Non-Specific Immune Response

The human body is constantly exposed to various microorganisms that can cause infections and diseases. However, not all of these microorganisms are able to enter the body and cause harm. This is because the body has a series of defense mechanisms that prevent or limit the invasion of pathogens. These defense mechanisms are called non-specific or innate immune response, as they do not require prior exposure or recognition of specific antigens. They are present from birth and act as the first line of defense against infection.

The non-specific immune response can be divided into two categories: defense mechanisms that precede infection and defense mechanisms that are evoked by infection. The former are the ones that prevent or reduce the entry of pathogens into the body, while the latter are the ones that eliminate or contain the pathogens that have already entered the body. In this article, we will focus on the defense mechanisms that precede infection and how they protect the body from various types of pathogens. These defense mechanisms include anatomical barriers, physiological barriers, cellular barriers and complements. We will discuss each of these in detail in the following sections.

Anatomical barriers are the first line of defense against pathogens that try to enter the body. They consist of the skin and the mucous membranes that cover the internal and external surfaces of the body.

The skin is the largest organ of the body and acts as a physical barrier that prevents the penetration of most microorganisms. The skin is composed of two layers: the epidermis and the dermis. The epidermis is the outermost layer that contains keratin, a tough protein that makes the skin waterproof and resistant to abrasion. The epidermis also has sebaceous glands that secrete sebum, an oily substance that lowers the pH of the skin and inhibits the growth of some bacteria and fungi. The dermis is the inner layer that contains blood vessels, nerves, hair follicles, sweat glands and other structures. The dermis also provides support and elasticity to the skin.

The mucous membranes are thin layers of epithelial tissue that line the openings of the body, such as the mouth, nose, eyes, ears, respiratory tract, digestive tract, urinary tract and reproductive tract. The mucous membranes secrete mucus, a sticky fluid that traps dust, dirt and microbes and prevents them from entering deeper into the body. The mucus also contains antimicrobial substances, such as lysozyme, an enzyme that breaks down the cell walls of some bacteria, and defensins, small peptides that kill or inhibit a wide range of microbes. Some mucous membranes also have cilia, hair-like projections that move mucus and trapped particles out of the body.

The skin and mucous membranes are effective anatomical barriers that protect the body from most pathogens. However, they can be breached by wounds, burns, insect bites or other injuries that allow microbes to enter the body. Therefore, other defense mechanisms are needed to eliminate the invaders and restore homeostasis.

Physiological barriers are the body`s natural ways of preventing or destroying pathogens that enter or try to enter the body. They include:

• Gastric acidity: The stomach produces hydrochloric acid that creates a very low pH environment (around 2) in the stomach. This acidic condition kills most bacteria and other microorganisms that are ingested with food or water. Some pathogens, such as Helicobacter pylori, can survive the gastric acidity by producing urease, an enzyme that neutralizes the acid. These pathogens can cause ulcers and gastritis in the stomach lining.
• Lysozyme: Lysozyme is an enzyme that breaks down the peptidoglycan layer of bacterial cell walls. It is found in many body fluids and secretions, such as tears, saliva, sweat, and mucus. Lysozyme can kill or weaken many types of bacteria that come in contact with the mucous membranes of the eyes, mouth, nose, and respiratory tract. Lysozyme also activates the complement system, which enhances the immune response against pathogens.
• Other physiological barriers: The body has other ways of creating unfavorable conditions for pathogens, such as high or low temperature, low oxygen levels, high salt concentration, and antimicrobial peptides. For example, the skin has a slightly acidic pH (around 5.5) that inhibits the growth of some bacteria. The sweat glands produce sweat that contains salt and lactic acid, which also lower the pH and create an osmotic pressure that dehydrates some microorganisms. The respiratory tract has cilia (tiny hair-like structures) that sweep mucus and trapped particles out of the lungs. The urinary tract has a high urine flow that flushes out potential pathogens. The vagina has a low pH (around 4) due to the production of lactic acid by lactobacilli bacteria that colonize the vaginal mucosa. The lactic acid inhibits the growth of other bacteria and fungi that can cause infections.

Physiological barriers are effective in preventing or reducing many infections, but they are not foolproof. Some pathogens have evolved mechanisms to overcome or evade these barriers, such as producing toxins, enzymes, capsules, or biofilms that protect them from the hostile environment. Therefore, physiological barriers are only one part of the non-specific immune response that works together with other defense mechanisms to protect the body from infection.

Cellular barriers are another type of defense mechanism that precede infection. They consist of two main types of cells: phagocytic cells and natural killer cells.

