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PUBLISHED DATE: - 14-11-2024
DOI: -
https://doi.org/10.37547/TAJMSPR/Volume06Issue11-03
PAGE NO.: - 11-18
THE ROLE OF HOMOCYSTEINE AS A
BIOMARKER OF CYTOKINE STORM IN
IMMUNOONCOLOGY AND THERAPY OF
COVID-19
Yulii Honskyi
President in Honskyi Scientific INC, USA
INTRODUCTION
Modern medicine faces a number of complex
challenges related to the diagnosis and treatment
of diseases characterized by pronounced
inflammatory reactions and immune system
dysfunctions. One such pathological condition is
the cytokine storm, observed in severe forms of
COVID-19 and various oncological diseases. A
cytokine storm represents an excessive activation
of the immune system, leading to the release of
large quantities of pro-inflammatory cytokines,
which causes systemic inflammation, tissue and
organ damage, and can potentially result in death.
In recent years, homocysteine, an amino acid
involved in methionine metabolism, has garnered
significant attention as a potential biomarker for
inflammatory processes, including cytokine
storms. Elevated homocysteine levels are
associated with various pathological conditions,
such
as
cardiovascular
diseases,
neurodegenerative disorders, and immune
dysfunctions, making it a promising target for
study in the context of new therapeutic
approaches.
The relevance of this topic is driven by the need to
identify and develop new biomarkers that could
not only signal the onset of inflammatory
processes but also serve as precise therapeutic
targets for intervention. In the context of the
COVID-19 pandemic and the rising incidence of
RESEARCH ARTICLE
Open Access
Abstract
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oncological diseases, it is crucial to have a deeper
understanding of the pathogenic mechanisms of
these conditions and their relationship with
homocysteine.
The aim of this study is to investigate the role of
homocysteine as a biomarker of cytokine storms,
its impact on the pathogenesis of immuno-
oncological diseases and COVID-19, and to assess
the prospects for using homocysteine in the
diagnosis and therapy of these conditions.
1. Mechanisms of Cytokine Storm Onset and Its
Role in Disease Pathogenesis
A cytokine storm is an acute immunopathological
condition characterized by the excessive release of
pro-inflammatory cytokines, leading to systemic
inflammation and multiple organ failure. Recent
developments over the last 5-10 years have clearly
linked this condition with two major contexts
(among others): immuno-oncology and, more
recently, COVID-19. Ongoing research focuses on
identifying potential biomarkers that can reliably
predict both the onset and progression of cytokine
storms, using advanced molecular profiling
techniques and large-scale clinical studies. The
mechanisms of cytokine storm development are
illustrated below in Figure 1.
Fig.1. Mechanisms of cytokine storm development [1].
Mechanisms
of cytokine
storm
development
Tissue and organ
damage
Dysregulation
Initiating an
immune
response
Coagulopathy
and vasculopathy
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The renin-angiotensin-aldosterone system (RAAS)
is a complex network of vasoactive peptides that
play a crucial role in regulating blood pressure,
circulating blood volume, and electrolyte balance,
as well as participating in inflammatory processes.
One of the central components of this system is
angiotensin-converting enzyme 2 (ACE2), which is
expressed in various organs, including the heart,
kidneys, lungs, testes, and gastrointestinal tract.
This enzyme catalyzes the conversion of
angiotensin I (AT I) into angiotensin 1-9 (AT 1-9),
which can subsequently be transformed into
angiotensin 1-7 (AT 1-7) under the action of ACE
or other peptidases. Moreover, ACE2 can directly
convert angiotensin II (AT II) into AT 1-7. The
peptide
AT
1-7
possesses
vasodilatory,
antiproliferative, antithrombotic, and anti-
inflammatory properties, allowing it to attenuate
the activity of type 1 angiotensin receptors (AT1R).
The interaction of AT 1-7 with the Mas receptor
(MasR) leads to a reduction in the expression of
inflammatory markers such as interleukin-6 (IL-
6), tumor necrosis factor α (TNFα), and
interleukin-8 (IL-8).
