Associating Changes in the Immune System with Clinical Diseases for Interpretation in Risk Assessment

Jamie C. DeWitt1, Dori R. Germolec2, Robert W. Luebke3, Victor J. Johnson4

1 Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, 2 Division of the National Toxicology Program, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, 3 Cardiopulmonary and Immunotoxicology Branch, United States Environmental Protection Agency, Research Triangle Park, North Carolina, 4 Burleson Research Technologies, Morrisville, North Carolina
Publication Name:  Current Protocols in Toxicology
Unit Number:  Unit 18.1
DOI:  10.1002/0471140856.tx1801s67
Online Posting Date:  February, 2016
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library


This overview is an update of the unit originally published in 2004. While the basic tenets of immunotoxicity have not changed in the past 10 years, several publications have explored the application of immunotoxicological data to the risk assessment process. Therefore, the goal of this unit is still to highlight relationships between xenobiotic‐induced immunosuppression and risk of clinical diseases progression. In immunotoxicology, this may require development of models to equate moderate changes in markers of immune functions to potential changes in incidence or severity of infectious diseases. For most xenobiotics, exposure levels and disease incidence data are rarely available, and safe exposure levels must be estimated based on observations from experimental models or human biomarker studies. Thus, it is important to establish a scientifically sound framework that allows accurate and quantitative interpretation of experimental or biomarker data in the risk assessment process. © 2016 by John Wiley & Sons, Inc.

Keywords: immunotoxicity; immunosuppression; xenobiotic exposure

PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • Diseases Associated With Immunosuppression
  • Considerations for the Use of Human Data in Immunotoxicology Risk Assessment
  • Immunosuppression and Relationship to Infectious Disease
  • Immune System, Disease, and Life Stage
  • Experimental Animal Models
  • Social and Economic Impacts of Common Pathogens
  • Conclusions
  • Acknowledgments
  • Disclaimer
  • Literature Cited
  • Figures
  • Tables
PDF or HTML at Wiley Online Library


PDF or HTML at Wiley Online Library



Literature Cited

Literature Cited
  Ahmed, S., Shapiro, N.L., and Bhattacharyya, N. 2014. Incremental health care utilization and costs for acute otitis media in children. Laryngoscope 124:301‐305. doi: 10.1002/lary.24190.
  ALA (American Lung Association). 2010a. Trends in pneumonia and influenza morbidity and mortality. Am. Lung Assoc. Res. Program Serv. Epidemiol. Stat. Unit. 2010. Washington, D.C.
  ALA (American Lung Association). 2010b. Influenza and pneumonia: State of lung disease in diverse communities. Washington, D.C.
  Ambruso, D.R., Bentwood, B., Henson, P.M., and Johnston, R.B. Jr. 1984. Oxidative metabolism of cord blood neutrophils: Relationship to content and degranulation of cytoplasmic granules. Pediatr. Res. 18:1148‐1153. doi: 10.1203/00006450‐198411000‐00019.
  André‐Schmutz, I., Six, E., Bonhomme, D., Rouiller, J., Dal Cortivo, L., Fischer, A., and Cavazzana‐Calvo, M. 2009. Shortening the immunodeficient period after hematopoietic stem cell transplantation. Immunol. Res. 44:54‐60. doi: 10.1007/s12026‐008‐8080‐7.
  Antonini, J.M. 2003. Health effects of welding. Crit. Rev. Toxicol. 33:61‐103. doi: 10.1080/713611032.
  Arndt, V., Vine, M.F., and Weigle, K. 1999. Environmental chemical exposures and risk of herpes zoster. Environ. Health Perspect. 107:835‐841. doi: 10.1289/ehp.99107835.
  Aspinall, R., Del Giudice, G., Effros, R.B., Grubeck‐Loebenstein, B., and Sambhara, S. 2007. Challenges for vaccination in the elderly. Immun. Ageing. 4:9. doi: 10.1186/1742‐4933‐4‐9.
  Atkinson, K., Champlin, R., Ritz, J., Fibbe, W.E., Ljungman, P., and Brenner, M.K. (eds.) 2000. Clinical Bone Marrow and Blood Stem Cell Transplantation, Cambridge University Press, Boston.
  Baken, K.A., Pennings, J.L., Jonker, M.J., Schaap, M.M., de Vries, A., van Steeg, H., Breit, T.M., and van Loveren, H. 2008. Overlapping gene expression profiles of model compounds provide opportunities for immunotoxicity screening. Toxicol. Appl. Pharmacol. 226:46‐59. doi: 10.1016/j.taap.2007.08.026.
  Biondi, M. and Zannino, L.G. 1997. Psychological stress, neuroimmunomodulation, and susceptibility to infectious diseases in animals and man: A review. Psychother. Psychosom. 66:3‐26. doi: 10.1159/000289101.
