Discovering the Cause of Wiskott–Aldrich Syndrome and Laying the Foundation for Understanding Immune Cell Structuring Emily M

Discovering the Cause of Wiskott−Aldrich Syndrome and Laying the Foundation for Understanding Immune Cell Structuring

This information is current as Emily M. Mace and Jordan S. Orange of September 24, 2021. J Immunol 2018; 200:3667-3670; ; doi: 10.4049/jimmunol.1800518 http://www.jimmunol.org/content/200/11/3667 Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Pillars of Immunology Immunology

Discovering the Cause of Wiskott–Aldrich Syndrome and Laying the Foundation for Understanding Immune Cell Structuring Emily M. Mace and Jordan S. Orange

he discovery of the Wiskott–Aldrich syndrome (WAS) WAS, characterized by loss of protein expression, as well as an protein gene (WASP, now known as WAS)byDerry additional spectrum of mutations that include milder forms of T et al. (1) in 1994 accelerated the ﬁeld of immune cell WAS, such as X-linked thrombocytopenia (XLT) (6), inter- biology and studies of the molecular basis of inborn human mittent XLT (7), and X-linked neutropenia, a disease that

immune defects, otherwise known as primary immunodefi- results from constitutively activated WASP (8). Downloaded from ciencies (PIDs). It was the “novel gene” described in this issue’s At the time of the discovery of the WASP gene, there was insight Pillars of Immunology article that allowed for the discovery of an into the biology of WAS. Previous linkage analysis had localized entire family of proteins that would help define how all cells gain the causative defect to the 1-Mbp region of Xp11.22–Xp11.23 their structural integrity and led to exciting and groundbreaking (9–14). XLT had been described and mapped to the same region, findings as to the cell biological requirements for human im- and it was speculated to arise from defects in the same gene (15, 16).

munity. Cited almost 1000 times, this article remains a foun- Diverse investigations uncovered important characteristics of http://www.jimmunol.org/ dation for our understanding of the intracellular mechanics that T cells from WAS patients, including electron micrographs underpin human immune function. showing absent or deformed microvillus projections from the WAS is a rare X-linked PID that was deﬁned by a classic triad cell surface (17, 18) accompanied by decreased or aberrant of thrombocytopenia, eczema, and recurrent otitis; later, WAS expression of CD43 (19, 20). This led to the brief speculation was known to be associated with increased incidence of many that CD43 was the causative gene of WAS, speculation that infections, autoimmunity, and malignancy (2). This was histor- was ended by the mapping of the CD43 gene to chromosome ically considered a fatal disease with a short life expectancy for 16 (21). Other clues as to the function of the protein that

affected patients, almost exclusively boys. The first patient co- by guest on September 24, 2021 would subsequently be identified as WASP included impaired hort was reported in 1937 by Wiskott (3), when he described transmembrane signaling (22), decreased chemotaxis, aberrant three brothers with low platelet counts, bloody diarrhea, skin O-linked glycosylation patterns, and impaired T cell proliferation rash, and recurrent ear infections. The brothers died as a result of their illness; however, it was noted that their sisters were (23–28). It was recognized that expression of the gene was unaffected, leading Wiskott to suggest that the syndrome was restricted to the lymphocytic and megakaryocytic lineages, hereditary. In 1954, Aldrich (4) painstakingly studied a large an observation that was criticalfortheproofofconceptthat Dutch family, describing similar symptoms to those first iden- mutations in WASP caused WAS. Despite these useful tified by Wiskott, and documented the X-linked inheritance insights, some of which would be direct demonstrations pattern of the disease, which was subsequently named WAS. of WASP function, the disease and its unifying biology Despite its early description and the devastating effect of this remained a great mystery until the gene was identified. disease on affected families, the molecular etiology of WAS To identify the WASP gene, yeast artificial chromosomes were remained unknown for over 50 years. During this time, on- assembled into a one-Mbp contig spanning the Xp11.22– going studies of these patients and the nature of their disease Xp11.23 region of interest. Affinity capture was used to identify laid the groundwork for molecular studies that would follow novel cDNA transcripts in combination with Northern hybrid- the discovery, in 1994, of the gene encoding WASP. ization to RNA from cultured lymphoblasts. This identified seven Currently, there are more than 440 known mutations causa- putative genes, including WASP. Notably, protein expression was tive of WAS (5). These include mutations that lead to classical restricted to lymphocytes and megakaryocytes, and RNA was not detected by Northern hybridization of lymphoblastoid-derived cell lines from two patients with classical WAS. Together, these Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030; and data linked the putative WASP gene with WAS. The entire Center for Human Immunobiology, Texas Children’s Hospital, Houston, TX 77030 WASP cDNA was then isolated from a T cell–derived cDNA ORCID: 0000-0003-0226-7393 (E.M.M.). library and sequenced; 10 introns and 11 exons were identified. Address correspondence and reprint requests to Dr. Jordan S. Orange, Center for Human Immunobiology, Texas Children’s Hospital, Feigin Center, Suite 330, 1102 Bates Street, Finally, WASP mutations as the cause of WAS were confirmed Houston, TX 77030-2698. E-mail address: [email protected] by PCR-based sequencing of patient DNA, which identified Abbreviations used in this article: IS, immunological synapse; PID, primary immuno- three independent mutations (T211 deletion and G291A and deficiency; WAS, Wiskott–Aldrich syndrome; XLT, X-linked thrombocytopenia. G291T transversions) in affected patients and also confirmed Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 heterozygosity in female carriers (1).

