IMMUNEXPACE

B lymphocytes are immune system cells whose main function is to produce antibodies that recognize and neutralize pathogens such as bacteria and viruses.

Moreover, B lymphocytes participate in antigen presentation and immune memory.

T lymphocytes are cells that regulate the immune response; two main types are distinguished:

Helper T lymphocytes, which assist other immune cells in responding to infections, and Cytotoxic T lymphocytes, which directly destroy infected or cancerous cells.

Measuring and monitoring the levels of total lymphocytes (B and T) is crucial to assess the state of the immune system and to identify any pathological conditions.

Lymphocytes, involved in both innate and acquired immune responses, enable the surveillance of damaged or mutated cells.

Alterations in their levels may indicate immune dysfunctions. Regarding immune surveillance, lymphocytes play a key role by identifying and removing cells with genomic instability (due to immune stress and chronic inflammation, which damage DNA) through the induction of apoptosis. When lymphocytes become dysfunctional, this defence mechanism may be compromised, allowing genetically unstable cells to proliferate.

The release of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) during inflammation increases the risk of mutations in lymphocytes and surrounding cells.

Furthermore, persistent production of pro-inflammatory cytokines such as IL-6 and TNF-α promotes cellular proliferation, causing replication errors which, in the long term, lead to genetic aberrations in lymphocytes. Such damage can predispose individuals to the development of lymphoproliferative diseases, such as lymphomas and leukemias.

AGING PROCESSES

The loss of stem cells impairs the generation of new lymphocytes, worsening immune decline and accelerating ageing phenomena.

In particular, we observe:

Immune decline: increased susceptibility to infections, tumours, and autoimmune diseases;

Inflammaging: senescent and dysfunctional lymphocytes contribute to a state of chronic inflammation, accelerating cellular and tissue damage;

Increase in degenerative diseases: Cardiovascular diseases (through systemic inflammation), Neurodegenerative diseases (through microinflammation in the central nervous system), Tumours (due to reduced immune surveillance).

B lymphocytes are crucial for the acquired immune response, as they produce antibodies and modulate inflammation. Alterations in the levels or function of B lymphocytes can affect genomic stability, increasing the risk of autoimmune diseases, tumours, and immunodeficiencies.

When B lymphocytes suffer DNA damage due to factors such as radiation, pollution, or increased ROS during inflammation, they can accumulate mutations that impair their function. The resulting genomic instability increases the risk of developing neoplasms such as lymphomas, leukaemias, and multiple myeloma.

Moreover, B lymphocytes regulate inflammation through cytokine secretion, and chronic inflammation can favour the accumulation of DNA-damaging molecules, extending the damage even to nearby cells, including stem cells.

Finally, excessive activation of B lymphocytes can lead to inappropriate immune responses, promoting the development of autoimmune diseases.

AGING PROCESSES

Damage to stem cells due to an inflammatory environment can accelerate ageing processes, as stem cells are critical for tissue regeneration and cellular renewal.

Their dysfunction leads to progressive deterioration.

With fewer functional stem cells available to repair and replace damaged cells, tissues may age more rapidly.

This accelerated ageing and genomic instability increase vulnerability to a range of chronic, degenerative, and neoplastic diseases.

Measuring T lymphocyte levels is fundamental for assessing the immune system’s status and identifying problems with the immune response. T lymphocytes are crucial in defence against infections, tumour surveillance, and control of autoimmune diseases.

Alterations in their levels or function can indicate immunodeficiencies, infections, or autoimmunity. Identifying such alterations allows for timely therapeutic interventions.

T lymphocytes are also fundamental for tumour surveillance. In particular, a reduction in CD8+ T lymphocytes may indicate an immunosuppressive tumour microenvironment, whereas high levels of activated T lymphocytes reflect an effective immune response.

When activated, T lymphocytes produce reactive oxygen species (ROS) which, if excessive, can damage DNA. In chronic inflammation, prolonged exposure to ROS increases the risk of DNA damage, and defects in DNA repair mechanisms (for example, in genes such as ATM and BRCA1/2) make T lymphocytes more vulnerable to genotoxicity and genomic instability.

AGING PROCESSES

The loss of stem cells limits immune regeneration, causing a decrease in both the number and diversity of T lymphocytes.

This immune decline amplifies the damage to stem cells, perpetuating the ageing cycle and promoting the pathologies related to it, through:

Immune decline: the loss of functional T lymphocytes and the reduction of the diversity of the TCR (T-cell receptor) compromise the ability to respond to new infections and tumours;

Systemic inflammation (inflammaging): senescent T lymphocytes contribute to a state of chronic inflammation, which accelerates tissue and cellular damage. In addition, damage to stem cells compromises the regenerative capacity of the body, accelerating the functional decline of different organs and tissues.

