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American Journal of  Medical 
Science and Innovation (AJMSI) 

Involvement of  Restored Treg Cells in the Immune Pathogenesis of  Parkinson’s Disease 
(PD) Running Title: Immune Pathogenesis of  Parkinson’s Disease

Faisal Alkhateeb Ahmad2, Ahmed Mohamed Mekkawy3, Ahmed Ghoneim3, Ehab Zahran3, Khaled Saad1*, Ahmad Roshdy 
Ahmad4, Khalid Hashim Mahmoud5, Eman F. Gad2, Mohamed Ezzat6, Hamad Ghaleb Dailah7, Ahmed Nabil Malek3

Volume 3 Issue 2, Year 2024
ISSN: 2836-8509 (Online)

DOI: https://doi.org/10.54536/ajmsi.v3i2.3094
https://journals.e-palli.com/home/index.php/ajmsi

Article Information ABSTRACT

Received: May 27, 2024
Accepted: June 30, 2024
Published: July 03, 2024

Neural regression with neuroinflammation and immune dysfunction through neuro-
degradative disorder is known as Parkinson’s disease (PD). Parkinson’s disease is a progressive 
degradative neuronal disorder. In this disease, the continuous depletion of  dopaminergic 
neurons and the existence of  protein Lewy bodies are the key points of  PD development. 
In PD patients, regulatory T cells (Tregs) are decreased in number and have an impaired 
proliferative capacity that affects the suppression of  T-cell characteristics. The thymus 
involution decline in the functionality of  T-cell development and consequently naïve T cells 
makes the immune system more vulnerable to losing its immune surveillance, increasing 
morbidity and mortality in aged individuals. The persistent process of  thymic involution 
with age vigorously contributes to a progressive reduction in thymic output. Genomic 
damage, cellular senescence, and epigenetic alterations are the hallmarks of  cellular or 
molecular damage in aging. Therapeutic potential for regeneration of  the thymus would 
improve immunity. Some strategies and approaches have focused on cell-based approaches, 
technology based on organoid and scaffold modulating of  endogenous and exogenous 
compounds to help in the thymus regeneration, and fabrication technologies that could be 
used as regenerative approaches. Last but not least the pluripotent stem cell therapies.

Keywords
Neuro-Degradation, Parkinson’s 
Disease, Thymic Involution, 
Pluripotent Stem Cell

1 Department of  Pediatrics, Faculty of  Medicine, Assiut University Children’s Hospital, Assiut, Egypt
2 Department of  Pediatrics, Faculty of  Medicine, Assiut University, Assiut, Egypt 
3 Department of  Cardiothoracic Surgery, Faculty of  Medicine, Assiut University Hospitals, Assiut, Egypt
4 Department of  Pediatrics, College of  Medicine, Jouf  University, Sakaka, Saudi Arabia
5 Department of  Pediatrics, Faculty of  Medicine, Shaqra University, Dawadmi, Saudi Arabia
6 Department of  Pediatrics, Faculty of  Medicine, Al Azhar University, Cairo, Egypt
7 Research and Scientific Studies Unit, College of  Nursing, Jazan University, Jazan, Saudi Arabia
* Corresponding author’s e-mail: khaled.ali@med.au.edu.eg

INTRODUCTION
Neural regression with neuroinflammation and immune 
dysfunction through neuro degradative disorder is known 
as Parkinson’s disease (PD). Parkinson’s disease is a 
progressive degradative neuronal disorder. In this disease, 
the continuous depletion of  dopaminergic neurons 
and the existence of  protein Lewy bodies are the key 
points of  PD development. Increased microgliosis along 
with dysfunction of  the peripheral immune were also 
indicated by several reports in the development of  PD 
(Balestrino & Schapira, 2020). Prevalence showed that 
it is the second chronic progressive neurodegenerative 
disease after Alzheimer’s, with environmental and genetic 
factors that interact to develop it in older age (Miri et al., 
2020) (Goldman, 2019). In PD patients, regulatory T cells 
(Tregs) are decreased in number and have an impaired 
proliferative capacity that affects the suppression of  T-cell 
characteristics. In animal models of  PD, restoring Tregs 
and their suppressive function reduces disease-associated 
inflammation and provides neuroprotection.
Similarly, in the field of  cancer- a disease no less dangerous 
than Parkinson’s disease (PD) - a Treg cell depletion 
restores and improves endogenous anti-tumor immunity. 
Accordingly, it becomes possible to promote regeneration 
and prevent the evolution to irreversible tissue damage 
by restoration of  Treg cells. Thus, the restored Treg cells 

