Primary atopic disorders

Journal of Experimental Medicine

Volumn 215, Issue 4, 2018, Pages 1009-1022

  Lyons, Jonathan J ^a   Milner, Joshua D ^a  

^a NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOKINE; T LYMPHOCYTE RECEPTOR;

ATOPY; CYTOSKELETON; GENE MUTATION; HOST RESISTANCE; HUMAN; IMMUNE DEFICIENCY; IMMUNOPATHOGENESIS; MAST CELL; METABOLIC DISORDER; MONOGENIC DISORDER; NONHUMAN; PERMEABILITY BARRIER; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SKIN; T LYMPHOCYTE; ANIMAL; ATOPIC DERMATITIS; HYPERSENSITIVITY; IMMUNOLOGY; PHENOTYPE;

ANIMALS; DERMATITIS, ATOPIC; HUMANS; HYPERSENSITIVITY; PHENOTYPE; SIGNAL TRANSDUCTION;

EID: 85044834464     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20172306     Document Type: Review

References (176)

1. Abonia, J.P., T. Wen, E.M. Stucke, T. Grotjan, M.S. Griffith, K.A. Kemme, M.H. Collins, P.E. Putnam, J.P. Franciosi, K.F. von Tiehl, et al. 2013. High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders. J. Allergy Clin. Immunol. 132:378-386. https:// doi .org/ 10 .1016/ j .jaci .2013 .02 .030
2. Aderibigbe, O.M., D.L. Priel, C.C. Lee, M.J. Ombrello, V.H. Prajapati, M.G. Liang, J.J. Lyons, D.B. Kuhns, E.W. Cowen, and J.D. Milner. 2015. Distinct Cutaneous Manifestations and Cold-Induced Leukocyte Activation Associated With PLCG2 Mutations. JAMA Dermatol. 151:627-634. https:// doi .org/ 10 .1001/ jamadermatol .2014 .5641
3. Akdis, C.A., and K. Blaser. 2001. Role of IL-10 in allergen-specific immunotherapy and normal response to allergens. Microbes Infect. 3:891-898. https:// doi .org/ 10 .1016/ S1286-4579(01)01449-6
4. Aksentijevich, I., C.D. Putnam, E.F. Remmers, J.L. Mueller, J. Le, R.D. Kolodner, Z. Moak, M. Chuang, F. Austin, R. Goldbach-Mansky, et al. 2007. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 56:1273-1285. https:// doi .org/ 10 .1002/ art .22491
5. Alroqi, F.J., L.M. Charbonnier, S. Keles, F. Ghandour, P. Mouawad, R. Sabouneh, R. Mohammed, A. Almutairi, J. Chou, M.J. Massaad, et al. 2017. DOCK8 Deficiency Presenting as an IPEX-Like Disorder. J. Clin. Immunol. 37:811-819. https:// doi .org/ 10 .1007/ s10875-017-0451-1
6. Ando, T., W. Xiao, P. Gao, S. Namiranian, K. Matsumoto, Y. Tomimori, H. Hong, H. Yamashita, M. Kimura, J. Kashiwakura, et al. 2014. Critical role for mast cell Stat5 activity in skin inflammation. Cell Reports. 6:366-376. https:// doi .org/ 10 .1016/ j .celrep .2013 .12 .029
7. Arora, M., P. Bagi, A. Strongin, J. Heimall, X. Zhao, M.G. Lawrence, A. Trivedi, C. Henderson, A. Hsu, M. Quezado, et al. 2017. Gastrointestinal Manifestations of STAT3-Deficient Hyper-IgE Syndrome. J. Clin. Immunol. 37:695-700. https:// doi .org/ 10 .1007/ s10875-017-0429-z
8. Arpaia, E., M. Shahar, H. Dadi, A. Cohen, and C.M. Roifman. 1994. Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap-70 kinase. Cell. 76:947-958. https:// doi .org/ 10 .1016/ 0092-8674(94)90368-9
9. Arstila, T.P., A. Casrouge, V. Baron, J. Even, J. Kanellopoulos, and P. Kourilsky. 1999. A direct estimate of the human alphabeta T cell receptor diversity. Science. 286:958-961. https:// doi .org/ 10 .1126/ science .286 .5441 .958
10. Bacchelli, C., F.A. Moretti, M. Carmo, S. Adams, H.C. Stanescu, K. Pearce, M. Madkaikar, K.C. Gilmour, A.K. Nicholas, C.G. Woods, et al. 2017. Mutations in linker for activation of T cells (LAT) lead to a novel form of severe combined immunodeficiency. J. Allergy Clin. Immunol. 139:634-642.e5. https:// doi .org/ 10 .1016/ j .jaci .2016 .05 .036
11. Balzar, S., H.W. Chu, P. Silkoff, M. Cundall, J.B. Trudeau, M. Strand, and S. Wenzel. 2005. Increased TGF-beta2 in severe asthma with eosinophilia. J. Allergy Clin. Immunol. 115:110-117. https:// doi .org/ 10 .1016/ j .jaci .2004 .09 .034
12. Bandapalli, O.R., S. Schuessele, J.B. Kunz, T. Rausch, A.M. Stütz, N. Tal, I. Geron, N. Gershman, S. Izraeli, J. Eilers, et al. 2014. The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse. Haematologica. 99:e188-e192. https:// doi .org/ 10 .3324/ haematol .2014 .104992
13. Barber, J.S., L.K. Yokomizo, V. Sheikh, A.F. Freeman, E. Garabedian, E. van Dijk, R. Sokolic, F. Candotti, N.P. Weng, I. Sereti, and J.D. Milner. 2013. Peptide library-based evaluation of T-cell receptor breadth detects defects in global and regulatory activation in human immunologic diseases. Proc. Natl. Acad. Sci. USA. 110:8164-8169. https:// doi .org/ 10 .1073/ pnas .1302103110
14. Ben-Khemis, L., N. Mekki, I. Ben-Mustapha, K. Rouault, F. Mellouli, M. Khemiri, M. Bejaoui, L. Essaddam, S. Ben-Becher, L. Boughamoura, et al. 2017. A founder mutation underlies a severe form of phosphoglutamase 3 (PGM3) deficiency in Tunisian patients. Mol. Immunol. 90:57-63. https:// doi .org/ 10 .1016/ j .molimm .2017 .06 .248
15. Bennett, C.L., J. Christie, F. Ramsdell, M.E. Brunkow, P.J. Ferguson, L. Whitesell, T.E. Kelly, F.T. Saulsbury, P.F. Chance, and H.D. Ochs. 2001. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27:20-21. https:// doi .org/ 10 .1038/ 83713
16. Bernth-Jensen, J.M., M. Holm, and M. Christiansen. 2016. Neonatal-onset T(-) B(-)NK(+) severe combined immunodeficiency and neutropenia caused by mutated phosphoglucomutase 3. J. Allergy Clin. Immunol. 137:321-324. https:// doi .org/ 10 .1016/ j .jaci .2015 .07 .047
17. Bertin, J., L. Wang, Y. Guo, M.D. Jacobson, J.L. Poyet, S.M. Srinivasula, S. Merriam, P.S. DiStefano, and E.S. Alnemri. 2001. CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAG UK) family members that interact with BCL10 and activate NF-kappa B. J. Biol. Chem. 276:11877-11882. https:// doi .org/ 10 .1074/ jbc .M010512200
18. Boos, A.C., B. Hagl, A. Schlesinger, B.E. Halm, N. Ballenberger, M. Pinarci, V. Heinz, D. Kreilinger, B.D. Spielberger, L.F. Schimke-Marques, et al. 2014. Atopic dermatitis, STAT3-and DOCK8-hyper-IgE syndromes differ in IgE-based sensitization pattern. Allergy. 69:943-953. https:// doi .org/ 10 .1111/ all .12416
