Current Pathobiology Reports

, Volume 6, Issue 3, pp 185–192 | Cite as

Mechanistic Clues to Overcome Spaceflight-Induced Immune Dysregulation

  • George Makedonas
  • Alexander Chouker
  • Satish Mehta
  • Richard Simpson
  • Raymond Stowe
  • Clarence Sams
  • Duane Pierson
  • Brian CrucianEmail author
Effects of the Space Environment on Human Pathobiology (R Kerschmann, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Effects of the Space Environment on Human Pathobiology


Purpose of Review

To recapitulate the latest findings from comprehensive studies of relatively long-duration spaceflight aboard the International Space Station, followed by exciting research published recently that illuminates the means by which we may be able to correct the immune system disturbances associated with spaceflight.

Recent Findings

While in space, most astronauts experience immune perturbations that may manifest as a form of immunodeficiency or, alternatively, a hypersensitivity reaction. When it occurs, the dysregulation persists stably for the duration of the mission. T lymphocytes – a population of the adaptive immune system that is essential for life – are particularly prone to spaceflight-induced malaise. Using cells from crewmembers during spaceflight, as well as cells in simulated microgravity model environments, researchers have begun to define specific alterations in antigen recognition, cell signaling, and gene expression patterns that may be responsible, in whole or in part, for the apparent depression in immune cell function.


Given the next major objective of the global space exploration community is voyage to Mars -- which means the missions will be of an unprecedented duration – it is reasonable to hypothesize the crewmembers’ health will be at greater risk than ever before. Thus, our communal goal is to devise a set of countermeasures that will obviate this risk. A prerequisite to this end is an understanding of the mechanisms underlying the immune perturbations.


Spaceflight-induced immune dysregulation Virus-specific immunity Herpesvirus reactivation Modeled microgravity T cells Gene expression 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict 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.