help in the immunopathogenesis of  Parkinson’s disease 
(PD) (Thome et al., 2021). In old age, thymus degradation 
is associated with decreased precursors of  T cell output, 
which reduces individuals’ activity in T cells. It increases 
susceptibility to infection and is prone to autoimmune 
disease and cancer. 
Thymic involution is the intense situation in which 
ubiquitous change is observed in the aging immune 
system, but the mechanisms underscore this process are 
still unclear (Barbouti et al., 2020). The prevalence of  
PD has increased day by day. Approximately 2.5 million 
individuals suffered it in 1990, while the prediction shows 
it will increase three-fold to 17.5 million in 2040. Reduces 
neuroprotection activities associated with environmental 
parameters, i.e., pollution, smoking, and boosted 
exposure to industrial byproducts (Schwab et al., 2020). 
Usually, it affects the old aged individual more than the 
adult once. Because it depends upon the immunological 
status of  humans. In old age, the body’s system becomes 
weaker timely, so the immune system is also affected by 
the side effects of  other pathological conditions such as 
hypertension, stroke, and other cardiovascular disorders 
(Mas-Bargues et al., 2021). The thymus gland begins 
to atrophy (shrinks) until we have little or none left. 
T-cells migrate towards the thymus to mature from the 
bone marrow because it is the primary lymphoid organ. 



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It is also involved in the development to improve the 
efficiency of   T-lymphocytes or T cells (Knight, 2021). 
Persistent age-associated atrophy is found in the thymus 
gland in which loss of  thymic epithelial space (TES), 
i.e., thymus involution or atrophy, leads to inhibition of  
thymic output (Rezzani et al., 2020). It was represented 
by its role in developing T-lymphocytes or T cells, an 
extremely important type of  white blood cell. T cells 
protect the body from potentially deadly pathogens like 
bacteria, viruses, and cancer. Such a regulatory role driven 
by T cells causes dysregulation in immune cells(Varadé et 
al., 2021). The dysregulated Immune cells lead to a pro-
inflammatory tumor microenvironment and promote 
the secretion of  growth factors, i.e., chemokines and 
cytokines/proteinases.
Additionally, the Intercellular communication between 
cancer and immune cells plays a key role in modulating 
the immune response, promoting cell migration, 
proliferation, and tumor progression (Schulz et al., 2019). 
The state of  chronic thymus involution in aged individuals 
creates a weaker immunity through a great decline in the 
functionality of  T-cell development and consequently 
naïve T cells. This makes the immune system more 
vulnerable to losing its immune surveillance, increasing 
morbidity and mortality (Schwab et al., 2020). 

Significance of  Thymus in the Human Body
Thymus, located right behind the collarbone, is the 
essential part of  the immune system. In the thymus, 
naive T immune cells develop through undifferentiated 
thymocytes specializing in specific pathogens or cancer 
cells. T cells serve a potential role in regulating the immune 
system. It has been important that the size of  thymus 
reduces progressively with age, termed thymic involution 
(Barbouti et al., 2020). The thymus’s immune benefit 
produces a class of  immune cells called T lymphocytes. 
These cells complement the B cells to constitute the 
adaptive immune system. Humans produce fewer and 
fewer T cells as humans age, and some recent literature 
reported that humans might not even produce any newer T 
cells after age 60 (Park et al., 2020). The persistent process 
of  thymic involution with age vigorously contributes to a 
progressive reduction in thymic output. Humans become 
more susceptible to cancer and infectious diseases in old 
age as their immunity weakens (Wiertsema et al., 2021). 

