Thymic involution

Last updated
Thymic involution
Specialty Imunology
Symptoms shrinking of thymus

Thymic involution is the shrinking (involution) of the thymus with age, resulting in changes in the architecture of the thymus and a decrease in tissue mass. [1] Thymus involution is one of the major characteristics of vertebrate immunology, and occurs in almost all vertebrates, from birds, teleosts, amphibians to reptiles, though the thymi of a few species of sharks are known not to involute. [1] [2] This process is genetically regulated, with the nucleic material responsible being an example of a conserved sequence — one maintained through natural selection (though the pressures shaping this are unclear as will be discussed) since it arose in a common ancestor of all species now exhibiting it, via a phenomenon known to bioinformaticists as an orthologic sequence homology.

Contents

T-cells are named for the thymus where T-lymphocytes migrate from the bone marrow to mature. Its regression has been linked to the reduction in immunosurveillance [3] and the rise of infectious disease and cancer incidence in the elderly (in some cases risk is inversely proportional to thymus size). [4] Though thymic involution has been linked to immunosenescence, it is not induced by senescence as the organ starts involuting from a young age: [5] in humans, as early as the first year after birth. [6]

Progression

Neonatal period

Though the thymus is fully developed before birth, [7] newborns have an essentially empty peripheral immune compartment immediately after birth. [8] [9] Hence, T lymphocytes are not present in the peripheral lymphoid tissues, where naïve, mature lymphocytes are stimulated to respond to pathogens. [1] In order to populate the peripheral system, the thymus increases in size and upregulates its function during the early neonatal period. [1]

Age-relatedness

Though some sources[ which? ] continue to cite puberty as the time of onset, studies have shown thymic involution to start much earlier. [1] The crucial distinction came from the observation that the thymus consists of two main components: the true thymic epithelial space (TES) and the perivascular space (PVS). [6] Thymopoiesis, or T-cell maturation, only occurs in the former. In humans, the TES starts decreasing from the first year of life at a rate of 3% until middle age (35–45 years of age), whereupon it decreases at a rate of 1% until death. [6] Hypothetically, the thymus should stop functioning at around 105 years of age; [10] but, studies with bone marrow transplant patients have shown that the thymi of the majority of patients over forty were unable to build a naïve T cell compartment. [11]

With both qualitative and quantitative changes to thymus production occurring as age increases, thymic involution corresponds with the progressive deterioration of the stroma of the thymus and a significant loss of thymic epithelial cells (TECs). Thymic epithelial cells aid in Thymopoiesis and the development of new T-cells. [12]

Effects of the involution

The ability of the immune system to mount a strong protective response depends on the receptor diversity of naive T cells (TCR). Thymic involution results in a decreased output of naïve T lymphocytes – mature T cells that are tolerant to self antigens, responsive to foreign antigens, but have not yet been stimulated by a foreign substance. In adults, naïve T-cells are hypothesized to be primarily maintained through homeostatic proliferation, or cell division of existing naïve T cells. Though homeostatic proliferation helps sustain TCR even with minimal to nearly absent thymic activity, it does not increase the receptor diversity. [13] For yet unknown reasons, TCR diversity drops drastically around age 65. [13] Loss of thymic function and TCR diversity is thought to contribute to weaker immunosurveillance of the elderly, including increasing instances of diseases such as cancers, autoimmunity, and opportunistic infections. [14]

Acute thymic involution and treatment implications

There is growing evidence that thymic involution is plastic and can be therapeutically halted or reversed in order to help boost the immune system. Under certain circumstances, the thymus has been shown to undergo acute thymic involution (alternatively called transient involution). [1] For example, transient involution has been induced in humans and other animals by stresses [15] such as infections, [16] [17] pregnancy, [18] and malnutrition. [17] [19] [20] The thymus has also been shown to decrease during hibernation and, in frogs, change in size depending on the season, growing smaller in the winter. [21] Studies on acute thymic involution may help in developing treatments for patients, who for example are unable to restore immune function after chemotherapy, ionizing radiation, or infections like HIV. [14] Research has shown the rate of thymus involution to reduce when, for men the testes, or for women the ovaries, were removed; demonstrating that sex hormones, and especially testosterone, have a marked influence on the involution process. However, the manner in which the sex hormones moderate this process is not yet fully understood. In other research the results of the Greg Fahy TRIIM trial showed clinically significant reversal of thymus involution after the administration of human growth hormone (HGH), Dehydroepiandrosterone (DHEA) and metformin. [22] The two results could mean that HGH and mTOR inhibition in autophagy reverses thymus involution with testosterone advancing thymus involution. [23]

Unknown selective pressures

Thymic involution remains an evolutionary mystery since it occurs in most vertebrates despite its negative effects.