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

  1. 1.
    Kimzey SL, Ritzmann SE, Mengel CE, Fischer CL. Skylab experiment results: hematology studies. Acta Astronaut. 1975 Jan-Feb;2(1–2):141–54.CrossRefPubMedGoogle Scholar
  2. 2.
    Borchers AT, Keen CL, Gershwin ME. Microgravity and immune responsiveness: implications for space travel. Nutrition 2002;18(10):889–898. ReviewGoogle Scholar
  3. 3.
    Sonnenfeld G, Shearer WT. Immune function during space flight. Nutrition. 2002;18(10):899–903. ReviewCrossRefPubMedGoogle Scholar
  4. 4.
    Guéguinou N, Huin-Schohn C, Bascove M, Bueb JL, Tschirhart E, Legrand-Frossi C, et al. Could spaceflight-associated immune system weakening preclude the expansion of human presence beyond Earth's orbit? J Leukoc Biol. 2009;86(5):1027–38. Epub 2009 Aug 18. ReviewCrossRefPubMedGoogle Scholar
  5. 5.
    • Crucian B, Babiak-Vazquez A, Johnston S, Pierson DL, Ott CM, Sams C. Incidence of clinical symptoms during long-duration orbital spaceflight. Int J Gen Med. 2016;9:383–91. eCollection 2016. PubMed PMID: 27843335; PubMed Central PMCID: PMC5098747. This report is significant because it argues the space environment poses an actual clinical risk to astronauts.Google Scholar
  6. 6.
    Crucian B, Johnston S, Mehta S, Stowe R, Uchakin P, Quiriarte H, Pierson D, Laudenslager ML, Sams C. A case of persistent skin rash and rhinitis with immune system dysregulation onboard the international Space Station. J Allergy Clin Immunol Pract 2016 Jul-Aug;4(4):759–762.e8. doi: Epub 2016 Mar 29.
  7. 7.
    Crucian B, Chouker A, Simpson RJ, Mehta S, Marshall G, Smith SM, Zwart SR, Heer M, Ponomarev S, Whitmire A, Frippiat JP, Douglas G, Lorenzi H, Buchheim JI, Makedonas G, Ginsburg GS, Ott MC, Pierson D, Krieger S, Baecker N, Sams C. Immune system dysregulation during spaceflight: potential countermeasures for deep space exploration missions. Front Immunol 2018; 9(1437) doi:
  8. 8.
    Tavassoli M. Anemia of spaceflight. Blood. 1982;60(5):1059–67.PubMedGoogle Scholar
  9. 9.
    Smith SM. Red blood cell and iron metabolism during space flight. Nutrition. 2002;18(10):864–6. ReviewCrossRefPubMedGoogle Scholar
  10. 10.
    Kunz H, Quiriarte H, Simpson RJ, Ploutz-Snyder R, McMonigal K, Sams C, et al. Alterations in hematologic indices during long-duration spaceflight. BMC Hematol. 2017;17(12) eCollection 2017. PubMed PMID: 28904800; PubMed Central PMCID: PMC5590186
  11. 11.
    Crucian B, Stowe R, Mehta S, Uchakin P, Quiriarte H, Pierson D, et al. Immune system dysregulation occurs during short duration spaceflight on board the space shuttle. J Clin Immunol. 2013;33(2):456–65. Epub 2012 Oct 26CrossRefPubMedGoogle Scholar
  12. 12.
    •• Crucian B, Stowe RP, Mehta S, Quiriarte H, Pierson D, Sams C. Alterations in adaptive immunity persist during long-duration spaceflight. NPJ Microgravity. 2015;1:15013. eCollection 2015. PubMed PMID: 28725716; PubMed Central PMCID: PMC5515498. This study is important because the data from long-duration spaceflight argue that immune dysfunction is not a transient stress response to space voyage, but a condition that persists throughout the space experience.
  13. 13.
    Liu W, Zhu X, Zhao L, Yang X, Cao F, Huang Y, Mu P. [Effects of simulated weightlessness on biological activity of human NK cells induced by IL-2]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2015;31(10):1297–1300, 1305. Chinese.Google Scholar
  14. 14.
    Simpson RJ, Bigley AB, Spielmann G, Kunz HE, Agha N, Baker F, et al. Long duration spaceflight impairs NK-cell function in astronauts. Med Sci Sports Exerc. 2016;48(5 Suppl 1):87.CrossRefGoogle Scholar
  15. 15.
    Mehta SK, Crucian BE, Stowe RP, Simpson RJ, Ott CM, Sams CF, et al. Reactivation of latent viruses is associated with increased plasma cytokines in astronauts. Cytokine. 2013;61(1):205–9. Epub 2012 Oct 26CrossRefPubMedGoogle Scholar
  16. 16.
    Mehta SK, Laudenslager ML, Stowe RP, Crucian BE, Sams CF, Pierson DL. Multiple latent viruses reactivate in astronauts during space shuttle missions. Brain Behav Immun. 2014;41:210–7. Epub 2014 Jun 2CrossRefPubMedGoogle Scholar
  17. 17.