  Boverhof, D.R., Ladics, G., Luebke, B., Botham, J., Evans, E., Germolec, D., Holsapple, M., Loveless, S.E., Lu, H., van der Laan, J.W., White, K.L., Jr., and Yang, Y. 2014. Approaches and considerations for the assessment of immunotoxicity for environmental chemicals: A workshop summary. Regul. Toxicol. Pharmacol. 68:96‐107. doi: 10.1016/j.yrtph.2013.11.012.
  Bradley, S.G. 1995b. Listeria host resistance model. In Methods in Immunotoxicology, (G.R. Burleson, J.H. Dean, and A.E. Munson, eds.) pp. 169‐179. Wiley‐Liss, New York.
  Burleson, F.G. and Burleson, G.R. 2008. Testing human biologicals in animal host resistance models. J. Immunotoxicol. 5:23‐31. doi: 10.1080/15476910801897557.
  Burleson, F.G. and Burleson, G.R. 2010. Host resistance assays including bacterial challenge models. Methods Mol. Biol. 598:97‐108. doi: 10.1007/978‐1‐60761‐401‐2_7.
  Chakrabarti, S., Collingham, K.E., Marshall, T., Holder, K., Gentle, T., Hale, G., Fegan, C.D., and Milligan, D.W. 2001. Respiratory virus infections in adult T cell‐depleted transplant recipients: The role of cellular immunity. Transplantation 72:1460‐1463. doi: 10.1097/00007890‐200110270‐00024.
  Chung, B., Montel‐Hagen, A., Ge, S., Blumberg, G., Kim, K., Klein, S., Zhu, Y., Parekh, C., Balamurugan, A., Yang, O.O., and Crooks, G.M. 2014. Engineering the human thymic microenvironment to support thymopoiesis in vivo. Stem Cells. 32:2386‐2396. doi: 10.1002/stem.1731.
  Ciccimarra, F. 1994. Fetal and neonatal immunology. J. Perinat. Med. 22(Supp. 1):84‐87. doi: 10.1515/jpme.1994.22.s1.84.
  Clark, K.R., Forsythe, J.L., Shenton, B.K., Lennard, T.W., Proud, G., and Taylor, R.M. 1993. Administration of ATG according to the absolute T lymphocyte count during therapy for steroid‐resistant rejection. Transpl. Int. 6:18‐21. doi: 10.1111/j.1432‐2277.1993.tb00738.x.
  Clover, R.D., Abell, T., Becker, L.A., Crawford, S., and Ramsey, C.N. Jr. 1989. Family functioning and stress as predictors of influenza B infection. J. Fam. Pract. 28:535‐539.
  Cohen, S. 1995. Psychological stress and susceptibility to upper respiratory infections. Am. J. Respir. Crit. Care Med. 152:S53‐S58. doi: 10.1164/ajrccm/152.4_Pt_2.S53.
  Cohen, S., Tyrrell, D.A., and Smith, A.P. 1991. Psychological stress and susceptibility to the common cold. N. Engl. J. Med. 325:606‐612. doi: 10.1056/NEJM199108293250903.
  Cohen, S., Doyle, W.J., and Skoner, D.P. 1999. Psychological stress, cytokine production, and severity of upper respiratory illness. Psychosom. Med. 61:175‐180. doi: 10.1097/00006842‐199903000‐00009.
  Cohen, S., Janicki‐Deverts, D., Doyle, W.J., Miller, G.E., Frank, E., Rabin, B.S., and Turner, R.B. 2012. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc. Natl. Acad. Sci. USA. 109:5995‐5999. doi: 10.1073/pnas.1118355109.
  Corsini E., Sokooti, M., Galli, C.L., Moretto, A., and Colosio, C. 2013. Pesticide induced immunotoxicity in humans: A comprehensive review of the existing evidence. Toxicology. 307:123‐135. doi: 10.1016/j.tox.2012.10.009.
  Damjanovic, A.K., Yang, Y., Glaser, R., Kiecolt‐Glaser, J.K., Nguyen, H., Laskowski, B., Zou, Y., Beversdorf, D.Q., and Weng, N.P. 2007. J. Immunol. 179:4249‐4254. doi: 10.4049/jimmunol.179.6.4249.
  De Barros, S.C., Zimmermann, V.S., and Taylor, N. 2013. Concise review: Hematopoietic stem cell transplantation: Targeting the thymus. Stem Cells. 31:1245‐1251. doi: 10.1002/stem.1378.
  Dietert, R.R., and DeWitt, J.C. 2010. Developmental immunotoxicity (DIT): the why, when, and how of DIT testing. Methods Mol. Biol. 598:17‐25. doi: 1007/978‐1‐60761‐401‐2_2.