Since it is not induced by senescence, many scientists have hypothesized that there may have been evolutionary pressures for the organ to involute. A few hypotheses are as follows:

In turn, it is well known from Williams' [25] theory of the evolution of senescence that strong selection for enhanced early function readily accommodates, through antagonistic pleiotropy, deleterious later occurring effects, thus potentially accounting for the especially early demise of the thymus.

Related Research Articles

<span class="mw-page-title-main">Thymus</span> Endocrine gland

The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or T cells mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. The thymus is located in the upper front part of the chest, in the anterior superior mediastinum, behind the sternum, and in front of the heart. It is made up of two lobes, each consisting of a central medulla and an outer cortex, surrounded by a capsule.

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens such as viruses or bacteria, or cells that are damaged in other ways.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.

A thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood.

MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.

In immunology, a naive T cell (Th0 cell) is a T cell that has differentiated in the thymus, and successfully undergone the positive and negative processes of central selection in the thymus. Among these are the naive forms of helper T cells (CD4+) and cytotoxic T cells (CD8+). Naive T cells, unlike activated or memory T cells, have not encountered its cognate antigen within the periphery. After this encounter, the naive T cell is considered a mature T cell.

<span class="mw-page-title-main">Intraepithelial lymphocyte</span>

Intraepithelial lymphocytes (IEL) are lymphocytes found in the epithelial layer of mammalian mucosal linings, such as the gastrointestinal (GI) tract and reproductive tract. However, unlike other T cells, IELs do not need priming. Upon encountering antigens, they immediately release cytokines and cause killing of infected target cells. In the GI tract, they are components of gut-associated lymphoid tissue (GALT).

Immunosenescence is the gradual deterioration of the immune system, brought on by natural age advancement. A 2020 review concluded that the adaptive immune system is affected more than the innate immune system. Immunosenescence involves both the host's capacity to respond to infections and the development of long-term immune memory. Age-associated immune deficiency is found in both long- and short-lived species as a function of their age relative to life expectancy rather than elapsed time.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance can also serve a purpose in preventing an immune response to harmless food antigens and allergens.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

<span class="mw-page-title-main">Lymphocyte-activation gene 3</span> Protein-coding gene in the species Homo sapiens

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

<span class="mw-page-title-main">Thymic stromal lymphopoietin</span> Cytokine, alarmin, and growth factor.

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-2-like cytokine, alarmin, and growth factor involved in numerous physiological and pathological processes, primarily those of the immune system. It shares a common ancestor with IL-7.

Mucosal-associated invariant T cells make up a subset of T cells in the immune system that display innate, effector-like qualities. In humans, MAIT cells are found in the blood, liver, lungs, and mucosa, defending against microbial activity and infection. The MHC class I-like protein, MR1, is responsible for presenting bacterially-produced vitamin B2 and B9 metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease, although definitive evidence is yet to be published.

Virtual memory T cells (TVM) are a subtype of T lymphocytes. These are cells that have a memory phenotype but have not been exposed to a foreign antigen. They are classified as memory cells but do not have an obvious memory function. They were first observed and described in 2009. The name comes from a computerized "virtual memory" that describes a working memory based on an alternative use of an existing space.

Thymus stromal cells are subsets of specialized cells located in different areas of the thymus. They include all non-T-lineage cells, such as thymic epithelial cells (TECs), endothelial cells, mesenchymal cells, dendritic cells, and B lymphocytes, and provide signals essential for thymocyte development and the homeostasis of the thymic stroma.