Monitoring and protecting the genomic integrity of T lymphocytes is crucial to prevent lymphoproliferative diseases, improve the immune response and mitigate the risks associated with genotoxic therapies and chronic inflammation.

Measuring T lymphocyte levels is fundamental for assessing the immune system’s status and identifying problems with the immune response. T lymphocytes are crucial in defence against infections, tumour surveillance, and control of autoimmune diseases.

Alterations in their levels or function can indicate immunodeficiencies, infections, or autoimmunity. Identifying such alterations allows for timely therapeutic interventions.

T lymphocytes are also fundamental for tumour surveillance. In particular, a reduction in CD8+ T lymphocytes may indicate an immunosuppressive tumour microenvironment, whereas high levels of activated T lymphocytes reflect an effective immune response.

When activated, T lymphocytes produce reactive oxygen species (ROS) which, if excessive, can damage DNA. In chronic inflammation, prolonged exposure to ROS increases the risk of DNA damage, and defects in DNA repair mechanisms (for example, in genes such as ATM and BRCA1/2) make T lymphocytes more vulnerable to genotoxicity and genomic instability.

AGING PROCESSES

The loss of stem cells limits immune regeneration, causing a decrease in both the number and diversity of T lymphocytes.

This immune decline amplifies the damage to stem cells, perpetuating the ageing cycle and promoting the pathologies related to it, through:

Immune decline: the loss of functional T lymphocytes and the reduction of the diversity of the TCR (T-cell receptor) compromise the ability to respond to new infections and tumours;

Systemic inflammation (inflammaging): senescent T lymphocytes contribute to a state of chronic inflammation, which accelerates tissue and cellular damage. In addition, damage to stem cells compromises the regenerative capacity of the body, accelerating the functional decline of different organs and tissues.

Monitoring and protecting the genomic integrity of T lymphocytes is crucial to prevent lymphoproliferative diseases, improve the immune response and mitigate the risks associated with genotoxic therapies and chronic inflammation.

Senescent CD8+ T lymphocytes contribute to chronic inflammation and alter the microenvironment of stem cells, particularly of hematopoietic stem cells.

Pro-inflammatory cytokines (such as IL-6 and TNF-α) secreted by damaged CD8+ T lymphocytes can impair the regenerative capacities of stem cells, promoting their depletion or premature differentiation.

CD8+ T lymphocytes, also called cytotoxic T cells, are key elements of the immune system, essential for eliminating tumour or virus-infected cells, ensuring constant surveillance over the body’s integrity.

During ageing, they undergo significant qualitative and quantitative changes that impair their efficiency and contribute to immune system decline. The total number of functional cells decreases, while dysfunctional subpopulations increase.

Furthermore, their cytotoxic capabilities diminish, and senescent CD8+ T lymphocytes accumulate, becoming less effective at responding to infections and tumours. These dysfunctional cells release pro-inflammatory cytokines that sustain a state of low-grade chronic inflammation (inflammaging), which in turn accelerates degenerative processes associated with ageing.

An additional crucial aspect concerns DNA damage accumulated by CD8+ T lymphocytes over time, due to oxidative stress, exposure to genotoxic factors (such as radiation and environmental toxins), and chronic inflammation itself. Such damage reduces the proliferative and functional capacities of these cells.

Moreover, genomic instability, characterised by mutations and chromosomal alterations, can render CD8+ T lymphocytes even less effective, leading them into a state of senescence or apoptosis. This further reduces the pool of functional cells available for infection and tumour control.

These changes create a pathological cycle where immunosenescence and chronic inflammation reinforce each other, accelerating immune and tissue decline. The loss of immune surveillance increases the organism’s vulnerability to infections and tumours, while the damage to the tissue microenvironment reduces regenerative capacity, aggravating ageing processes.

AGEING PROCESSES

Genotoxic damage and genomic instability in stem cells reduce their ability to produce new immune cells, impair tissue regeneration, and contribute to systemic organ deterioration. This generates a vicious cycle in which the decline of functional CD8+ T lymphocytes amplifies damage to the stem cell pool.

Dysfunctional CD8+ T lymphocytes perpetuate a pro-inflammatory environment that accelerates the loss of stem cells, contributing to the decline in tissue regeneration typically observed with ageing.

Monitoring their levels is therefore essential to better understand their functional changes and their role in immune and systemic decline.