19. Boyden, S.E., A. Desai, G. Cruse, M.L. Young, H.C. Bolan, L.M. Scott, A.R. Eisch, R.D. Long, C.C. Lee, C.L. Satorius, et al. 2016. Vibratory Urticaria Associated with a Missense Variant in ADG RE2. N. Engl. J. Med. 374:656-663. https:// doi .org/ 10 .1056/ NEJMoa1500611
20. Brunkow, M.E., E.W. Jeffery, K.A. Hjerrild, B. Paeper, L.B. Clark, S.A. Yasayko, J.E. Wilkinson, D. Galas, S.F. Ziegler, and F. Ramsdell. 2001. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27:68-73. https:// doi .org/ 10 .1038/ 83784
21. Carlson, R.J., M.R. Bond, S. Hutchins, Y. Brown, L.A. Wolfe, C. Lam, C. Nelson, T. DiMaggio, N. Jones, S.D. Rosenzweig, et al. 2017. Detection of phosphoglucomutase-3 deficiency by lectin-based flow cytometry. J. Allergy Clin. Immunol. 140:291-294.e4. https:// doi .org/ 10 .1016/ j .jaci .2016 .12 .951
22. Caudy, A.A., S.T. Reddy, T. Chatila, J.P. Atkinson, and J.W. Verbsky. 2007. 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. https:// doi .org/ 10 .1016/ j .jaci .2006 .10 .007
23. Chan, A.C., T.A. Kadlecek, M.E. Elder, A.H. Filipovich, W.L. Kuo, M. Iwashima, T.G. Parslow, and A. Weiss. 1994. ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science. 264:1599-1601. https:// doi .org/ 10 .1126/ science .8202713
24. Chatila, T.A., F. Blaeser, N. Ho, H.M. Lederman, C. Voulgaropoulos, C. Helms, and A.M. Bowcock. 2000. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J. Clin. Invest. 106:R75-R81. https:// doi .org/ 10 .1172/ JCI11679
25. Chavanas, S., C. Bodemer, A. Rochat, D. Hamel-Teillac, M. Ali, A.D. Irvine, J.L. Bonafé, J. Wilkinson, A. Taïeb, Y. Barrandon, et al. 2000. Mutations in SPI NK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat. Genet. 25:141-142. https:// doi .org/ 10 .1038/ 75977
26. Chen, C., K. Akiyama, D. Wang, X. Xu, B. Li, A. Moshaverinia, F. Brombacher, L. Sun, and S. Shi. 2015. mTOR inhibition rescues osteopenia in mice with systemic sclerosis. J. Exp. Med. 212:73-91. https:// doi .org/ 10 .1084/ jem .20140643
27. Coca, A. F., R.A. Cooke 1923. On the Classification of the Phenomena of Hypersensitiveness. J. Immunol. 8:163-182
28. Constant, S.L., and K. Bottomly. 1997. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu. Rev. Immunol. 15:297-322. https:// doi .org/ 10 .1146/ annurev .immunol .15 .1 .297
29. Cooke, R.A. 1947. Allergy in Theory and Practice. W.B. Saunders Company, Philadelphia
30. Crequer, A., C. Picard, E. Patin, A. D'Amico, A. Abhyankar, M. Munzer, M. Debré, S.Y. Zhang, G. de Saint-Basile, A. Fischer, et al. 2012. Inherited MST1 deficiency underlies susceptibility to EV-HPV infections. PLoS One. 7:e44010. https:// doi .org/ 10 .1371/ journal .pone .0044010
31. Dadi, H., Jones, T. A., Merico, D., Sharfe, N., Ovadia, A., Schejter, Y., Reid, B., Sun, M., Vong, L., Atkinson, A., Lavi, S., Pomerantz, J. L. & Roifman, C. M.2017. Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11). J. Allergy Clin. Immunol
32. Dasouki, M., K.C. Okonkwo, A. Ray, C.K. Folmsbeel, D. Gozales, S. Keles, J.M. Puck, and T. Chatila. 2011. Deficient T Cell Receptor Excision Circles (TRECs) in autosomal recessive hyper IgE syndrome caused by DOCK8 mutation: implications for pathogenesis and potential detection by newborn screening. Clin. Immunol. 141:128-132. https:// doi .org/ 10 .1016/ j .clim .2011 .06 .003
33. Deenick, E.K., D.T. Avery, A. Chan, L.J. Berglund, M.L. Ives, L. Moens, J.L. Stoddard, J. Bustamante, S. Boisson-Dupuis, M. Tsumura, et al. 2013. Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells. J. Exp. Med. 210:2739-2753. https:// doi .org/ 10 .1084/ jem .20130323
34. Del Bel, K.L., R.J. Ragotte, A. Saferali, S. Lee, S.M. Vercauteren, S.A. Mostafavi, R.A. Schreiber, J.S. Prendiville, M.S. Phang, J. Halparin, et al. 2017. JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome. J. Allergy Clin. Immunol. 139:2016-2020.e5. https:// doi .org/ 10 .1016/ j .jaci .2016 .12 .957
35. Delgoffe, G.M., K.N. Pollizzi, A.T. Waickman, E. Heikamp, D.J. Meyers, M.R. Horton, B. Xiao, P.F. Worley, and J.D. Powell. 2011. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12:295-303. https:// doi .org/ 10 .1038/ ni .2005
36. Dietz, H.C., G.R. Cutting, R.E. Pyeritz, C.L. Maslen, L.Y. Sakai, G.M. Corson, E.G. Puffenberger, A. Hamosh, E.J. Nanthakumar, S.M. Curristin, et al. 1991. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 352:337-339. https:// doi .org/ 10 .1038/ 352337a0
37. Doong, J.C., K. Chichester, E.T. Oliver, L.B. Schwartz, and S.S. Saini. 2017. Chronic Idiopathic Urticaria: Systemic Complaints and Their Relationship with Disease and Immune Measures. J. Allergy Clin. Immunol. Pract. 5:1314-1318. https:// doi .org/ 10 .1016/ j .jaip .2016 .11 .037
38. Elder, M.E., D. Lin, J. Clever, A.C. Chan, T.J. Hope, A. Weiss, and T.G. Parslow. 1994. Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science. 264:1596-1599. https:// doi .org/ 10 .1126/ science .8202712
39. Erlich, T.H., Z. Yagil, G. Kay, A. Peretz, H. Migalovich-Sheikhet, S. Tshori, H. Nechushtan, F. Levi-Schaffer, A. Saada, and E. Razin. 2014. Mitochondrial STAT3 plays a major role in IgE-antigen-mediated mast cell exocytosis. J. Allergy Clin. Immunol. 134:460-469.e10. https:// doi .org/ 10 .1016/ j .jaci .2013 .12 .1075
40. Fellinger, C., W. Hemmer, S. Wöhrl, G. Sesztak-Greinecker, R. Jarisch, and F. Wantke. 2014. Clinical characteristics and risk profile of patients with elevated baseline serum tryptase. Allergol. Immunopathol. (Madr.). 42:544-552. https:// doi .org/ 10 .1016/ j .aller .2014 .05 .002
41. Frischmeyer-Guerrerio, P.A., A.L. Guerrerio, G. Oswald, K. Chichester, L. Myers, M.K. Halushka, M. Oliva-Hemker, R.A. Wood, and H.C. Dietz. 2013. TGFβ receptor mutations impose a strong predisposition for human allergic disease. Sci. Transl. Med. 5:195ra94. https:// doi .org/ 10 .1126/ scitranslmed .3006448
42. Galli, S.J., and M. Tsai. 2010. Mast cells in allergy and infection: versatile effector and regulatory cells in innate and adaptive immunity. Eur. J. Immunol. 40:1843-1851. https:// doi .org/ 10 .1002/ eji .201040559
