Body Lines of Defense- Innate and Acquired Immunity

The human body is constantly exposed to various foreign invaders, such as viruses, bacteria, and fungi, that can cause infections and diseases. To protect itself from these harmful agents, the body has developed a sophisticated system of defense mechanisms that can recognize and eliminate them. This system is called the immune system.

The immune system consists of two types of defense systems: innate and acquired. Innate defense systems are present at birth and provide the first and second lines of defense against any pathogen that enters the body. Acquired defense systems are developed during the lifetime and provide the third line of defense against specific pathogens that have been encountered before.

Innate Defense Systems

Innate defense systems are also known as natural or non-specific defense systems because they do not distinguish between different types of pathogens and respond in the same way to all of them. They are composed of physical and chemical barriers, cellular and molecular components, and inflammatory responses that act together to prevent or limit the spread of infections.

Physical and Chemical Barriers

Physical and chemical barriers form the first line of defense against the invasion of pathogens. They include:

• The skin, which is a tough and waterproof layer that covers the entire body surface and prevents most pathogens from entering.
• The mucous membranes, which line the internal cavities that are exposed to the external environment, such as the respiratory, digestive, urinary, and reproductive tracts. They produce mucus, a sticky substance that traps pathogens and foreign particles and expels them by coughing, sneezing, swallowing, or urination.
• The cilia, which are hair-like structures that cover some mucous membranes, such as those in the nose and lungs. They beat in a coordinated manner to move mucus and trapped pathogens out of the body.
• The tears, saliva, sweat, earwax, gastric juice, urine, and vaginal secretions, which contain various chemicals and enzymes that can kill or inhibit the growth of pathogens. For example, lysozyme is an enzyme found in tears, saliva, and sweat that can break down the cell walls of bacteria. Gastric juice is highly acidic and can destroy most pathogens that enter the stomach through food or drink.
• The normal microbiota, which are harmless or beneficial microorganisms that colonize various parts of the body, such as the skin, mouth, gut, and vagina. They compete with pathogens for nutrients and space and produce substances that inhibit their growth or stimulate the immune system.

Cellular and Molecular Components

Cellular and molecular components form the second line of defense against the pathogens that manage to cross the physical and chemical barriers. They include:

• The phagocytes, which are specialized white blood cells that can engulf and digest pathogens and other foreign particles. They include neutrophils, monocytes, macrophages, and dendritic cells. Neutrophils are the most abundant and first to arrive at the site of infection. Monocytes circulate in the blood and differentiate into macrophages or dendritic cells when they enter tissues. Macrophages are large phagocytes that reside in various tissues and organs and can activate other immune cells by presenting antigens. Dendritic cells are phagocytes that capture antigens from tissues and migrate to lymph nodes to activate adaptive immune responses.
• The natural killer (NK) cells, which are a type of lymphocyte that can recognize and kill virus-infected cells or tumor cells without prior exposure or activation. They release chemicals that induce apoptosis (programmed cell death) or perforate the cell membrane of their targets.
• The complement system, which is a group of plasma proteins that can be activated by pathogens or antibodies to enhance phagocytosis,

Innate and acquired immunity are two types of body responses against invaders: Innate (Natural/Non-specific response) and Acquired (Adaptive/Specific) responses. They differ in several aspects, such as:

• Time of occurrence: Innate immunity is present from birth, while acquired immunity develops gradually after exposure to pathogens .
• Specificity of response: Innate immunity can identify a wide range of foreign pathogens but cannot differentiate between them. Thus it generates a non-specific response. Acquired immunity identifies and differentiates foreign antigens. Thus, it generates a highly specific and sensitive response towards a respective antigen .
• Response time: Innate immunity produces a rapid response in very less time, while acquired immunity takes a longer time to react .
• Memory: Innate immunity does not have memory, which means it does not remember the pathogens it encounters. Thus, the response does not last for long. Acquired immunity has memory, which means it remembers the pathogens it encounters. Thus, the response is long-lasting and stronger on subsequent exposures .
• Components: Innate immunity employs phagocytic cells such as neutrophils, monocytes and macrophages, and natural killer (NK) cells. However, acquired immunity involves antigen-specific B and T cells or antigen-presenting cells (APCs) .
• Lines of defense: Innate immunity comprises the first and second line of defense, which include physical, chemical, and biological barriers, and immune cells and proteins. Acquired immunity includes the third line of defense, which involves the adaptive immune system .

