Top

Published in:

01-01-2020 | Primary Immunodeficiency | How I Manage

How I Manage Natural Killer Cell Deficiency

Author: Jordan S. Orange

Published in: Journal of Clinical Immunology | Issue 1/2020

Abstract

Natural killer (NK) cell deficiency (NKD) is a subset of primary immunodeficiency disorders (PID) in which an abnormality of NK cells represents a major immunological defect resulting in the patient’s clinical immunodeficiency. This is distinct from a much larger group of PIDs that include an NK cell abnormality as a minor component of the immunodeficiency. Patients with NKD most frequently have atypical consequences of herpesviral infections. There are now 6 genes that have been ascribed to causing NKD, some exclusively and others that also cause other known immunodeficiencies. This list has grown in recent years and as such the mechanistic and molecular clarity around what defines an NKD is an emerging and important field of research. Continued increased clarity will allow for more rational approaches to the patients themselves from a therapeutic standpoint. Having evaluated numerous individuals for NKD, I share my perspective on approaching the diagnosis and managing these patients.

Lim AI, Di Santo JP. ILC-poiesis: ensuring tissue ILC differentiation at the right place and time. Eur J Immunol. 2019;49(1):11–8. https://doi.org/10.1002/eji.201747294.CrossRefPubMed

Orange JS, Mace EM, French AR, Yokoyama WM, Fehniger TA, Cooper MA. Comment on: evidence of innate lymphoid cell redundancy in humans. Nat Immunol. 2018;19(8):788–9. https://doi.org/10.1038/s41590-018-0164-5.CrossRefPubMedPubMedCentral

Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–10. https://doi.org/10.1038/ni1582.CrossRefPubMed

Ali A, Gyurova IE, Waggoner SN. Mutually assured destruction: the cold war between viruses and natural killer cells. Curr Opin Virol. 2019;34:130–9. https://doi.org/10.1016/j.coviro.2019.02.005.CrossRefPubMedPubMedCentral

Malmberg KJ, Carlsten M, Bjorklund A, Sohlberg E, Bryceson YT, Ljunggren HG. Natural killer cell-mediated immunosurveillance of human cancer. Semin Immunol. 2017;31:20–9. https://doi.org/10.1016/j.smim.2017.08.002.CrossRefPubMed

Sojka DK, Yang L, Yokoyama WM. Uterine natural killer cells: to protect and to nurture. Birth Defects Res. 2018;110(20):1531–8. https://doi.org/10.1002/bdr2.1419.CrossRefPubMedPubMedCentral

Angelo LS, Banerjee PP, Monaco-Shawver L, Rosen JB, Makedonas G, Forbes LR, et al. Practical NK cell phenotyping and variability in healthy adults. Immunol Res. 2015;62(3):341–56. https://doi.org/10.1007/s12026-015-8664-y.CrossRefPubMedPubMedCentral

Freud AG, Mundy-Bosse BL, Yu J, Caligiuri MA. The broad spectrum of human natural killer cell diversity. Immunity. 2017;47(5):820–33. https://doi.org/10.1016/j.immuni.2017.10.008.CrossRefPubMedPubMedCentral

Geary CD, Sun JC. Memory responses of natural killer cells. Semin Immunol. 2017;31:11–9. https://doi.org/10.1016/j.smim.2017.08.012.CrossRefPubMedPubMedCentral

10.

Sivori S, Vacca P, Del Zotto G, Munari E, Mingari MC, Moretta L. Human NK cells: surface receptors, inhibitory checkpoints, and translational applications. Cell Mol Immunol. 2019;16(5):430–41. https://doi.org/10.1038/s41423-019-0206-4.CrossRefPubMed

11.

Rajalingam R. Diversity of killer cell immunoglobulin-like receptors and disease. Clin Lab Med. 2018;38(4):637–53. https://doi.org/10.1016/j.cll.2018.08.001.CrossRefPubMed

12.

Vitale M, Cantoni C, Della Chiesa M, Ferlazzo G, Carlomagno S, Pende D, et al. An historical overview: the discovery of how NK cells can kill enemies, recruit defense troops, and more. Front Immunol. 2019;10:1415. https://doi.org/10.3389/fimmu.2019.01415.CrossRefPubMedPubMedCentral

13.

Orange JS, Fassett MS, Koopman LA, Boyson JE, Strominger JL. Viral evasion of natural killer cells. Nat Immunol. 2002;3(11):1006–12. https://doi.org/10.1038/ni1102-1006.CrossRefPubMed

14.