  Deseda‐Tous, J., Cherry, J.D., Spencer, M.J., Welliver, R.C., Boyer, K.M., Dudley, J.P., Zahradnik, J.M., Krause, P.J., and Walbergh, E.W. 1978. Measles revaccination. Persistence and degree of antibody titer by type of immune response. Am. J. Dis. Child. 132:287‐290. doi: 10.1001/archpedi.1978.02120280071015.
  Dewailly, E., Ayotte, P., Bruneau, S., Gingras, S., Belles‐Isles, M., and Roy, R. 2000. Susceptibility to infections and immune status in Inuit infants exposed to organochlorines. Environ. Health Perspect. 108:205‐211. doi: 10.1289/ehp.00108205.
  Emmett, E.A., Zhang, H., Shofer, F.S., Freeman, D., Rodway, N.V., Desai, C., and Shaw, L.M. 2006. Community exposure to perfluorooctanoate: Relationships between serum levels and certain health parameters. J. Occup. Environ. Med. 48:771‐779. doi: 10.1097/01.jom.0000233380.13087.37.
  Esterling, B.A., Antoni, M.H., Kumar, M., and Schneiderman, N. 1993. Defensiveness, trait anxiety, and Epstein‐Barr viral capsid antigen antibody titers in healthy college students. Health Psychol. 12:132‐139. doi: 10.1037/0278‐6133.12.2.132.
  Faden, H. 2001. The microbiologic and immunologic basis for recurrent otitis media in children. Eur. J. Pediatr. 160:407‐413. doi: 10.1007/s004310100754.
  Faqundes, C.P., Glaser, R., and Kiecolt‐Glaser, J.K. 2013. Stressful early life experiences and immune dysregulation across the lifespan. Brain Behave. Immun. 27:8‐12. doi: 10.1016/j.bbi.2012.06.014.
  Faqundes, C.P., Jaremka, L.M., Glaser, R., Alfano, C.M., Povoski, S.P., Lipari, A.M., Agnese, D.M., Yee, L.D., Carson, W.E., 3rd, Farrar, W.B., Malarkey, W.B., Chen, M., and Kiecolt‐Glaser, J.K. 2014. Attachment anxiety is related to Epstein‐Barr virus latency. Brain Behave. Immun. 41:232‐238. doi: 10.1016/j.bbi.2014.04.002.
  Fletcher, T., Steenland, K., and Savitz, D. 2009. Status report: PFOA and immune biomarkers in adults exposed to PFOA in drinking water in the mid Ohio valley. C8 Science Panel.
  Gardner, D.E. 2001. Bioaerosols and disease. In Patty's Industrial Hygiene and Toxicology, (E. Bingham, B. Cohrssen, and C.H. Powell, eds.) pp. 679‐711. Wiley, New York.
  Gavazzi, G. and Krause, K.H. 2002. Aging and infection. Lancet Infect. Dis. 2:659‐666. doi: 10.1016/S1473‐3099(02)00437‐1.
  Germolec, D.R. 2003. Selectivity and predictivity in immunotoxicity testing: Immune endpoints and disease resistance. Toxcol. Lett. 149:109‐114. doi:10.1016/j.toxlet.2003.12.025
  Glaser, R., Sheridan, J., Malarkey, W.B., MacCallum, R.C., and Kiecolt‐Glaser, J.K. 2000. Chronic stress modulates the immune response to a pneumococcal pneumonia vaccine. Psychosom. Med. 62:804‐807. doi: 10.1097/00006842‐200011000‐00010.
  Glaser, R., Kiecolt‐Glaser, J.K., Bonneau, R.H., Malarkey, W., Kennedy, S., and Hughes, J. 1992. Stress‐induced modulation of the immune response to recombinant hepatitis B vaccine. Psychosom. Med. 54:22‐29. doi: 10.1097/00006842‐199201000‐00005.
  Glaser, R., Pearson, G.R., Bonneau, R.H., Esterling, B.A., Atkinson, C., and Kiecolt‐Glaser, J.K. 1993. Stress and the memory T‐cell response to the Epstein‐Barr virus in healthy medical students. Health Psychol. 12:435‐442. doi: 10.1037/0278‐6133.12.6.435.
  Glaser, R., Rice, J., Sheridan, J., Fertel, R., Stout, J., Speicher, C., Pinsky, D., Kotur, M., Post, A., Beck, M., and Kiecolt‐Glaser, J. 1987. Stress‐related immune suppression: Health implications. Brain. Behav. Immun. 1:7‐20. doi: 10.1016/0889‐1591(87)90002‐X.