In summary, innate and acquired immunity are complementary systems that work together to protect the body from harmful pathogens.

The innate and acquired immune systems are composed of different types of cells that work together to protect the body from foreign invaders. The following table summarizes the main cells involved in each system and their functions.

The innate immune system is the first line of defense against pathogens and is characterized by rapid and non-specific responses. The acquired immune system is the second line of defense that is activated by the innate system and is characterized by specific and memory responses. The two systems are interconnected and cooperate to eliminate pathogens and prevent infections.

The first line of defense (or outside defense system) includes physical and chemical barriers that are always ready and prepared to defend the body from infection. These include your skin, tears, mucus, cilia, stomach acid, urine flow, ‘friendly’ bacteria and white blood cells called neutrophils.

• Physical defenses: These include physical barriers and mechanical defenses that block the entry point of pathogens such as intact skin and mucus. Skin has three layers: the epidermis, the dermis, and the hypodermis. The topmost layer, the epidermis is packed with keratin along with dead skin cells. These dead cells are frequently being shed and replaced. The keratin is highly water-resistant and mechanically tough hence, resists microbial growth. Nasal hairs filter air contaminated with microbes, dust, and dirt while microscopic cilia lining the respiratory tract, sweep mucus and trap particles inhaled towards body openings where they can be removed from the body. Mucous membranes lining respiratory, urinary, and reproductive tracts, produce mucus, a slimy substance that traps foreign particles and directs them out of the body by mechanical actions such as shedding, coughing, peristalsis, and flushing of bodily fluids (e.g. urination, tears).
• Chemical defenses: These comprise chemicals and enzymes in body fluids, a variety of plasma protein mediators, cytokines, antimicrobial peptides, inflammation- eliciting mediators that destroy pathogens on the outer body surface, at body openings, and on inner body linings. Sweat, tears, mucus, and saliva contain enzymes that kill pathogens. Lysozyme, an enzyme found in tears, perspiration, and saliva can break down the cell walls of bacteria and kill them. Likewise, secretory IgA function in a similar manner by attacking peptidoglycans in the cell wall of bacteria. Antimicrobial peptides (AMPs) include dermcidin, cathelicidin, defensins, histatins, and bacteriocins. AMPs are produced in response to pathogens on the skin. Cerumen or ear wax contains fatty acids thereby lowering the pH between 3 and 5 which protects the auditory canal from foreign particles like microbes. Gastric juice (pH 2-3) is highly acidic in nature and those pathogens that enter the stomach through the oral cavity or nasal tract are destroyed by it. Urine flow which is acidic in pH kills microbes and directs them out of the urethra. Serum (unsaturated fatty acids) reduces water loss as well as inhibits microbial growth however it is found to have certain compounds that facilitate to provide nutrition for certain microbes.

• Biological defenses: These are provided by living microorganisms that are friendly and beneficial. These are resident natural flora that reside on our skin, in our bowel and in other places such as the mouth, gut, reproductive part etc. These prevent pathogen adherence and their colonization by creating an acidic environment with the help of fermentation of sugars to acids occupying available cellular binding sites and competing with them for available nutrients. Thus resident normal microbiota also contributes to chemical defenses as they produce bacteriocins that perform antibacterial activity.
  
  Second Line of Defense: Immune System and Phagocytes

When the first line of defense is breached by pathogens, the body activates the second line of defense, which is also known as the immune system. The immune system consists of cells, molecules, and organs that work together to protect the body from infections and diseases. The immune system can be divided into two main branches: the innate immune system and the adaptive immune system. The innate immune system is the focus of this section.

The innate immune system is the body`s natural or non-specific response to pathogens. It does not require prior exposure or recognition of specific antigens, but rather responds to general features of pathogens, such as their surface molecules or their patterns of DNA or RNA. The innate immune system is composed of various types of cells and molecules that act as barriers, sensors, and effectors of immunity.