43. Gandhi, C., C. Healy, A.A. Wanderer, and H.M. Hoffman. 2009. Familial atypical cold urticaria: description of a new hereditary disease. J. Allergy Clin. Immunol. 124:1245-1250. https:// doi .org/ 10 .1016/ j .jaci .2009 .09 .035
44. Gell, P.G.H., and R.R.A. Coombs, editors. 1963. Clinical aspects of immunology. Blackwell, Oxford
45. Glocker, E.O., D. Kotlarz, K. Boztug, E.M. Gertz, A.A. Schäffer, F. Noyan, M. Perro, J. Diestelhorst, A. Allroth, D. Murugan, et al. 2009. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361:2033-2045. https:// doi .org/ 10 .1056/ NEJMoa0907206
46. Glocker, E.O., N. Frede, M. Perro, N. Sebire, M. Elawad, N. Shah, and B. Grimbacher. 2010. Infant colitis-it's in the genes. Lancet. 376:1272. https:// doi .org/ 10 .1016/ S0140-6736(10)61008-2
47. Gonzalez-Quintela, A., L. Vizcaino, F. Gude, J. Rey, L. Meijide, C. Fernandez-Merino, A. Linneberg, and C. Vidal. 2010. Factors influencing serum total tryptase concentrations in a general adult population. Clin. Chem. Lab. Med. 48:701-706. https:// doi .org/ 10 .1515/ CCLM .2010 .124
48. Greil, J., T. Rausch, T. Giese, O.R. Bandapalli, V. Daniel, I. Bekeredjian-Ding, A.M. Stütz, C. Drees, S. Roth, J. Ruland, et al. 2013. Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency. J. Allergy Clin. Immunol. 131:1376-1383.e3. https:// doi .org/ 10 .1016/ j .jaci .2013 .02 .012
49. Hamilton, K.S., B. Phong, C. Corey, J. Cheng, B. Gorentla, X. Zhong, S. Shiva, and L.P. Kane. 2014. T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10. Sci. Signal. 7:ra55. https:// doi .org/ 10 .1126/ scisignal .2005169
50. Haribhai, D., J.B. Williams, S. Jia, D. Nickerson, E.G. Schmitt, B. Edwards, J. Ziegelbauer, M. Yassai, S.H. Li, L.M. Relland, et al. 2011. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity. 35:109-122. https:// doi .org/ 10 .1016/ j .immuni .2011 .03 .029
51. Hershey, G.K., M.F. Friedrich, L.A. Esswein, M.L. Thomas, and T.A. Chatila. 1997. The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. N. Engl. J. Med. 337:1720-1725. https:// doi .org/ 10 .1056/ NEJM199712113372403
52. Hirota, T., A. Takahashi, M. Kubo, T. Tsunoda, K. Tomita, M. Sakashita, T. Yamada, S. Fujieda, S. Tanaka, S. Doi, et al. 2012. Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat. Genet. 44:1222-1226. https:// doi .org/ 10 .1038/ ng .2438
53. Holland, S.M., F.R. DeLeo, H.Z. Elloumi, A.P. Hsu, G. Uzel, N. Brodsky, A.F. Freeman, A. Demidowich, J. Davis, M.L. Turner, et al. 2007. STAT3 mutations in the hyper-IgE syndrome. N. Engl. J. Med. 357:1608-1619. https:// doi .org/ 10 .1056/ NEJMoa073687
54. Hosken, N.A., K. Shibuya, A.W. Heath, K.M. Murphy, and A. O'Garra. 1995. The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model. J. Exp. Med. 182:1579-1584. https:// doi .org/ 10 .1084/ jem .182 .5 .1579
55. Howell, M.D., B.E. Kim, P. Gao, A.V. Grant, M. Boguniewicz, A. Debenedetto, L. Schneider, L.A. Beck, K.C. Barnes, and D.Y. Leung. 2007. Cytokine modulation of atopic dermatitis filaggrin skin expression. J. Allergy Clin. Immunol. 120:150-155. https:// doi .org/ 10 .1016/ j .jaci .2007 .04 .031
56. Hox, V., M.P. O'Connell, J.J. Lyons, P. Sackstein, T. Dimaggio, N. Jones, C. Nelson, M. Boehm, S.M. Holland, A.F. Freeman, et al. 2016. Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis. J. Allergy Clin. Immunol. 138:187-199. https:// doi .org/ 10 .1016/ j .jaci .2015 .11 .024
57. Huang, Y.S., N.Y. Chiang, C.H. Hu, C.C. Hsiao, K.F. Cheng, W.P. Tsai, S. Yona, M. Stacey, S. Gordon, G.W. Chang, and H.H. Lin. 2012. Activation of myeloid cell-specific adhesion class G protein-coupled receptor EMR2 via ligation-induced translocation and interaction of receptor subunits in lipid raft microdomains. Mol. Cell. Biol. 32:1408-1420. https:// doi .org/ 10 .1128/ MCB .06557-11
58. Humblet-Baron, S., B. Sather, S. Anover, S. Becker-Herman, D.J. Kasprowicz, S. Khim, T. Nguyen, K. Hudkins-Loya, C.E. Alpers, S.F. Ziegler, et al. 2007. Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis. J. Clin. Invest. 117:407-418. https:// doi .org/ 10 .1172/ JCI29539
59. Hvid, M., C. Vestergaard, K. Kemp, G.B. Christensen, B. Deleuran, and M. Deleuran. 2011. IL-25 in atopic dermatitis: a possible link between inflammation and skin barrier dysfunction? J. Invest. Dermatol. 131:150-157. https:// doi .org/ 10 .1038/ jid .2010 .277
60. Irvine, A.D., W.H. McLean, and D.Y. Leung. 2011. Filaggrin mutations associated with skin and allergic diseases. N. Engl. J. Med. 365:1315-1327. https:// doi .org/ 10 .1056/ NEJMra1011040
61. Ishida-Yamamoto, A., C. Deraison, C. Bonnart, E. Bitoun, R. Robinson, T.J. O'Brien, K. Wakamatsu, S. Ohtsubo, H. Takahashi, Y. Hashimoto, et al. 2005. LEK TI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum. J. Invest. Dermatol. 124:360-366. https:// doi .org/ 10 .1111/ j .0022-202X .2004 .23583 .x
62. Jabara, H.H., T. Ohsumi, J. Chou, M.J. Massaad, H. Benson, A. Megarbane, E. Chouery, R. Mikhael, O. Gorka, A. Gewies, et al. 2013. A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency. J. Allergy Clin. Immunol. 132:151-158. https:// doi .org/ 10 .1016/ j .jaci .2013 .04 .047
63. Jakob, T., G.V. Köllisch, M. Howaldt, M. Bewersdorff, B. Rathkolb, M.L. Müller, N. Sandholzer, L. Nitschke, M. Schiemann, M. Mempel, et al. 2008. Novel mouse mutants with primary cellular immunodeficiencies generated by genome-wide mutagenesis. J. Allergy Clin. Immunol. 121:179-184. e7. https:// doi .org/ 10 .1016/ j .jaci .2007 .07 .018
64. Janssen, E., H. Morbach, S. Ullas, J.M. Bannock, C. Massad, L. Menard, I. Barlan, G. Lefranc, H. Su, M. Dasouki, et al. 2014. Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells. J. Allergy Clin. Immunol. 134:1365-1374. https:// doi .org/ 10 .1016/ j .jaci .2014 .07 .042