References

  1. 1 2 3 4 5 6 7 Shanley D.P.; Danielle A.W.; Manley N.R.; Palmer D.B.; et al. (2009). "An evolutionary perspective on the mechanisms of immunosenescence" (PDF). Trends in Immunology . 30 (7): 374–381. doi:10.1016/j.it.2009.05.001. PMID   19541538.
  2. ↑ Zakharova L.A. (2009). "Evolution of adaptive immunity". Izvestiia Rossiĭskoĭ Akademii Nauk. Seriia Biologicheskaia. 2 (2): 143–154. PMID   19391473.
  3. ↑ Linton P.J.; Dorshkind K. (2004). "Age-related changes in lymphocyte development and function". Nature Immunology. 5 (2): 133–139. doi:10.1038/ni1033. PMID   14749784. S2CID   12485241.
  4. ↑ Palmer S.; Albergante L.; Blackburn C.C.; Newman T.J. (2018). "Thymic involution and rising disease incidence with age". Proceedings of the National Academy of Sciences of the United States of America . 115 (8): 1883–1888. Bibcode:2018PNAS..115.1883P. doi: 10.1073/pnas.1714478115 . PMC   5828591 . PMID   29432166.
  5. ↑ Taub D.D.; Long D.L. (2005). "Insights into thymic aging and regeneration". Immunological Reviews. 205: 72–93. doi:10.1111/j.0105-2896.2005.00275.x. PMID   15882346. S2CID   24461464.
  6. 1 2 3 Steinmann G.G.; Klaus B.; Muller-Hermelin H.K.; et al. (1985). "The involution of the aging human thymic epithelium is independent of puberty. A morphometric study". Scandinavian Journal of Immunology. 22 (5): 563–75. doi:10.1111/j.1365-3083.1985.tb01916.x. PMID   4081647. S2CID   40226062.
  7. ↑ Parham, P. 2005. The immune system: Second edition Garland Science.
  8. ↑ Min B.; McHugh R.; Sempowski G.D.; Mackall C.; Foucras G.; Paul W.E.; et al. (2003). "Neonates support lymphopenia-induced proliferation". Immunity . 18 (1): 131–140. doi: 10.1016/S1074-7613(02)00508-3 . PMID   12530982.
  9. ↑ Schuler T.; Hammerling G.J.; Arnold B.; et al. (2004). "Cutting edge: IL-7-dependent homeostatic proliferation of CD8+ T cells in neonatal mice allows the generation of long-lived natural memory T cells". Journal of Immunology . 172 (1): 15–19. doi: 10.4049/jimmunol.172.1.15 . PMID   14688303.
  10. 1 2 George A.J.; Ritter M.A. (1996). "Thymic involution with ageing: obsolescence or good housekeeping?". Immunology Today . 17 (6): 267–272. doi:10.1016/0167-5699(96)80543-3. PMID   8962629.
  11. ↑ Hakim F.; Memon S.; Cepeda R.; Jones E.; Chow C.; Kasten-Sportes C.; Odom J.; Vance B.; Christensen B.; et al. (2005). "Age-dependent incidence, time course, and consequences of thymic renewal in adults". Journal of Clinical Investigation . 115 (4): 930–939. doi:10.1172/JCI22492. PMC   1064981 . PMID   15776111.
  12. ↑ Gui, J.; Mustachio, L. M.; Su, D. M.; Craig, R. W. (2012). "Thymus Size and Age-related Thymic Involution: Early Programming, Sexual Dimorphism, Progenitors and Stroma". Aging and Disease. 3 (3): 280–290. PMC   3375084 . PMID   22724086.
  13. 1 2 Naylor K.; Li G.; Vallejo A.N.; Lee W.W.; Koetz K.; Bryl E.; Witkowski J.; Fulbright J.; Weyand C.M.; et al. (2005). "The influence of age on T cell generation and TCR diversity". Journal of Immunology . 174 (11): 7446–7452. doi: 10.4049/jimmunol.174.11.7446 . PMID   15905594.
  14. 1 2 Lynch H.E.; Goldberg G.L.; Chidgey A.; Boyd R.; Sempowski G.D.; et al. (2009). "Thymic involution and immune reconstitution". Trends in Immunology . 30 (7): 366–373. doi:10.1016/j.it.2009.04.003. PMC   2750859 . PMID   19540807.
