Anatomical Barriers of Immune System- Skin and Mucus

The skin is the largest organ in the body and a critical anatomic barrier against pathogens. It covers the entire surface of the body and protects the underlying tissues and organs from physical damage, dehydration, and microbial invasion. The skin consists of two main layers: the epidermis and the dermis. The epidermis is the outermost layer that is in direct contact with the external environment. The dermis is the inner layer that supports and nourishes the epidermis and contains blood vessels, nerves, hair follicles, sweat glands, and sebaceous glands.

The epidermis is composed largely of specialized epithelial cells called keratinocytes that produce a waterproofing protein called keratin. Keratin is not easily degraded by many microorganisms, which makes skin penetration difficult. The epidermis also contains other types of cells that contribute to skin defense, such as melanocytes that produce melanin to protect against ultraviolet radiation, Langerhans cells that act as antigen-presenting cells to activate adaptive immunity, and intraepidermal lymphocytes that are mostly T cells that recognize and eliminate infected or abnormal cells.

The skin has several mechanisms to prevent or limit microbial growth on its surface. These include:

• The relatively dry skin with high salt concentration in drying sweat is inhibitory or lethal to many microbes.
• Skin secretes sebum, which prevents growth of many microorganisms. Sebum consists of lactic acid and fatty acids that maintain the pH of the skin between 3 and 5, which is inhibitory to many bacteria.
• Epithelial cells also produce antimicrobial peptides such as defensins and cathelicidins that kill microbes by disrupting their membranes or interfering with their metabolism.
• The outer surface of the skin consists of dead cells that are continuously shed, causing the organisms to dislodge and also preventing viruses that require living cells for their replication.
• Keratinocytes also secrete a number of cytokines that may function to induce a local inflammatory reaction and recruit immune cells to the site of infection.

The skin is not only a passive barrier but also an active participant in immune responses. It contains various types of immune cells that can detect and respond to pathogens that have breached the skin barrier. These include:

• Langerhans cells, which are skin-resident dendritic cells that internalize antigen by phagocytosis. These Langerhans cells undergo maturation and migrate from the epidermis to regional lymph nodes, where they function as potent activators of naive T cells.
• Dermal dendritic cells, which are similar to Langerhans cells but reside in the dermis and can also present antigen to T cells in lymph nodes.
• Macrophages, which are phagocytic cells that can engulf and destroy microbes and also secrete cytokines and chemokines to modulate inflammation and immunity.
• Mast cells, which are granular cells that release histamine and other mediators that cause vasodilation, increased vascular permeability, smooth muscle contraction, and itching. These effects facilitate the entry of immune cells and fluids into the infected tissue and also act as an alarm signal to alert the host of a potential threat.
• Natural killer (NK) cells, which are cytotoxic lymphocytes that can recognize and kill infected or abnormal cells without prior sensitization. They also secrete cytokines such as interferon-gamma (IFN-gamma) that enhance the activity of macrophages and other immune cells.
• B cells and plasma cells, which are antibody-producing lymphocytes that can bind to specific antigens on pathogens or their products and neutralize them or mark them for destruction by other immune mechanisms.
• T cells, which are divided into helper T (Th) cells and cytotoxic T (Tc) cells based on their functions. Th cells secrete cytokines that regulate the activation and differentiation of other immune cells such as B cells, macrophages, NK cells, and Tc cells. Tc cells kill infected or abnormal cells by releasing perforin and granzymes that induce apoptosis.

The skin is a complex organ that provides both physical and immunological barriers against pathogens. It has multiple layers of defense mechanisms that work together to prevent or limit microbial invasion and infection. The skin also interacts with other components of the immune system to coordinate effective responses against pathogens that have breached the skin barrier.

The epidermal layer is the outermost layer of the skin that forms a protective barrier against pathogens. It is composed mainly of specialized epithelial cells called keratinocytes, which produce a waterproofing protein called keratin. Keratin is not easily degraded by many microorganisms, which makes skin penetration difficult. Keratinocytes also secrete a number of cytokines that may function to induce a local inflammatory reaction and attract immune cells to the site of infection.