65. Janssen, E., M. Tohme, M. Hedayat, M. Leick, S. Kumari, N. Ramesh, M.J. Massaad, S. Ullas, V. Azcutia, C.C. Goodnow, et al. 2016. A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton. J. Clin. Invest. 126:3837-3851. https:// doi .org/ 10 .1172/ JCI85774
66. Janssen, E., S. Kumari, M. Tohme, S. Ullas, V. Barrera, J.M. Tas, M. Castillo-Rama, R.T. Bronson, S.M. Usmani, D.J. Irvine, et al. 2017. DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs. JCI Insight. 2:e94298. https:// doi .org/ 10 .1172/ jci .insight .94298
67. Johansson, S.G., T. Bieber, R. Dahl, P.S. Friedmann, B.Q. Lanier, R.F. Lockey, C. Motala, J.A. Ortega Martell, T.A. Platts-Mills, J. Ring, et al. 2004. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J. Allergy Clin. Immunol. 113:832-836. https:// doi .org/ 10 .1016/ j .jaci .2003 .12 .591
68. Jonca, N., E.A. Leclerc, C. Caubet, M. Simon, M. Guerrin, and G. Serre. 2011. Corneodesmosomes and corneodesmosin: from the stratum corneum cohesion to the pathophysiology of genodermatoses. Eur. J. Dermatol. 21(Suppl 2):35-42
69. Jorritsma, P.J., J.L. Brogdon, and K. Bottomly. 2003. Role of TCR-induced extracellular signal-regulated kinase activation in the regulation of early IL-4 expression in naive CD4+ T cells. J. Immunol. 170:2427-2434. https:// doi .org/ 10 .4049/ jimmunol .170 .5 .2427
70. Josefowicz, S.Z., R.E. Niec, H.Y. Kim, P. Treuting, T. Chinen, Y. Zheng, D.T. Umetsu, and A.Y. Rudensky. 2012. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature. 482:395-399. https:// doi .org/ 10 .1038/ nature10772
71. Joshi, A.Y., E.K. Ham, N.B. Shah, X. Dong, S.P. Khan, and R.S. Abraham. 2012. Atypical Omenn Syndrome due to Adenosine Deaminase Deficiency. Case Reports Immunol. 2012:919241. https:// doi .org/ 10 .1155/ 2012/ 919241
72. Jun, J.E., L.E. Wilson, C.G. Vinuesa, S. Lesage, M. Blery, L.A. Miosge, M.C. Cook, E.M. Kucharska, H. Hara, J.M. Penninger, et al. 2003. Identifying the MAG UK protein Carma-1 as a central regulator of humoral immune responses and atopy by genome-wide mouse mutagenesis. Immunity. 18:751-762. https:// doi .org/ 10 .1016/ S1074-7613(03)00141-9
73. Jungersted, J.M., H. Scheer, M. Mempel, H. Baurecht, L. Cifuentes, J.K. Høgh, L.I. Hellgren, G.B. Jemec, T. Agner, and S. Weidinger. 2010. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema. Allergy. 65:911-918. https:// doi .org/ 10 .1111/ j .1398-9995 .2010 .02326 .x
74. Kahr, W.H., F.G. Pluthero, A. Elkadri, N. Warner, M. Drobac, C.H. Chen, R.W. Lo, L. Li, R. Li, Q. Li, et al. 2017. Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease. Nat. Commun. 8:14816. https:// doi .org/ 10 .1038/ ncomms14816
75. Kanai, T., J. Jenks, and K.C. Nadeau. 2012. The STAT5b Pathway Defect and Autoimmunity. Front. Immunol. 3:234. https:// doi .org/ 10 .3389/ fimmu .2012 .00234
76. Kane, A., A. Lau, R. Brink, S.G. Tangye, and E.K. Deenick. 2016. B-cell-specific STAT3 deficiency: Insight into the molecular basis of autosomal-dominant hyper-IgE syndrome. J. Allergy Clin. Immunol. 138:1455-1458.e3. https:// doi .org/ 10 .1016/ j .jaci .2016 .05 .018
77. Kawakami, T., T. Ando, and Y. Kawakami. 2015. Hypothetical Atopic Dermatitis-Myeloproliferative Neoplasm Syndrome. Front. Immunol. 6:434. https:// doi .org/ 10 .3389/ fimmu .2015 .00434
78. Ke, H., J.U. Kazi, H. Zhao, and J. Sun. 2016. Germline mutations of KIT in gastrointestinal stromal tumor (GIST) and mastocytosis. Cell Biosci. 6:55. https:// doi .org/ 10 .1186/ s13578-016-0120-8
79. Keller, B., I. Zaidman, O.S. Yousefi, D. Hershkovitz, J. Stein, S. Unger, K. Schachtrup, M. Sigvardsson, A.A. Kuperman, A. Shaag, et al. 2016. Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT. J. Exp. Med. 213:1185-1199. https:// doi .org/ 10 .1084/ jem .20151110
80. Kezic, S., G.M. O'Regan, R. Lutter, I. Jakasa, E.S. Koster, S. Saunders, P. Caspers, P.M. Kemperman, G.J. Puppels, A. Sandilands, et al. 2012. Filaggrin lossof-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency. J. Allergy Clin. Immunol. 129:1031-1039.e1. https:// doi .org/ 10 .1016/ j .jaci .2011 .12 .989
81. Kotlarz, D., R. Beier, D. Murugan, J. Diestelhorst, O. Jensen, K. Boztug, D. Pfeifer, H. Kreipe, E.D. Pfister, U. Baumann, et al. 2012. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology. 143:347-355. https:// doi .org/ 10 .1053/ j .gastro .2012 .04 .045
82. Kottke, M.D., E. Delva, and A.P. Kowalczyk. 2006. The desmosome: cell science lessons from human diseases. J. Cell Sci. 119:797-806. https:// doi .org/ 10 .1242/ jcs .02888
83. Kreins, A.Y., M.J. Ciancanelli, S. Okada, X.F. Kong, N. Ramírez-Alejo, S.S. Kilic, J. El Baghdadi, S. Nonoyama, S.A. Mahdaviani, F. Ailal, et al. 2015. Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome. J. Exp. Med. 212:1641-1662. https:// doi .org/ 10 .1084/ jem .20140280
84. Kucharewicz, I., A. Bodzenta-Lukaszyk, W. Szymanski, B. Mroczko, and M. Szmitkowski. 2007. Basal serum tryptase level correlates with severity of hymenoptera sting and age. J. Investig. Allergol. Clin. Immunol. 17:65-69
85. Küçük, C., B. Jiang, X. Hu, W. Zhang, J.K. Chan, W. Xiao, N. Lack, C. Alkan, J.C. Williams, K.N. Avery, et al. 2015. Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells. Nat. Commun. 6:6025. https:// doi .org/ 10 .1038/ ncomms7025
86. Kuijpers, T.W., A.T.J. Tool, I. van der Bijl, M. de Boer, M. van Houdt, I.M. de Cuyper, D. Roos, F. van Alphen, K. van Leeuwen, E.L. Cambridge, et al. 2017. Combined immunodeficiency with severe inflammation and allergy caused by ARPC1B deficiency. J. Allergy Clin. Immunol. 140:273-277.e10. https:// doi .org/ 10 .1016/ j .jaci .2016 .09 .061
87. Lanzi, G., D. Moratto, D. Vairo, S. Masneri, O. Delmonte, T. Paganini, S. Parolini, G. Tabellini, C. Mazza, G. Savoldi, et al. 2012. A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP. J. Exp. Med. 209:29-34. https:// doi .org/ 10 .1084/ jem .20110896
