Nutritional imbalances and infections affect the thymus: Consequences on T-cell-mediated immune responses
Open accessAbstract
The thymus gland, where T lymphocyte development occurs, is targeted in malnutrition secondary to protein energy deficiency. There is a severe thymic atrophy, resulting from massive thymocyte apoptosis (particularly affecting the immature CD4+CD8+ cell subset) and decrease in cell proliferation. The thymic microenvironment (the non-lymphoid compartment that drives intrathymic T-cell development) is also affected in malnutrition: morphological changes in thymic epithelial cells were found, together with a decrease of thymic hormone production, as well as an increase of intrathymic contents of extracellular proteins. Profound changes in the thymus can also be seen in deficiencies of vitamins and trace elements. Taking Zn deficiency as an example, there is a substantial thymic atrophy. Importantly, marginal Zn deficiency in AIDS subjects, children with diarrhoea and elderly persons, significantly impairs the host's immunity, resulting in an increased risk of opportunistic infections and mortality; effects that are reversed by Zn supplementation. Thymic changes also occur in acute infectious diseases, including a severe thymic atrophy, mainly due to the depletion of CD4+CD8+ thymocytes, decrease in thymocyte proliferation, in parallel to densification of the epithelial network and increase in the extracellular matrix contents, with consequent disturbances in thymocyte migration and export. In conclusion, the thymus is targeted in several conditions of malnutrition as well as in acute infections. These changes are related to the impaired peripheral immune response seen in malnourished and infected individuals. Thus, strategies inducing thymus replenishment should be considered as adjuvant therapeutics to improve immunity in malnutrition and/or acute infectious diseases.
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An adequate supply of micronutrients that affect the thymus is also important; for example, even marginal zinc deficiency is known to result in thymic atrophy and can increase the risk of infection.
“An adequate supply of micronutrients that affect the thymus is also important; for example, even marginal zinc deficiency is known to result in thymic atrophy and can increase the risk of infection [97].”
From Immune function and micronutrient requirements change over the life course (2018) · cites this paper as [97]
Zinc deficiency can increase thymic atrophy, decrease lymphocyte number and activity, and increase oxidative stress and inflammation by altering cytokine production.
“For example, zinc deficiency can increase thymic atrophy, decrease lymphocyte number and activity, and increase oxidative stress and inflammation by altering cytokine production [14,97].”
From Immune function and micronutrient requirements change over the life course (2018) · cites this paper as [97]
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Cites
Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression
Lord, G. M., Matarese, G., Howard, J. K., Baker, R. J., Bloom, S. R., & Lechler, R. I. (1998) · Nature · doi:10.1038/29795 · Cited by 2,150 · see citing works
Zinc and immune function: the biological basis of altered resistance to infection
Shankar, A. H., & Prasad, A. S. (1998) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/68.2.447s · Cited by 1,606 · see citing works
Farooqi, I. S., Matarese, G., Lord, G. M., Keogh, J. M., Lawrence, E., Agwu, C., Sanna, V., Jebb, S. A., Perna, F., Fontana, S., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15693 · Cited by 1,359 · see citing works
Farooqi, I. S., Matarese, G., Lord, G. M., Keogh, J. M., Lawrence, E., Agwu, C., Sanna, V., Jebb, S. A., Perna, F., Fontana, S., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215693 · Cited by 1,105 · see citing works
Handbook of Nutritionally Essential Mineral Elements