  Glynn, A., Thuvander, A., Aune, M., Johannisson, A., Darnerud, P.O., Ronquist, G., and Cnattingius, S. 2008. Environ. Health. 7:62. doi: 10.1186/1476‐069X‐7‐62.
  Gouin, J.P., Hantsoo, L., and Kiecolt‐Glaser, J.K. 2008. Immune dysfunction and chronic stress among older adults: A review. Neuroimmunomodulation 15:251‐259. doi: 10.1159/000156468.
  Granum, B., Haug, L.S., Namork, E., Stølevik, S.B., Thomsen, C., Aaberge, I.S., van Loveren, H., Løvik, M., and Nygaard, U.C. 2013. Pre‐natal exposure to perfluoroalkyl substances may be associated with altered vaccine antibody levels and immune‐related health outcomes in early childhood. J. Immunotoxicol. 10:373‐379. doi: 10.3109/1547691X.2012.755580.
  Hartevelt, M.M., Bavinck, J.N., Kootte, A.M., Vermeer, B.J., and Vandenbroucke, J.P. 1990. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation 49:506‐509. doi: 10.1097/00007890‐199003000‐00006.
  Herberman, R.B. 2001. Immunotherapy. In Clinical Oncology., (R.E. Jr. Lenhard, R.T. Osteen, and T. Gansler, eds.) pp. 215‐223. American Cancer Society, Atlanta.
  Heron, M. 2013. Deaths: Leading causes for 2010. Natl Vital Stat Rep. 62(6). National Center for Health Statistics, Hyattsville, MD.
  Herzyk, D.J., Ruggieri, E.V., Cunningham, L., Polsky, R., Herold, C., Klinkner, A.M., Badger, A., Kerns, W.D., and Bugelski, P.J. 1997. Single‐organism model of host defense against infection: A novel immunotoxicologic approach to evaluate immunomodulatory drugs. Toxicol. Pathol. 25:351‐362. doi: 10.1177/019262339702500403.
  Hochstenbach, K. van Leeuwen, D.M., Gmuender, H., Stølevik, S.B., Nygaard, U.C., Løvik, M., Granum, B., Namork, E., van Delft, J.H., and van Loveren, H. 2010. Transcriptomic profile indicative of immunotoxic exposure: In vitro studies in peripheral blood mononuclear cells. Toxicol. Sci. 118:19‐30. doi: 10.1093/toxsci/kfq239.
  House, R.V. 2010. Fundamentals of clinical immunotoxicology. In Immunotoxicity Testing (R.R. Dietert, ed.) pp. 363‐384. Humana Press, Totowa, N.J.
  Jamil, B., Nicholls, K., Becker, G.J., and Walker, R.G. 1999. Impact of acute rejection therapy on infections and malignancies in renal transplant recipients. Transplantation 68:1597‐1603. doi: 10.1097/00007890‐199911270‐00027.
  Karmaus, W., Kuehr, J., and Kruse, H. 2001. Infections and atopic disorders in childhood and organochlorine exposure. Arch. Environ. Health 56:485‐492. doi: 10.1080/00039890109602896.
  Kasl, S.V., Evans, A.S., and Niederman, J.C. 1979. Psychosocial risk factors in the development of infectious mononucleosis. Psychosom. Med. 41:445‐466. doi: 10.1097/00006842‐197910000‐00002.
  Kawecki, D., Pacholczyk, M., Lagiewska, B., Sawicka‐Grzelak, A., Durlik, M., Mlynarczyk, G., and Chmura, A. 2014. Bacterial and fungal infections in the early post‐transplantation period after liver transplantation: Etiologic agents and their susceptibility. Transplant. Proc. 46:2777‐2781. doi: 10.1016/j.transproceed.2014.08.031.
  Keil, D., Luebke, R.W., and Pruett, S.B. 2001. Quantifying the relationship between multiple immunological parameters and host resistance: Probing the limits of reductionism. J. Immunol. 167:4543‐4552. doi: 10.4049/jimmunol.167.8.4543.
  Kiecolt‐Glaser, J.K., McGuire, L., Robles, T.F., and Glaser, R. 2002. Psychoneuroimmunology: Psychological influences on immune function and health. J. Consult. Clin. Psychol. 70:537‐547. doi: 10.1037/0022‐006X.70.3.537.
  Kiecolt‐Glaser, J.K., Glaser, R., Gravenstein, S., Malarkey, W.B., and Sheridan, J. 1996. Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc. Natl. Acad. Sci. U. S. A. 93:3043‐3047. doi: 10.1073/pnas.93.7.3043.
  Kiecolt‐Glaser, J.K., Glaser, R., Shuttleworth, E.C., Dyer, C.S., Ogrocki, P., and Speicher, C.E. 1987. Chronic stress and immunity in family caregivers of Alzheimer's disease victims. Psychosom. Med. 49:523‐535. doi: 10.1097/00006842‐198709000‐00008.