88. Lawrence, M.G., J.S. Barber, R.A. Sokolic, E.K. Garabedian, A.N. Desai, M. O'Brien, N. Jones, P. Bali, M.S. Hershfield, K.D. Stone, et al. 2013. Elevated IgE and atopy in patients treated for early-onset ADA-SCID. J. Allergy Clin. Immunol. 132:1444-1446.e5. https:// doi .org/ 10 .1016/ j .jaci .2013 .05 .040
89. Lexmond, W.S., J.A. Goettel, J.J. Lyons, J. Jacobse, M.M. Deken, M.G. Lawrence, T.H. DiMaggio, D. Kotlarz, E. Garabedian, P. Sackstein, et al. 2016. FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy. J. Clin. Invest. 126:4030-4044. https:// doi .org/ 10 .1172/ JCI85129
90. Liang, Y., M. Cucchetti, R. Roncagalli, T. Yokosuka, A. Malzac, E. Bertosio, J. Imbert, I.J. Nijman, M. Suchanek, T. Saito, et al. 2013. The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells. Nat. Immunol. 14:858-866. https:// doi .org/ 10 .1038/ ni .2634
91. Lindsay, M.E., and H.C. Dietz. 2014. The genetic basis of aortic aneurysm. Cold Spring Harb. Perspect. Med. 4:a015909. https:// doi .org/ 10 .1101/ cshperspect .a015909
92. Loeys, B.L., U. Schwarze, T. Holm, B.L. Callewaert, G.H. Thomas, H. Pannu, J.F. De Backer, G.L. Oswald, S. Symoens, S. Manouvrier, et al. 2006. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N. Engl. J. Med. 355:788-798. https:// doi .org/ 10 .1056/ NEJMoa055695
93. Lyons, J.J., G. Sun, K.D. Stone, C. Nelson, L. Wisch, M. O'Brien, N. Jones, A. Lindsley, H.D. Komarow, Y. Bai, et al. 2014. Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities. J. Allergy Clin. Immunol. 133:1471-1474. https:// doi .org/ 10 .1016/ j .jaci .2013 .11 .039
94. Lyons, J.J., X. Yu, J.D. Hughes, Q.T. Le, A. Jamil, Y. Bai, N. Ho, M. Zhao, Y. Liu, M.P. O'Connell, et al. 2016. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPS AB1 copy number. Nat. Genet. 48:1564-1569. https:// doi .org/ 10 .1038/ ng .3696
95. Lyons, J.J., Y. Liu, C.A. Ma, X. Yu, M.P. O'Connell, M.G. Lawrence, Y. Zhang, K. Karpe, M. Zhao, A.M. Siegel, et al. 2017. ERB IN deficiency links STAT3 and TGF-β pathway defects with atopy in humans. J. Exp. Med. 214:669-680. https:// doi .org/ 10 .1084/ jem .2016143503082017c
96. Ma, C.S., N. Wong, G. Rao, D.T. Avery, J. Torpy, T. Hambridge, J. Bustamante, S. Okada, J.L. Stoddard, E.K. Deenick, et al. 2015. Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. J. Allergy Clin. Immunol. 136:993-1006.e1. https:// doi .org/ 10 .1016/ j .jaci .2015 .05 .036
97. Ma, C.A., J.R. Stinson, Y. Zhang, J.K. Abbott, M.A. Weinreich, P.J. Hauk, P.R. Reynolds, J.J. Lyons, C.G. Nelson, E. Ruffo, et al. 2017. Germline hypomorphic CARD11 mutations in severe atopic disease. Nat. Genet. 49:1192-1201. https:// doi .org/ 10 .1038/ ng .3898
98. Ma, C.A., L. Xi, B. Cauff, A. DeZure, A.F. Freeman, S. Hambleton, G. Kleiner, T.R. Leahy, M. O'Sullivan, M. Makiya, et al. 2017. Somatic STAT5b gainof-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. Blood. 129:650-653. https:// doi .org/ 10 .1182/ blood-2016-09-737817
99. Maillard, M.H., V. Cotta-de-Almeida, F. Takeshima, D.D. Nguyen, P. Michetti, C. Nagler, A.K. Bhan, and S.B. Snapper. 2007. The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells. J. Exp. Med. 204:381-391. https:// doi .org/ 10 .1084/ jem .20061338
100. Marangoni, F., S. Trifari, S. Scaramuzza, C. Panaroni, S. Martino, L.D. Notarangelo, Z. Baz, A. Metin, F. Cattaneo, A. Villa, et al. 2007. WASP regulates suppressor activity of human and murine CD4(+)CD25(+)FOXP3(+) natural regulatory T cells. J. Exp. Med. 204:369-380. https:// doi .org/ 10 .1084/ jem .20061334
101. Mark, B.J., B.A. Becker, D.R. Halloran, A.F. Bree, R. Sindwani, M.D. Fete, K.J. Motil, S.W. Srun, and T.J. Fete. 2012. Prevalence of atopic disorders and immunodeficiency in patients with ectodermal dysplasia syndromes. Ann. Allergy Asthma Immunol. 108:435-438. https:// doi .org/ 10 .1016/ j .anai .2012 .04 .010
102. Markert, M.L., M.J. Alexieff, J. Li, M. Sarzotti, D.A. Ozaki, B.H. Devlin, G.D. Sempowski, M.E. Rhein, P. Szabolcs, L.P. Hale, et al. 2004. Complete DiGeorge syndrome: development of rash, lymphadenopathy, and oligoclonal T cells in 5 cases. J. Allergy Clin. Immunol. 113:734-741. https:// doi .org/ 10 .1016/ j .jaci .2004 .01 .766
103. Massaad, M.J., B. Cangemi, W. Al-Herz, G. LeFranc, A. Freeman, S. Baxi, S. Keles, A. Metin, M. Dasouki, A. Sobh, et al. 2017. DOCK8 and STAT3 dependent inhibition of IgE isotype switching by TLR9 ligation in human B cells. Clin. Immunol. 183:263-265. https:// doi .org/ 10 .1016/ j .clim .2017 .08 .020
104. McAleer, M.A., E. Pohler, F.J. Smith, N.J. Wilson, C. Cole, S. MacGowan, J.L. Koetsier, L.M. Godsel, R.M. Harmon, R. Gruber, et al. 2015. Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N-terminal plakin domain of desmoplakin. J. Allergy Clin. Immunol. 136:1268-1276. https:// doi .org/ 10 .1016/ j .jaci .2015 .05 .002
105. McKinnon, M.L., J. Rozmus, S.Y. Fung, A.F. Hirschfeld, K.L. Del Bel, L. Thomas, N. Marr, S.D. Martin, A.K. Marwaha, J.J. Priatel, et al. 2014. Combined immunodeficiency associated with homozygous MALT1 mutations. J. Allergy Clin. Immunol. 133:1458-1462.e7. https:// doi .org/ 10 .1016/ j .jaci .2013 .10 .045
106. Meiler, F., J. Zumkehr, S. Klunker, B. Rückert, C.A. Akdis, and M. Akdis. 2008. In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J. Exp. Med. 205:2887-2898. https:// doi .org/ 10 .1084/ jem .20080193
107. Miajlovic, H., P.G. Fallon, A.D. Irvine, and T.J. Foster. 2010. Effect of filaggrin breakdown products on growth of and protein expression by Staphylococcus aureus. J. Allergy Clin. Immunol. 126:1184-1190.e3. https:// doi .org/ 10 .1016/ j .jaci .2010 .09 .015
108. Milner, J.D., J.M. Ward, A. Keane-Myers, and W.E. Paul. 2007. Lymphopenic mice reconstituted with limited repertoire T cells develop severe, multiorgan, Th2-associated inflammatory disease. Proc. Natl. Acad. Sci. USA. 104:576-581. https:// doi .org/ 10 .1073/ pnas .0610289104
109. Milner, J.D., N. Fazilleau, M. McHeyzer-Williams, and W. Paul. 2010. Cutting edge: lack of high affinity competition for peptide in polyclonal CD4+ responses unmasks IL-4 production. J. Immunol. 184:6569-6573. https:// doi .org/ 10 .4049/ jimmunol .1000674