AT 1-7 exerts a positive effect through the
activation of the MasR receptor, which is expressed
in epithelial and smooth muscle cells of the
bronchi. This allows AT 1-7 to participate in the
regulation of both acute and chronic inflammatory
processes in the lungs. Additionally, AT 1-7
influences the synthesis of interleukin-10 (IL-10),
which stimulates the differentiation of type 2
helper T cells responsible for producing anti-
inflammatory cytokines such as IL-4, IL-5, IL-9, and
IL-13. Interleukin-10 may also play a role in
preventing tissue damage.
Clinical data indicate that disruption of the RAAS
plays a significant role in the pathogenesis of acute
respiratory distress syndrome (ARDS) in COVID-
19 [1]. Specifically, patients with COVID-19 exhibit
elevated levels of AT II, which correlate with the
severity of lung damage. Moreover, the use of ACE
inhibitors and angiotensin receptor blockers for
treating arterial hypertension is associated with a
milder disease course and lower IL-6 levels in
COVID-19 patients. A meta-analysis involving
24,676 COVID-19 patients confirmed that the use
of RAAS inhibitors reduces the risk of death and/or
severe conditions by 23% [1].
Clinical and epidemiological data suggest that
patients with initially reduced ACE2 expression or
impaired RAAS function (e.g., elderly men, as well
as individuals with diabetes, hypertension, or
obesity) experience more severe disease when
ACE2 is depleted by the action of SARS-CoV-2 [1].
The kallikrein-kinin system also plays an
important role in the pathogenesis of COVID-19.
This system includes kininogen precursors, from
which bradykinin and its active metabolite des-
Arg9-bradykinin are formed under the action of
kallikrein. These peptides interact with bradykinin
receptors of the first and second types, leading to
vasodilation, lowered blood pressure, or the
release of pro-inflammatory cytokines, depending
on the receptor type. The kallikrein-kinin system is
closely linked to the RAAS, as ACE2 is involved in
the inactivation of bradykinin, and a decrease in its
activity leads to an enhanced inflammatory
response through the BKB1R receptor. The
expression of kininogen and kallikrein genes in
COVID-19 patients was significantly higher
compared to the control group, accompanied by
decreased ACE2 levels and increased bradykinin
receptor expression.
The complement system, which includes proteins
and their cleavage products, coordinates the
inflammatory response to infection. Activation of
the complement system can occur through the
classical, lectin, and alternative pathways. The
lectin pathway, involving mannose-binding serine
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protease 2 (MASP-2), directly contributes to lung
damage in coronavirus infection. The nucleocapsid
protein of SARS-CoV-2 activates MASP-2, leading
to a cascade of inflammatory reactions and lung
tissue damage. Biomarkers that can identify a
cytokine storm are shown in Figure 2. The next
section will discuss homocysteine in more detail as
a biomarker.
Fig.2. Potential biomarkers [2].
2. Homocysteine as a Biomarker: Biochemical
Foundations and Clinical Significance
Homocysteine is an amino acid formed during the
breakdown of methionine, which enters the human
div through protein-rich foods such as meat, fish,
eggs, and others (Fig. 3).
Potential
biomarkers
Ferritin
C-reactive
protein
(CRP)
Interleukin-6
(IL-6)
Neutrophil to
lymphocyte
ratio (NLR)
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Fig.3. Homocysteine.
It is important to emphasize that these are some of
the most prominent potential biomarkers
currently under close scrutiny, with the group of
interleukins leading the list.
In modern medicine, significant attention is given
to studying factors that can affect endothelial
damage. Endothelial dysfunction is fundamental to
the pathogenesis of various diseases across the
cardiorenal continuum, including cardiovascular,
neurological,
and
obstetric-gynecological
pathologies. These conditions are associated with
the development of serious complications, which
in turn lead to increased mortality and disability.