  Kiecolt‐Glaser, J.K., Glaser, R., Strain, E.C., Stout, J.C., Tarr, K.L., Holliday, J.E., and Speicher, C.E. 1986. Modulation of cellular immunity in medical students. J. Behav. Med. 9:5‐21. doi: 10.1007/BF00844640.
  Kishi, R., Kobayahsi, S., Ikeno, T., Araki, A., Miyashita, C., Itoh, S., Sasaki, S., Okada, E., Kobayashi, S., Kashino, I., Itoh, K., Nakajima, S., and Members of the Hokkaido Study on Environment and Children's Health. 2013. Ten years of progress in the Hokkaido birth cohort study on environment and children's health: Cohort profile—updated 2013. Environ. Health. Prev. Med. 18:429‐450. doi: 10.1007/s12199‐013‐0357‐3.
  Leigh, J.P., Yasmeen, S., and Miller, T.R. 2003. Medical costs of fourteen occupational illnesses in the United States in 1999. Scand. J. Work. Environ. Health 29:304‐313. doi: 10.5271/sjweh.735.
  Lesourd, B.M. 1997. Nutrition and immunity in the elderly: Modification of immune responses with nutritional treatments. Am. J. Clin. Nutr. 66:478S‐484S.
  Lesourd, B. 1999. Immune response during disease and recovery in the elderly. Proc. Nutr. Soc. 58:85‐98. doi: 10.1079/PNS19990013.
  Levy, O., Martin, S., Eichenwald, E., Ganz, T., Valore, E., Carroll, S.F., Lee, K., Goldmann, D., and Thorne, G.M. 1999. Impaired innate immunity in the newborn: Newborn neutrophils are deficient in bactericidal/permeability‐increasing protein. Pediatrics 104:1327‐1333. doi: 10.1542/peds.104.6.1327.
  Looker, C., Luster, M.I., Calafat, A.M., Johnson, V.J., Burleson, G.R., Burleson, F.G., and Fletcher, T. 2014. Influenza vaccine response in adults exposed to perfluorooctanoate and perfluorooctanesulfonate. Toxicol. Sci. 138:76‐88. doi: 10.1093/toxsci/kft269.
  Lu, Y.C. and Wu, Y.C. 1985. Clinical findings and immunological abnormalities in Yu‐Cheng patients. Environ. Health Perspect. 59:17‐29. doi: 10.2307/3429869.
  Luebke, R.W. 1995. Assessment of host resistance to infection with rodent malaria. In Methods in Immunotoxicology (G.R. Burleson, J.H. Dean, and A.E. Munson, eds.) pp. 221‐242. Wiley‐Liss, New York.
  Luebke, R.W. 2002. Pesticide‐induced immunotoxicity: Are humans at risk? Human Ecol. Risk Assess. 8:293‐303. doi: 10.1080/20028091056926.
  Luebke, R.W. 2010. Parasite challenge as host resistance models for immunotoxicity testing. Methods Mol. Biol. 598:119‐141. doi: 10.1007/978‐1‐60761‐401‐2_9.
  Luebke, R.W., Parks, C., and Luster, M.I. 2004. Suppression of immune function and susceptibility to infections in humans: Association of immune function with clinical disease. J. Immunotoxicol. 1:15‐24. doi: 10.1080/15476910490438342.
  Luebke, R.W., Holsapple, M.P., Ladics, G.S., Luster, M.I., Selgrade, M., Smialowicz, R.J., Woolhiser, M.R., and Germolec, D.R. 2006. Immunotoxicogenomics: The potential of genomics technology in the immunotoxicology risk assessment process. Toxicol. Sci. 94:22‐27. doi: 10.1093/toxsci/kfl074.
  Luster, M.I., Johnson, V.J., Yucesoy, B., and Simeonova, P.P. 2005. Biomarkers to assess potential developmental immunotoxicity in children. Toxicol. Appl. Pharmacol. 206:229‐236. doi: 10.1016/j.taap.2005.02.010.
  Luster, M.I., Munson, A.E., Thomas, P.T., Holsapple, M.P., Fenters, J.D., White, K.L. Jr., Lauer, L.D., Germolec, D.R., Rosenthal, G.J., and Dean, J.H. 1988. Development of a testing battery to assess chemical‐induced immunotoxicity: National Toxicology Program's guidelines for immunotoxicity evaluation in mice. Fundam. Appl. Toxicol. 10:2‐19. doi: 10.1016/0272‐0590(88)90247‐3.