Jonjic S, Babic M, Polic B, Krmpotic A. Immune evasion of natural killer cells by viruses. Curr Opin Immunol. 2008;20(1):30–8. https://doi.org/10.1016/j.coi.2007.11.002.CrossRefPubMedPubMedCentral

15.

Martinez-Vicente P, Farre D, Sanchez C, Alcami A, Engel P, Angulo A. Subversion of natural killer cell responses by a cytomegalovirus-encoded soluble CD48 decoy receptor. PLoS Pathog. 2019;15(4):e1007658. https://doi.org/10.1371/journal.ppat.1007658.CrossRefPubMedPubMedCentral

16.

Mace EM, Dongre P, Hsu HT, Sinha P, James AM, Mann SS, et al. Cell biological steps and checkpoints in accessing NK cell cytotoxicity. Immunol Cell Biol. 2014;92(3):245–55. https://doi.org/10.1038/icb.2013.96.CrossRefPubMedPubMedCentral

17.

Gwalani LA, Orange JS. Single degranulations in NK cells can mediate target cell killing. J Immunol. 2018;200(9):3231–43. https://doi.org/10.4049/jimmunol.1701500.CrossRefPubMedPubMedCentral

18.

Orange JS. Formation and function of the lytic NK-cell immunological synapse. Nat Rev Immunol. 2008;8(9):713–25. https://doi.org/10.1038/nri2381.CrossRefPubMedPubMedCentral

19.

Sepulveda FE, de Saint Basile G. Hemophagocytic syndrome: primary forms and predisposing conditions. Curr Opin Immunol. 2017;49:20–6. https://doi.org/10.1016/j.coi.2017.08.004.CrossRefPubMed

20.

Chinn IK, Eckstein OS, Peckham-Gregory EC, Goldberg BR, Forbes LR, Nicholas SK, et al. Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis. Blood. 2018;132(1):89–100. https://doi.org/10.1182/blood-2017-11-814244.CrossRefPubMedPubMedCentral

21.

Huntington ND. The unconventional expression of IL-15 and its role in NK cell homeostasis. Immunol Cell Biol. 2014;92(3):210–3. https://doi.org/10.1038/icb.2014.1.CrossRefPubMed

22.

Ham H, Billadeau DD. Human immunodeficiency syndromes affecting human natural killer cell cytolytic activity. Front Immunol. 2014;5:2. https://doi.org/10.3389/fimmu.2014.00002.CrossRefPubMedPubMedCentral

23.

Mace EM, Orange JS. Emerging insights into human health and NK cell biology from the study of NK cell deficiencies. Immunol Rev. 2019;287(1):202–25. https://doi.org/10.1111/imr.12725.CrossRefPubMedPubMedCentral

24.

Orange JS. Human natural killer cell deficiencies and susceptibility to infection. Microbes Infect. 2002;4(15):1545–58.CrossRef

25.

Orange JS. NK cell deficiency syndromes. In: Rose B, (ed) UpToDate. Waltham 2018. https://www.uptodate.com/home/how-use-uptodate-presentation

26.

Orange JS. Natural killer cell deficiency. J Allergy Clin Immunol. 2013;132(3):515–25. https://doi.org/10.1016/j.jaci.2013.07.020.CrossRefPubMedPubMedCentral

27.

Voss M, Bryceson YT. Natural killer cell biology illuminated by primary immunodeficiency syndromes in humans. Clin Immunol. 2017;177:29–42. https://doi.org/10.1016/j.clim.2015.11.004.CrossRefPubMed

28.

Mace EM. Requirements for human natural killer cell development informed by primary immunodeficiency. Curr Opin Allergy Clin Immunol. 2016;16(6):541–8. https://doi.org/10.1097/ACI.0000000000000317.CrossRefPubMed

29.

Orange JS. Natural killer cell deficiency. In: Sullivan KE, Stiehm ER, editors. Stiehm’s immune deficiencies. London: Elsevier/AP; 2014. p. 765–72.CrossRef

30.

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. https://doi.org/10.1182/blood-2012-09-453969.CrossRefPubMedPubMedCentral

31.

Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123(6):809–21. https://doi.org/10.1182/blood-2013-07-515528.CrossRefPubMedPubMedCentral

32.

Cottineau J, Kottemann MC, Lach FP, Kang YH, Vely 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. https://doi.org/10.1172/JCI90727.CrossRefPubMedPubMedCentral

33.

Mace EM, Bigley V, Gunesch JT, Chinn IK, Angelo LS, Care MA, et al. Biallelic mutations in IRF8 impair human NK cell maturation and function. J Clin Invest. 2017;127(1):306–20. https://doi.org/10.1172/JCI86276.CrossRefPubMed

34.