110. Milner, J.D., T.P. Vogel, L. Forbes, C.A. Ma, A. Stray-Pedersen, J.E. Niemela, J.J. Lyons, K.R. Engelhardt, Y. Zhang, N. Topcagic, et al. 2015. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gainof-function mutations. Blood. 125:591-599. https:// doi .org/ 10 .1182/ blood-2014-09-602763
111. Minegishi, Y., M. Saito, T. Morio, K. Watanabe, K. Agematsu, S. Tsuchiya, H. Takada, T. Hara, N. Kawamura, T. Ariga, et al. 2006. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 25:745-755. https:// doi .org/ 10 .1016/ j .immuni .2006 .09 .009
112. Minegishi, Y., M. Saito, S. Tsuchiya, I. Tsuge, H. Takada, T. Hara, N. Kawamura, T. Ariga, S. Pasic, O. Stojkovic, et al. 2007. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 448:1058-1062. https:// doi .org/ 10 .1038/ nature06096
113. Mingueneau, M., R. Roncagalli, C. Grégoire, A. Kissenpfennig, A. Miazek, C. Archambaud, Y. Wang, P. Perrin, E. Bertosio, A. Sansoni, et al. 2009. Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor. Immunity. 31:197-208. https:// doi .org/ 10 .1016/ j .immuni .2009 .05 .013
114. Morgan, A.W., S.B. Pearson, S. Davies, H.C. Gooi, and H.A. Bird. 2007. Asthma and airways collapse in two heritable disorders of connective tissue. Ann. Rheum. Dis. 66:1369-1373. https:// doi .org/ 10 .1136/ ard .2006 .062224
115. Nadeau, K., V. Hwa, and R.G. Rosenfeld. 2011. STAT5b deficiency: an unsuspected cause of growth failure, immunodeficiency, and severe pulmonary disease. J. Pediatr. 158:701-708. https:// doi .org/ 10 .1016/ j .jpeds .2010 .12 .042
116. Nakaya, M., Y. Xiao, X. Zhou, J.H. Chang, M. Chang, X. Cheng, M. Blonska, X. Lin, and S.C. Sun. 2014. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity. 40:692-705. https:// doi .org/ 10 .1016/ j .immuni .2014 .04 .007
117. Nelson, H.S. 2013. Introducing atopy. In Landmark Papers in Allergy: Seminal Papers in Allergy with Expert Commentaries. A. Sheikh, T. Platts-Mills, and A. Worth, editors. Oxford University Press, Oxford, UK. 56-58
118. Nishida, T., S. Hirota, M. Taniguchi, K. Hashimoto, K. Isozaki, H. Nakamura, Y. Kanakura, T. Tanaka, A. Takabayashi, H. Matsuda, and Y. Kitamura. 1998. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat. Genet. 19:323-324. https:// doi .org/ 10 .1038/ 1209
119. Noval Rivas, M., O.T. Burton, P. Wise, L.M. Charbonnier, P. Georgiev, H.C. Oettgen, R. Rachid, and T.A. Chatila. 2015. Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity. 42:512-523. https:// doi .org/ 10 .1016/ j .immuni .2015 .02 .004
120. Ochs, H.D. 2009. Mutations of the Wiskott-Aldrich Syndrome Protein affect protein expression and dictate the clinical phenotypes. Immunol. Res. 44:84-88. https:// doi .org/ 10 .1007/ s12026-008-8084-3
121. Oetjen, L.K., M.R. Mack, J. Feng, T.M. Whelan, H. Niu, C.J. Guo, S. Chen, A.M. Trier, A.Z. Xu, S.V. Tripathi, et al. 2017. Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell. 171:217-228. e13. https:// doi .org/ 10 .1016/ j .cell .2017 .08 .006
122. Ogawa, K., Y. Tanaka, T. Uruno, X. Duan, Y. Harada, F. Sanematsu, K. Yamamura, M. Terasawa, A. Nishikimi, J.F. Côté, and Y. Fukui. 2014. DOCK5 functions as a key signaling adaptor that links FceRI signals to microtubule dynamics during mast cell degranulation. J. Exp. Med. 211:1407-1419. https:// doi .org/ 10 .1084/ jem .20131926
123. Oji, V., K.M. Eckl, K. Aufenvenne, M. Nätebus, T. Tarinski, K. Ackermann, N. Seller, D. Metze, G. Nürnberg, R. Fölster-Holst, et al. 2010. Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease. Am. J. Hum. Genet. 87:274-281. https:// doi .org/ 10 .1016/ j .ajhg .2010 .07 .005
124. Olson, M.R., F.F. Verdan, M.M. Hufford, A.L. Dent, and M.H. Kaplan. 2016. STAT3 Impairs STAT5 Activation in the Development of IL-9-Secreting T Cells. J. Immunol. 196:3297-3304. https:// doi .org/ 10 .4049/ jimmunol .1501801
125. Ombrello, M.J., E.F. Remmers, G. Sun, A.F. Freeman, S. Datta, P. Torabi-Parizi, N. Subramanian, T.D. Bunney, R.W. Baxendale, M.S. Martins, et al. 2012. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N. Engl. J. Med. 366:330-338. https:// doi .org/ 10 .1056/ NEJMoa1102140
126. Picard, C., S. Dogniaux, K. Chemin, Z. Maciorowski, A. Lim, F. Mazerolles, F. Rieux-Laucat, M.C. Stolzenberg, M. Debre, J.P. Magny, et al. 2009. Hypomorphic mutation of ZAP70 in human results in a late onset immunodeficiency and no autoimmunity. Eur. J. Immunol. 39:1966-1976. https:// doi .org/ 10 .1002/ eji .200939385
127. Pivniouk, V.I., S.B. Snapper, A. Kettner, H. Alenius, D. Laouini, H. Falet, J. Hartwig, F.W. Alt, and R.S. Geha. 2003. Impaired signaling via the high-affinity IgE receptor in Wiskott-Aldrich syndrome protein-deficient mast cells. Int. Immunol. 15:1431-1440. https:// doi .org/ 10 .1093/ intimm/ dxg148
128. Punwani, D., H. Wang, A.Y. Chan, M.J. Cowan, J. Mallott, U. Sunderam, M. Mollenauer, R. Srinivasan, S.E. Brenner, A. Mulder, et al. 2015. Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation. J. Clin. Immunol. 35:135-146. https:// doi .org/ 10 .1007/ s10875-014-0125-1
129. Rajala, H.L., S. Eldfors, H. Kuusanmäki, A.J. van Adrichem, T. Olson, S. Lagström, E.I. Andersson, A. Jerez, M.J. Clemente, Y. Yan, et al. 2013. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood. 121:4541-4550. https:// doi .org/ 10 .1182/ blood-2012-12-474577
130. Ramsdell, F., and S.F. Ziegler. 2014. FOXP3 and scurfy: how it all began. Nat. Rev. Immunol. 14:343-349. https:// doi .org/ 10 .1038/ nri3650
131. Rawson, R., T. Yang, R.O. Newbury, M. Aquino, A. Doshi, B. Bell, D.H. Broide, R. Dohil, R. Kurten, and S.S. Aceves. 2016. TGF-β1-induced PAI-1 contributes to a profibrotic network in patients with eosinophilic esophagitis. J. Allergy Clin. Immunol. 138:791-800.e4. https:// doi .org/ 10 .1016/ j .jaci .2016 .02 .028