The epidermal layer consists of four or five sublayers, depending on the body region. The sublayers are:

• The stratum basale, which is the deepest layer of the epidermis and contains stem cells that divide and give rise to new keratinocytes.
• The stratum spinosum, which is the thickest layer of the epidermis and contains keratinocytes that are connected by desmosomes, which provide mechanical strength and resistance to shear forces.
• The stratum granulosum, which contains keratinocytes that start to produce keratohyalin granules, which help to cross-link keratin filaments and form a tough matrix.
• The stratum lucidum, which is present only in thick skin (such as the palms and soles) and contains keratinocytes that are flattened and transparent, with densely packed keratin filaments.
• The stratum corneum, which is the outermost layer of the epidermis and consists of dead keratinocytes that are filled with keratin and surrounded by a lipid-rich extracellular matrix. This layer provides a physical and chemical barrier against pathogens, water loss, and environmental factors.

Scattered among the keratinocytes of the epidermis are other types of cells that play important roles in skin defense. These include:

• Langerhans cells, which are skin-resident dendritic cells that internalize antigen by phagocytosis. These Langerhans cells undergo maturation and migrate from the epidermis to regional lymph nodes, where they function as potent activators of naive T cells.
• Melanocytes, which are pigment-producing cells that synthesize melanin, a brown-black pigment that absorbs ultraviolet (UV) radiation and protects the skin from sun damage. Melanin also has antimicrobial properties and can inhibit the growth of some bacteria and fungi.
• Merkel cells, which are mechanoreceptors that sense touch and pressure. They also secrete neuropeptides that modulate inflammation and immunity in the skin.
• Intraepidermal lymphocytes, which are predominantly T cells that reside in the epidermis and recognize antigens presented by Langerhans cells or keratinocytes. They are believed to play a role in combating infections that enter through the skin.

Keratinocytes are the most abundant type of cells in the epidermis, the outermost layer of the skin. They are named after keratin, a tough protein that forms a protective barrier against pathogens and environmental damage. Keratinocytes also play an active role in skin defense by producing and secreting various molecules that have antimicrobial, inflammatory, and immunomodulatory effects.

Some of these molecules are:

• Defensins: These are small peptides that can directly kill bacteria, fungi, and viruses by disrupting their membranes. Defensins also attract and activate immune cells such as neutrophils and macrophages to the site of infection.
• Cathelicidins: These are another family of antimicrobial peptides that have similar functions as defensins. Cathelicidins also help to regulate the balance between inflammation and tissue repair by modulating the production of cytokines and growth factors.
• Cytokines: These are signaling molecules that coordinate the immune response by regulating the activation, proliferation, differentiation, and migration of various immune cells. Keratinocytes secrete cytokines such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interferons (IFNs) in response to microbial stimuli or tissue damage. These cytokines can induce inflammation, recruit immune cells, enhance phagocytosis, and stimulate the production of antibodies and other antimicrobial molecules.
• Langerhans cells: These are specialized dendritic cells that reside in the epidermis and act as sentinels for foreign antigens. Langerhans cells can capture and process antigens from microbes or damaged cells and present them to T cells in the regional lymph nodes. This initiates an adaptive immune response that can generate specific and long-lasting immunity against the invading pathogens.

Keratinocytes are therefore not only passive barriers but also active participants in skin defense. They can sense and respond to microbial threats by producing and releasing various molecules that can directly kill pathogens or activate other immune cells. Keratinocytes also cooperate with Langerhans cells to initiate adaptive immunity by presenting antigens to T cells. Keratinocytes thus play a crucial role in maintaining the integrity and immunity of the skin.

The skin produces various secretions that can inhibit or kill microorganisms. One of these secretions is sebum, which is produced by sebaceous glands in the skin. Sebum is a mixture of fatty acids, triglycerides, cholesterol, and other lipids that coats the surface of the skin and hair. Sebum has several functions, such as lubricating the skin, preventing water loss, and regulating body temperature. However, sebum also has antimicrobial properties, as it lowers the pH of the skin to between 3 and 5, which is acidic enough to prevent the growth of many bacteria and fungi . Sebum also contains lactic acid, which can inhibit the growth of some gram-positive bacteria by disrupting their cell wall . Additionally, sebum contains squalene, which is a precursor of cholesterol and steroid hormones. Squalene has been shown to have antifungal activity against some dermatophytes, which are fungi that cause skin infections .

Another secretion that the skin produces is sweat, which is produced by sweat glands in the skin. Sweat is mostly water, but it also contains salts, urea, ammonia, and other substances. Sweat helps to cool the body by evaporating from the skin surface. However, sweat also has antimicrobial properties, as it contains lysozyme, which is an enzyme that can break down the peptidoglycan layer of bacterial cell walls . Sweat also contains dermcidin, which is a peptide that can kill bacteria and fungi by forming pores in their membranes . Moreover, sweat can create a hypertonic environment on the skin surface, which means that it has a higher concentration of solutes than the surrounding fluid. This can cause water to move out of microbial cells by osmosis, leading to their dehydration and death .

