Advertisement

The Impact of Immunodeficiency on NK Cell Maturation and Function

  • Alexander Vargas-Hernández
  • Lisa R. ForbesEmail author
Immune Deficiency and Dysregulation (Caroline Kuo, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Immune Deficiency and Dysregulation

Abstract

Purpose of Review

Natural killer cells are innate lymphoid cells (ILCs) that play critical roles in human host defense and are especially useful in combating viral pathogens and malignancy.

Recent Findings

The NK cell deficiency (NKD) is particularly underscored in patients with a congenital immunodeficiency in which NK cell development or function is affected. The classical NK cell deficiency (cNKD) is a result of absent or a profound decrease in the number of circulating NK cells. In contrast, functional NKD (fNKD) is characterized by abnormal NK cell function but with normal number of NK cells. The combined immune deficiencies with significant impact on NK cells are not considered classical or functional NK cell deficiencies. In these disorders, the impairment of NK cells represents an important aspect of the overall immunodeficiency. In turn, this leads to improved insights on the NK cell development and function.

Summary

Here, we detail the NK cell biology based upon recent natural killer cell defects described in combined immune deficiencies.

Keywords

Natural killer cells NK cell deficiency 

Notes

Acknowledgments

We acknowledge Dr. Emily Mace, for her critical review of the manuscript.