132. Roncagalli, R., M. Cucchetti, N. Jarmuzynski, C. Grégoire, E. Bergot, S. Audebert, E. Baudelet, M.G. Menoita, A. Joachim, S. Durand, et al. 2016. The scaffolding function of the RLT PR protein explains its essential role for CD28 co-stimulation in mouse and human T cells. J. Exp. Med. 213:2437-2457. https:// doi .org/ 10 .1084/ jem .20160579
133. Sahiner, U.M., S.T. Yavuz, B. Buyuktiryaki, O. Cavkaytar, E.A. Yilmaz, A. Tuncer, and C. Sackesen. 2014. Serum basal tryptase may be a good marker for predicting the risk of anaphylaxis in children with food allergy. Allergy. 69:265-268. https:// doi .org/ 10 .1111/ all .12317
134. Samuelov, L., O. Sarig, R.M. Harmon, D. Rapaport, A. Ishida-Yamamoto, O. Isakov, J.L. Koetsier, A. Gat, I. Goldberg, R. Bergman, et al. 2013. Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting. Nat. Genet. 45:1244-1248. https:// doi .org/ 10 .1038/ ng .2739
135. Sandilands, A., A. Terron-Kwiatkowski, P.R. Hull, G.M. O'Regan, T.H. Clayton, R.M. Watson, T. Carrick, A.T. Evans, H. Liao, Y. Zhao, et al. 2007. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat. Genet. 39:650-654. https:// doi .org/ 10 .1038/ ng2020
136. Sandilands, A., C. Sutherland, A.D. Irvine, and W.H. McLean. 2009. Filaggrin in the frontline: role in skin barrier function and disease. J. Cell Sci. 122:1285-1294. https:// doi .org/ 10 .1242/ jcs .033969
137. Sassi, A., S. Lazaroski, G. Wu, S.M. Haslam, M. Fliegauf, F. Mellouli, T. Patiroglu, E. Unal, M.A. Ozdemir, Z. Jouhadi, et al. 2014. Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels. J. Allergy Clin. Immunol. 133:1410-1419.e13. https:// doi .org/ 10 .1016/ j .jaci .2014 .02 .025
138. Schalkwijk, J., M.C. Zweers, P.M. Steijlen, W.B. Dean, G. Taylor, I.M. van Vlijmen, B. van Haren, W.L. Miller, and J. Bristow. 2001. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. N. Engl. J. Med. 345:1167-1175. https:// doi .org/ 10 .1056/ NEJMoa002939
139. Schober, T., T. Magg, M. Laschinger, M. Rohlfs, N.D. Linhares, J. Puchalka, T. Weisser, K. Fehlner, J. Mautner, C. Walz, et al. 2017. A human immunodeficiency syndrome caused by mutations in CAR MIL2. Nat. Commun. 8:14209. https:// doi .org/ 10 .1038/ ncomms14209
140. Seguchi, T., C.Y. Cui, S. Kusuda, M. Takahashi, K. Aisu, and T. Tezuka. 1996. Decreased expression of filaggrin in atopic skin. Arch. Dermatol. Res. 288:442-446. https:// doi .org/ 10 .1007/ BF02505232
141. Shearer, W.T., E. Dunn, L.D. Notarangelo, C.C. Dvorak, J.M. Puck, B.R. Logan, L.M. Griffith, D.B. Kohn, R.J. O'Reilly, T.A. Fleisher, et al. 2014. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J. Allergy Clin. Immunol. 133:1092-1098. https:// doi .org/ 10 .1016/ j .jaci .2013 .09 .044
142. Siberry, G.K., E. Leister, D.L. Jacobson, S.B. Foster, G.R. Seage III, S.E. Lipshultz, M.E. Paul, M. Purswani, A.A. Colin, G. Scott, and W.T. Shearer. 2012. Increased risk of asthma and atopic dermatitis in perinatally HIV-infected children and adolescents. Clin. Immunol. 142:201-208. https:// doi .org/ 10 .1016/ j .clim .2011 .10 .005
143. Siegel, A.M., K.D. Stone, G. Cruse, M.G. Lawrence, A. Olivera, M.Y. Jung, J.S. Barber, A.F. Freeman, S.M. Holland, M. O'Brien, et al. 2013. Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation. J. Allergy Clin. Immunol. 132:1388-1396.e3. https:// doi .org/ 10 .1016/ j .jaci .2013 .08 .045
144. Simpson, E.L., J.R. Chalmers, J.M. Hanifin, K.S. Thomas, M.J. Cork, W.H. McLean, S.J. Brown, Z. Chen, Y. Chen, and H.C. Williams. 2014. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J. Allergy Clin. Immunol. 134:818-823. https:// doi .org/ 10 .1016/ j .jaci .2014 .08 .005
145. Singh, A.K., A. Eken, D. Hagin, K. Komal, G. Bhise, A. Shaji, T. Arkatkar, S.W. Jackson, E. Bettelli, T.R. Torgerson, and M. Oukka. 2017. DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling. JCI Insight. 2:e94275. https:// doi .org/ 10 .1172/ jci .insight .94275
146. Smith, F.J., A.D. Irvine, A. Terron-Kwiatkowski, A. Sandilands, L.E. Campbell, Y. Zhao, H. Liao, A.T. Evans, D.R. Goudie, S. Lewis-Jones, et al. 2006. Lossof-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat. Genet. 38:337-342. https:// doi .org/ 10 .1038/ ng1743
147. Somech, R., A. Lev, Y.N. Lee, A.J. Simon, O. Barel, G. Schiby, C. Avivi, I. Barshack, M. Rhodes, J. Yin, et al. 2017. Disruption of Thrombocyte and T Lymphocyte Development by a Mutation inARPC1B. J. Immunol. 199:4036-4045. https:// doi .org/ 10 .4049/ jimmunol .1700460
148. Sommerhoff, C.P. 2001. Mast cell tryptases and airway remodeling. Am. J. Respir. Crit. Care Med. 164(supplement_2):S52-S58. https:// doi .org/ 10 .1164/ ajrccm .164 .supplement 2 .2106058
149. Spector, S.L., and R.S. Farr. 1976. Atopy reconsidered. Clin. Allergy. 6:83-90. https:// doi .org/ 10 .1111/ j .1365-2222 .1976 .tb01416 .x
150. Stepensky, P., B. Keller, M. Buchta, A.K. Kienzler, O. Elpeleg, R. Somech, S. Cohen, I. Shachar, L.A. Miosge, M. Schlesier, et al. 2013. Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects. J. Allergy Clin. Immunol. 131:477-485.e1. https:// doi .org/ 10 .1016/ j .jaci .2012 .11 .050
151. Stray-Pedersen, A., P.H. Backe, H.S. Sorte, L. Mørkrid, N.Y. Chokshi, H.C. Erichsen, T. Gambin, K.B. Elgstøen, M. Bjørås, M.W. Wlodarski, et al. Baylor-Johns Hopkins Center for Mendelian Genomics. 2014. PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia. Am. J. Hum. Genet. 95:96-107. https:// doi .org/ 10 .1016/ j .ajhg .2014 .05 .007
152. Tangye, S.G., B. Pillay, K.L. Randall, D.T. Avery, T.G. Phan, P. Gray, J.B. Ziegler, J.M. Smart, J. Peake, P.D. Arkwright, et al. 2017. Dedicator of cytokinesis 8-deficient CD4+T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells. J. Allergy Clin. Immunol. 139:933-949. https:// doi .org/ 10 .1016/ j .jaci .2016 .07 .016
153. Tao, X., C. Grant, S. Constant, and K. Bottomly. 1997. Induction of IL-4-producing CD4+ T cells by antigenic peptides altered for TCR binding. J. Immunol. 158:4237-4244