  15. ↑ Dominguez-Gerpe L; Rey-Mendez M (2003). "Evolution of the Thymus Size in Response to Physiological and Random Events Throughout Life". Microscopy Research and Technique . 62 (6): 464–476. doi: 10.1002/jemt.10408 . PMID   14635139. S2CID   45341750.
  16. ↑ Savino W (2006). "The thymus is a common target organ in infectious diseases". PLOS Pathogens. 2 (6): 472–483. doi: 10.1371/journal.ppat.0020062 . PMC   1483230 . PMID   16846255.
  17. 1 2 Savino W; Dardenne M; Velloso LA; Silva-Barbosa SD (2007). "The thymus is a common target in malnutrition and infection". British Journal of Nutrition . 98: S11 –S16. doi: 10.1017/s0007114507832880 . PMID   17922946.
  18. ↑ Kendall M.D.; Clarke A.G. (2000). "The thymus in the mouse changes its activity during pregnancy: a study of the microenvironment". Journal of Anatomy . 197 (3): 393–411. doi:10.1046/j.1469-7580.2000.19730393.x. PMC   1468141 . PMID   11117626.
  19. ↑ Cromi A.; Ghezzi F.; Raffaelli R.; Bergamini V.; Siesto G.; Bolis P.; et al. (2009). "Ultrasonographic measurement of thymus size in IUGR fetuses: a marker of the fetal immunoendocrine response to malnutrition". Ultrasound in Obstetrics & Gynecology . 33 (4): 421–426. doi: 10.1002/uog.6320 . PMID   19306477. S2CID   5473679.
  20. ↑ Howard J.K.; Lord G.M.; Matarese G.; Vendetti S.; Ghatei M.A.; Ritter M.A.; Lechler R.I.; Bloom S.R.; et al. (1999). "Leptin protects mice from starvation induced lymphoid atrophy and increases thymic cellularity in ob/ob mice" (PDF). Journal of Clinical Investigation . 104 (8): 1051–1059. doi:10.1172/JCI6762. PMC   408574 . PMID   10525043.
  21. ↑ Wytycz, B., Mica, J., Jozkowir, A. & Bigaj J. 1996. Letters: Plasticity of thymuses of ectothermic vertebrates. Immunology Today (Comment). 442: No.9.
  22. ↑ "Reversing Thymic Involution – Intervene Immune" . Retrieved 2020-12-31.
  23. ↑ Sutherland, Jayne S.; Goldberg, Gabrielle L.; Hammett, Maree V.; Uldrich, Adam P.; Berzins, Stuart P.; Heng, Tracy S.; Blazar, Bruce R.; Millar, Jeremy L.; Malin, Mark A.; Chidgey, Ann P.; Boyd, Richard L. (2005-08-15). "Activation of Thymic Regeneration in Mice and Humans following Androgen Blockade". The Journal of Immunology. 175 (4): 2741–2753. doi: 10.4049/jimmunol.175.4.2741 . ISSN   0022-1767. PMID   16081852.
  24. ↑ Turke P (1995). "Microbial parasites versus developing T cells: an evolutionary arms race with implications for the timing of thymic involution and HIV pathenogenesis". Thymus. 24 (1): 29–40. PMID   8629277.
  25. ↑ Williams G. C. (1957). "Pleiotropy, natural selection, and the evolution of senescence". Evolution. 11 (4): 398–411. doi:10.2307/2406060. JSTOR   2406060.
  26. ↑ Aronson M (1991). "Hypothesis: involution of the thymus with aging–programmed and beneficial". Thymus. 18 (1): 7–13. PMID   1926291.
  27. ↑ Dowling M.R.; Hodgkin P.D. (2009). "Why does the thymus involute? A selection-based hypothesis". Trends in Immunology . 30 (7): 295–300. doi:10.1016/j.it.2009.04.006. PMID   19540805.
  28. ↑ Mocchegiani E, Muzzioli M, Cipriano C, Giacconi R (1998). "Zinc, T-cell pathways, aging: role of metallothioneins". Mechanisms of Ageing and Development. 106 (1–2): 183–204. doi:10.1016/S0047-6374(98)00115-8. PMID   9883983. S2CID   43299065.
Listen to this article (8 minutes)
Sound-icon.svg
This audio file was created from a revision of this article dated 5 May 2020 (2020-05-05), and does not reflect subsequent edits.
(Audio help  · More spoken articles)
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.