Phagocytic cells are specialized white blood cells that can ingest and destroy foreign particles, such as bacteria, fungi, and protozoa. They are found in the blood, lymph, and tissues of the body. There are several types of phagocytic cells, such as neutrophils, macrophages, dendritic cells, and monocytes. They use different receptors to recognize and bind to the surface of foreign particles. Then, they engulf them into a membrane-bound vesicle called a phagosome. The phagosome fuses with a lysosome, which contains digestive enzymes and toxic substances that kill and degrade the foreign particle. The remnants of the particle are either released or presented to other immune cells for further recognition.

Natural killer cells are another type of white blood cells that can kill abnormal cells, such as tumor cells and virus-infected cells. They are part of the innate immune system and do not require prior exposure to the target cell. They use different receptors to detect the presence or absence of certain molecules on the surface of the target cell. For example, they can recognize molecules that indicate stress or infection, such as heat shock proteins and viral antigens. They can also recognize molecules that indicate self-identity, such as major histocompatibility complex (MHC) class I molecules. If the target cell has low or no MHC class I molecules, it is considered abnormal and susceptible to natural killer cell attack. Natural killer cells release perforins and granzymes that create pores in the membrane of the target cell and induce apoptosis (programmed cell death).

Cellular barriers are an important part of the non-specific immune response because they can eliminate potential pathogens and abnormal cells before they cause harm to the body. They also interact with other components of the immune system, such as complements and cytokines, to enhance their functions and coordinate a more effective response.

Complements are a group of non-specific serum proteins that augment the functions of immune system. They play essential role in resistance against infection by activating a sequential cascade of active proteins that lyse foreign cells and also are the principle mediators of inflammatory response.

Complements are synthesized mainly by the liver and circulate in the blood plasma in an inactive form. They can be activated by two pathways: the classical pathway and the alternative pathway. The classical pathway is initiated by the binding of antibodies to antigens on the surface of foreign cells, forming antigen-antibody complexes. The alternative pathway is triggered by the direct contact of complements with certain molecules on the surface of pathogens, such as lipopolysaccharides or polysaccharides.

Both pathways converge to form a common intermediate called C3 convertase, which cleaves a complement protein called C3 into two fragments: C3a and C3b. C3a is an anaphylatoxin that stimulates mast cells to release histamine and other inflammatory mediators. C3b is an opsonin that coats the surface of pathogens and enhances their phagocytosis by macrophages and neutrophils. C3b also forms another enzyme called C5 convertase, which cleaves another complement protein called C5 into two fragments: C5a and C5b. C5a is another anaphylatoxin that attracts and activates phagocytes and increases vascular permeability. C5b initiates the formation of a complex called membrane attack complex (MAC), which consists of several complement proteins (C5b, C6, C7, C8 and C9) that insert into the membrane of foreign cells and create pores that disrupt their integrity and cause cell lysis.

Complements are thus important components of innate immunity that help to eliminate pathogens and promote inflammation. They also link innate and adaptive immunity by facilitating the presentation of antigens to lymphocytes and enhancing the antibody response. However, complements can also cause damage to host tissues if they are activated inappropriately or excessively. Therefore, there are several regulatory mechanisms that control the activation and activity of complements, such as inhibitors, receptors and soluble factors.

When the non-specific immune response fails to prevent the entry of pathogens into the body, it activates other defense mechanisms that are evoked by infection. These include fever, inflammation and interferons.

Fever

Fever is an elevation of body temperature above the normal range. It is caused by pyrogens, which are substances that induce fever. Pyrogens can be either exogenous (such as bacterial toxins) or endogenous (such as cytokines released by immune cells). Pyrogens act on the hypothalamus, the part of the brain that regulates body temperature, and increase its set point. This triggers a series of physiological responses that raise the body temperature, such as shivering, vasoconstriction and increased metabolism.

Fever has several benefits during infection. It inhibits the growth and multiplication of many microorganisms, especially bacteria, by creating an unfavorable environment for them. It also enhances the activity and efficiency of immune cells, such as phagocytes and lymphocytes, by increasing their mobility, proliferation and production of antibodies. Moreover, fever stimulates the production of acute phase proteins, such as C-reactive protein and fibrinogen, which have anti-inflammatory and anti-microbial effects.