One of the most important types of cells in the innate immune system is the phagocyte. Phagocytes are white blood cells that can engulf and destroy pathogens by a process called phagocytosis. Phagocytes include neutrophils, monocytes, macrophages, dendritic cells, and mast cells. Each type of phagocyte has a different function and location in the body.

• Neutrophils are the most abundant and the first to arrive at the site of infection. They can squeeze through the walls of blood vessels and migrate to the tissues where they encounter and kill bacteria and fungi.
• Monocytes are large cells that circulate in the blood and differentiate into macrophages or dendritic cells when they enter the tissues.
• Macrophages are tissue-resident phagocytes that patrol and scavenge for pathogens, dead cells, and debris. They also secrete cytokines and present antigens to activate other immune cells.
• Dendritic cells are specialized phagocytes that capture and process antigens from pathogens and present them to T cells in the lymph nodes. They are essential for linking the innate and adaptive immune systems.
• Mast cells are granular cells that reside in the mucous membranes and skin. They release histamine and other inflammatory mediators when they encounter allergens or pathogens.

The mechanism of phagocytosis involves several steps:

1. Recognition: The phagocyte recognizes and binds to a pathogen or a foreign particle through receptors on its surface. These receptors can recognize molecules such as lipopolysaccharide (LPS), peptidoglycan, mannose, or complement proteins that are common to many pathogens but not present on host cells.
2. Engulfment: The phagocyte extends its plasma membrane around the pathogen and forms a vesicle called a phagosome.
3. Fusion: The phagosome fuses with a lysosome, which is an organelle that contains digestive enzymes and acidic pH.
4. Degradation: The lysosomal enzymes break down the pathogen into smaller fragments that can be either recycled or expelled by exocytosis.
5. Antigen presentation: Some phagocytes, such as macrophages and dendritic cells, can also display fragments of the degraded pathogen on their surface bound to major histocompatibility complex (MHC) molecules. These MHC-antigen complexes can be recognized by T cells, which initiate an adaptive immune response.

Phagocytosis is a crucial mechanism for eliminating pathogens and preventing infections from spreading. However, some pathogens have evolved strategies to evade or resist phagocytosis, such as producing capsules, toxins, or enzymes that interfere with recognition, engulfment, fusion, or degradation. Therefore, phagocytosis alone is not sufficient to protect the body from all types of pathogens, and other components of the innate and adaptive immune systems are needed to mount an effective defense.

When the first line of defense is breached by pathogens, the body activates the second line of defense, which consists of a group of cells, tissues, and organs that work together to protect the body. This is the immune system. The immune system uses various mechanisms to recognize and eliminate any non-specific pathogen that has entered the body. Some of these mechanisms are:

• Phagocytosis: This is the process by which certain immune cells, called phagocytes, engulf and destroy pathogens or foreign particles. Phagocytes include neutrophils, monocytes, macrophages, and dendritic cells. Phagocytes recognize pathogens by their surface molecules, such as lipopolysaccharides (LPS) on bacteria or glycoproteins on viruses. Phagocytes also have receptors for antibodies and complement proteins, which can coat pathogens and mark them for phagocytosis. Once a pathogen is engulfed by a phagocyte, it is enclosed in a vesicle called a phagosome, which fuses with a lysosome containing digestive enzymes and toxic substances. The lysosome breaks down the pathogen and its components, which are then either recycled or excreted by the phagocyte.

• Natural killer (NK) cells: These are a type of lymphocyte that can kill virus-infected cells or tumor cells without prior activation or exposure. NK cells have receptors that can detect abnormal or stressed cells, such as those infected by viruses or transformed by cancer. NK cells release perforins and granzymes, which form pores in the target cell membrane and induce apoptosis (programmed cell death). NK cells also secrete cytokines, such as interferons and tumor necrosis factor (TNF), which can inhibit viral replication and activate other immune cells.

• Inflammatory response: This is a local reaction that occurs when tissues are damaged or infected by pathogens. The inflammatory response involves four main signs: redness, heat, swelling, and pain. These signs are caused by various factors, such as:

  • Histamine: This is a chemical released by mast cells and basophils in response to injury or infection. Histamine causes vasodilation (widening) of blood vessels, which increases blood flow and brings more immune cells and nutrients to the site of inflammation. Histamine also increases vascular permeability (leakiness), which allows plasma and immune cells to exit the blood vessels and enter the tissues.