Funding

Chao Physician Scientist Junior Faculty Award, Baylor College of Medicine

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Mace EM, et al. Biallelic mutations in IRF8 impair human NK cell maturation and function. J Clin Invest. 2017;127(1):306–20.PubMedGoogle Scholar
  2. 2.
    •• Vargas-Hernandez A, et al. Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations. J Allergy Clin Immunol. 2018;141(6):2142–2155 e5 This study shows that JAK inibition can partially rescue NK cell function in STAT1-GOF patients. PubMedGoogle Scholar
  3. 3.
    Voss M, Bryceson YT. Natural killer cell biology illuminated by primary immunodeficiency syndromes in humans. Clin Immunol. 2017;177:29–42.PubMedGoogle Scholar
  4. 4.
    Ham H, Billadeau DD. Human immunodeficiency syndromes affecting human natural killer cell cytolytic activity. Front Immunol. 2014;5:2.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Orange JS. Natural killer cell deficiency. J Allergy Clin Immunol. 2013;132(3):515–25.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Mace EM, Orange JS. Genetic causes of human NK cell deficiency and their effect on NK cell subsets. Front Immunol. 2016;7:545.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Mace EM, Hsu AP, Monaco-Shawver L, Makedonas G, Rosen JB, Dropulic L, et al. Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56(bright) subset. Blood. 2013;121(14):2669–77.PubMedPubMedCentralGoogle Scholar
  8. 8.
    de Vries E, Koene HR, Vossen JM, Gratama JW, von dem Borne A, Waaijer JL, et al. Identification of an unusual Fc gamma receptor IIIa (CD16) on natural killer cells in a patient with recurrent infections. Blood. 1996;88(8):3022–7.PubMedGoogle Scholar
  9. 9.
    Grier JT, Forbes LR, Monaco-Shawver L, Oshinsky J, Atkinson TP, Moody C, et al. Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity. J Clin Invest. 2012;122(10):3769–80.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Jawahar S, Moody C, Chan M, Finberg R, Geha R, Chatila T. Natural killer (NK) cell deficiency associated with an epitope-deficient Fc receptor type IIIA (CD16-II). Clin Exp Immunol. 1996;103(3):408–13.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Vinh DC, Patel SY, Uzel G, Anderson VL, Freeman AF, Olivier KN, et al. Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood. 2010;115(8):1519–29.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Hsu AP, Sampaio EP, Khan J, Calvo KR, Lemieux JE, Patel SY, et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood. 2011;118(10):2653–5.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Kazenwadel J, Secker GA, Liu YJ, Rosenfeld JA, Wildin RS, Cuellar-Rodriguez J, et al. Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood. 2012;119(5):1283–91.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Dickinson RE, Griffin H, Bigley V, Reynard LN, Hussain R, Haniffa M, et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood. 2011;118(10):2656–8.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Gineau L, Cognet C, Kara N, Lach FP, Dunne J, Veturi U, et al. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J Clin Invest. 2012;122(3):821–32.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Hughes CR, Guasti L, Meimaridou E, Chuang CH, Schimenti JC, King PJ, et al. MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest. 2012;122(3):814–20.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Eidenschenk C, Dunne J, Jouanguy E, Fourlinnie C, Gineau L, Bacq D, et al. A novel primary immunodeficiency with specific natural-killer cell deficiency maps to the centromeric region of chromosome 8. Am J Hum Genet. 2006;78(4):721–7.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Cottineau J, Kottemann MC, Lach FP, Kang YH, Vély F, Deenick EK, et al. Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. J Clin Invest. 2017;127(5):1991–2006.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Eidenschenk C, Jouanguy E, Alcais A, Mention JJ, Pasquier B, Fleckenstein IM, et al. Familial NK cell deficiency associated with impaired IL-2- and IL-15-dependent survival of lymphocytes. J Immunol. 2006;177(12):8835–43.PubMedGoogle Scholar
  20. 20.
    Etzioni A, Eidenschenk C, Katz R, Beck R, Casanova JL, Pollack S. Fatal varicella associated with selective natural killer cell deficiency. J Pediatr. 2005;146(3):423–5.PubMedGoogle Scholar
  21. 21.
    Lenart M, Trzyna E, Rutkowska M, Bukowska-Strakova K, Szaflarska A, Pituch-Noworolska A, et al. The loss of the CD16 B73.1/Leu11c epitope occurring in some primary immunodeficiency diseases is not associated with the FcgammaRIIIa-48L/R/H polymorphism. Int J Mol Med. 2010;26(3):435–42.PubMedGoogle Scholar
  22. 22.
    Ilves I, Petojevic T, Pesavento JJ, Botchan MR. Activation of the MCM2-7 helicase by association with Cdc45 and GINS proteins. Mol Cell. 2010;37(2):247–58.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Fedick AM, Shi L, Jalas C, Treff NR, Ekstein J, Kornreich R, et al. Carrier screening of RTEL1 mutations in the Ashkenazi Jewish population. Clin Genet. 2015;88(2):177–81.PubMedGoogle Scholar
  24. 24.
    Ballew BJ, Joseph V, de S, Sarek G, Vannier JB, Stracker T, et al. A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. PLoS Genet. 2013;9(8):e1003695.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Ballew BJ, Yeager M, Jacobs K, Giri N, Boland J, Burdett L, et al. Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in dyskeratosis congenita. Hum Genet. 2013;132(4):473–80.PubMedPubMedCentralGoogle Scholar