Compared to separately measuring CD4+ and CD8+ T lymphocyte levels, assessing the ratio between these two white blood cell populations provides a more comprehensive and dynamic overview of immune function.

Although CD4+ and CD8+ T lymphocytes have distinct roles, they are interdependent and work together to maintain immune system balance. CD4+ cells coordinate the immune response by activating and regulating other immune cells, while CD8+ cells act directly against infected or cancerous cells. Their balance is therefore essential for the effectiveness of the immune response.

The ratio between these two populations offers deeper insight into the overall immune response, providing crucial clues about immune dysfunctions that may not be evident when analysed separately. Furthermore, this ratio is a sensitive indicator of immune alterations related to processes such as ageing, genotoxicity and chronic inflammation.

A change in the CD4+/CD8+ ratio may indicate a loss of balance between immune responses, impairing immune surveillance and increasing susceptibility to infections and tumours, while also promoting chronic inflammation. Alterations in this ratio are associated with numerous conditions, including immunosenescence, autoimmune diseases, chronic infections, and cancer.

AGING PROCESSES

Reduced stem cell functionality and the accumulation of genetic damage in tissues can accelerate ageing processes. This leads to increased cellular senescence (i.e. the loss of proliferative capacity of cells) and reduced tissue regeneration.

In this context, the body’s ability to repair and replace damaged tissues diminishes, while susceptibility to age-related diseases (such as cardiovascular, neurodegenerative and autoimmune disorders) increases.

At the same time, a dysfunctional immune system and reduced numbers of functional stem cells increase vulnerability to a wide range of diseases, including not only infectious diseases, but also autoimmune, degenerative, and neoplastic conditions. For example, a compromised immune system may be unable to respond effectively to infections or to recognize and destroy cancer cells.

In this way, the deterioration of the immune system contributes to the overall ageing process, making the body more susceptible to diseases which, if uncontrolled, further accelerate physiological decline.

Monocytes are an important component of the immune system; three subtypes are known: classical, intermediate, and non-classical.

An imbalance in the ratio between classical and intermediate monocytes—particularly a low ratio—impairs phagocytic capacity, leading to the accumulation of senescent and apoptotic cells. This promotes a pro-inflammatory microenvironment that amplifies DNA damage and hinders genomic repair mechanisms, contributing to genotoxicity, genomic instability, and conditions such as cardiovascular diseases, cancer, autoimmunity, and accelerated ageing.

Monitoring and correcting these immune alterations is crucial to preserving cellular and tissue health and, in turn, promoting longevity.

Specifically:

Classical monocytes: play a crucial role in the initial immune response by phagocytosing cellular debris, pathogens, and damaged cells. In response to oxidative stress or inflammation, they release pro-inflammatory cytokines that increase reactive oxygen species (ROS) levels, thereby contributing to DNA damage and genotoxicity in surrounding cells.

Intermediate monocytes: highly active in modulating inflammation, they are key mediators of chronic inflammation. Their increase perpetuates tissue damage and genomic instability through the release of cytokines that harm the DNA of target cells.

In atherosclerotic plaques, they contribute to endothelial damage and genotoxicity in vascular cells. In tumours, they foster a pro-inflammatory microenvironment that sustains genotoxicity and the survival of unstable tumour cells. In autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus, they are associated with tissue damage and ROS-induced genomic injury.

Classical/intermediate monocyte ratio: a low ratio implies reduced phagocytic capacity, leading to the accumulation of senescent and apoptotic cells. This promotes a pro-inflammatory microenvironment that exacerbates DNA damage and impairs genomic repair mechanisms.

Intermediate Monocytes are a subtype of monocytes characterized by high pro-inflammatory activity.

They release large quantities of pro-inflammatory cytokines and reactive oxygen species (ROS), playing a central role in acute inflammation and immune responses.

They are considered key mediators of chronic inflammation and can contribute to tissue damage and genomic instability.

Non-classical Monocytes, on the other hand, are specialized in tissue surveillance and the resolution of inflammation.

They produce lower levels of ROS and pro-inflammatory cytokines compared to intermediate monocytes, promoting the control of inflammation and tissue regeneration.

They play an important role in maintaining tissue homeostasis and in tissue repair.

Alteration of the ratio between intermediate and non-classical monocytes significantly influences immune function, inflammatory responses, and tissue repair mechanisms.

All these factors contribute to increased genotoxicity, genomic instability, and the decline of stem cell functions. These changes accelerate ageing and predispose individuals to degenerative and age-related diseases.