  • Cytokines: These are small proteins secreted by various immune cells, such as macrophages, dendritic cells, T helper cells, and NK cells. Cytokines act as messengers between immune cells and regulate their functions. Some cytokines can enhance inflammation by attracting more immune cells to the site of infection or injury, such as chemokines, interleukins (ILs), and TNF. Other cytokines can modulate inflammation by inhibiting or resolving it, such as IL-10 and transforming growth factor beta (TGF-beta).

  • Complement system: This is a group of plasma proteins that can act as an innate nonspecific defense while also serving to connect innate and adaptive immunity. The complement system can be activated by three pathways: the classical pathway (triggered by antibodies bound to pathogens), the alternative pathway (triggered by pathogen surfaces), and the lectin pathway (triggered by mannose-binding lectin bound to pathogens). All three pathways converge to form a complex called C3 convertase, which cleaves C3 into C3a and C3b. C3a acts as an inflammatory mediator that attracts phagocytes and enhances vascular permeability. C3b acts as an opsonin that coats pathogens and facilitates their phagocytosis. C3b can also form another complex called C5 convertase, which cleaves C5 into C5a and C5b. C5a acts as another inflammatory mediator that attracts more phagocytes and activates mast cells. C5b initiates the formation of the membrane attack complex (MAC), which consists of C6-C9 proteins that insert into the pathogen membrane and create pores that cause lysis.

The inflammatory response helps to contain and eliminate pathogens at the site of infection or injury, while also preparing for the activation of the adaptive immune system.

The adaptive immune system, also known as the acquired or specific immune system, is a subsystem of the immune system that is composed of specialized cells and processes that eliminate specific pathogens or prevent their growth. The adaptive immune system is different from the innate immune system in several ways:

• It is not present at birth, but develops during the lifetime of the organism as it encounters various foreign substances.
• It is highly specific to each particular pathogen and can recognize millions of different antigens.
• It creates immunological memory after an initial response to a specific pathogen, and leads to an enhanced response to future encounters with that pathogen.
• It takes longer to develop than the innate immune response, but it can provide long-lasting protection, sometimes for the person`s entire lifetime.

The adaptive immune system includes two main types of responses: humoral immunity and cell-mediated immunity. Humoral immunity involves the production of antibodies by B cells, which are a type of lymphocyte (white blood cell) that originate and mature in the bone marrow. Antibodies are proteins that bind to specific antigens and mark them for destruction by other immune cells or mechanisms. Cell-mediated immunity involves the activation of T cells, which are another type of lymphocyte that originate in the bone marrow but mature in the thymus. T cells can directly kill infected or abnormal cells, or help other immune cells by secreting cytokines (chemical messengers).

Both B cells and T cells have receptors on their surface that can recognize specific antigens. However, they cannot recognize free antigens in the body fluids; they need the help of antigen-presenting cells (APCs), such as macrophages, dendritic cells, or B cells themselves. APCs are cells that can engulf and process antigens, and display fragments of them on their surface bound to special molecules called major histocompatibility complex (MHC). MHC molecules are like identification tags that allow the immune system to distinguish between self and non-self. There are two types of MHC molecules: MHC class I and MHC class II. MHC class I molecules are found on almost all nucleated cells in the body, and present antigens derived from inside the cell (such as viral or tumor antigens). MHC class II molecules are found only on APCs, and present antigens derived from outside the cell (such as bacterial or parasitic antigens).

When a naive (unactivated) B cell or T cell encounters an antigen that matches its receptor, it becomes activated and undergoes clonal expansion, which means it divides rapidly and produces many identical copies of itself. Some of these clones differentiate into effector cells, which carry out the immune response against the antigen. Some of them differentiate into memory cells, which persist in the body for a long time and provide a faster and stronger response if the same antigen is encountered again.

The adaptive immune system is highly adaptable because it can generate new receptors with different specificities through a process called somatic recombination, which involves random rearrangement of gene segments that encode for the receptor chains. This process occurs during the development of B cells and T cells in the bone marrow and thymus, respectively. Another process that increases the diversity of receptors is called somatic hypermutation, which involves random mutations in the antibody-coding genes during B cell activation. This allows antibodies with novel specificity to be created.