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. https://doi.org/10.1172/JCI61014.CrossRefPubMedPubMedCentral

35.

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. https://doi.org/10.1172/JCI60224.CrossRefPubMedPubMedCentral

36.

Hanna S, Beziat V, Jouanguy E, Casanova JL, Etzioni A. A homozygous mutation of RTEL1 in a child presenting with an apparently isolated natural killer cell deficiency. J Allergy Clin Immunol. 2015;136(4):1113–4. https://doi.org/10.1016/j.jaci.2015.04.021.CrossRefPubMed

37.

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. https://doi.org/10.1172/JCI64837.CrossRefPubMedPubMedCentral

38.

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.CrossRef

39.

Jouanguy E, Gineau L, Cottineau J, Beziat V, Vivier E, Casanova JL. Inborn errors of the development of human natural killer cells. Curr Opin Allergy Clin Immunol. 2013;13(6):589–95. https://doi.org/10.1097/ACI.0000000000000011.CrossRefPubMedPubMedCentral

40.

Mace EM, Orange JS. Genetic causes of human NK cell deficiency and their effect on NK cell subsets. Front Immunol. 2016;7:545. https://doi.org/10.3389/fimmu.2016.00545.CrossRefPubMedPubMedCentral

41.

Biron CA, Byron KS, Sullivan JL. Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med. 1989;320(26):1731–5.CrossRef

42.

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.CrossRef

43.

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.CrossRef

44.

Bernard F, Picard C, Cormier-Daire V, Eidenschenk C, Pinto G, Bustamante JC, et al. A novel developmental and immunodeficiency syndrome associated with intrauterine growth retardation and a lack of natural killer cells. Pediatrics. 2004;113(1 Pt 1):136–41.CrossRef

45.

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. https://doi.org/10.4049/jimmunol.177.12.8835.CrossRefPubMed

46.

Fleisher G, Starr S, Koven N, Kamiya H, Douglas SD, Henle W. A non-x-linked syndrome with susceptibility to severe Epstein-Barr virus infections. J Pediatr. 1982;100(5):727–30. https://doi.org/10.1016/s0022-3476(82)80572-6.CrossRefPubMed

47.

Moon WY, Powis SJ. Does natural killer cell deficiency (NKD) increase the risk of cancer? NKD may increase the risk of some virus induced cancer. Front Immunol. 2019;10:1703. https://doi.org/10.3389/fimmu.2019.01703.CrossRefPubMedPubMedCentral

48.

Orange JS, Ramesh N, Remold-O’Donnell E, Sasahara Y, Koopman L, Byrne M, et al. Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc Natl Acad Sci U S A. 2002;99(17):11351–6. https://doi.org/10.1073/pnas.162376099.CrossRefPubMedPubMedCentral

49.

Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr. 1994;125(6 Pt 1):876–85. https://doi.org/10.1016/s0022-3476(05)82002-5.CrossRefPubMed

50.

Reiche EM, Nunes SO, Morimoto HK. Stress, depression, the immune system, and cancer. Lancet Oncol. 2004;5(10):617–25. https://doi.org/10.1016/S1470-2045(04)01597-9.CrossRefPubMed

51.

Zorrilla EP, Luborsky L, McKay JR, Rosenthal R, Houldin A, Tax A, et al. The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun. 2001;15(3):199–226. https://doi.org/10.1006/brbi.2000.0597.CrossRefPubMed

52.

Goyos A, Fort M, Sharma A, Lebrec H. Current concepts in natural killer cell biology and application to drug safety assessments. Toxicol Sci. 2019. https://doi.org/10.1093/toxsci/kfz098.

53.

Cederbrant K, Marcusson-Stahl M, Condevaux F, Descotes J. NK-cell activity in immunotoxicity drug evaluation. Toxicology. 2003;185(3):241–50.CrossRef

54.

Alsweed A, Alsuhibani M, Casanova JL, Al-Hajjar S. Approach to recurrent herpes simplex encephalitis in children. Int J Pediatr Adolesc Med. 2018;5(2):35–8. https://doi.org/10.1016/j.ijpam.2018.05.004.CrossRefPubMedPubMedCentral

55.

Mahapatra S, Mace EM, Minard CG, Forbes LR, Vargas-Hernandez A, Duryea TK, et al. High-resolution phenotyping identifies NK cell subsets that distinguish healthy children from adults. PLoS One. 2017;12(8):e0181134. https://doi.org/10.1371/journal.pone.0181134.CrossRefPubMedPubMedCentral

56.