(1997) · CRC Press eBooks · doi:10.1201/9781482273106 · Cited by 649 · see citing works
Howard, J. K., Lord, G. M., Matarese, G., Vendetti, S., Ghatei, M. A., Ritter, M. A., Lechler, R. I., & Bloom, S. R. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6762 · Cited by 566 · see citing works
Molecular and anatomical determinants of central leptin resistance
Münzberg, H., & Myers, M. G. (2005) · Nature Neuroscience · doi:10.1038/nn1454 · Cited by 550 · see citing works
Mechanisms of nutrient modulation of the immune response
Cunningham–Rundles, S., McNeeley, D. F., & Moon, A. (2005) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2005.04.036 · Cited by 535 · see citing works
The Dynamic Link between the Integrity of the Immune System and Zinc Status
Fraker, P. J., King, L. E., Laakko, T., & Vollmer, T. L. (2000) · Journal of Nutrition · doi:10.1093/jn/130.5.1399s · Cited by 459 · see citing works
Zoned Out: Functional Mapping of Stromal Signaling Microenvironments in the Thymus
Petrie, H. T., & Zúñiga-Pflücker, J. C. (2007) · Annual Review of Immunology · doi:10.1146/annurev.immunol.23.021704.115715 · Cited by 454 · see citing works
Impairment of cell-mediated immunity functions by dietary zinc deficiency in mice
Fernandes, G., Nair, M., Onoé, K., Tanaka, T., Floyd, R. A., & Good, R. A. (1979) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.76.1.457 · Cited by 336 · see citing works
Serum thymulin in human zinc deficiency
Prasad, A. S., Meftah, S., Abdallah, J., Kaplan, J., Brewer, G. J., Bach, J. F., & Dardenne, M. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113717 · Cited by 335 · see citing works
Self-citationNeuroendocrine Control of Thymus Physiology
Savino, W., & Dardenne, M. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.4.0402 · Cited by 302 · see citing works
Self-citationThe Thymus Is a Common Target Organ in Infectious Diseases
Savino, W. (2006) · PLoS Pathogens · doi:10.1371/journal.ppat.0020062 · Cited by 298 · see citing works
Self-citationThe thymus as an inductive site for T lymphopoiesis.
Ciofani, M., & Zúñiga-Pflücker, J. (2007) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.23.090506.123547 · Cited by 247 · see citing works
The thymus gland is a target in malnutrition
Savino, W. (2002) · European Journal of Clinical Nutrition · doi:10.1038/sj.ejcn.1601485 · Cited by 194 · see citing works
Self-citationRegeneration of T-cell helper function in zinc-deficient adult mice
Fraker, P. J., DePasquale-Jardieu, P., Zwickl, C. M., & Luecke, R. W. (1978) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.75.11.5660 · Cited by 188 · see citing works
Neuroendocrine Control of Thymus Physiology
Savino, W. (2000) · Endocrine Reviews · doi:10.1210/er.21.4.412 · Cited by 187 · see citing works
Self-citationThe thymus is a common target in malnutrition and infection
Savino, W., Dardenne, M., Velloso, L. A., & Silva-Barbosa, S. D. (2007) · British Journal Of Nutrition · doi:10.1017/s0007114507832880 · Cited by 185 · see citing works
Self-citationHuman Nutrition-A Comprehensive Treatise
Chandrasekhar, U. (1984) · The Indian Journal of Nutrition and Dietetics · Cited by 173 · see citing works
Protein-Energy Malnutrition and Immunological Responses
Chandra, R. K. (1992) · Journal of Nutrition · doi:10.1093/jn/122.suppl_3.597 · Cited by 168 · see citing works
Intrathymic T-cell migration: a combinatorial interplay of extracellular matrix and chemokines?
Savino, W., Mendes‐da‐Cruz, D. A., Silva, J. S., Dardenne, M., & Cotta-de-Almeida, V. (2002) · Trends in Immunology · doi:10.1016/s1471-4906(02)02224-x · Cited by 144 · see citing works
Self-citationSavino, W., Mendes‐da‐Cruz, D. A., Smaniotto, S., Silva, E., & Villa‐Verde, D. M. S. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.1003455 · Cited by 144 · see citing works
Self-citationPrenatal Undernutrition and Postnatal Growth Are Associated with Adolescent Thymic Function