The adaptive immune system is also regulated by various mechanisms that prevent excessive or inappropriate responses that could harm the host. For example, some T cells act as regulatory T cells (Tregs), which suppress other T cells and prevent autoimmunity (when the immune system attacks self tissues). Another example is feedback inhibition, which occurs when high levels of antibodies or cytokines signal to stop further production of them.

The adaptive immune system is the basis of vaccination, which is a method of artificially inducing immunity to a specific pathogen by exposing the body to a weakened or killed form of it, or a part of it. This stimulates an adaptive immune response that produces memory cells without causing disease. If the person is exposed to the same pathogen later in life, they will have a rapid and effective response that prevents infection.

Humoral immunity is one of the two types of adaptive immune responses, along with cell-mediated immunity. It involves mainly B cells and antibodies that fight against pathogens that are free in the blood and lymph. Humoral immunity is also called antibody-mediated immunity because antibodies are the main effector molecules of this response.

How humoral immunity works

• Humoral immunity begins when a pathogen enters the body and its antigens are recognized by B cells. B cells are lymphocytes that originate and mature in the bone marrow. They have antigen receptors called B cell receptors (BCRs) on their surface, which are membrane-bound antibodies that can bind to specific antigens.
• When a B cell binds to an antigen, it internalizes it and processes it into smaller fragments. Then, it displays the antigen fragments on its surface along with major histocompatibility complex (MHC) class II molecules. This makes the B cell an antigen-presenting cell (APC) that can activate helper T cells.
• Helper T cells are another type of lymphocytes that originate in the bone marrow but mature in the thymus. They have antigen receptors called T cell receptors (TCRs) that can recognize antigen-MHC complexes on APCs. When a helper T cell binds to a B cell presenting an antigen, it secretes cytokines that stimulate the B cell to proliferate and differentiate into plasma cells and memory B cells.
• Plasma cells are effector B cells that secrete large amounts of antibodies into the blood and lymph. Antibodies are proteins that have the same specificity as the BCRs of the original B cell. They can bind to the same antigens and neutralize or eliminate them by various mechanisms, such as opsonization, agglutination, neutralization, complement activation, and antibody-dependent cellular cytotoxicity.
• Memory B cells are long-lived B cells that retain the memory of the antigen and can quickly respond to a secondary exposure by producing more plasma cells and antibodies. This provides long-lasting immunity and protection against reinfection.

Types of antibodies

There are five classes of antibodies, also known as immunoglobulins (Ig), that differ in their structure, function, and distribution. They are IgM, IgG, IgA, IgE, and IgD.

• IgM is the first antibody produced in response to an infection. It is mainly found in the blood and lymph and forms pentamers (five units) that can bind to multiple antigens at once. It is very effective at activating the complement system, which enhances phagocytosis and inflammation.
• IgG is the most abundant antibody in the blood and lymph. It is also the only antibody that can cross the placenta and provide passive immunity to the fetus. It can bind to various antigens and trigger different effector functions, such as opsonization, complement activation, neutralization, and antibody-dependent cellular cytotoxicity.
• IgA is the main antibody found in mucosal secretions, such as saliva, tears, breast milk, and intestinal fluids. It forms dimers (two units) that can protect mucosal surfaces from pathogens by preventing their attachment and invasion. It also plays a role in neutralization and immune regulation.
• IgE is the least abundant antibody in the blood and lymph. It binds to mast cells and basophils, which are granulocytes that release histamine and other inflammatory mediators when activated by antigens. IgE is involved in allergic reactions and defense against parasites.
• IgD is mainly found on the surface of naive B cells, where it acts as a co-receptor with IgM for antigen recognition. Its function in the blood and lymph is not well understood.