Therefore, the skin secretions of sebum and sweat can create an unfavorable environment for many microorganisms, preventing them from colonizing or infecting the skin.

The outermost layer of the epidermis, called the stratum corneum, consists of flattened, dead keratinocytes that are constantly shed from the surface of the skin. This process of desquamation helps to remove any microorganisms that may have adhered to the skin surface or penetrated the epidermal layer. By shedding dead cells, the skin also prevents viruses from using them as hosts for their replication. The rate of desquamation is influenced by various factors, such as temperature, humidity, friction, and inflammation. In response to infection or injury, the skin may increase its rate of desquamation to enhance its defense mechanism. However, excessive shedding of skin cells can also lead to dryness, irritation, and impaired barrier function. Therefore, the skin maintains a balance between shedding and renewal of its cells to protect itself from pathogens.

Cytokines are small proteins that act as chemical messengers between cells. They are involved in various aspects of immunity, inflammation, and tissue repair. Keratinocytes, the main type of cells in the epidermis, can produce and secrete different cytokines in response to microbial invasion or tissue damage. Some of these cytokines include:

• Interleukin-1 (IL-1): This cytokine stimulates the production of other cytokines, such as IL-6 and IL-8, and enhances the expression of adhesion molecules on endothelial cells. This facilitates the recruitment of inflammatory cells, such as neutrophils and monocytes, to the site of infection or injury.
• Interleukin-6 (IL-6): This cytokine promotes the differentiation of B cells into antibody-producing plasma cells and activates T cells. It also induces the production of acute-phase proteins, such as C-reactive protein (CRP), by the liver. These proteins help to opsonize microbes and activate the complement system.
• Interleukin-8 (IL-8): This cytokine is a potent chemokine that attracts neutrophils and other leukocytes to the site of inflammation. It also enhances the phagocytic and bactericidal activity of these cells.
• Tumor necrosis factor-alpha (TNF-alpha): This cytokine has multiple effects on inflammation and immunity. It induces the expression of adhesion molecules on endothelial cells and leukocytes, increases the permeability of blood vessels, stimulates the production of other cytokines and chemokines, and activates macrophages and natural killer (NK) cells. It also induces apoptosis (programmed cell death) in some cells, such as tumor cells or virus-infected cells.

These cytokines act in a coordinated manner to initiate and amplify the inflammatory response and to activate the adaptive immune system. They also help to limit the spread of infection and to promote tissue repair.

Langerhans cells are specialized dendritic cells that reside in the epidermis. They function as antigen-presenting cells (APCs) that capture and process antigens from microbes or damaged cells. They then migrate to the regional lymph nodes, where they present the antigens to naive T cells and activate them. Langerhans cells also express toll-like receptors (TLRs) that recognize microbial components and stimulate the production of cytokines and co-stimulatory molecules. These molecules enhance the antigen presentation and T cell activation functions of Langerhans cells.

Langerhans cells play a crucial role in linking the innate and adaptive immune responses in the skin. They help to initiate specific immune responses against pathogens that have breached the skin barrier.

The mucous membrane, also known as the mucosa, is a layer of epithelial tissue that lines various cavities and passages of the body that are exposed to the external environment. These include the respiratory, gastrointestinal, and urogenital tracts and the ducts of the salivary, lacrimal, and mammary glands. The mucous membrane serves as an anatomical barrier against pathogens by providing both physical and chemical protection. The mucous membrane consists of three layers: the epithelium, the lamina propria, and the muscularis mucosae. The epithelium is the outermost layer that contacts the external environment and secretes mucus, a viscous fluid that traps and removes microorganisms. The lamina propria is a layer of connective tissue that contains blood vessels, lymphatic vessels, and immune cells. The muscularis mucosae is a thin layer of smooth muscle that contracts and relaxes to facilitate the movement of mucus and other substances. The mucous membrane also contains specialized structures called mucosa-associated lymphoid tissue (MALT), which are clusters of lymphoid cells that initiate immune responses against pathogens that penetrate the mucosal barrier. MALT includes tonsils, adenoids, Peyer`s patches, appendix, and bronchus-associated lymphoid tissue (BALT). The mucous membrane is an important part of the innate immune system, which provides the first line of defense against infections. In addition to its role in immunity, the mucous membrane also performs other functions such as lubrication, absorption, secretion, and sensation.