McDade, T. W., Beck, M. A., Kuzawa, C. W., & Adair, L. S. (2001) · Journal of Nutrition · doi:10.1093/jn/131.4.1225 · Cited by 138 · see citing works
Apoptosis Plays a Distinct Role in the Loss of Precursor Lymphocytes during Zinc Deficiency in Mice
King, L. E., Osati-Ashtiani, F., & Fraker, P. J. (2002) · Journal of Nutrition · doi:10.1093/jn/132.5.974 · Cited by 120 · see citing works
Zinc Status in Human Immunodeficiency Virus Infection
Baum, M. K., Shor‐Posner, G., & Campa, A. L. (2000) · Journal of Nutrition · doi:10.1093/jn/130.5.1421s · Cited by 118 · see citing works
Roggero, E., Pérez, A. R., Kakazu, M. T., Piazzón, I., Nepomnaschy, I., Besedovsky, H. O., Bottasso, O. A., & del Rey, A. (2006) · Journal of Endocrinology · doi:10.1677/joe.1.06642 · Cited by 105 · see citing works
Cytokines and cell adhesion receptors in the regulation of immunity to Trypanosoma cruzi
Savino, W., Villa‐Verde, D. M. S., Mendes‐da‐Cruz, D. A., Silva, E., Pérez, A. R., Aoki, M. P., Bottasso, O. A., Guiñazú, N. L., Silva-Barbosa, S. D., & Gea, S. (2007) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2007.01.010 · Cited by 99 · see citing works
Self-citationThe thymus: a barometer of malnutrition
Prentice, A. M. (1999) · British Journal Of Nutrition · doi:10.1017/s0007114599000628 · Cited by 98 · see citing works
Roles for Cell Death in Zinc Deficiency
Fraker, P. J. (2005) · Journal of Nutrition · doi:10.1093/jn/135.3.359 · Cited by 96 · see citing works
Malpuech‐Brugère, C., Nowacki, W., Gueux, E., Kuryszko, J. J., Rock, E., Rayssiguier, Y., & Mazur, A. (1999) · British Journal Of Nutrition · doi:10.1017/s0007114599000690 · Cited by 92 · see citing works
Studies on the thymus in chagas' disease
Savino, W., Leite‐de‐Moraes, M., Hontebeyrie-Joskowicz, M., & Dardenne, M. (1989) · European Journal of Immunology · doi:10.1002/eji.1830190930 · Cited by 90 · see citing works
Self-citationFraker, P. J., Caruso, R., & KIERSZENBAUM, F. (1982) · Journal of Nutrition · doi:10.1093/jn/112.6.1224 · Cited by 88 · see citing works
Thymus size at birth is associated with infant mortality: a community study from Guinea-Bissau
Aaby, P., Marx, C., Trautner, S. L., Rudaa, D., Hasselbalch, H. C., Jensen, H., & Lisse, I. M. (2002) · Acta Paediatrica · doi:10.1111/j.1651-2227.2002.tb03305.x · Cited by 81 · see citing works
Hypothalamus–pituitary–adrenal axis during Trypanosoma cruzi acute infection in mice
Corrêa-de-Santana, E., Páez-Pereda, M., Theodoropoulou, M., Nihei, O. K., Grübler, Y., Bozza, M. T., ARZT, E. S., Villa‐Verde, D. M. S., Renner, U., Stalla, J., et al. (2006) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2005.08.015 · Cited by 81 · see citing works
Self-citationThymic epithelium in AIDS. An immunohistologic study.
Savino, W., Dardenne, M., Marche, C., et al. (1986) · PubMed · Cited by 76 · see citing works
Self-citationZinc Status in Human Immunodeficiency Virus Type 1 Infection and Illicit Drug Use
Baum, M. K., Campa, A. L., Lai, S., et al. (2003) · Clinical Infectious Diseases · doi:10.1086/375875 · Cited by 75 · see citing works
Parent, G., Chevalier, P., Zalles, L., Sevilla, R., Bustos, M., Dhenin, J.-M., & Jambón, B. (1994) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/60.2.274 · Cited by 74 · see citing works
Fraker, P. J., Osati-Ashtiani, F., Wagner, M. A., & King, L. E. (1995) · Journal of the American College of Nutrition · doi:10.1080/07315724.1995.10718467 · Cited by 73 · see citing works
Leite‐de‐Moraes, M., Hontebeyrie-Joskowicz, M., Leboulenger, F., et al. (1991) · Scandinavian Journal of Immunology · doi:10.1111/j.1365-3083.1991.tb01772.x · Cited by 70 · see citing works
Increased apoptosis in a variety of tissues of zinc-deficient rats
Nodera, M., Yanagisawa, H., & Wada, O. (2001) · Life Sciences · doi:10.1016/s0024-3205(01)01252-8 · Cited by 69 · see citing works
Low Serum Thymic Hormone Levels in Patients with Acquired Immunodeficiency Syndrome