Inflammation

Inflammation is a local response to tissue injury or infection. It is characterized by four cardinal signs: redness, heat, swelling and pain. These signs are caused by various mediators of inflammation, such as histamine, prostaglandins and cytokines, which are released by damaged cells or immune cells. These mediators cause vasodilation (widening of blood vessels), increased vascular permeability (leakage of fluid and proteins from blood vessels) and recruitment of leukocytes (white blood cells) to the site of injury or infection.

Inflammation has several functions during infection. It prevents the spread of pathogens to other tissues by forming a physical barrier of clotting factors and fibrin. It disposes of dead or damaged cells and foreign materials by phagocytosis and enzymatic digestion. It also initiates tissue repair by stimulating angiogenesis (formation of new blood vessels), fibroblast proliferation (production of connective tissue) and epithelialization (regeneration of epithelial cells).

Interferons

Interferons are a group of glycoproteins that are produced by virus-infected cells or immune cells in response to viral infections. They act as signaling molecules that interfere with viral replication and spread. They do this by binding to specific receptors on neighboring cells and inducing them to produce antiviral proteins that degrade viral RNA or DNA, inhibit viral protein synthesis or assembly, or activate apoptosis (programmed cell death). Interferons also modulate the immune response by enhancing the activity of natural killer cells, macrophages and cytotoxic T cells, which can directly kill virus-infected cells or tumor cells.

Interferons play a vital role in protecting the body against viral infections. They limit the viral load and prevent systemic dissemination of viruses. They also confer resistance to reinfection by the same or related viruses. Furthermore, they have anti-tumor effects by inhibiting cell proliferation and angiogenesis and inducing apoptosis in cancer cells.

Fever is a common symptom of infection and inflammation, and it is defined as a rise in body temperature above the normal range of 36.5 to 37.5°C. Fever is caused by substances called pyrogens, which are produced by the immune system or by invading pathogens. Pyrogens act on the hypothalamus, the part of the brain that regulates body temperature, and trigger a series of responses that increase heat production and reduce heat loss. These responses include shivering, increased metabolism, vasoconstriction and behavioral changes such as seeking warmth and reducing activity.

Fever is not a disease itself, but rather a beneficial defense mechanism that helps the body fight infection. Fever has several advantages, such as:

• Inhibiting microbial growth: Many pathogens have optimal growth temperatures that are lower than the normal body temperature, and they cannot survive or multiply well at higher temperatures. For example, some bacteria produce enzymes that are inactivated by heat, and some viruses have lipid envelopes that are disrupted by heat. Therefore, fever creates an unfavorable environment for pathogens and reduces their virulence.
• Enhancing immune response: Fever stimulates the activity and proliferation of immune cells such as lymphocytes, macrophages and natural killer cells, which are essential for eliminating pathogens and infected cells. Fever also increases the production of cytokines, which are signaling molecules that coordinate the immune response and mediate inflammation. Moreover, fever enhances the expression of heat shock proteins, which are molecules that help protect cells from stress and damage and also act as antigens that activate the adaptive immune system.
• Increasing metabolic rate: Fever increases the rate of chemical reactions in the body, which provides more energy and resources for the immune system to function efficiently. Fever also accelerates tissue repair and wound healing by increasing blood flow and oxygen delivery to the damaged areas.

Fever is usually a self-limiting and harmless condition that resolves when the infection is cleared. However, fever can also have some negative effects, such as dehydration, electrolyte imbalance, increased heart rate and respiratory rate, fatigue, headache and delirium. Therefore, fever should be monitored and treated if it becomes too high (above 40°C) or lasts too long (more than three days), as it may indicate a serious infection or a complication. Fever can be reduced by using antipyretics (such as aspirin or ibuprofen), drinking fluids, resting and applying cool compresses.

In conclusion, fever is a natural and beneficial response to infection that helps the body fight off pathogens by inhibiting their growth, enhancing the immune response and increasing the metabolic rate. However, fever can also cause discomfort and complications if it is too high or prolonged, so it should be managed appropriately.

Inflammation is a complex biological process that occurs when the body tissues are damaged by physical injury, infection, toxins, heat or any other cause. The main purpose of inflammation is to eliminate the cause of tissue injury, clear out dead cells and debris, and initiate tissue repair. Inflammation is one of the most important non-specific immune responses that helps the body to fight against infections and heal wounds.