Among the many markers indicating endothelial
dysfunction,
homocysteine
has
received
considerable attention.
Homocysteine is an amino acid structurally similar
to cysteine but differing by one methylene group.
This chemical component was first described in
1932 and is formed in the human div from
methionine, which is obtained from animal
proteins. Excess homocysteine can be converted
back into methionine, and this process depends on
the availability of vitamins such as folic acid,
pyridoxine, and cyanocobalamin. A deficiency in
these substances can lead to elevated
homocysteine levels in the blood, a condition
known as hyperhomocysteinemia.
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The relationship between high homocysteine
levels and arterial diseases was noted as early as
the 1960s [3]. Cases were found where a deficiency
in the enzyme cystathionine synthase, which is
involved in homocysteine metabolism, led to
severe disorders such as homocystinuria,
intellectual disability, and bone deformities. These
conditions were typically accompanied by early
development of cardiovascular diseases and
thromboembolism, often resulting in death before
the age of 30. In 1975, based on these observations,
it was proposed that homocysteine be considered
one of the key risk factors for atherosclerosis.
Subsequent research has supported this
hypothesis, highlighting the need for further study
of this issue.
A review of the literature revealed a strong
correlation between elevated homocysteine levels
in the human div and an increased risk of heart
and coronary diseases. Additionally, data indicate
that patients with cytokine storms caused by
COVID-19 also have elevated levels of this
biomarker.
The normal range of homocysteine levels in the
blood varies, with different sources providing
different values that reflect age and physiological
changes. For example, the normal level in
adolescents and adults ranges from 5-15 µmol/L,
while in pregnant women, this indicator may be
lower due to physiological changes during
pregnancy. Some researchers believe that the
lower limit of normal should be considered even
lower than is currently accepted.
The term "hyperhomocysteinemia" is often used
when homocysteine concentrations exceed 15
µmol/L. A moderate increase in homocysteine
levels can be observed in chronic kidney failure
and folate deficiency. This condition may also be
due to hereditary factors, such as a mutation in the
methylenetetrahydrofolate reductase gene, which
reduces the activity of the enzyme involved in folic
acid metabolism, leading to elevated homocysteine
levels.
The role of homocysteine in the development of
endothelial dysfunction is well-studied. High levels
of this amino acid contribute to hemostatic
disorders, increasing the risk of thrombosis and
the progression of atherosclerosis. Homocysteine
also affects nitric oxide synthesis, reducing its
bioavailability, which may explain the decreased
effectiveness of vasodilators in patients with
elevated homocysteine levels. Experimental
studies confirm that hyperhomocysteinemia
accelerates the development of atherosclerotic
changes, but appropriate vitamin therapy,
particularly involving B vitamins, has been shown
to slow this process.
Furthermore, homocysteine is associated with the
development of extragenital diseases, such as
diabetes and its complications, as well as an
increased risk of cerebrovascular disorders.
Experimental models and clinical studies have
confirmed
the
link
between
elevated
homocysteine levels and cognitive impairment,
stroke, and diseases like Alzheimer's and
Parkinson's.
Homocysteine has a significant impact on
pregnancy, causing endothelial dysfunction and
increasing the risk of complications such as
preeclampsia and fetoplacental insufficiency.
Elevated homocysteine levels can lead to
thrombosis and impaired placental blood flow,
which in turn may cause fetal hypoxia and low
birth weight.
Studies indicate that polymorphic variants of the
methylenetetrahydrofolate reductase gene can be
an independent risk factor for pregnancy loss. This
is supported by research in various populations,
including Asian and European. Finally, folate
deficiency is associated with the development of
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neural tube defects in the fetus, making folic acid
supplementation before and during pregnancy
essential.
For adequate correction of the folate cycle, it is
important to use a comprehensive therapy that
includes B vitamins and nicotinic acid. The correct
dosage of folates and other vitamins remains a
subject of debate, requiring further research.