Lamy T, Moignet A, Loughran TP Jr. LGL leukemia: from pathogenesis to treatment. Blood. 2017;129(9):1082–94. https://doi.org/10.1182/blood-2016-08-692590.CrossRefPubMed

57.

Rubin TS, Zhang K, Gifford C, Lane A, Choo S, Bleesing JJ, et al. Perforin and CD107a testing is superior to NK cell function testing for screening patients for genetic HLH. Blood. 2017;129(22):2993–9. https://doi.org/10.1182/blood-2016-12-753830.CrossRefPubMedPubMedCentral

58.

Gotlieb N, Rosenne E, Matzner P, Shaashua L, Sorski L, Ben-Eliyahu S. The misleading nature of in vitro and ex vivo findings in studying the impact of stress hormones on NK cell cytotoxicity. Brain Behav Immun. 2015;45:277–86. https://doi.org/10.1016/j.bbi.2014.12.020.CrossRefPubMed

59.

Shaw RK, Issekutz AC, Fraser R, Schmit P, Morash B, Monaco-Shawver L, et al. Bilateral adrenal EBV-associated smooth muscle tumors in a child with a natural killer cell deficiency. Blood. 2012;119(17):4009–12. https://doi.org/10.1182/blood-2011-10-385377.CrossRefPubMedPubMedCentral

60.

Cohen JI. GATA2 Deficiency and Epstein-Barr virus disease. Front Immunol. 2017;8:1869. https://doi.org/10.3389/fimmu.2017.01869.CrossRefPubMedPubMedCentral

61.

Santoli D, Trinchieri G, Koprowski H. Cell-mediated cytotoxicity against virus-infected target cells in humans. II. Interferon induction and activation of natural killer cells. J Immunol. 1978;121(2):532–8.PubMed

62.

Bolay H, Karabudak R, Aybay C, Candemir H, Varli K, Imir T, et al. Alpha interferon treatment in myasthenia gravis: effects on natural killer cell activity. J Neuroimmunol. 1998;82(2):109–15.CrossRef

63.

Evans A, Main E, Zier K, Ikegaki N, Tartaglione M, Kennett R, et al. The effects of gamma interferon on the natural killer and tumor cells of children with neuroblastoma. A preliminary report. Cancer. 1989;64(7):1383–7.CrossRef

64.

Trinchieri G, Matsumoto-Kobayashi M, Clark SC, Seehra J, London L, Perussia B. Response of resting human peripheral blood natural killer cells to interleukin 2. J Exp Med. 1984;160(4):1147–69.CrossRef

65.

Caligiuri MA, Murray C, Robertson MJ, Wang E, Cochran K, Cameron C, et al. Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. J Clin Invest. 1993;91(1):123–32. https://doi.org/10.1172/JCI116161.CrossRefPubMedPubMedCentral

66.

Jyonouchi S, Gwafila B, Gwalani LA, Ahmad M, Moertel C, Holbert C, et al. Phase I trial of low-dose interleukin 2 therapy in patients with Wiskott-Aldrich syndrome. Clin Immunol. 2017;179:47–53. https://doi.org/10.1016/j.clim.2017.02.001.CrossRefPubMed

67.

Notarangelo LD, Mazzolari E. Natural killer cell deficiencies and severe varicella infection. J Pediatr. 2006;148(4):563–4 author reply 4.CrossRef

68.

Naik S, Nicholas SK, Martinez CA, Leen AM, Hanley PJ, Gottschalk SM, et al. Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes. J Allergy Clin Immunol. 2016;137(5):1498–505 e1. https://doi.org/10.1016/j.jaci.2015.12.1311.CrossRefPubMedPubMedCentral

Title: How I Manage Natural Killer Cell Deficiency
Author: Jordan S. Orange
Publication date: 01-01-2020
Publisher: Springer US
Keywords: Primary Immunodeficiency
Immunodeficiency
Published in: Journal of Clinical Immunology / Issue 1/2020
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-019-00711-7

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

How I Manage Natural Killer Cell Deficiency

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2020

MiR-608 Exerts Anti-inflammatory Effects by Targeting ELANE in Monocytes

Unreported Missense Mutation in the Dimerization Domain of ADA2 Leads to ADA2 Deficiency Associated with Severe Oral Ulcers and Neutropenia in a Female Somalian Patient—Addendum to the Genotype-Phenotype Puzzle

Prophylactic Antibiotics Versus Immunoglobulin Replacement in Specific Antibody Deficiency

Extended Follow-up After Hematopoietic Cell Transplantation for IκBα Deficiency with Disseminated Mycobacterium avium Infection

A Large Cohort of RAG1/2-Deficient SCID Patients—Clinical, Immunological, and Prognostic Analysis

Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page