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800518 3668 PILLARS OF IMMUNOLOGY

This article proposed “a direct interaction of WASP with day, immunologists have risen to the challenge of studying the cytoskeleton” and led to the mechanistic discovery that small, highly motile, and diverse cells by being early adopters WASP and its homologous family members are critical reg- of sophisticated imaging technologies, including superresolu- ulators of actin cytoskeletal remodeling and are required for tion microscopy, intravital imaging, and microfabrication. hematopoiesis and immune cell function. At the time of The study of lymphocytes from patients with WAS led to early writing, Derry et al. (1) suggested the function of the newly insight into the importance of actin branching in immune cell discovered WASP gene in cytoskeletal rearrangement based function and provided important understanding into the origin upon previous cell biological studies. It is difficult, however, of disease in these patients (42, 43). This led the way for further to overstate the importance of understanding the contribution studies that combined high-resolution imaging with analyses of of WASP to immune cell function and cell biology in general. IS structure and function to make seminal discoveries about the WASP was the first identified actin nucleation–promoting cytoskeleton and human immunity (44–46). Immune defects in factor now known to be part of the molecular complex that WAS result from decreased T and B cell numbers and function adds an actin monomer onto an existing actin filament so that and impaired NK cell function. In healthy cells, WASP is a new filament can grow at a 70˚ angle to the original. This recruited to the IS, where it acts as a scaffold to promote local- represents nature’s construction work of assembling the ized assembly of branched actin filaments that are required for structural framework of living cells, akin to joining the cell adhesion, receptor recruitment, and cell polarization. The girders in a building, providing integrity and form. loss of WASP function leads not only to impaired lytic effec-

In addition to driving countless discoveries about the cell tor T cell function but also to impaired proliferation and Downloaded from biology of immune cells, it became clear that the critical IL-2 production, increased apoptosis, and decreased numbers function of WASP family members also reaches beyond im- of circulating T cells in WAS patients (23, 47–50). The munity through N-WASP and SCAR/WAVE1–3, which have impairment of NK cell effector function is a signiﬁcant more ubiquitous tissue expression, and WASP-like proteins contributor to the devastating infections experienced by WAS WASH and WHAMM, which have functions similar to patients, including those resulting from abnormal susceptibility

