**3. If peace is in the hands of the thymus, then what would happen if that does not work?**

The thymus-mediated effects including the production of neuropeptides and also development of T cell repertoire are what may be called the function of the pacemaker [7]. However, the thymus is vulnerable to be exposed to both acute and chronic injuries. A variety of pathological conditions that range from infections and immunodeficiency to inflammatory and autoimmune disorders and tumors may cause the thymus to turn into malfunctioning or functionless. In a broader sense, the thymus undergoes physiological changes that occur with age and during pregnancy. Below is to represent dysregulation of immune homeostasis as the inevitable consequence of a failure in central self-tolerance system, i.e., the thymus.

#### **3.1 The effects of thymic infection on thymopoiesis**

#### *3.1.1 The thymus gets sick*

The thymus is not immune-privileged, but rather invading pathogens can adversely affect its structure and/or function, thymopoiesis, through indirect (systemic) and direct (local) ways. Pathogens that are able to penetrate into the different thymic location(s), e.g., cortex, CMJ, or medulla, and thereby directly infect thymic cells, include a number of viruses (human immunodeficiency virus, *Simian immunodeficiency virus*, influenza virus, lymphocytic choriomeningitis virus, *Murine leukemia virus*, mouse hepatitis virus, human cytomegalovirus, measles virus, coxsackievirus, Epstein-Barr virus, Junin virus, and poliovirus), bacteria (*Mycobacterium avium*, *Mycobacterium tuberculosis*, *Francisella tularensis*, and *Salmonella enterica*), fungi (*Paracoccidioides brasiliensis* and *Cryptococcus neoformans*), and parasites (*Trypanosoma cruzi*, *Plasmodium berghei*, and *Toxoplasma gondii*). In addition, pathogens can act indirectly by altering the systemic expression of glucocorticoids, cytokines, chemokines, and antigens. Then, these soluble factors can reach the village of the thymus and readily result in changes of its microenvironment [8].

Without regard to the nature of its invading pathogens, the infected thymus may encounter atrophy and architectural changes. The infected thymus is consequently liable to induce apoptosis, pathogen-specific immune responses, T cells that are tolerant to pathogens, and self-reactive T cells [8].

### *3.1.2 The thymus can cope with infection*

Less is understood for mechanisms of thymic escape from infection and/or survival after being infected. However, it is suggested that the thymus may be affected by seeding of cells from other peripheral sites of infection. Therefore, elimination of infection from other peripheral sites might help in the prevention of seeding and development of infection in the thymus. When it gets infected, there is evidence on the presence of antigen-specific CD4+ or CD8+ T cells of other peripheral organs. This would imply that the thymus might in time profit from responses mediated by effector T cells that recirculate between peripheral tissues [8].

#### **3.2 The role of thymic involution in the aging immune system**

#### *3.2.1 The thymus gets old*

Older individuals have higher rates of diseases, e.g., infections, malignancies, and autoimmune diseases, demonstrate lower responsiveness to vaccines, and are less capable of immune restoration following chemotherapy, radiotherapy, and infections. This is plainly a reflection of the aging immune system, referred to as immune senescence, related to increased mortality and morbidity in the aged population. The immune cells mostly affected by aging are naïve T cells [9]. Yet the number of memory cells is proportionally increased. The process of T cell-mediated immunity becoming deteriorated gradually occurs, and both extrinsic and intrinsic factors may play a role [10].

Rather than being influenced by bone marrow aging, age-related deterioration of T cell-mediated immunity is influenced by the thymic involution. Both are, however, seated to serve as co-directors of this process. When the thymus undergoes aging, its architecture does not remain well defined. Cellular changes associated with thymic involution include reduction in the number of thymic epithelial cells and thymocytes in contrast to an increase in perivascular spaces and adipose tissue. Aging will affect the bone marrow in parallel to the thymus, making the quantity and quality of progenitor T cells that migrate from the bone marrow to the thymus go down. When "progenitor T cells" are not inputted to the "thymus" machine, then the output "naïve T cells" would not be logic anymore. In this manner, aging causes a decline in naïve T cells exported from the thymus to the periphery, and consequently memory T cells will predominate in the periphery.