  Luster, M.I., Portier, C., Pait, D.G., Rosenthal, G.J., Germolec, D.R., Corsini, E., Blaylock, B.L., Pollock, P., Kouchi, Y., Craig, W., White, K.L., Munson, A.E., and Comment, C.E. 1993. Risk assessment in immunotoxicology. II. Relationships between immune and host resistance tests. Fundam. Appl. Toxicol. 21:71‐82. doi: 10.1006/faat.1993.1074.
  Marsland, A.L., Bachen, E.A., Cohen, S., Rabin, B., and Manuck, S.B. 2002. Stress, immune reactivity and susceptibility to infectious disease. Physiol. Behav. 77:711‐716. doi: 10.1016/S0031‐9384(02)00923‐X.
  Mathews, T.J. and MacDorman, M.F. 2013. Infant mortality statistics from the 2010 period linked birth/infant death data set. Natl. Vital. Stat. Rep. 62(8). National Center for Health Statistics, Hyattsville, MD
  Meyer, R.J. and Haggerty, R.J. 1962. Streptococcal infections in families. Factors altering individual susceptibility. Pediatrics 29:539‐549.
  Mouton, C.P., Bazaldua, O.V., Pierce, B., and Espino, D.V. 2001. Common infections in older adults. Health Care Food Nutr. Focus. 18:3‐7.
  Nakanishi, Y., Shigematsu, N., Kurita, Y., Matsuba, K., Kanegae, H., Ishimaru, S., and Kawazoe, Y. 1985. Respiratory involvement and immune status in yusho patients. Environ. Health Perspect. 59:31‐36. doi: 10.2307/3429870.
  Nish, S. and Medzhitov, R. 2011. Host defense pathways: A role of redundancy and compensation in infectious disease phenotypes. Immunity. 34:629‐636. doi: 10.1016/j.immuni.2011.05.009.
  O'Shea, D.T. and Humar, A. 2013. Life‐threatening infection in transplant recipients. Crit. Care Clin. 29:953‐973. doi: 10.1016/j.ccc.2013.06.012.
  Ochs, L., Shu, X.O., Miller, J., Enright, H., Wagner, J., Filipovich, A., Miller, W., and Weisdorf, D. 1995. Late infections after allogeneic bone marrow transplantations: Comparison of incidence in related and unrelated donor transplant recipients. Blood 86:3979‐3986.
  Orange, J.S. 2002. Human natural killer cell deficiencies and susceptibility to infection. Microbes Infect. 4:1545‐1558. doi: 10.1016/S1286‐4579(02)00038‐2.
  Palmer, K.T. and Cosgrove, M. 2012. Vaccinating welders against pneumonia. Occup. Environ. Med. 69:932. doi: 10.1136/oemed‐2012‐101057.
  Paramore, L.C., Ciuryla, V., Ciesla, G., and Liu, L. 2004. Economic impact of respiratory syncytial virus‐related illness in the US: An analysis of national databases. Pharmacoeconomics 22:275‐284. doi: 10.2165/00019053‐200422050‐00001.
  Pedersen, M. and Seetharam, A. 2014. Infections after orthotopic liver transplantation. J. Clin. Exp. Hepatol. 4:347‐360. doi: 10.1016/j.jceh.2014.07.004.
  Penn, I. 2000. Post‐transplant malignancy: The role of immunosuppression. Drug Saf. 23:101‐113. doi: 10.2165/00002018‐200023020‐00002.
  Petit, J.C. 1980. Resistance to listeriosis in mice that are deficient in the fifth component of complement. Infect. Immun. 27:61‐67.
  Routes, J., Abinun, M., Al‐Herz, W., Bustamante, J., Condino‐Neto, A., De La Morena, M.T., Etzioni A., Gambineri, E., Haddad, E., Kobrynski, L., Le Deist, F., Nonoyama, S., Oliveira, J.B., Perez, E., Picard, C., Rezaei, N., Sleasman, J., Sullivan, K.E., and Torgerson, T. 2014. ICON: The early diagnosis of congenital immunodeficiencies. J. Clin. Immunol. 34:369‐424.
  Saif, M.A., Bonney, D.K., Bigger, B., Forsythe, L., Williams, N., Page, J., Babiker, Z.O., Guiver, M., Turner, A.J., Hughes, S., and Wynn, R.F. 2011. Chronic norovirus infection in pediatric hematopoietic stem cell transplant recipients: A cause of prolonged intestinal failure requiring intensive nutritional support. Pediatr. Transplant. 15:505‐509. doi: 10.1111/j.1399‐3046.2011.01500.x.
  Schultz, C., Reiss, I., Bucsky, P., Gopel, W., Gembruch, U., Ziesenitz, S., and Gortner, L. 2000. Maturational changes of lymphocyte surface antigens in human blood: Comparison between fetuses, neonates and adults. Biol. Neonate 78:77‐82. doi: 10.1159/000014253.