WASP in immune cell actin dynamics (29–33). Rapid char- to herpesviruses (46, 51). These defects can be partially http://www.jimmunol.org/ acterization of the WASP protein, following the discovery alleviated by the administration of IL-2, which accesses the by Derry et al., led to understanding of its structure and function of WAVE2 to mediate actin branching in NK cells function (reviewed in Ref. 34). Containing a verprolin ho- in the absence of WASP function (52). Although WAVE2 has mology domain–coﬁlin homology domain–acidic region baseline function in T cells, in NK cells this function is induced domain, GTPase binding domain, and proline-rich domain, following cytokine stimulation. As such, IL-2 therapy can alle- WASP is held in an autoinhibited conformation through in- viate low NK cell function in WAS patients, with promising teractions between the verprolin homology domain–coﬁlin results in a clinical trial (53). Finally, although WAS remains

homology domain–acidic region domain and GTPase bind- the most common PID as a result of mutations in this family of by guest on September 24, 2021 ing domains and stabilized by WASP-interacting protein. proteins, a patient with features of WAS has subsequently been Binding of GTPases, primarily Cdc42, relieves this autoinhi- identified with deleterious homozygous mutations in WASP- bition and enables binding to the Arp2/3 complex to promote interacting protein (WIPF1)(54). actin nucleation upon an existing actin filament. The poly- In addition to acting as the foundation for the study of proline region of WASP was noted in the 1994 article and immune cell biology, this article was among the first to define predicted to bind SH3 domain–containing proteins; we now the molecular basis of a PID. Today, when whole-exome se- know that Src and Tec family kinases bind this region and can quencing is de rigueur, the identification of mutation-causing activate WASP through tyrosine phosphorylation. Actin genes includes a significant density of genetic information remodeling mediated by WASP is required for processes in- that is generated by the study of a patient and his or her family cluding directed secretion, cell migration, phagocytic cup members. The challenge lies in first identifying rational can- formation, and neutrophil effector functions. Although less didate genes and then proving causation of disease. However, well understood, the role of WASP in platelet and megakar- the same tenets still apply for linking a causative gene to hu- yocyte formation and function is strikingly underscored by man disease that were demonstrated in this Pillars of Immunology the defects in these cells in WAS patients. article. The meticulous sequencing efforts, supported by the The identification of the WASP gene coincided with demonstration of mutations in affected family members that technological advances that led to the generation and rapid are present in heterozygous female carriers, but not 100 advance of the field of immune cell biology. Namely, the healthy donors, set the high standard that the emerging field development of microscopes and imaging systems that en- of PID research would follow (55). In addition, this article abled the high-resolution study of immune processes launched set the stage for an early molecular test for PID, the flow an explosion of studies into the immunological synapse (IS), cytometry–based assay for WASP expression (56), and pre- with the importance of WASP-mediated actin remodeling at dicted the prospect of gene therapy for WAS. Although the forefront. Although the T cell IS was first conceptually hematopoietic stem cell transplant is still the most common proposed in 1984 (35), it wasn’t until 1999 that the T cell– therapy for WAS, this prospect became a reality in 2010 APC IS was visualized and functionally dissected, featuring with the treatment of 10 WAS patients by retroviral gene synaptic actin accumulation (36, 37). This was rapidly fol- therapy (57). The risk of oncogenic transformation has led lowed by description of other ISs, including CTL synapses to the redesign of gene therapy vectors, and success of lenti- (38), NK cell activating and inhibitory synapses (39), B cell viral gene therapy has been reported recently in these pa- synapses (40), NK cell–dendritic cell synapses (41), and so tients (58). The efficacy of gene therapy was in part forth. Beginning with these studies, and continuing to this monitored by understanding the cell biological impact of The Journal of Immunology 3669