  26. 26.
    James AM, Hsu HT, Dongre P, Uzel G, Mace EM, Banerjee PP, et al. Rapid activation receptor- or IL-2-induced lytic granule convergence in human natural killer cells requires Src, but not downstream signaling. Blood. 2013;121(14):2627–37.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Kohl S, et al. Defective natural killer cytotoxicity and polymorphonuclear leukocyte antibody-dependent cellular cytotoxicity in patients with LFA-1/OKM-1 deficiency. J Immunol. 1984;133(6):2972–8.PubMedGoogle Scholar
  28. 28.
    Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016;127(25):3154–64.PubMedPubMedCentralGoogle Scholar
  29. 29.
    van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LAB, Gilissen C, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011;365(1):54–61.PubMedGoogle Scholar
  30. 30.
    Sampaio EP, Hsu AP, Pechacek J, Bax HI, Dias DL, Paulson ML, et al. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol. 2013;131(6):1624–34.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011;208(8):1635–48.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Toth B, et al. Herpes in STAT1 gain-of-function mutation [corrected]. Lancet. 2012;379(9835):2500.PubMedGoogle Scholar
  33. 33.
    Tabellini G, Vairo D, Scomodon O, Tamassia N, Ferraro RM, Patrizi O, et al. Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations. J Allergy Clin Immunol. 2017;140(2):553–64 e4.PubMedGoogle Scholar
  34. 34.
    Caldirola MS, Rodríguez Broggi MG, Gaillard MI, Bezrodnik L, Zwirner NW. Primary immunodeficiencies unravel the role of IL-2/CD25/STAT5b in human natural killer cell maturation. Front Immunol. 2018;9:1429.PubMedPubMedCentralGoogle Scholar
  35. 35.
    •• Ruiz-Garcia R, et al. Mutations in PI3K110delta cause impaired natural killer cell function partially rescued by rapamycin treatment. J Allergy Clin Immunol. 2018;142(2):605–617 e7 PI3K110delta mutations impair natural killer cell function which can be partially rescued with rapamycin treatment.PubMedGoogle Scholar
  36. 36.
    •• Salzer E, et al. RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nat Immunol. 2016;17(12):1352–60 Cytoskeletal dynamics are essential to NK cell function. RASGRP1 deficient NK cells have decreased cytotoxicity.PubMedPubMedCentralGoogle Scholar
  37. 37.
    •• Dobbs K, et al. Natural killer cells from patients with recombinase-activating gene and non-homologous end joining gene defects comprise a higher frequency of CD56(bright) NKG2A(+++) cells, and yet display increased degranulation and higher perforin content. Front Immunol. 2017;8:798 RAG mutations can affect NK cell maturation leading to abnormal expression of developmental markers and NK inhibitory receptors.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Mossner R, et al. Ruxolitinib induces interleukin 17 and ameliorates chronic mucocutaneous candidiasis caused by STAT1 gain-of-function mutation. Clin Infect Dis. 2016;62(7):951–3.PubMedGoogle Scholar
  39. 39.
    Weinacht KG, Charbonnier LM, Alroqi F, Plant A, Qiao Q, Wu H, et al. Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation. J Allergy Clin Immunol. 2017;139(5):1629–40 e2.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Hwa V, Camacho-Hübner C, Little BM, David A, Metherell LA, el-Khatib N, 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. 2007;68(5):218–24.PubMedGoogle Scholar
  41. 41.
    Nadeau K, Hwa V, Rosenfeld RG. STAT5b deficiency: an unsuspected cause of growth failure, immunodeficiency, and severe pulmonary disease. J Pediatr. 2011;158(5):701–8.PubMedGoogle Scholar
  42. 42.
    Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003;349(12):1139–47.PubMedGoogle Scholar
  43. 43.
    Cohen AC, Nadeau KC, Tu W, Hwa V, Dionis K, Bezrodnik L, et al. Cutting edge: decreased accumulation and regulatory function of CD4+ CD25(high) T cells in human STAT5b deficiency. J Immunol. 2006;177(5):2770–4.PubMedGoogle Scholar
  44. 44.
    Bernasconi A, Marino R, Ribas A, Rossi J, Ciaccio M, Oleastro M, et al. Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics. 2006;118(5):e1584–92.PubMedGoogle Scholar
  45. 45.
    Ma CA, Xi L, Cauff B, DeZure A, Freeman AF, Hambleton S, et al. Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. Blood. 2017;129(5):650–3.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A, et al. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med. 2009;206(1):25–34.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Mrozek E, et al. Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells. Blood. 1996;87(7):2632–40.PubMedGoogle Scholar
  48. 48.
    Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866–71.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. Dominant-activating germline mutations in the gene encoding the PI(3) K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88–97.PubMedGoogle Scholar
  50. 50.
    Chantry D, Vojtek A, Kashishian A, Holtzman DA, Wood C, Gray PW, et al. p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem. 1997;272(31):19236–41.PubMedGoogle Scholar
  51. 51.
    Kok K, Nock GE, Verrall EAG, Mitchell MP, Hommes DW, Peppelenbosch MP, et al. Regulation of p110delta PI 3-kinase gene expression. PLoS One. 2009;4(4):e5145.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Kok K, Geering B, Vanhaesebroeck B. Regulation of phosphoinositide 3-kinase expression in health and disease. Trends Biochem Sci. 2009;34(3):115–27.PubMedGoogle Scholar