STEM CELL CONCENTRATION

An environment dominated by intermediate monocytes, with an altered ratio compared to non-classical monocytes, generates a state of chronic inflammation that profoundly compromises stem cells. The continuous release of pro-inflammatory cytokines and ROS by intermediate monocytes damages the DNA of stem cells and alters their microenvironment, leading to a loss of their functional plasticity, reducing their ability to self-renew and respond effectively to tissue regeneration needs.

NK cells are a type of lymphocyte that plays a fundamental role in the immune system, acting as a defense against infected, tumoral, or damaged cells. Unlike T and B lymphocytes, NK cells do not require previous exposure to the pathogen to become activated. They recognise and rapidly destroy abnormal cells through cytotoxic mechanisms and the release of cytokines that modulate the immune response.

NK cells are also essential for maintaining genomic stability because they eliminate cells with damaged or unstable DNA, which could otherwise develop into tumours or contribute to chronic diseases. A compromised immune system, where NK cell functionality is impaired, can result in reduced immune surveillance. This increases the risk of genotoxicity, genomic instability, and regenerative decline. Such imbalances are often associated with the onset of tumours, degenerative diseases, and the ageing process.

Monitoring the status and functionality of NK cells allows an evaluation of immune efficiency and helps in preventing diseases linked to degenerative processes or the failure to eliminate abnormal cells.

IMMUNE RESPONSE AND GENOTOXICITY

NK cells are crucial for detecting and eliminating cells with DNA damage, mutations, or tumour-like characteristics. They recognise stressed or altered cells (such as tumour or virus-infected cells) through specific surface signals.

NK cells modulate the immune microenvironment through the release of cytokines, such as IFN-γ (interferon gamma), which:

Regulate the immune response, activating other immune cells (such as macrophages and T lymphocytes) and amplifying the defensive response;

Promote DNA repair and control inflammation, fostering a microenvironment that enhances DNA damage repair and prevents chronic inflammation, which could cause further genetic damage.

Thus, compromised NK cell functionality enhances the risk of tumor progression and contributes to systemic degeneration.

STEM CELL CONCENTRATION

Natural Killer (NK) cells play a key role in maintaining tissue homeostasis. Alterations in the function or number of NK cells can negatively affect stem cells and accelerate ageing processes in several ways:

Effect on the microenvironment of Stem Cells: NK cells regulate inflammation through the release of cytokines. Hyperactivation or a reduction in their function can alter the tissue microenvironment in which stem cells reside. A chronic pro-inflammatory environment, resulting from a dysfunction of the NK, can damage stem cells, reducing their ability to self-renew and differentiate.

Indirect damage through Inflammation: when the function of NK cells is impaired, an increase in senescent and damaged cells can occur, which release inflammatory mediators. This condition, known as cellular senescence, creates a vicious cycle that amplifies the stress to which stem cells are subjected, accelerating their depletion and contributing to the decline in tissue functionality.

Genomic instability in stem cells: dysfunctional NK cells may have a reduced ability to eliminate potentially harmful cells, such as precancerous ones. This increases the risk of mutations, exposing stem cells to signals that promote genomic instability and reduced their viability.

CD56^bright cells are a subpopulation of natural killer (NK) cells specialised in the production of cytokines that influence the immune microenvironment, DNA repair, and the suppression or promotion of cellular senescence.

Monitoring CD56^bright NK cells is essential to understanding the functioning of the immune system in various contexts, including inflammatory and infectious diseases, cancer, ageing, and pregnancy.

Their ability to regulate inflammation and modulate the immune response makes them a useful marker for assessing general immune status.

They play a crucial role in responding to genotoxicity and genomic instability by recognising damaged cells, producing regulatory cytokines, and supporting DNA repair mechanisms.

Alterations in their function can impair the immune system’s capacity to manage genomic instability, thereby contributing to the progression of cancer, autoimmune diseases, chronic infections, and degenerative processes such as ageing.

ACCELERATION OF AGEING PROCESSES

The reduction in stem cell concentration and functionality is a key feature of ageing.

If CD56^bright NK cells are unable to maintain proper immune balance, the risk of infectious and cancerous diseases may increase, and degenerative processes in tissues may accelerate, contributing to premature ageing.

The interaction between NK cell-mediated immunity and ageing is complex, with evidence suggesting that immune dysfunction can accelerate functional decline in various age-related diseases.

The CD56^–/CD16⁺ ratio represents a crucial indicator of the status of the innate immune system, providing insights into the function and balance of Natural Killer (NK) cells.

These cells are essential for controlling cells with genomic damage, particularly in the context of chronic diseases, tumours, and ageing.