WAS gene replacement by studying the NK cell IS in these sialophorin (CD43), the lymphocyte surface sialoglycoprotein defective in Wiskott-Aldrich syndrome. Proc. Natl. Acad. Sci. USA 86: 2819–2823. patients. 22. Simon, H. U., G. B. Mills, S. Hashimoto, and K. A. Siminovitch. 1992. Evidence In summary, the work of Derry et al. holds the unique for defective transmembrane signaling in B cells from patients with Wiskott-Aldrich syndrome. J. Clin. Invest. 90: 1396–1405. distinction of both closing one chapter of a longstanding 23. Ochs, H. D., S. J. Slichter, L. A. Harker, W. E. Von Behrens, R. A. Clark, and medical mystery, namely the identification of WASP as the R. J. Wedgwood. 1980. The Wiskott-Aldrich syndrome: studies of lymphocytes, disease-causing gene for WAS, and launching new fields of granulocytes, and platelets. Blood 55: 243–252. 24. Oppenheim, J. J., R. M. Blaese, and T. A. Waldmann. 1970. Defective lymphocyte discovery into the role of actin branching in immune cell transformation and delayed hypersensitivity in Wiskott-Aldrich syndrome. function and immunity. J. Immunol. 104: 835–844. 25. Greer, W. L., E. Higgins, D. R. Sutherland, A. Novogrodsky, I. Brockhausen, M. Peacocke, L. A. Rubin, M. Baker, J. W. Dennis, and K. A. Siminovitch. 1989. Altered expression of leucocyte sialoglycoprotein in Wiskott-Aldrich syndrome is associated with a specific defect in O-glycosylation. Biochem. Cell Biol. 67: 503–509. Disclosures 26. Piller, F., F. Le Deist, K. I. Weinberg, R. Parkman, and M. Fukuda. 1991. Altered The authors have no financial conflicts of interest. O-glycan synthesis in lymphocytes from patients with Wiskott-Aldrich syndrome. J. Exp. Med. 173: 1501–1510. 27. Higgins, E. A., K. A. Siminovitch, D. L. Zhuang, I. Brockhausen, and J. W. Dennis. 1991. Aberrant O-linked oligosaccharide biosynthesis in lymphocytes and References platelets from patients with the Wiskott-Aldrich syndrome. J. Biol. Chem. 266: 1. Derry, J. M., H. D. Ochs, and U. Francke. 1994. Isolation of a novel gene mutated 6280–6290. in Wiskott-Aldrich syndrome. Cell 78: 635–644. 28. Molina, I. J., J. Sancho, C. Terhorst, F. S. Rosen, and E. Remold-O’Donnell. 1993. 2. Online Mendelian Inheritance in Man. 2012. OMIM #300392. Baltimore, MD: T cells of patients with the Wiskott-Aldrich syndrome have a restricted defect in Johns Hopkins University. Available at: https://www.omim.org/entry/300392. proliferative responses. J. Immunol. 151: 4383–4390. Accessed: March 8, 2018. 29. Miki, H., K. Miura, and T. Takenawa. 1996. N-WASP, a novel actin-depolymerizing Downloaded from 3. Wiskott, A. 1937. Familia¨rer, angeborener morbus Werlhofii? Monatsschr. Kind- protein, regulates the cortical cytoskeletal rearrangement in a PIP2-dependent manner erheilkd. 68: 212–216. downstream of tyrosine kinases. EMBO J. 15: 5326–5335. 4. Aldrich, R. A., A. G. Steinberg, and D. C. Campbell. 1954. Pedigree demonstrating 30. Bear, J. E., J. F. Rawls, and C. L. Saxe, III. 1998. SCAR, a WASP-related protein, a sex-linked recessive condition characterized by draining ears, eczematoid derma- isolated as a suppressor of receptor defects in late Dictyostelium development. J. Cell titis and bloody diarrhea. Pediatrics 13: 133–139. Biol. 142: 1325–1335. 5. Imai, K., T. Morio, Y. Zhu, Y. Jin, S. Itoh, M. Kajiwara, J. Yata, S. Mizutani, 31. Suetsugu, S., H. Miki, and T. Takenawa. 1999. Identification of two human H. D. Ochs, and S. Nonoyama. 2004. Clinical course of patients with WASP gene WAVE/SCAR homologues as general actin regulatory molecules which associate