Predisposing Factors of  Thymic Involution
The shrinkage of  the thymus in old age, this phenomenon 
is known as involution. An ancient and evolutionarily 
conserved process showed that thymic involution 
occurred in many vertebrates (Rezzani et al., 2020). Thymic 
aging is marked by lowered production of  (new) naive T 
cells and adipose tissue instead of  lymphosarcoma thymic 
zones (Cakala-Jakimowicz et al., 2021). Literature shows 
that thymus shrinkage is an age-dependent program. The 
infiltration of  adipocytes (fat cells) is initiated in puberty 
or earlier and will take over in middle age. Age changes 

in the thymus into fatty tissue from a primary lymphoid 
organ(Velardi et al., 2021). Besides fat deposition, many 
other factors of  age-associated changes may trigger 
thymic involution. Firstly, the decrease in bone marrow 
output is the source of  hematopoietic stem cells (HSC). 
This comprised of  T cell progenitors anonymously enter 
the blood circulation and relate thymic epithelial cells 
to get matured, defined as the developmental program. 
The decline was observed in T-cell progenitor cells 
and hematopoietic stem cells by age (Liu et al., 2020). 
Second fibrosis, by the age of  thymopoiesis replaced by 
fibroblasts after signaling by specialized thymic epithelial 
cells. Fibrosis is also observed in various organs, i.e., the 
liver, kidney and heart, as a common aging signature 
(Borgoni et al., 2021). Thymic involution consists of  a 
two-stage process, growth-dependent thymic involution 
during puberty and age-dependent thymic involution 
(Sekai et al., 2019). 

Formation of  Intrathymic T Cell Receptors (TCRs)
The T cells mature in the thymus, migrate from the bone 
marrow as pre-T cells, and pass through the thymus. 
They form their T cell receptors (TCRs) with their two 
chains (α and β). These TCRs give the T cell its specificity 
through a process of  genetic recombination. They go 
through positive and negative selection in the thymus. So, 
if  a TCR binds to self  too strongly (they would cause 
autoimmunity), they are deleted. If  they cannot bind self-
enough, they would be unable to make antigen recognition 
bound by MHC molecules, which is typically required for 
T cells then they are also deleted. Those that can loosely 
bind MHC but not so strong that they would be self-
reactive mature T cells reach the secondary lymphoid 
organs before they can remain in the blood circulate (i.e., 
spleen, lymph nodes, etc.) (Smith & Göbel, 2022). 

Intrathymic Integration of  T Cell Migration and 
Thymocyte Differentiation 
The thymus gland is necessary for producing T lymphocytes, 
central to cellular immunity, humoral immunity, and some 
of  the body’s nonspecific defenses. Chemokine receptors, 
such as CC-chemokine receptor 7 (CCR7), CCR9 and 
CXCR4 are responsible for the recruitment and entry of  
bone marrow-derived T lymphoid cell progenitors, called 
thymocytes. Two events for the maturation of  thymocytes 
were reported: the rearrangement of  the gene of  the 
TCR and association with coreceptors CD4 and CD8 
(Granadier et al., 2021). Thymocytes’ progress depends 
upon three developmental stages with an expression of  
the CD4 and CD8 coreceptors. Double-negative (DN) 
thymocytes do not express CD4 and CD8 in T-cells after 
attaching with coreceptors CD4 and CD8. TCR consists 
of  α and β subunits having alternate sequences. This 
variation shows the randomization of  gene segments and 
foreign antigen thymocytes, which can recognize as major 
histocompatibility complex (MCH) molecules (Cosway et 
al., 2021). T cells increase their affinity by self-peptides 