Alterations in this ratio indicate impaired immune surveillance, with an increased risk of progression of infectious, autoimmune, and neoplastic diseases.

This imbalance promotes a chronic inflammatory microenvironment, which amplifies DNA damage and compromises stem cell functionality within tissues.

As a result, it contributes not only to genotoxicity but also to the acceleration of ageing processes.

STEM CELL CONCENTRATION

An imbalance in the CD56^–/CD16⁺ ratio impairs the ability of stem cells to maintain their functional pool:

Apoptosis: Damaged stem cells undergo programmed cell death, reducing the number of regenerative elements available.

Cellular senescence: Stem cells lose their proliferative capacity, entering a state of permanent cell cycle arrest.

Stem cell pool exhaustion: Prolonged exposure to a pro-inflammatory and genotoxic environment leads to a progressive depletion of the stem cell reserve, worsening with age.

These alterations directly affect tissue functionality, particularly in:

Skin: Reduced stem cell numbers result in slower wound healing and loss of elasticity.

Bones: Declining bone regeneration increases the risk of osteoporosis.

Muscles: Loss of stem cells contributes to sarcopenia, causing muscle weakness and loss of mass.

ACCELERATION OF AGEING PROCESSES

An altered CD56^–/CD16⁺ ratio fuels a vicious cycle of chronic inflammation and immune stress. By further damaging the DNA of stem cells, it reduces the quality of the remaining cells and increases the risk of mitotic errors and pathological transformations.

Moreover, the resulting alteration of the tissue microenvironment impairs effective regeneration and promotes premature ageing.

Restoring the physiological balance between CD56^– and CD16⁺ is essential to preserving stem cell function and slowing ageing processes: integrated approaches, including anti-inflammatory, antioxidant, immunomodulatory, and regenerative therapies, can reduce chronic inflammation, limit DNA damage, and protect the stem cell reserve.

Targeted interventions not only support healthier ageing but also reduce the risk of degenerative and autoimmune diseases associated with immune decline.

ROLE OF VITAMIN D

Vitamin D is in fact a prohormone. In the liver, it is converted into calcidiol (25(OH)D), and then in the kidneys into calcitriol (1,25(OH)₂D), the biologically active form.

It is present in foods in two forms: vitamin D2 (ergocalciferol), found in plant-based sources, and vitamin D3 (cholecalciferol), found in animal-based foods.

Vitamin D3 is also synthesized by the skin upon sun exposure.

In the blood, the level of 25(OH)D is measured as it has a longer half-life and is the best indicator of the body’s overall vitamin D status. Once activated, vitamin D is essential for calcium metabolism and immune system function.

Monitoring 25(OH)D levels is crucial for maintaining overall health and preventing chronic diseases. Identifying deficiencies or excesses allows for personalised preventive and therapeutic interventions, improving quality of life and reducing long-term complications.

ROLE OF VITAMIN D IN THE IMMUNE SYSTEM

Vitamin D regulates the metabolism of calcium and phosphorus, maintains bone health and supports the immune system. It modulates the production of inflammatory cytokines, improving the efficiency of the innate and adaptive immune response.

Effects on immune cells:

In monocytes: it reduces the production of inflammatory molecules and influences the response to antigens.

In macrophages: it stimulates the production of antimicrobial molecules and reduces inflammation.

In dendritic cells: it regulates the production of inflammatory mediators, helping to control chronic inflammation.

On NK (Natural Killer) cells: it enhances the ability to eliminate abnormal or infected cells.

In neutrophils: reduces the risk of autoimmune reactions.

On B and T lymphocytes: it directly influences them, promoting the balance between pro-inflammatory and anti-inflammatory molecules.

ACCELERATION OF AGEING PROCESSES

The accumulation of unrepaired oxidative damage in stem cells leads to:

Apoptosis: cell death programmed to protect the body;

Cellular senescence: permanent shutdown of the cell cycle with the release of inflammatory cytokines;

Acceleration of Ageing Processes: reduced tissue regeneration capacity, with functional decline manifested by loss of skin elasticity, bone fragility and reduced ability to repair damaged tissues.

Damaged stem cells that enter senescence release pro-inflammatory cytokines, perpetuating a state of low-grade chronic inflammation and secondary damage to the surrounding tissues.

Adequate levels of vitamin D (25-(OH)D within the range of 30-50 ng/mL) protect the genome, improving the ability of cells to respond to DNA damage and limiting the formation of mutations. This reduces the risk of genotoxicity induced by external agents such as ionising radiation or chemical agents.