Antibody-mediated immune response, also known as humoral immunity, involves the production of antibodies by B cells that bind to specific antigens and neutralize or eliminate them. The mechanism of antibody-mediated immune response can be summarized as follows:

• When a naive B cell encounters an antigen that matches its surface receptor, it internalizes the antigen and processes it into fragments.
• The B cell then displays the antigen fragments on its surface bound to major histocompatibility complex (MHC) class II molecules. This makes the B cell an antigen-presenting cell (APC).
• The B cell then interacts with a helper T cell that recognizes the same antigen fragment-MHC complex. The helper T cell activates the B cell by providing co-stimulatory signals and cytokines, such as interleukin-4 (IL-4) and interleukin-21 (IL-21).
• The activated B cell undergoes clonal expansion and differentiation into plasma cells and memory B cells. Plasma cells are antibody-secreting cells that release large amounts of antibodies into the blood and lymph. Memory B cells are long-lived cells that retain the antigen specificity and can quickly respond to a subsequent exposure to the same antigen.

• The antibodies produced by plasma cells have various functions to eliminate the antigens. Some of these functions are:

  • Neutralization: Antibodies bind to the surface of pathogens or toxins and prevent them from attaching to or entering host cells.
  • Opsonization: Antibodies coat the surface of pathogens and enhance their recognition and phagocytosis by macrophages and neutrophils.
  • Complement activation: Antibodies activate the complement system, a cascade of proteins that can lyse pathogens, opsonize them, or trigger inflammation and chemotaxis.
  • Agglutination: Antibodies cross-link multiple pathogens or antigenic particles into clumps that are easier to phagocytose or clear from the body.
  • Antibody-dependent cellular cytotoxicity (ADCC): Antibodies bind to the surface of infected or abnormal cells and recruit natural killer (NK) cells or other cytotoxic cells that can kill them.

The antibody-mediated immune response provides protection against extracellular pathogens, such as bacteria, fungi, parasites, and some viruses. It also contributes to immunity against toxins, allergens, and transplanted tissues. The antibody-mediated immune response is regulated by various feedback mechanisms that involve other immune cells, such as regulatory T cells, follicular helper T cells, and follicular regulatory T cells.

Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages and NK-cells, the production of antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen . Cellular immunity protects the body by:

• Activating antigen-specific cytotoxic T-lymphocytes (CTLs) that are able to destroy body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens;
• Activating macrophages and NK cells, enabling them to destroy intracellular pathogens; and
• Stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.

Cell-mediated immunity is directed primarily against microbes that survive in phagocytes and microbes that infect non-phagocytic cells. It is most effective in destroying virus-infected cells, intracellular bacteria, and cancers. It also plays a major role in delayed transplant rejection.

The main cells involved in cell-mediated immunity are T lymphocytes, antigen-presenting cells (APCs) such as macrophages, B cells, and dendritic cells, and various cytokines. T lymphocytes are divided into four types: T-helper cells, T-killer cells, T-suppressor cells, and T-memory cells.

• T-helper cells (CD4+) secrete cytokines that stimulate cell division of B cells and their maturation into plasma and memory cells, activation of macrophages to bring about phagocytosis, and clonal expansion of T-helper cells and T-killer cells.
• T-killer cells (CD8+) secrete cytotoxins and perforins that destroy pathogens or infected cells by inducing apoptosis or creating holes in their cell membranes.
• T-suppressor cells (Treg) regulate the immune response by preventing excessive immune reactions and autoimmune diseases by shutting down T cell-mediated immunity once the pathogen has been eliminated.
• T-memory cells provide long-lasting memory and quick response to subsequent exposure to the same antigen by differentiating into cytotoxic T cells and killing the pathogen.

The mechanism of cell-mediated immune response involves the following steps :

• When APCs present antigenic fragments on their surface bound to MHC II molecules, naive T-helper cells interact with them through their T-cell receptors (TCRs) and co-stimulatory molecules. This activates the T-helper cells to proliferate and differentiate into effector and memory T-helper cells.
• The activated T-helper cells secrete cytokines such as interleukin-2 (IL-2) that stimulate the proliferation and differentiation of naive T-killer cells into effector and memory T-killer cells. The effector T-killer cells recognize and bind to target cells that display the same antigen bound to MHC I molecules through their TCRs and co-stimulatory molecules. This triggers the release of cytotoxins and perforins that kill the target cells.
• The activated T-helper cells also secrete cytokines such as interleukin-4 (IL-4) that stimulate the activation and differentiation of B cells into plasma and memory B cells. The plasma B cells produce antibodies that bind to the same antigen and mark it for destruction by other immune mechanisms.
• The activated T-helper cells also secrete cytokines such as interferon-gamma (IFN-gamma) that activate macrophages and NK-cells to destroy intracellular pathogens by enhancing their phagocytic and cytolytic abilities.