  Selgrade, M.K., Daniels, M.J., and Dean, J.H. 1992. Correlation between chemical suppression of natural killer cell activity in mice and susceptibility to cytomegalovirus: Rationale for applying murine cytomegalovirus as a host resistance model and for interpreting immunotoxicity testing in terms of risk of disease. J. Toxicol. Environ. Health 37:123‐137. doi: 10.1080/15287399209531660.
  Sheridan, J.F., Tutschka, P.J., Sedmak, D.D., and Copelan, E.A. 1990. Immunoglobulin G subclass deficiency and pneumococcal infection after allogeneic bone marrow transplantation. Blood 75:1583‐1586.
  Sia, I.G. and Paya, C.V. 1998. Infectious complications following renal transplantation. Surg. Clin. North Am. 78:95‐112. doi: 10.1016/S0039‐6109(05)70637‐X.
  Sleijffers, A., Yucesoy, B., Kashon, M., Garssen, J., De Gruijl, F.R., Boland, G.J., Van Hattum, J., Luster, M.I., and van Loveren, H. 2003. Cytokine polymorphisms play a role in susceptibility to ultraviolet B‐induced modulation of immune responses after hepatitis B vaccination. J. Immunol. 170:3423‐3428. doi: 10.4049/jimmunol.170.6.3423.
  Small, T.N., Papadopoulos, E.B., Boulad, F., Black, P., Castro‐Malaspina, H., Childs, B.H., Collins, N., Gillio, A., George, D., Jakubowski, A., Heller, G., Fazzari, M., Kernan, N., MacKinnon, S., Szabolcs, P., Young, J.W., and O'Reilly, R.J. 1999. Comparison of immune reconstitution after unrelated and related T‐cell‐depleted bone marrow transplantation: Effect of patient age and donor leukocyte infusions. Blood 93:467‐480.
  Steele, C., Zheng, M., Young, E., Marrero, L., Shellito, J.E., and Kolls, J.K. 2002. Increased host resistance against Pneumocystis carinii pneumonia in gammadelta T‐cell‐deficient mice: Protective role of gamma interferon and CD8(+) T cells. Infect. Immun. 70:5208‐5215. doi: 10.1128/IAI.70.9.5208‐5215.2002.
  Stiehm, E.R. and Fudenberg, H.H. 1966. Serum levels of immune globulins in health and disease: A survey. Pediatrics 37:715‐727.
  Storek, J., Gooley, T., Witherspoon, R.P., Sullivan, K.M., and Storb, R. 1997. Infectious morbidity in long‐term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am. J. Hematol. 54:131‐138. doi: 10.1002/(SICI)1096‐8652(199702)54:2%3c131::AID‐AJH6%3e3.0.CO;2‐Y.
  Storek, J., Espino, G., Dawson, M.A., Storer, B., Flowers, M.E., and Maloney, D.G. 2000. Low B‐cell and monocyte counts on day 80 are associated with high infection rates between days 100 and 365 after allogeneic marrow transplantation. Blood 96:3290‐3293.
  Targonski, P.V., Jacobson, R.M., and Poland, G.A. 2007. Immunosenescence: Role and measurement in influenza vaccine response among the elderly. Vaccine 25:3066‐3069. doi: 10.1016/j.vaccine.2007.01.025.
  Thomas, P.S., Yates, D.H., and Barnes, P.J. 1995. Tumor necrosis factor‐α increases airway responsiveness and sputum neutrophilia in normal human subjects. Am. J. Respir. Crit. Care Med. 152:76‐80. doi: 10.1164/ajrccm.152.1.7599866.
  Tuschl, H., Weber, E., and Kovac, R. 1997. Investigations on immune parameters in welders. J. Appl. Toxicol. 17:377‐383. doi: 10.1002/(SICI)1099‐1263(199711/12)17:6%3c377::AID‐JAT454%3e3.0.CO;2‐8.
  Upham, J.W., Lee, P.T., Holt, B.J., Heaton, T., Prescott, S.L., Sharp, M.J., Sly, P.D., and Holt, P.G. 2002. Development of interleukin‐12‐producing capacity throughout childhood. Infect. Immun. 70:6583‐6588. doi: 10.1128/IAI.70.12.6583‐6588.2002.
  van Loveren, H., Luebke, R.W., and Vos, J.G. 1995. Assessment of immunotoxicity with the parasitic infection model Trichinella spiralis. In Methods in Immunotoxicology (G.R. Burleson, J.H. Dean, and A.E. Munson, eds.) pp. 243‐271. Wiley‐Liss, New York.
  van Loveren, H., van Amsterdam, J.G., Vandebriel, R.J., Kimman, T.G., Rumke, H.C., Steerenberg, P.S., and Vos, J.G. 2001. Vaccine‐induced antibody responses as parameters of the influence of endogenous and environmental factors. Environ. Health Perspect. 109:757‐764. doi: 10.1289/ehp.01109757.