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bound to (pMHC) for positive selection and peripheral 
survival. Mature TCRs with CD4 and CD8 coreceptors in 
the same cell are double-positive (DP) thymocytes. 
TCR-self-pMHC interactions promote DP thymocyte 
survival and convert it into a single positive (SP) stage. 
This outcome is called positive selection (Kisielow, 2019). 
Apoptosis is generated If  TCR is not involved in self-
pMHC, and high affinity (strong signaling) generated after 
self-pMHCs are known as non-selection and negative 
selection, respectively. (Srinivasan et al., 2021) Self-MHC 
bond TCRs are restricted, mature and self-tolerant. When 
expressed CD4 or CD8, it becomes single positive (SP) 
thymocytes, also known as clonal selection (Helgeland et 
al., 2020). The binding of  CD4 or CD8 and TCR to the 
MHC molecule forms the TCR–CD3 complex through 
noncovalent interaction with CD3 γ, δ, ε, and ζ proteins 
of  the intracellular domain. (Shah et al., 2021)
Expression of  chemokine receptor CCR7 After positive 
selection tests of  thymocytes as an additional requirement 
fulfill an in the medulla of  the thymus. The medullary 
epithelial cells of  the thymic produce CCR7 cytokines that 
enhance the negative selection of  potentially autoreactive 
thymocytes. After development in the thymus, thymocytes 
migrate to the lymphoid organs through the bloodstream 
and are considered antigen-presenting cells. These 
lymphoid organs initiate protective immune responses in 
immunological challenges (Kadouri et al., 2020).  

Thymic Involution and Immune Econstitution
The thymus serves as the development of  self-restricted 
and tolerated along with immunocompetent T cells. 
Thymus loses the characteristic of  self-renewal. Therefore, 
the continuous replenishment of  new T cell progenitors 
comes from the bone marrow. After proliferation series 
and stages of  differentiation on the guideline of  the 
specialized thymic microenvironment, these cells become 
Maturated. The anatomical structure of  the human 
thymus gland is composed of  the thymic epithelial space 
(TES) of  the human thymus. Thymopoiesis continues on 
the nonhematopoietic perivascular area (PVS), including 
adipocytes, peripheral lymphocytes, and stroma. Reduce 
the efficiency of  T-cell development and decreased 
migration of  naïve T cells observed in aging characterized 
as chronic thymus involution (Sergi, 2020)
The progress on the therapeutic thymus restoration and 
peripheral immune reconstitution in adults. Restoring 
immunity in old age remains a challenge that needs 
further investigation. All older adults will be considered 
to have weak immune systems and reduced immunity due 
to vitamin D deficiency unless a supplement is taken. The 
weak immune function is associated with less responsive 
to drugs and more inclined toward infections in old 
individuals. Similarly, a study observed that the expression 
of  activation markers and T cell memory phenotype 
distribution is affected by age, body fat content, and 
pathogen status throughout the Lifespan. (Mittelbrunn & 
Kroemer, 2021)

Inflammation and Treg Cell
Genomic damage, cellular senescence and epigenetic 
alterations are the hallmarks of  cellular or molecular 
damage in aging (Ermolaeva et al., 2018). Literature showed 
that imbalance protein and proteostasis conditions along 
with essential nutrient lacking were observed in aging-
related diseases (Deng et al., 2022). 
According to De Cecco et al. 2019  chronic inflammation 
happens as self-antigens action due to pro-inflammatory 
reactions in aged persons (De Cecco et al., 2019). 
Therefore, an imbalance of  Th17/Treg cells was found 
to cause inflammation in aged people (Deng et al., 
2022). Previous studies showed that IL-6 also acts as a 
pro-inflammatory cytokine and helps to balance Th17/
Treg cells in the human body but high serum TNF and 
IL-1 level imbalance the Treg cells in aged individuals 
(Pansarasa et al., 2019). Reduced DCAF1 regulation was 
reported in Treg cells, which caused an imbalance rate 
of  activation of  T cells in the immune system of  aged 
individuals compared to younger ones. Downregulation 
in DCAF1 ultimately increases the reactive oxygen 
species, directly affecting the interleukin 6 and interleukin 
17 that imbalance the RORγτ+   FOXP3 and caused 
Chronic inflammation by dysfunction immunity in aging 
(Guo et al., 2020).

