Thymic involution

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One of the major characteristics of vertebrate immunology is thymic involution, the shrinking (involution) of the thymus with age, resulting in changes in the architecture of the thymus and a decrease in tissue mass. [1] 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. The thymus involutes 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] 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]

Contents

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]

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. [12] For yet unknown reasons, TCR diversity drops drastically around age 65. [12] 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. [13]

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. In fact, 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 [14] such as infections, [15] [16] pregnancy, [17] and malnutrition. [16] [18] [19] 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 [20] 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. [13]

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: Developing T cells that interact strongly with antigen being presented within the thymus are induced to undergo programmed cell death. The intended effect is deletion of self-reactive T cells. This works well when the antigen being presented within the thymus is truly of self origin, but antigen from pathogenic microbes that happens to infiltrate the thymus has the potential to subvert the entire process. Rather than deleting T cells that would cause autoimmunity, T cells capable of eliminating the infiltrating pathogen are deleted instead. It has been proposed that one way to minimize this problem is to produce as many long-lived T cells as possible during the time of life when the thymus is most likely to be pristine, which generally would be when organisms are very young and under the protection of a functional maternal immune system. [21] Thus, in mice and humans, for example, the best time to have a prodigiously functional thymus is prior to birth. In turn, it is well known from Williams' [22] 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. The disposable soma hypothesis and life history hypothesis say similarly that tradeoffs are involved in thymic involution. Since the immune system must compete with other bodily systems, notably reproduction, for limited physiological resources, the body must invest in the immune system differentially at different stages of life. There is high immunological investment in youth since immunological memory is low. [1] There are also hypotheses that suggest that thymic involution is directly adaptive. For example, some hypotheses have proposed that thymic involution may help in avoidance of autoimmunity or other dangers, [23] prevention of infection, [10] and production of an optimal repertoire of T-cells. [24] Zinc deficiency may also play a role. [25]

Related Research Articles

Immune system A biological system that protects an organism against disease

The immune system is a host defense system comprising many biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from the organism's own healthy tissue. In many species, there are two major subsystems of the immune system: the innate immune system and the adaptive immune system. Both subsystems use humoral immunity and cell-mediated immunity to perform their functions. In humans, the blood–brain barrier, blood–cerebrospinal fluid barrier, and similar fluid–brain barriers separate the peripheral immune system from the neuroimmune system, which protects the brain.

Thymus organ of the immune system

The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, T cells mature. T cells are critical to the adaptive immune system, where the body adapts specifically to 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.

T cell Type of lymphocyte

A T cell is a type of lymphocyte, which develops in the thymus gland and plays a central role in the immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor on the cell surface. These immune cells originate as precursor cells, derived from bone marrow, and develop into several distinct types of T cells once they have migrated to the thymus gland. T cell differentiation continues even after they have left the thymus.

Cytotoxic T cell T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell is a T lymphocyte that kills cancer cells, cells that are infected, or cells that are damaged in other ways.

The T helper cells (Th cells), also known as CD4+ cells, are a type of T cell that play an important role in the immune system, particularly in the adaptive immune system. They help the activity of other immune cells by releasing T cell cytokines. These cells help suppress or regulate immune responses. They are essential in B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages.

Superantigen

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically it causes non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body's T-cells are activated, these SAgs are capable of activating up to 20% of the body's T-cells. Furthermore, Anti-CD3 and Anti-CD28 antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens.

Adaptive immune system Subsystem of the immune system that is composed of specialized, systemic cells and processes

The adaptive immune system, also referred as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminates pathogens by preventing their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.

Central tolerance, also known as negative selection, is the process of eliminating any developing T or B lymphocytes that are reactive to self. 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 cell Subset of T lymphocytes that might have some of the same functions as memory B cells.

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.

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.

A naive T cell is a T cell that has differentiated in bone marrow, 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+). A naive T cell is considered immature and, unlike activated or memory T cells, has not encountered its cognate antigen within the periphery.

Intraepithelial lymphocyte

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 refers to the gradual deterioration of the immune system brought on by natural age advancement. The adaptive immune system is affected more than the innate immune system.

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.

Gamma delta T cells are T cells that have a distinctive 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, gamma delta (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, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

Clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes. This prevents recognition and destruction of self host cells, making it a type of negative selection or central tolerance. Central tolerance prevents B and T lymphocytes from reacting to self. Thus, clonal deletion can help protect individuals against autoimmunity. Clonal deletion is thought to be the most common type of negative selection. It is one method of immune tolerance.

Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.

Medullary thymic epithelial cells (mTECs) represent a unique stromal cell population of the thymus which plays an essential role in the establishment of central tolerance. Therefore, mTECs rank among cells relevant for the development of functional mammal immune system.

Inflamm-aging is a chronic low-grade inflammation that develops with advanced age. It is believed to accelerate the process of biological aging and to worsen many age-related diseases.

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.

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