  Vial, T., Nicolas, B., and Descotes, J. 1996. Clinical immunotoxicity of pesticides. J. Toxicol. Environ. Health 48:215‐229. doi: 10.1080/009841096161294.
  Vine, M.F., Stein, L., Weigle, K., Schroeder, J., Degnan, D., Tse, C.K., and Backer, L. 2001. Plasma 1,1‐dichloro‐2,2‐bis(p‐chlorophenyl) ethylene (DDE) levels and immune response. Am. J. Epidemiol. 153:53‐63. doi: 10.1093/aje/153.1.53.
  Vine, M.F., Stein, L., Weigle, K., Schroeder, J., Degnan, D., Tse, C.K., Hanchette, C., and Backer, L. 2000. Effects on the immune system associated with living near a pesticide dump site. Environ. Health Perspect. 108:1113‐1124. doi: 10.1289/ehp.001081113.
  Voccia, I., Blakley, B., Brousseau, P., and Fournier, M. 1999. Immunotoxicity of pesticides: A review. Toxicol. Ind. Health 15:119‐132. doi: 10.1191/074823399678846637.
  Weaver, J.L., Broud, D.D., McKinnon, K., and Germolec, D.R. 2002. Serial phenotypic analysis of mouse peripheral blood leukocytes. Toxicol. Mech. Methods 12:95‐118. doi: 10.1080/10517230290075341.
  Weisglas‐Kuperus, N., Patandin, S., Berbers, G.A., Sas, T.C., Mulder, P.G., Sauer, P.J., and Hooijkaas, H. 2000. Immunologic effects of background exposure to polychlorinated biphenyls and dioxins in Dutch preschool children. Environ. Health Perspect. 108:1203‐1207. doi: 10.1289/ehp.001081203.
  Wieneke, H., Otte, B., Lang, D., and Heidenreich, S. 1996. Predictive value of IgG subclass levels for infectious complications in renal transplant recipients. Clin. Nephrol. 45:22‐28.
  Wilson, C.B. 1986. Immunologic basis for increased susceptibility of the neonate to infection. J. Pediatr. 108:1‐12. doi: 10.1016/S0022‐3476(86)80761‐2.
  Wilson, S.D., McCay, J.A., Butterworth, L.F., Munson, A.E., and White, K.L. Jr. 2001. Correlation of suppressed natural killer cell activity with altered host resistance models in B6C3F1 mice. Toxicol. Appl. Pharmacol. 177:208‐218. doi: 10.1006/taap.2001.9298.
  Wolach, B., Carmi, D., Gilboa, S., Satar, M., Segal, S., Dolfin, T., and Schlesigner, M. 1994. Some aspects of the humoral immunity and the phagocytic function in newborn infants. Israeli J. Med. Sci. 30:331‐335.
  Wong, A., Marrie, T.J., Garg, S., Kellner, J.D., Tyrrell, G.J., and SPAT Group. 2010. Welders are at increased risk for invasive pneumococcal disease. Int. J. Infect. Dis. 14:e796‐799. doi: 10.1016/j.ijid.2010.02.2268.
  Yang, E.V. and Glaser, R. 2000. Stress‐induced immunomodulation: Impact on immune defenses against infectious disease. Biomed. Pharmacother. 54:245‐250. doi: 10.1016/S0753‐3322(00)80066‐9.
  Yoshikawa, T.T. 1983. Geriatric infectious diseases: An emerging issue. J. Amer. Geriatr. Soc. 31:34‐39. doi: 10.1111/j.1532‐5415.1983.tb06285.x.
  Yu, M.L., Hsin, J.W., Hsu, C.C., Chan, W.C., and Guo, Y.L. 1998. The immunologic evaluation of the Yucheng children. Chemosphere 37:1855‐1865. doi: 10.1016/S0045‐6535(98)00251‐3.
  Yucesoy, B., Vallyathan, V., Landsittel, D.P., Sharp, D.S., Weston, A., Burleson, G.R., Simeonova, P., McKinstry, M., and Luster, M.I. 2001. Association of tumor necrosis factor‐alpha and interleukin‐1 gene polymorphisms with silicosis. Toxicol. Appl. Pharmacol. 172:75‐82. doi: 10.1006/taap.2001.9124.
  Zeidler‐Erdely, P.C., Erdely, A., and Antonini, J.M. 2012. Immunotoxicology of arc welding fume: Worker and experimental animal studies. J. Immunotoxicol. 9:411‐425. doi: 10.3109/1547691X.2011.652783.
PDF or HTML at Wiley Online Library