mutations. Blood 103: 456–464. with the Arp2/3 complex. Biochem. Biophys. Res. Commun. 260: 296–302. http://www.jimmunol.org/ 6. Derry, J. M., J. A. Kerns, K. I. Weinberg, H. D. Ochs, V. Volpini, X. Estivill, 32. Linardopoulou, E. V., S. S. Parghi, C. Friedman, G. E. Osborn, S. M. Parkhurst, A. P. Walker, and U. Francke. 1995. WASP gene mutations in Wiskott-Aldrich and B. J. Trask. 2007. Human subtelomeric WASH genes encode a new subclass of syndrome and X-linked thrombocytopenia. Hum. Mol. Genet. 4: 1127–1135. the WASP family. PLoS Genet. 3: e237. 7. Notarangelo, L. D., C. Mazza, S. Giliani, C. D’Aria, F. Gandellini, C. Ravelli, 33. Campellone, K. G., N. J. Webb, E. A. Znameroski, and M. D. Welch. 2008. M. G. Locatelli, D. L. Nelson, H. D. Ochs, and L. D. Notarangelo. 2002. Missense WHAMM is an Arp2/3 complex activator that binds microtubules and functions in mutations of the WASP gene cause intermittent X-linked thrombocytopenia. Blood ER to Golgi transport. Cell 134: 148–161. 99: 2268–2269. 34. Thrasher, A. J., and S. O. Burns. 2010. WASP: a key immunological multitasker. 8. Devriendt, K., A. S. Kim, G. Mathijs, S. G. Frints, M. Schwartz, J. J. Van Den Oord, Nat. Rev. Immunol. 10: 182–192. G. E. Verhoef, M. A. Boogaerts, J. P. Fryns, D. You, et al. 2001. Constitutively ac- 35. Norcross, M. A. 1984. A synaptic basis for T-lymphocyte activation. Ann. Immunol. tivating mutation in WASP causes X-linked severe congenital neutropenia. Nat. Genet. (Paris) 135D: 113–134. 27: 313–317. 36. Grakoui, A., S. K. Bromley, C. Sumen, M. M. Davis, A. S. Shaw, P. M. Allen, and