Overall, high homocysteine levels in the blood are
a serious predictor of various pathologies,
necessitating a comprehensive approach to their
prevention and treatment [4].
Thus, homocysteine remains an important subject
of research, capable of shedding light on the
mechanisms of many diseases and aiding in the
development of effective methods for their
prevention and treatment.
3. The Role of Homocysteine in Immuno-
Oncology and COVID-19 Therapy: Prospects
and Challenges
Under normal conditions, homocysteine is rapidly
neutralized through interactions with vitamins B6,
B12, and folic acid, which facilitate its conversion
into harmless substances. However, when these
vitamins are deficient, homocysteine levels in the
blood begin to rise, leading to negative
consequences for the div. Studies show that a 5
µmol/L increase in homocysteine levels is
associated with a 30-70% increase in the risk of
cardiovascular
diseases
and
mortality.
Hyperhomocysteinemia is also linked to an
increased risk of cerebrovascular disorders and
peripheral vascular pathology. This condition can
be accompanied by secondary autoimmune
reactions, making it a potential cause of
antiphospholipid syndrome [5].
In immuno-oncology, homocysteine is considered
a biomarker due to its ability to induce oxidative
stress, leading to the formation of free radicals.
These radicals, in turn, can damage DNA,
contributing
to mutations
that
underlie
carcinogenesis. Additionally, homocysteine plays a
role in maintaining chronic inflammation, a known
factor in tumor progression. Chronic inflammation
creates a microenvironment that is conducive to
tumor growth and metastasis [6].
Regarding the role of homocysteine in COVID-19, it
influences inflammatory processes and vascular
conditions.
Since
homocysteine
promotes
thrombosis, this is particularly relevant in the
context of COVID-19. Thrombotic complications,
such as venous thromboembolism, significantly
worsen the prognosis for COVID-19 patients, and
elevated homocysteine levels may contribute to
their development. Furthermore, homocysteine
can exacerbate inflammation and promote the
development of the so-called cytokine storm, a key
factor in severe cases of COVID-19. This is due to
its ability to modulate the immune response,
enhancing the production of pro-inflammatory
cytokines.
Research indicates that one of the key
manifestations of COVID-19 is endothelial
dysfunction, accompanied by coagulopathy, which
is associated with more severe lung damage and a
higher risk of fatal outcomes. Systemic
inflammation plays a significant role in the
development of these pathological conditions.
Observations suggest that folate and one-carbon
metabolism, which are critical for purine synthesis
and the antioxidant glutathione, are hijacked by
the coronavirus for replication in infected cells.
Metabolic disturbances, such as decreased folate
and vitamin B12 levels in the blood serum and
increased homocysteine levels, are commonly
observed in COVID-19 patients [6].
Clinical studies [7] have identified a correlation
between the severity of COVID-19 and increased
homocysteine levels in the blood serum. Carriers of
the minor allele of the MTHFR C677T single
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nucleotide polymorphism, involved in folate
metabolism,
are
at
higher
risk
for
hyperhomocysteinemia and vascular diseases, as
well as increased morbidity and mortality from
COVID-19.
The
negative
impact
of
hyperhomocysteinemia on the progression of
vascular damage in various diseases, along with
the activation of angiotensin II type 1 receptors
induced by homocysteine, suggests that
homocysteine levels and genetic markers of folate
metabolism could be considered potential
predictors of adverse outcomes in COVID-19 [7].
CONCLUSION
Thus, homocysteine not only serves as a biomarker
but also plays an active role in the pathological
processes linked to cytokine storms, particularly
through its contribution to oxidative stress and
endothelial dysfunction. Elevated homocysteine
levels
are
associated
with
heightened
inflammatory responses and oxidative stress,
making it a key element for a more precise
understanding of the pathogenesis of these
conditions and the development of targeted
therapeutic
approaches.
Incorporating
homocysteine into the monitoring and treatment
of these diseases could contribute to improved
clinical outcomes and personalized treatment
strategies.
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