    •• Mehta SK, Laudenslager ML, Stowe RP, Crucian BE, Feiveson AH, Sams CF, et al. Latent virus reactivation in astronauts on the international space station. NPJ Microgravity. 2017;3:11. eCollection 2017. PubMed PMID: 28649633; PubMed Central PMCID: PMC5445581. This study attests that the incidence of herpesvirus reactivation is higher in astronauts in space than what is observed in humans on Earth. Furthermore, viral shedding among crewmembers persists throughout long-duration missions, and may approach levels seen in patients with overt disease.
  18. 18.
    Pierson DL, Stowe RP, Phillips TM, Lugg DJ, Mehta SK. Epstein-Barr virus shedding by astronauts during space flight. Brain Behav Immun. 2005;19(3):235–42.CrossRefPubMedGoogle Scholar
  19. 19.
    Ward C, Rettig TA, Hlavacek S, Bye BA, Pecaut MJ, Chapes SK. Effects of spaceflight on the immunoglobulin repertoire of unimmunized C57BL/6 mice. Life Sci Space Res (Amst). 2018;16:63–75. Epub 2017 Dec 2. PubMed PMID: 29475521; PubMed Central PMCID: PMC5826609CrossRefGoogle Scholar
  20. 20.
    Bradley JH, Stein R, Randolph B, Molina E, Arnold JP. Gregg RK. T cell resistance to activation by dendritic cells requires long-term culture in simulated microgravity. Life Sci Space Res (Amst). 2017;15:55–61. Epub 2017 Aug 8CrossRefGoogle Scholar
  21. 21.
    Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492–9. ReviewCrossRefPubMedGoogle Scholar
  22. 22.
    Kahan SM, Wherry EJ, Zajac AJ. T cell exhaustion during persistent viral infections. Virology. 2015:479, 180–80, 193. Epub 2015 Jan 22. Review. PubMed PMID: 25620767; PubMed Central PMCID:PMC4424083
  23. 23.
    Kulpa DA, Lawani M, Cooper A, Peretz Y, Ahlers J, Sékaly RP. PD-1 coinhibitory signals: the link between pathogenesis and protection. Semin Immunol. 2013;25(3):219–27. Epub 2013 Mar 31 Review. PubMed PMID: 23548749; PubMed Central PMCID: PMC3795833CrossRefPubMedGoogle Scholar
  24. 24.
    Wang C, Luo H, Zhu L, Yang F, Chu Z, Tian H, et al. Microgravity inhibition of lipopolysaccharide-induced tumor necrosis factor-α expression in macrophage cells. Inflamm Res. 2014;63(1):91–8. Epub 2013 Nov 6CrossRefPubMedGoogle Scholar
  25. 25.
    Wang C, Chen H, Luo H, Zhu L, Zhao Y, Tian H, et al. Microgravity activates p38 MAPK-C/EBPβ pathway to regulate the expression of arginase and inflammatory cytokines in macrophages. Inflamm Res. 2015;64(5):303–11. Epub 2015 Mar 25CrossRefPubMedGoogle Scholar
  26. 26.
    Tauber S, Lauber BA, Paulsen K, Layer LE, Lehmann M, Hauschild S, et al. Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity. PLoS One. 2017;12(4):e0175599. eCollection 2017. PubMed PMID: 28419128; PubMed Central PMCID: PMC5395169CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Tauber S, Hauschild S, Crescio C, Secchi C, Paulsen K, Pantaleo A, et al. Signal transduction in primary human T lymphocytes in altered gravity - results of the MASER-12 suborbital space flight mission. Cell Commun Signal. 2013;11(1):32. PubMed PMID: 23651740; PubMed Central PMCID: PMC3653714CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Tauber S, Hauschild S, Paulsen K, Gutewort A, Raig C, Hürlimann E, et al. Signal transduction in primary human T lymphocytes in altered gravity during parabolic flight and clinostat experiments. Cell Physiol Biochem. 2015;35(3):1034–51. Epub 2015 Feb 2CrossRefPubMedGoogle Scholar
  29. 29.
    Thiel CS, Paulsen K, Bradacs G, Lust K, Tauber S, Dumrese C, et al. Rapid alterations of cell cycle control proteins in human T lymphocytes in microgravity. Cell Commun Signal. 2012;10(1):1. PubMed PMID: 22273506; PubMed Central PMCID: PMC3275513CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    •• Hughes-Fulford M, Chang TT, Martinez EM, Li CF. Spaceflight alters expression of microRNA during T-cell activation. FASEB J. 2015;29(12):4893–900. Epub 2015 Aug 14. PubMed PMID: 26276131; PubMed Central PMCID: PMC4653058. This study proves that gene expression in human immune cells is downregulated in space relative to that on Earth.
  31. 31.
    •• Martinez EM, Yoshida MC, Candelario TL, Hughes-Fulford M. Spaceflight and simulated microgravity cause a significant reduction of key gene expression in early T-cell activation. Am J Physiol Regul Integr Comp Physiol. 2015;308(6):R480–8. Epub 2015 Jan 7. PubMed PMID: 25568077; PubMed Central PMCID: PMC4360066. This study used mice in space and on Earth to prove that altered gravity inhibits the expression of key early activation genes in T cells.
  32. 32.