9. Peacocke, M., and K. A. Siminovitch. 1987. Linkage of the Wiskott-Aldrich syn- M. L. Dustin. 1999. The immunological synapse: a molecular machine controlling by guest on September 24, 2021 drome with polymorphic DNA sequences from the human X chromosome. Proc. T cell activation. Science 285: 221–227. Natl. Acad. Sci. USA 84: 3430–3433. 37. Monks, C. R., B. A. Freiberg, H. Kupfer, N. Sciaky, and A. Kupfer. 1998. Three- 10. Kwan, S. P., L. A. Sandkuyl, M. Blaese, L. M. Kunkel, G. Bruns, R. Parmley, dimensional segregation of supramolecular activation clusters in T cells. Nature 395: S. Skarshaug, D. C. Page, J. Ott, and F. S. Rosen. 1988. Genetic mapping of the 82–86. Wiskott-Aldrich syndrome with two highly-linked polymorphic DNA markers. 38. Stinchcombe, J. C., G. Bossi, S. Booth, and G. M. Griffiths. 2001. The immu- Genomics 3: 39–43. nological synapse of CTL contains a secretory domain and membrane bridges. 11. Kwan, S. P., T. Lehner, T. Hagemann, B. Lu, M. Blaese, H. Ochs, R. Wedgwood, Immunity 15: 751–761. J. Ott, I. W. Craig, and F. S. Rosen. 1991. Localization of the gene for the Wiskott- 39. Davis, D. M., I. Chiu, M. Fassett, G. B. Cohen, O. Mandelboim, and Aldrich syndrome between two flanking markers, TIMP and DXS255, on Xp11.22- J. L. Strominger. 1999. The human natural killer cell immune synapse. Proc. Natl. Xp11.3. Genomics 10: 29–33. Acad. Sci. USA 96: 15062–15067. 12. de Saint Basile, G., B. Arveiler, N. J. Fraser, Y. Boyd, I. W. Graig, G. Griscelli, and 40. Batista, F. D., D. Iber, and M. S. Neuberger. 2001. B cells acquire antigen from A. Fischer. 1989. Close linkage of hypervariable marker DXS255 to disease locus of target cells after synapse formation. Nature 411: 489–494. Wiskott-Aldrich syndrome. Lancet 2: 1319–1321. 41. Borg, C., A. Jalil, D. Laderach, K. Maruyama, H. Wakasugi, S. Charrier, B. Ryffel, 13. Greer, W. L., M. M. Mahtani, P. C. Kwong, L. A. Rubin, M. Peacocke, A. Cambi, C. Figdor, W. Vainchenker, et al. 2004. NK cell activation by dendritic H. F. Willard, and K. A. Siminovitch. 1989. Linkage studies of the Wiskott-Aldrich cells (DCs) requires the formation of a synapse leading to IL-12 polarization syndrome: polymorphisms at TIMP and the X chromosome centromere are in- in DCs. Blood 104: 3267–3275. formative markers for genetic prediction. Hum. Genet. 83: 227–230. 42. Gallego, M. D., M. Santamarıá, J. Penã, and I. J. Molina. 1997. Defective actin 14. Greer, W. L., P. C. Kwong, M. Peacocke, P. Ip, L. A. Rubin, and K. A. Siminovitch. reorganization and polymerization of Wiskott-Aldrich T cells in response to 1989. X-chromosome inactivation in the Wiskott-Aldrich syndrome: a marker for CD3-mediated stimulation. Blood 90: 3089–3097. detection of the carrier state and identification of cell lineages expressing the gene 43. Zhang, J., A. Shehabeldin, L. A. da Cruz, J. Butler, A. K. Somani, M. McGavin, defect. Genomics 4: 60–67. I. Kozieradzki, A. O. dos Santos, A. Nagy, S. Grinstein, et al. 1999. Antigen 15. Donne´r, M., M. Schwartz, K. U. Carlsson, and L. Holmberg. 1988. Hereditary receptor-induced activation and cytoskeletal rearrangement are impaired in X-linked thrombocytopenia maps to the same chromosomal region as the Wiskott- Wiskott-Aldrich syndrome protein-deficient lymphocytes. J. Exp. Med. 190: Aldrich syndrome. Blood 72: 1849–1853. 1329–1342. 16. Standen, G. R., D. P. Lillicrap, N. Matthews, and A. L. Bloom. 1986. Inherited 44. Wulfing,€ C., and M. M. Davis. 1998. A receptor/cytoskeletal movement triggered thrombocytopenia, elevated serum IgA and renal disease: identification as a variant by costimulation during T cell activation. Science 282: 2266–2269. of the Wiskott-Aldrich syndrome. Q. J. Med. 59: 401–408. 45. Sasahara, Y., R. Rachid, M. J. Byrne, M. A. de la Fuente, R. T. Abraham, 17. Kenney, D., L. Cairns, E. Remold-O’Donnell, J. Peterson, F. S. Rosen, and N. Ramesh, and R. S. Geha. 2002. Mechanism of recruitment of WASP to the R. Parkman. 1986. Morphological abnormalities in the lymphocytes of patients immunological synapse and of its activation following TCR ligation. Mol. Cell 10: with the Wiskott-Aldrich syndrome. Blood 68: 1329–1332. 1269–1281. 18. Molina, I. J., D. M. Kenney, F. S. Rosen, and E. Remold-O’Donnell. 1992. T cell 46. Orange, J. S., N. Ramesh, E. Remold-O’Donnell, Y. Sasahara, L. Koopman, lines characterize events in the pathogenesis of the Wiskott-Aldrich syndrome. M. Byrne, F. A. Bonilla, F. S. Rosen, R. S. Geha, and J. L. Strominger. 2002. J. Exp. Med. 176: 867–874. Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and coloc- 19. Remold-O’Donnell, E., D. M. Kenney, R. Parkman, L. Cairns, B. Savage, and alizes with actin to NK cell-activating immunologic synapses. Proc. Natl. Acad. Sci. F. S. Rosen. 1984. Characterization of a human lymphocyte surface sialoglycopro- USA 99: 11351–11356. tein that is defective in Wiskott-Aldrich syndrome. J. Exp. Med. 159: 1705–1723. 47. De Meester, J., R. Calvez, S. Valitutti, and L. Dupre´. 2010. The Wiskott-Aldrich 20. Remold-O’Donnell, E., C. Zimmerman, D. Kenney, and F. S. Rosen. 1987. syndrome protein regulates CTL cytotoxicity and is required for efficient killing of Expression on blood cells of sialophorin, the surface glycoprotein that is defective B cell lymphoma targets. J. Leukoc. Biol. 88: 1031–1040. in Wiskott-Aldrich syndrome. Blood 70: 104–109. 48. Park, J. Y., M. Kob, A. P. Prodeus, F. S. Rosen, A. Shcherbina, and E. Remold- 21. Shelley, C. S., E. Remold-O’Donnell, A. E. Davis, III, G. A. Bruns, F. S. Rosen, O’Donnell. 2004. Early deficit of lymphocytes in Wiskott-Aldrich syndrome: possible M. C. Carroll, and A. S. Whitehead. 1989. Molecular characterization of role of WASP in human lymphocyte maturation. Clin. Exp. Immunol. 136: 104–110. 3670 PILLARS OF IMMUNOLOGY