154. Thrasher, A.J., and S.O. Burns. 2010. WASP: a key immunological multitasker. Nat. Rev. Immunol. 10:182-192. https:// doi .org/ 10 .1038/ nri2724
155. Torres, J.M., R. Martinez-Barricarte, S. García-Gómez, M.S. Mazariegos, Y. Itan, B. Boisson, R. Rholvarez, A. Jiménez-Reinoso, L. del Pino, R. Rodríguez-Pena, et al. 2014. Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity. J. Clin. Invest. 124:5239-5248. https:// doi .org/ 10 .1172/ JCI77493
156. Tuano, K.S., J.S. Orange, K. Sullivan, C. Cunningham-Rundles, F.A. Bonilla, and C.M. Davis. 2015. Food allergy in patients with primary immunodeficiency diseases: prevalence within the US Immunodeficiency Network (USI DNET). J. Allergy Clin. Immunol. 135:273-275. https:// doi .org/ 10 .1016/ j .jaci .2014 .09 .024
157. Turul, T., I. Tezcan, H. Artac, S. de Bruin-Versteeg, B.H. Barendregt, I. Reisli, O. Sanal, J.J. van Dongen, and M. van der Burg. 2009. Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency. Eur. J. Pediatr. 168:87-93. https:// doi .org/ 10 .1007/ s00431-008-0718-x
158. Ui, H., T. Andoh, J.B. Lee, H. Nojima, and Y. Kuraishi. 2006. Potent pruritogenic action of tryptase mediated by PAR-2 receptor and its involvement in anti-pruritic effect of nafamostat mesilate in mice. Eur. J. Pharmacol. 530:172-178. https:// doi .org/ 10 .1016/ j .ejphar .2005 .11 .021
159. Uzel, G., E.P. Sampaio, M.G. Lawrence, A.P. Hsu, M. Hackett, M.J. Dorsey, R.J. Noel, J.W. Verbsky, A.F. Freeman, E. Janssen, et al. 2013. 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. https:// doi .org/ 10 .1016/ j .jaci .2012 .11 .054
160. Valent, P., C. Akin, and D.D. Metcalfe. 2017. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 129:1420-1427. https:// doi .org/ 10 .1182/ blood-2016-09-731893
161. van den Berg, A., A. van Zwol, H.A. Moll, W.P. Fetter, and R.M. van Elburg. 2007. Glutamine-enriched enteral nutrition in very low-birth-weight infants: effect on the incidence of allergic and infectious diseases in the first year of life. Arch. Pediatr. Adolesc. Med. 161:1095-1101. https:// doi .org/ 10 .1001/ archpedi .161 .11 .1095
162. van Panhuys, N., F. Klauschen, and R.N. Germain. 2014. T-cell-receptor-dependent signal intensity dominantly controls CD4(+) T cell polarization In Vivo. Immunity. 41:63-74. https:// doi .org/ 10 .1016/ j .immuni .2014 .06 .003
163. Villa, A., L.D. Notarangelo, and C.M. Roifman. 2008. Omenn syndrome: inflammation in leaky severe combined immunodeficiency. J. Allergy Clin. Immunol. 122:1082-1086. https:// doi .org/ 10 .1016/ j .jaci .2008 .09 .037
164. Vissers, J.L., B.C. van Esch, G.A. Hofman, M.L. Kapsenberg, F.R. Weller, and A.J. van Oosterhout. 2004. Allergen immunotherapy induces a suppressive memory response mediated by IL-10 in a mouse asthma model. J. Allergy Clin. Immunol. 113:1204-1210. https:// doi .org/ 10 .1016/ j .jaci .2004 .02 .041
165. Wada, T., S.H. Schurman, E.K. Garabedian, A. Yachie, and F. Candotti. 2005. Analysis of T-cell repertoire diversity in Wiskott-Aldrich syndrome. Blood. 106:3895-3897. https:// doi .org/ 10 .1182/ blood-2005-06-2336
166. Wang, Y., C.S. Ma, Y. Ling, A. Bousfiha, Y. Camcioglu, S. Jacquot, K. Payne, E. Crestani, R. Roncagalli, A. Belkadi, et al. 2016. Dual T cell-and B cell-intrinsic deficiency in humans with biallelic RLT PR mutations. J. Exp. Med. 213:2413-2435. https:// doi .org/ 10 .1084/ jem .20160576
167. Wesemann, D.R., J.M. Magee, C. Boboila, D.P. Calado, M.P. Gallagher, A.J. Portuguese, J.P. Manis, X. Zhou, M. Recher, K. Rajewsky, et al. 2011. Immature B cells preferentially switch to IgE with increased direct Sμ to Se recombination. J. Exp. Med. 208:2733-2746. https:// doi .org/ 10 .1084/ jem .20111155
168. Wildin, R.S., F. Ramsdell, J. Peake, F. Faravelli, J.L. Casanova, N. Buist, E. Levy-Lahad, M. Mazzella, O. Goulet, L. Perroni, et al. 2001. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27:18-20. https:// doi .org/ 10 .1038/ 83707
169. Wu, G., P.G. Hitchen, M. Panico, S.J. North, M.R. Barbouche, D. Binet, H.R. Morris, A. Dell, and S.M. Haslam. 2016. Glycoproteomic studies of IgE from a novel hyper IgE syndrome linked to PGM3 mutation. Glycoconj. J. 33:447-456. https:// doi .org/ 10 .1007/ s10719-015-9638-y
170. Yamane, H., and W.E. Paul. 2013. Early signaling events that underlie fate decisions of naive CD4(+) T cells toward distinct T-helper cell subsets. Immunol. Rev. 252:12-23. https:// doi .org/ 10 .1111/ imr .12032
171. Yang, X.P., K. Ghoreschi, S.M. Steward-Tharp, J. Rodriguez-Canales, J. Zhu, J.R. Grainger, K. Hirahara, H.W. Sun, L. Wei, G. Vahedi, et al. 2011. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat. Immunol. 12:247-254. https:// doi .org/ 10 .1038/ ni .1995
172. Yu, X., J.R. Almeida, S. Darko, M. van der Burg, S.S. DeRavin, H. Malech, A. Gennery, I. Chinn, M.L. Markert, D.C. Douek, and J.D. Milner. 2014. Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development. J. Allergy Clin. Immunol. 133:1109-1115.e14. https:// doi .org/ 10 .1016/ j .jaci .2013 .11 .018
173. Zhang, Q., J.C. Davis, I.T. Lamborn, A.F. Freeman, H. Jing, A.J. Favreau, H.F. Matthews, J. Davis, M.L. Turner, G. Uzel, et al. 2009. Combined immunodeficiency associated with DOCK8 mutations. N. Engl. J. Med. 361:2046-2055. https:// doi .org/ 10 .1056/ NEJMoa0905506
174. Zhang, Q., C.G. Dove, J.L. Hor, H.M. Murdock, D.M. Strauss-Albee, J.A. Garcia, J.N. Mandl, R.A. Grodick, H. Jing, D.B. Chandler-Brown, et al. 2014. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. J. Exp. Med. 211:2549-2566. https:// doi .org/ 10 .1084/ jem .20141307
175. Zhang, Y., X. Yu, M. Ichikawa, J.J. Lyons, S. Datta, I.T. Lamborn, H. Jing, E.S. Kim, M. Biancalana, L.A. Wolfe, et al. 2014. Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment. J. Allergy Clin. Immunol. 133:1400-1409.e5. https:// doi .org/ 10 .1016/ j .jaci .2014 .02 .013
176. Zigmond, S.H. 2000. How WASP regulates actin polymerization. J. Cell Biol. 150:F117-F120. https:// doi .org/ 10 .1083/ jcb .150 .6 .F117