• The activated T-suppressor cells secrete cytokines such as transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) that inhibit the activity of other immune cells and terminate the immune response once the pathogen has been cleared.

  Mechanism of cell-mediated immune response

Cell-mediated immune response is an immune response that does not involve antibodies but rather involves the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen . Cell-mediated immunity is directed primarily against microbes that survive in phagocytes and microbes that infect non-phagocytic cells, such as virus-infected cells, intracellular bacteria, and cancer cells .

The mechanism of cell-mediated immune response involves the following steps:

• Antigen presentation: Antigen-presenting cells (APCs), such as macrophages, dendritic cells, and B cells, ingest and process foreign antigens and display them on their surface bound to major histocompatibility complex (MHC) molecules. MHC molecules are proteins that help T cells recognize antigens. There are two types of MHC molecules: MHC class I and MHC class II. MHC class I molecules present antigens from intracellular pathogens or abnormal cells to cytotoxic T cells (CD8+), while MHC class II molecules present antigens from extracellular pathogens or vaccines to helper T cells (CD4+) .
• T cell activation: Naive T cells, which are immature T cells that have not encountered an antigen before, circulate in the blood and lymphatic system and enter lymph nodes or other secondary lymphoid organs where they encounter APCs. When a T cell receptor (TCR) on a naive T cell binds to a specific antigen-MHC complex on an APC, the T cell becomes activated and undergoes clonal expansion and differentiation into effector T cells . The activation of T cells also requires co-stimulatory signals from the APCs, such as cytokines or surface molecules. The type of co-stimulatory signals determines the type of effector T cells that are produced .

• Effector functions: Effector T cells perform different functions depending on their type and the nature of the antigen. There are four main types of effector T cells: cytotoxic T cells (Tc), helper T cells (Th), regulatory T cells (Treg), and memory T cells .

  • Cytotoxic T cells (Tc): These are also called CD8+ T cells or killer T cells. They recognize and kill infected or abnormal cells by releasing perforin and granzymes that induce apoptosis or by expressing Fas ligand that binds to Fas receptor on the target cell and triggers cell death . Cytotoxic T cells are important for eliminating virus-infected cells, intracellular bacteria, and cancer cells .
  • Helper T cells (Th): These are also called CD4+ T cells or helper-inducer T cells. They secrete various cytokines that regulate the activity of other immune cells, such as B cells, macrophages, NK cells, and cytotoxic T cells . Helper T cells can be further classified into different subsets based on their cytokine profile and function: Th1, Th2, Th17, and Tfh .
    • Th1: These secrete interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) that activate macrophages and cytotoxic T cells to enhance cell-mediated immunity against intracellular pathogens .
    • Th2: These secrete interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-10 (IL-10), and interleukin-13 (IL-13) that stimulate B cells to produce antibodies and eosinophils to combat extracellular parasites and allergens .
    • Th17: These secrete interleukin-17 (IL-17) and interleukin-22 (IL-22) that recruit neutrophils and monocytes to the site of infection and inflammation. They are involved in defense against extracellular bacteria and fungi as well as autoimmune diseases .
    • Tfh: These secrete interleukin-21 (IL-21) and express CD40 ligand that help B cells undergo class switch recombination, somatic hypermutation, affinity maturation, and differentiation into plasma cells or memory B cells in the germinal centers of lymphoid follicles. They are essential for humoral immunity .
  • Regulatory T cells (Treg): These are also called suppressor T cells or CD4+CD25+Foxp3+ T cells. They suppress the activity of other effector T cells by secreting anti-inflammatory cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) or by direct cell-cell contact. They maintain self-tolerance and prevent excessive immune responses .
  • Memory T cells: These are long-lived T cells that persist after an infection is cleared. They can quickly respond to a subsequent encounter with the same antigen by proliferating and differentiating into effector T cells without requiring co-stimulation. They provide immunological memory and confer protection against reinfection .

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