Dardenne, M., Bach, J., & Safai, B. (1983) · New England Journal of Medicine · doi:10.1056/nejm198307073090112 · Cited by 68 · see citing works
Self-citationKuvibidila, S. R., Dardenne, M., Savino, W., & Lepault, F. (1990) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/51.2.228 · Cited by 67 · see citing works
Self-citationDifferential Regional Immune Response in Chagas Disease
de Meis, J., Morrot, A., Farias-de-Oliveira, D. A., et al. (2009) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0000417 · Cited by 64 · see citing works
In vivo and in vitro studies of thymulin in marginally zinc‐deficient mice
Dardenne, M., Savino, W., Wade, S., Kaiserlian, D., Lemonnier, D., & Bach, J. (1984) · European Journal of Immunology · doi:10.1002/eji.1830140513 · Cited by 63 · see citing works
Self-citationMendes‐da‐Cruz, D. A., Silva, J. S., Cotta‐de‐Almeida, V., & Savino, W. (2006) · European Journal of Immunology · doi:10.1002/eji.200535629 · Cited by 58 · see citing works
Self-citationAltered thymic structure and mitogen responsiveness in postnatally zinc-deprived mice
Beach, R. S., Gershwin, M. E., & Hurley, L. S. (1979) · Developmental & Comparative Immunology · doi:10.1016/s0145-305x(79)80065-8 · Cited by 57 · see citing works
Cotta-de-Almeida, V., Bonomo, A. C., Mendes‐da‐Cruz, D. A., et al. (2003) · European Journal of Immunology · doi:10.1002/eji.200323860 · Cited by 56 · see citing works
Barone, K. S., O’Brien, P. C., & Stevenson, J. R. (1993) · Cellular Immunology · doi:10.1006/cimm.1993.1105 · Cited by 53 · see citing works
The Impact of Infectious Diseases upon Neuroendocrine Circuits
Pérez, A. R., Bottasso, O. A., & Savino, W. (2009) · NeuroImmunoModulation · doi:10.1159/000180264 · Cited by 48 · see citing works
Self-citationThymic extracellular matrix in human malnutrition
Lyra, J. S. P. O., Madi, K., Maeda, C. T., & Savino, W. (1993) · The Journal of Pathology · doi:10.1002/path.1711710312 · Cited by 47 · see citing works
Self-citationThymulin (facteur thymique serique) and zinc contents of the thymus glands of malnourished children
Jambón, B., Ziegler, O., Maire, B., et al. (1988) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/48.2.335 · Cited by 43 · see citing works
de la Cruz, A. J. M. D. A., Burguera, J. L., Burguera, M., & Áñez, N. (1993) · Biological Trace Element Research · doi:10.1007/bf02789401 · Cited by 36 · see citing works
Mitsumori, K., Takegawa, K., Shimo, T., Onodera, H., Yasuhara, K., & Takahashi, M. (1996) · Archives of Toxicology · doi:10.1007/s002040050343 · Cited by 34 · see citing works
Analysis of the effect of leptin on immune function in vivo using diet-induced obese mice
Mito, N., Yoshino, H., Hosoda, T., & Sato, K. (2004) · Journal of Endocrinology · doi:10.1677/joe.0.1800167 · Cited by 34 · see citing works
Thymic alterations in Plasmodium berghei-infected mice
Andrade, C. F., Gameiro, J., Nagib, P. R. A., et al. (2008) · Cellular Immunology · doi:10.1016/j.cellimm.2008.06.001 · Cited by 33 · see citing works
Leite‐de‐Moraes, M., Minoprio, P. M. C., Dy, M., et al. (1994) · Scandinavian Journal of Immunology · doi:10.1111/j.1365-3083.1994.tb03339.x · Cited by 32 · see citing works
Mittal, A., Woodward, B. D., & Chandra, R. K. (1988) · Experimental and Molecular Pathology · doi:10.1016/0014-4800(88)90059-7 · Cited by 32 · see citing works
Low Circulating Thymulin-like Activity in Children with Aids and Aids-related Complex
Incefy, G. S., Pahwa, S. G., Pahwa, R., et al. (1986) · Aids Research · doi:10.1089/aid.1.1986.2.109 · Cited by 30 · see citing works
Pleiotropic modulation of thymic functions by growth hormone: from physiology to therapy
Savino, W., & Dardenne, M. (2010) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2010.04.002 · Cited by 29 · see citing works
Self-citationMittal, A., & Woodward, B. D. (1985) · Experimental Biology and Medicine · doi:10.3181/00379727-178-42021 · Cited by 29 · see citing works
[Immuno-nutritional recovery of children with severe malnutrition].
