lymphotoxin receptor is required for the migration and selection of autoreactive T cells in thymic medulla. J. Immunol. 179, 8069–8075 (2007).
This paper showed that lymphotoxin-dependent crosstalk between thymocytes and thymic epithelial cells is required for efficient deletion of autoreactive T cells. The effect was not mediated by defects in the AIRE-dependent expression pathway, but rather due to alterations in the thymic microarchitecture.
Chin, R. K. et al. Lymphotoxin pathway directs thymic Aire expression. Nature Immunol. 4, 1121–1127 (2003).
Rossi, S. W. et al. RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med. 204, 1267–1272 (2007).
Liston, A. et al. Gene dosage limiting role of Aire in thymic expression, clonal deletion and organ-specific autoimmunity. J. Exp. Med. 200, 1015–1026 (2004).
Kieper, W. C. & Jameson, S. C. Homeostatic expansion and phenotypic conversion of naive T cells in response to self peptide/MHC ligands. Proc. Natl Acad. Sci. USA 96, 13306–13311 (1999).
Goldrath, A. W. & Bevan, M. J. Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 11, 183–190 (1999).
Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nature Immunol. 1, 426–432 (2000).
Fazekas de St. Groth, B. DCs and peripheral T cell tolerance. Semin. Immunol. 13, 311–322 (2001).
Shklovskaya, E. & Fazekas de St. Groth, B. Severely impaired clonal deletion of CD4+ T cells in low-dose irradiated mice: role of T cell antigen receptor and IL-7 receptor signals. J. Immunol. 177, 8320–8330 (2006).
This study found that when TCR-transgenic cells are transferred into lymphopaenic mice, they show a reduced efficiency in clonal deletion and increased efficiency of clonal expansion. Importantly, the TCR transgene itself does not support spontaneous lymphopaenia-induced clonal expansion.
Ramanathan, S. & Poussier, P. BB rat lyp mutation and type 1 diabetes. Immunol. Rev. 184, 161–171 (2001).
Vang, T. et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nature Genet. 37, 1317–1319 (2005).
Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature Genet. 36, 337–338 (2004).
References 124 and 125 describe the initial association of the R620W gain-of-function variant of PTPN22 with type 1 diabetes, implying that reductions in T-cell activation can contribute to autoimmune disease.
Smerdel, A. et al. Genetic association between juvenile rheumatoid arthritis and polymorphism in the SH2D2A gene. Genes Immun. 5, 310–312 (2004).
Gregory, S. G. et al. Interleukin 7 receptor α chain (IL7R) shows allelic and functional association with multiple sclerosis. Nature Genet. 39, 1083–1091 (2007).
In this gene-association study, polymorphisms in the IL7RA gene are found to be associated with risk of developing multiple sclerosis. The susceptibility allele of IL7RA has altered splicing efficiency and increased production of a mRNA transcript encoding soluble IL-7Rα.
Todd, J. A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. 39, 857–864 (2007).
Santagata, S., Villa, A., Sobacchi, C., Cortes, P. & Vezzoni, P. The genetic and biochemical basis of Omenn syndrome. Immunol. Rev. 178, 64–74 (2000).
Aleman, K., Noordzij, J. G., de Groot, R., van Dongen, J. J. & Hartwig, N. G. Reviewing Omenn syndrome. Eur. J. Pediatr. 160, 718–725 (2001).
Dupuis-Girod, S. et al. Autoimmunity in Wiskott–Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics 111, e622–e627 (2003).
Kolluri, R. et al. Identification of WASP mutations in patients with Wiskott–Aldrich syndrome and isolated thrombocytopenia reveals allelic heterogeneity at the WAS locus. Hum. Mol. Genet. 4, 1119–1126 (1995).
Schopfer, K. et al. Systemic lupus erythematosus in Staphylococcus aureus hyperimmunoglobulinaemia E syndrome. Br. Med. J. (Clin. Res. Ed) 287, 524–526 (1983).
Renner, E. D. et al. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J. Pediatr. 144, 93–99 (2004).
Cunningham-Rundles, C. & Bodian, C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin. Immunol. 92, 34–48 (1999).
Sullivan, K. E. et al. Juvenile rheumatoid arthritis-like polyarthritis in chromosome 22q11.2 deletion syndrome (DiGeorge anomalad/velocardiofacial syndrome/conotruncal anomaly face syndrome). Arthritis Rheum. 40, 430–436 (1997).
Jawad, A. F., McDonald-Mcginn, D. M., Zackai, E. & Sullivan, K. E. Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J. Pediatr. 139, 715–723 (2001).
Chinen, J., Rosenblatt, H. M., Smith, E. O., Shearer, W. T. & Noroski, L. M. Long-term assessment of T-cell populations in DiGeorge syndrome. J. Allergy Clin. Immunol. 111, 573–579 (2003).
Roifman, C. M. & Melamed, I. A novel syndrome of combined immunodeficiency, autoimmunity and spondylometaphyseal dysplasia. Clin. Genet. 63, 522–529 (2003).
Holst, J. et al. Scalable signaling mediated by T cell antigen receptor–CD3 ITAMs ensures effective negative selection and prevents autoimmunity. Nature Immunol. 9, 658–666 (2008).