The inflammation response involves four main steps:

• Vasodilation and increased blood flow: When tissue damage occurs, chemical mediators such as histamine, prostaglandins and cytokines are released by the injured cells, mast cells and macrophages. These mediators cause the blood vessels in the affected area to dilate and become more permeable, allowing more blood to flow to the site of injury. This results in redness and heat at the inflamed area.
• Leukocyte migration and phagocytosis: The increased blood flow also brings more white blood cells (leukocytes) to the site of injury, especially neutrophils and monocytes. These cells squeeze through the gaps between the endothelial cells of the blood vessels (a process called diapedesis) and enter the tissue space. They then migrate towards the source of injury by following chemical signals (a process called chemotaxis). Once they reach the site of injury, they engulf and destroy the foreign particles, microbes, dead cells and debris by phagocytosis. This results in swelling and pain at the inflamed area.
• Clotting and fibrin formation: The increased permeability of the blood vessels also allows plasma proteins such as fibrinogen and prothrombin to leak into the tissue space. These proteins form a meshwork of fibrin threads that trap blood cells and form a clot. The clot acts as a barrier to prevent further bleeding and infection, and also provides a scaffold for tissue repair.
• Tissue repair and resolution: The final step of inflammation is to restore the normal structure and function of the injured tissue. This involves two processes: regeneration and fibrosis. Regeneration is the replacement of damaged cells by new cells of the same type, which restores the original tissue architecture. Fibrosis is the formation of scar tissue by fibroblasts, which produces collagen fibers that fill in the gaps left by tissue damage. Fibrosis may compromise the function of some tissues, but it also provides strength and stability to the wound.

Inflammation is usually a beneficial response that helps the body to heal and recover from injury. However, sometimes inflammation can become chronic or excessive, which can cause tissue damage and disease. Some examples of chronic inflammatory diseases are rheumatoid arthritis, asthma, inflammatory bowel disease and atherosclerosis. Therefore, inflammation needs to be regulated and controlled by anti-inflammatory agents such as corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and cytokine inhibitors.

Interferons are a type of cytokines, which are proteins that act as messengers between cells. They are produced by various cells in response to viral infections, and they have the ability to interfere with viral replication and spread. Interferons are named according to the type of cells that produce them or the receptors that bind them. There are three major types of interferons: alpha, beta and gamma.

• Alpha interferons are produced by leukocytes (white blood cells) and have antiviral and antitumor effects. They also stimulate natural killer cells and macrophages to destroy infected or abnormal cells.
• Beta interferons are produced by fibroblasts (connective tissue cells) and have similar effects as alpha interferons. They also modulate the immune response and reduce inflammation.
• Gamma interferons are produced by T lymphocytes (a type of white blood cell) and natural killer cells. They have immunoregulatory and antimicrobial effects. They also activate macrophages and enhance the expression of major histocompatibility complex (MHC) molecules, which help the immune system recognize foreign antigens.

Interferons exert their effects by binding to specific receptors on the surface of target cells. This triggers a cascade of intracellular events that lead to the expression of hundreds of genes that encode proteins with antiviral, antiproliferative and immunomodulatory functions. Some of these proteins include:

• Protein kinase R (PKR), which phosphorylates and inhibits a protein called eukaryotic initiation factor 2 (eIF2), which is essential for protein synthesis. This blocks viral protein production and cell growth.
• 2`,5`-oligoadenylate synthetase (OAS), which synthesizes a molecule called 2`,5`-oligoadenylate (2-5A), which activates an enzyme called RNase L, which degrades viral and cellular RNA. This prevents viral replication and induces apoptosis (cell death).
• Mx proteins, which interfere with viral assembly and transport within the cell.
• Interferon-stimulated gene 15 (ISG15), which modifies other proteins by adding a molecule called ubiquitin-like modifier (UBL), which alters their function or stability. This affects various cellular processes such as signaling, transcription, translation and degradation.

Interferons play a vital role in the innate immune system, which is the first line of defense against pathogens. They also influence the adaptive immune system, which is the second line of defense that involves specific recognition and memory. Interferons can enhance the activity of B lymphocytes (which produce antibodies) and cytotoxic T lymphocytes (which kill infected or abnormal cells). Interferons can also regulate the balance between Th1 and Th2 responses, which are two types of helper T lymphocytes that secrete different cytokines and mediate different aspects of immunity.

Interferons have been used as therapeutic agents for various diseases such as viral infections, cancer, autoimmune disorders and multiple sclerosis. However, they also have some adverse effects such as flu-like symptoms, fatigue, depression, liver toxicity and bone marrow suppression. Therefore, interferon therapy requires careful monitoring and dose adjustment.

Interferons are one of the most important defense mechanisms against viral infections. They not only inhibit viral replication and spread, but also modulate the immune response and enhance resistance against infection. Interferons are an example of how the body uses its own molecules to fight against foreign invaders.

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