  53. 53.
    Dornan GL, Siempelkamp BD, Jenkins ML, Vadas O, Lucas CL, Burke JE. Conformational disruption of PI3Kdelta regulation by immunodeficiency mutations in PIK3CD and PIK3R1. Proc Natl Acad Sci U S A. 2017;114(8):1982–7.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597–606 e4.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Marti F, Xu CW, Selvakumar A, Brent R, Dupont B, King PD. LCK-phosphorylated human killer cell-inhibitory receptors recruit and activate phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A. 1998;95(20):11810–5.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Eissmann P, Beauchamp L, Wooters J, Tilton JC, Long EO, Watzl C. Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244). Blood. 2005;105(12):4722–9.PubMedGoogle Scholar
  57. 57.
    Kanakaraj P, Duckworth B, Azzoni L, Kamoun M, Cantley LC, Perussia B. Phosphatidylinositol-3 kinase activation induced upon fc gamma RIIIA-ligand interaction. J Exp Med. 1994;179(2):551–8.PubMedGoogle Scholar
  58. 58.
    Ebinu JO, Bottorff DA, Chan EY, Stang SL, Dunn RJ, Stone JC. RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. Science. 1998;280(5366):1082–6.PubMedGoogle Scholar
  59. 59.
    Roose J, Weiss A. T cells: getting a GRP on Ras. Nat Immunol. 2000;1(4):275–6.PubMedGoogle Scholar
  60. 60.
    Lee SH, Yun S, Lee J, Kim MJ, Piao ZH, Jeong M, et al. RasGRP1 is required for human NK cell function. J Immunol. 2009;183(12):7931–8.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Rivera-Munoz P, Malivert L, Derdouch S, Azerrad C, Abramowski V, Revy P, et al. DNA repair and the immune system: from V(D) J recombination to aging lymphocytes. Eur J Immunol. 2007;37(Suppl 1):S71–82.PubMedGoogle Scholar
  62. 62.
    Lee YN, Frugoni F, Dobbs K, Tirosh I, du L, Ververs FA, et al. Characterization of T and B cell repertoire diversity in patients with RAG deficiency. Sci Immunol. 2016;1(6):eaah6109.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Notarangelo LD, Kim MS, Walter JE, Lee YN. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016;16(4):234–46.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Niehues T, Perez-Becker R, Schuetz C. More than just SCID—the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin Immunol. 2010;135(2):183–92.PubMedGoogle Scholar
  65. 65.
    Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, et al. RAG mutations in human B cell-negative SCID. Science. 1996;274(5284):97–9.PubMedGoogle Scholar
  66. 66.
    Villa A, Santagata S, Bozzi F, Giliani S, Frattini A, Imberti L, et al. Partial V(D) J recombination activity leads to Omenn syndrome. Cell. 1998;93(5):885–96.PubMedGoogle Scholar
  67. 67.
    de Villartay JP, Lim A, al-Mousa H, Dupont S, Déchanet-Merville J, Coumau-Gatbois E, et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest. 2005;115(11):3291–9.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Ehl S, Schwarz K, Enders A, Duffner U, Pannicke U, Kühr J, et al. A variant of SCID with specific immune responses and predominance of gamma delta T cells. J Clin Invest. 2005;115(11):3140–8.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Felgentreff K, Perez-Becker R, Speckmann C, Schwarz K, Kalwak K, Markelj G, et al. Clinical and immunological manifestations of patients with atypical severe combined immunodeficiency. Clin Immunol. 2011;141(1):73–82.PubMedGoogle Scholar
  70. 70.
    Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, et al. An immunodeficiency disease with RAG mutations and granulomas. N Engl J Med. 2008;358(19):2030–8.PubMedGoogle Scholar
  71. 71.
    De Ravin SS, et al. Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood. 2010;116(8):1263–71.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Henderson LA, et al. Expanding the spectrum of recombination-activating gene 1 deficiency: a family with early-onset autoimmunity. J Allergy Clin Immunol. 2013;132(4):969–71 e1-2.PubMedGoogle Scholar
  73. 73.
    Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, et al. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J Clin Invest. 2016;126(11):4389.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, et al. A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. J Allergy Clin Immunol. 2014;133(4):1099–108.PubMedGoogle Scholar
  75. 75.
    Notarangelo LD, Mazzolari E. Natural killer cell deficiencies and severe varicella infection. J Pediatr. 2006;148(4):563–4 author reply 564.PubMedGoogle Scholar
  76. 76.
    Cuellar-Rodriguez J, Gea-Banacloche J, Freeman AF, Hsu AP, Zerbe CS, Calvo KR, et al. Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. Blood. 2011;118(13):3715–20.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Genovese P, Schiroli G, Escobar G, di Tomaso T, Firrito C, Calabria A, et al. Targeted genome editing in human repopulating haematopoietic stem cells. Nature. 2014;510(7504):235–40.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Kuo CY. Advances in site-specific gene editing for primary immune deficiencies. Curr Opin Allergy Clin Immunol. 2018;18:453–8.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Alexander Vargas-Hernández
    • 1
    • 2
  • Lisa R. Forbes
    • 1
    • 2
    Email author
  1. 1.Department of Pediatrics, Immunology Allergy and RheumatologyBaylor College of MedicineHoustonUSA
  2. 2.Center for Human Immunobiology, William T Shearer Center for Human ImmunobiologyTexas Children’s HospitalHoustonUSA

Personalised recommendations