#### *3.2.2 The thymus has the ability to sustain life*

Thymic involution is characterized by a continuous flow from the first year of life that gets pronounced at puberty and during pregnancy. After puberty, the thymus gradually decreases in size, weight, and cellularity as we age, and by the seventh decade of life, the thymic epithelial space drops to less than 10 percent of total tissue. This fact that the thymus feels old when the levels of sex steroids and hormones rise [9] provides, as a result, a role for sex steroids in the aging of the thymus. It also will open our eyes to see sex steroid ablation as a potential means of regenerating the thymus and consequently reversing immune senescence. There is reasonable evidence to believe that the prevention and/or reversal of thymic

**5**

*Introductory Chapter: Thymus - The Central Self-Tolerance System*

function associated with aging is possible with sex steroid ablation using surgical

Thymopoiesis is an active complex process. Growth-stimulating factors, such as hematopoietic cytokines (interleukin-1, interleukin-3, interleukin-6, interleukin-7, interleukin-21, and interleukin-22, stem cell factor, and FMS-like tyrosine kinase 3 ligand), growth factors (transforming growth factor beta, oncostatin M, keratinocyte growth factor, bone morphogenetic protein 4, leukemia inhibitory factor), and hormones (growth hormone, insulin growth factor 1, and ghrelin), are, thus, needed to facilitate the cooperation between the two parties, i.e., thymocytes and T cells, involved in thymopoiesis. There are reports that the age-associated defects in the immune function and/or structure of the thymus could be returned by the administration of these factors (for review, see [11–13]). In particular, interleukin-21 has provided the most interesting results, as explained in preclinical studies [12]. Similarly, bioengineering thymus organoids [14], thymus transplantation, and cell-based therapies have been effective in immune reconstitution and establishing

*DOI: http://dx.doi.org/10.5772/intechopen.90491*

and pharmaceutical approaches [11].

immune tolerance to allografts.

**Author details**

Amene Saghazadeh1,2 and Nima Rezaei1,3,4\*

Sciences (TUMS), Tehran, Iran

1 Research Center for Immunodeficiencies, Children's Medical Center,

Scientific Education and Research Network (USERN), Tehran, Iran

2 Systematic Review and Meta-analysis Expert Group (SRMEG), Universal

3 Department of Immunology, School of Medicine, Tehran University of Medical

4 Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Tehran University of Medical Sciences (TUMS), Tehran, Iran

\*Address all correspondence to: rezaei\_nima@yahoo.com

provided the original work is properly cited.

#### *Introductory Chapter: Thymus - The Central Self-Tolerance System DOI: http://dx.doi.org/10.5772/intechopen.90491*

function associated with aging is possible with sex steroid ablation using surgical and pharmaceutical approaches [11].

Thymopoiesis is an active complex process. Growth-stimulating factors, such as hematopoietic cytokines (interleukin-1, interleukin-3, interleukin-6, interleukin-7, interleukin-21, and interleukin-22, stem cell factor, and FMS-like tyrosine kinase 3 ligand), growth factors (transforming growth factor beta, oncostatin M, keratinocyte growth factor, bone morphogenetic protein 4, leukemia inhibitory factor), and hormones (growth hormone, insulin growth factor 1, and ghrelin), are, thus, needed to facilitate the cooperation between the two parties, i.e., thymocytes and T cells, involved in thymopoiesis. There are reports that the age-associated defects in the immune function and/or structure of the thymus could be returned by the administration of these factors (for review, see [11–13]). In particular, interleukin-21 has provided the most interesting results, as explained in preclinical studies [12].

Similarly, bioengineering thymus organoids [14], thymus transplantation, and cell-based therapies have been effective in immune reconstitution and establishing immune tolerance to allografts.