Chevalier, P., Sevilla, R., Zalles, L., et al. (1997) · PubMed · Cited by 26 · see citing works
Thymulin (Zn-facteur thymique serique) activity in anorexia nervosa patients
Wade, S., Bleiberg, F., Mosse, A., et al. (1985) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/42.2.275 · Cited by 25 · see citing works
Gameiro, J., Nagib, P. R. A., Francelin, C., et al. (2009) · Immunology · doi:10.1111/j.1365-2567.2009.03177.x · Cited by 20 · see citing works
Lymphocyte subsets and cell proliferation analysis in rabies-infected mice.
Lf, C. P., Matos, D. S., Chaves Leal, E., et al. (1995) · PubMed · Cited by 19 · see citing works
Effect of folic acid deficiency upon lymphocyte subsets from lymphoid organs in mice
Dhur, A., Galan, P., Christidès, J., de Courcy, G. P., Preziosi, P., & Herçberg, S. (1991) · Comparative Biochemistry and Physiology Part A Physiology · doi:10.1016/0300-9629(91)90526-i · Cited by 13 · see citing works
Burguera, J. L., Burguera, M., Alarcón, O. M., et al. (1988) · PubMed · Cited by 6 · see citing works
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Research works printed but not linked: 1
- Kuvibidila S, Yu L, Ode D et al. (1993) The immune response in protein-energy malnutrition and single nutrient deficiencies. In Human Nutrition: A Comprehensive Treatise, pp. 121-157 [DM Klurfeld, editor]. New York: Plenum Press.
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Immune function and micronutrient requirements change over the life course
Maggini, S., Pierre, A., & Calder, P. C. (2018) · Nutrients · doi:10.3390/nu10101531 · Cited by 710 · see citing works
Stool microbiota and vaccine responses of infants
Huda, M. N., Lewis, Z., Kalanetra, K. M., Rashid, M., Ahmad, S. M., Raqib, R., Qadri, F., Underwood, M. A., Mills, D. A., & Stephensen, C. B. (2014) · PEDIATRICS · doi:10.1542/peds.2013-3937 · Cited by 392 · see citing works
- Authors
- Savino, W., & Dardenne, M.
- Affiliations
- Instituto Oswaldo Cruz (BR)
- Hôpital Necker-Enfants Malades (FR)
- Corresponding author
- Savino, Wilson
- ORCID
- Savino, Wilson
- Venue
- Proceedings of The Nutrition Society
- Publisher
- Cambridge University Press (CUP)
- Published
- 2010-09-22
- Volume
- 69
- Issue
- 4
- Pages
- 636-643
- ISSN
- 0029-6651 (ISSN-L)
- 1475-2719
- OpenAlex
- W2123450707
- Cited by
- 109
- References
- 67
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 7 · 2023: 4 · 2022: 11 · 2021: 4 · 2020: 13 · 2019: 7 · 2018: 9 · 2017: 8 · 2015: 6 · 2014: 10 · 2013: 9 · 2012: 8
- FWCI
- 0.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of The Nutrition Society (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- HAL (submittedVersion)
- Americanae (AECID Library) (submittedVersion, other-oa)
- Arca - Repositório Institucional da Fiocruz (submittedVersion, other-oa)
- Funders
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Centre National de la Recherche Scientifique
- Fundação Oswaldo Cruz
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- thymus, thymic atrophy, malnutrition, protein-energy malnutrition, thymocyte apoptosis, CD4+CD8+ thymocytes, thymic microenvironment, thymic epithelial cells, thymic hormones, zinc deficiency, AIDS, diarrhea, acute infection, T cell development, thymocyte migration, extracellular matrix, immunodeficiency, zinc supplementation
- MeSH terms
- Deficiency Diseases, Humans, Immunity, Cellular, Infections, Protein-Energy Malnutrition, T-Lymphocytes, Thymus Gland, Micronutrients
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