    Thiel CS, Huge A, Hauschild S, Tauber S, Lauber BA, Polzer J, et al. Stability of gene expression in human T cells in different gravity environments is clustered in chromosomal region 11p15.4. NPJ Microgravity. 2017;3:22. eCollection 2017. PubMed PMID: 28868355; PubMed Central PMCID: PMC5579209CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Pecaut MJ, Mao XW, Bellinger DL, Jonscher KR, Stodieck LS, Ferguson VL, et al. Gridley DS. Is spaceflight-induced immune dysfunction linked to systemic changes in metabolism? PLoS One. 2017;12(5):e0174174. eCollection 2017. PubMed PMID: 28542224; PubMed Central PMCID: PMC5443495CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    •• Barrila J, Ott CM, LeBlanc C, Mehta SK, Crabbé A, Stafford P, et al. Spaceflight modulates Gene Expression in the whole blood of astronauts. NPJ Microgravity. 2016;2:16039. eCollection 2016. PubMed PMID: 28725744; PubMed Central PMCID: PMC5515525. This study demonstrates that the gene expression pattern in astronauts changed after spaceflight. The genes most affected included those related to DNA repair, oxidative stress, and protein folding; mechanisms important for proper cellular function.
  35. 35.
    Fernandez-Gonzalo R, Baatout S, Moreels M. Impact of particle irradiation on the immune system: from the clinic to Mars. Front Immunol. 2017;8:177. eCollection 2017. Review. PubMed PMID: 28275377; PubMed Central PMCID: PMC5319970CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Girardi C, De Pittà C, Casara S, Sales G, Lanfranchi G, Celotti L, et al. Analysis of miRNA and mRNA expression profiles highlights alterations in ionizing radiation response of human lymphocytes under modeled microgravity. PLoS One. 2012;7(2):e31293. Epub 2012 Feb 9. PubMed PMID: 22347458; PubMed Central PMCID: PMC3276573CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Musilova K, Mraz M. MicroRNAs in B-cell lymphomas: how a complex biology gets more complex. Leukemia. 2015;29(5):1004–17. Epub 2014 Dec 26. ReviewCrossRefPubMedGoogle Scholar
  38. 38.
    Wu K, Li L, Li S. Circulating microRNA-21 as a biomarker for the detection of various carcinomas: an updated meta-analysis based on 36 studies. Tumour Biol. 2015;36(3):1973–81. Epub 2014 Dec 20CrossRefPubMedGoogle Scholar
  39. 39.
    Patrick DM, Montgomery RL, Qi X, Obad S, Kauppinen S, Hill JA, et al. Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice. J Clin Invest. 2010;120(11):3912–6. Epub 2010 Oct 18. PubMed PMID: 20978354; PubMed Central PMCID: PMC2964990CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Mehta A, Baltimore D. MicroRNAs as regulatory elements in immune system logic. Nat Rev Immunol. 2016;16(5):279–94. ReviewCrossRefPubMedGoogle Scholar
  41. 41.
    Kelsen J, Bartels LE, Dige A, Hvas CL, Frings-Meuthen P, Boehme G, et al. 21 days head-down bed rest induces weakening of cell-mediated immunity - some spaceflight findings confirmed in a ground-based analog. Cytokine. 2012;59(2):403–9. Epub 2012 May 15CrossRefPubMedGoogle Scholar
  42. 42.
    Feuerecker M(1), Feuerecker B, Matzel S, Long M, Strewe C, Kaufmann I, Hoerl M, Schelling G, Rehm M, Choukèr A. Five days of head-down-tilt bed rest induces noninflammatory shedding of L-selectin. J Appl Physiol (1985) 2013;115(2):235–242. doi: Epub 2013 May 16. PubMed PMID: 23681910.
  43. 43.
    Van Walleghem M, Tabury K, Fernandez-Gonzalo R, Janssen A, Buchheim JI, Choukèr A, et al. Gravity-related immunological changes in human whole blood cultured under simulated microgravity using an in vitro cytokine release assay. J Interf Cytokine Res. 2017 Dec;37(12):531–40. Scholar

Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2018

Authors and Affiliations

  • George Makedonas
    • 1
  • Alexander Chouker
    • 2
  • Satish Mehta
    • 1
  • Richard Simpson
    • 3
  • Raymond Stowe
    • 4
  • Clarence Sams
    • 5
  • Duane Pierson
    • 5
  • Brian Crucian
    • 5
    Email author
  1. 1.JES TechHoustonUSA
  2. 2.Department of AnesthesiologyHospital of the Ludwig-Maximilians-UniversityMunichGermany
  3. 3.Laboratory of Integrated Physiology, Department of Health and Human PerformanceUniversity of HoustonHoustonUSA
  4. 4.Microgen LaboratoriesLa MarqueUSA
  5. 5.Biomedical Research and Environmental Sciences DivisionNASA Johnson Space CenterHoustonUSA

Personalised recommendations