49. Kawabata, K., M. Nagasawa, T. Morio, H. Okawa, and J. Yata. 1996. Decreased 54. Lanzi, G., D. Moratto, D. Vairo, S. Masneri, O. Delmonte, T. Paganini, alpha/beta heterodimer among CD8 molecules of peripheral blood T cells in S. Parolini, G. Tabellini, C. Mazza, G. Savoldi, et al. 2012. A novel primary human Wiskott-Aldrich syndrome. Clin. Immunol. Immunopathol. 81: 129–135. immunodeficiency due to deficiency in the WASP-interacting protein WIP. J. Exp. 50. Rawlings, S. L., G. M. Crooks, D. Bockstoce, L. W. Barsky, R. Parkman, and Med. 209: 29–34. K. I. Weinberg. 1999. Spontaneous apoptosis in lymphocytes from patients with 55. Casanova, J. L., M. E. Conley, S. J. Seligman, L. Abel, and L. D. Notarangelo. Wiskott-Aldrich syndrome: correlation of accelerated cell death and attenuated bcl- 2014. Guidelines for genetic studies in single patients: lessons from primary 2 expression. Blood 94: 3872–3882. immunodeficiencies. J. Exp. Med. 211: 2137–2149. 51. Gismondi, A., L. Cifaldi, C. Mazza, S. Giliani, S. Parolini, S. Morrone, J. Jacobelli, 56. Kawai, S., M. Minegishi, Y. Ohashi, Y. Sasahara, S. Kumaki, T. Konno, H. Miki, E. Bandiera, L. Notarangelo, and A. Santoni. 2004. Impaired natural and CD16- J. Derry, S. Nonoyama, T. Miyawaki, et al. 2002. Flow cytometric determination of mediated NK cell cytotoxicity in patients with WAS and XLT: ability of IL-2 to intracytoplasmic Wiskott-Aldrich syndrome protein in peripheral blood lymphocyte correct NK cell functional defect. Blood 104: 436–443. subpopulations. J. Immunol. Methods 260: 195–205. 52. Orange, J. S., S. Roy-Ghanta, E. M. Mace, S. Maru, G. D. Rak, K. B. Sanborn, 57. Boztug, K., M. Schmidt, A. Schwarzer, P. P. Banerjee, I. A. Dıéz, R. A. Dewey, A. Fasth, R. Saltzman, A. Paisley, L. Monaco-Shawver, et al. 2011. IL-2 induces M. Bo¨hm, A. Nowrouzi, C. R. Ball, H. Glimm, et al. 2010. Stem-cell gene therapy a WAVE2-dependent pathway for actin reorganization that enables WASp- for the Wiskott-Aldrich syndrome. N. Engl. J. Med. 363: 1918–1927. independent human NK cell function. J. Clin. Invest. 121: 1535–1548. 58. Aiuti, A., L. Biasco, S. Scaramuzza, F. Ferrua, M. P. Cicalese, C. Baricordi, 53. Jyonouchi,S.,B.Gwafila,L.A.Gwalani,M.Ahmad,C.Moertel,C.Holbert,J.Y.Kim, F. Dionisio, A. Calabria, S. Giannelli, M. C. Castiello, et al. 2013. Lentiviral N. Kobrinsky, S. Roy-Ghanta, and J. S. Orange. 2017. Phase I trial of low-dose inter- hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. leukin 2 therapy in patients with Wiskott-Aldrich syndrome. Clin. Immunol. 179: 47–53. Science 341: 1233151. Downloaded from http://www.jimmunol.org/ by guest on September 24, 2021