Figure 1: Chronic inflammation in aging due to 
imbalanced RORγτ+   FOXP3

Approaches to Regenerate Thymus
Therapeutic potential for regeneration of  the thymus 
would improve immunity. Some strategies and approaches 
have focused on cell-based approaches, technology based 
on organoid and scaffold modulating of  endogenous 
and exogenous compounds to help in the thymus 
regeneration, and biofabrication technologies could be 
used as regenerative approaches. Last but not the least, 
the pluripotent stem cell therapies.
Literature showed that in vitro thymic epithelial 



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progenitors of  humans could be generated through 
Embryonic stem cells (ESCs) with the help of  Activin 
A, which can produce CD4+ and CD8+ T cells along 
with CD3 complex. Organoids technology extracts 
TECs by scaffolds through pluripotent stem cells (Table 
1)(Sharma & Moroni, 2021). The progressive disease is 

still untreated, but the cell replacement technique will be 
in consideration. Human pluripotent stem cell therapies 
are used as a regenerative strategy through straight 
differentiation for midbrain dopamine (mDA) neurons 
(Kim et al., 2020), (Elsworth, 2020).

Table 1: Therapeutic Approaches to Regenerate Thymus.
Approaches  Mode Action References
OPDLL1system  with 
HSCs

Synthesis of  magnetic DLL1 
ligands adds on VCAM-1 
ligand.

Develop modification and 
enhance the Efficiency of   T cells 
to make them diverse, functional, 
and produce cytokines

(Awong et al., 2009)

Embryonic stem cells to 
Thymic epithelial cells

ESCs used to produce TEC T cells are Diverse and 
responsive toward stimuli.

(Su et al., 2015)

Reprogramming of  
thymic epithelial cells

Protocol to generate by 
FOXN1 transcription factor 
to increase cell count 

The heterogeneous resemblance 
with endogenous ratio CD4:CD8  

(Otsuka et al., 2020)

Thymic epithelial 
cells generated from 
Scaffolding

Decellularized tissue by 
Synthetic or natural polymers

Bulk production with desired 
properties.

(Bortolomai et al., 
2019) (Barthlott et 
al., 2021)

Thymic organoids 
(Artificial)

MS5-DLL1 cells cultured Differentiation of   T cell (Seet et al., 2017) 
(Montel-Hagen et 
al., 2019)

CONCLUSION
Globally, PD is the most common chronic progressive 
neurodegenerative incurable disorder affecting elderly 
individuals over 65. The incurable PD, with its deteriorated 
motor function and devastating symptoms such as 
postural instability, bradykinesia, and quivering, suggests 
impairment of  the patient’s life. The Treg dysfunction in 
the pathogenesis of  progressive Parkinson’s disease may 
broadly improve our understanding of  the pathology of  
this incurable disorder and assists in developing proper 
treatments for Parkinson’s disease (PD) in the future. The 
possible CD4+CD25+Treg cells Treg dysfunction may 
be crucial in triggering and releasing dopamine chemicals 
(neurotransmitters) in the brain. Thus, suggesting that 
Treg dysfunction is associated with the pathogenesis 
of  progressive Parkinson’s disease. In this context, the 
possible contribution of  CD4+/CD25+ regulatory T 
cells (Tregs) is to mobilize themselves to get rid of  the 
PD pathology significantly. Therefore, the functional 
existence of  highly regulated, adaptive immunopathogenic 
mechanisms will ultimately lead to developing future 
novel therapeutics for Parkinson’s disease (PD).  

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