Mucous membranes are thin layers of epithelial cells that line the internal surfaces of the body that are exposed to the external environment, such as the respiratory, digestive, urinary and reproductive tracts. Mucous membranes act as an anatomical barrier against pathogens by employing a number of non-specific defense mechanisms.

One of these mechanisms is the production of mucus, a thick and sticky fluid that traps and immobilizes microorganisms and foreign particles. Mucus also contains various antimicrobial substances that can kill or inhibit the growth of pathogens, such as lysozyme, lactoferrin, lactoperoxidase and secretory IgA.

Another mechanism is the ciliary escalator, which is found in the respiratory tract. The ciliary escalator consists of ciliated epithelial cells that beat in a coordinated manner to move mucus and trapped particles upward toward the throat, where they can be swallowed or expelled.

A third mechanism is the flushing action of body fluids, such as saliva, tears, urine and vaginal secretions. These fluids help to wash away potential invaders and prevent them from adhering to the mucosal surfaces.

A fourth mechanism is the acidic pH of some mucosal secretions, such as gastric juice, vaginal fluid and urine. The acidic pH creates an unfavorable environment for many microorganisms and inhibits their growth.

A fifth mechanism is the presence of normal microbiota on the mucosal surfaces. Normal microbiota are harmless or beneficial microorganisms that colonize the body and compete with pathogens for nutrients and attachment sites. They also produce substances that inhibit or kill pathogens, such as bacteriocins, organic acids and hydrogen peroxide.

These non-specific defense mechanisms of mucous membranes help to prevent or limit the entry of pathogens into the body and contribute to the innate immunity. However, some pathogens can overcome these barriers and cause infections. Therefore, mucous membranes also rely on specific defense mechanisms involving adaptive immunity, such as MALT.

Mucus is a thick, sticky substance that covers and protects the mucous membranes of the respiratory, gastrointestinal, and urogenital tracts and the ducts of the salivary, lacrimal, and mammary glands. Mucus is produced by specialized epithelial cells called goblet cells and by submucosal glands. The composition and amount of mucus vary depending on the location and function of the mucous membrane.

Mucus has several properties and functions that help prevent the entry and spread of pathogens through the mucous membranes. Some of these are:

• Physical barrier: Mucus forms a layer that coats the mucous membrane and traps microorganisms, dust, allergens, and other foreign particles. This prevents them from adhering to the epithelial cells and penetrating deeper into the tissues. Mucus also lubricates the mucous membrane and reduces friction and damage caused by mechanical forces.
• Clearance mechanism: Mucus is constantly moved by cilia, tiny hair-like structures on the surface of some epithelial cells, or by muscular contractions, such as peristalsis in the gastrointestinal tract. This movement propels the mucus and the trapped particles towards the openings of the body, where they can be expelled by coughing, sneezing, swallowing, or urinating.
• Antimicrobial activity: Mucus contains various substances that have antibacterial, antiviral, antifungal, or anti-inflammatory effects. These include lysozyme, an enzyme that breaks down the cell wall of bacteria; immunoglobulin A (IgA), an antibody that binds to pathogens and prevents them from attaching to epithelial cells; lactoferrin, a protein that sequesters iron and deprives microbes of this essential nutrient; lactoperoxidase, an enzyme that produces reactive oxygen species that damage microbes; defensins and cathelicidins, peptides that disrupt the membrane of microbes; and cytokines and chemokines, molecules that modulate inflammation and recruit immune cells to the site of infection.
• Mucosal immunity: Mucus also serves as a medium for transporting antigens from the mucosal surface to the underlying mucosa-associated lymphoid tissue (MALT), where they can be recognized by immune cells and initiate adaptive immune responses. MALT consists of aggregates of lymphocytes, macrophages, dendritic cells, and other immune cells that are strategically located in various mucosal sites. MALT can produce specific IgA antibodies that are secreted into the mucus layer and provide local protection against pathogens.

Mucus is thus an essential component of the anatomical barrier of the immune system that protects the body from external threats. By combining physical, chemical, and immunological mechanisms, mucus creates a hostile environment for pathogens and facilitates their elimination.

Mucosa-associated lymphoid tissue (MALT) is a collection of lymphoid cells and structures that are located in close proximity to the mucous membranes of various organs. MALT plays an important role in the mucosal defense against pathogens by providing both innate and adaptive immune responses.

MALT consists of several types of lymphoid cells, such as B cells, T cells, dendritic cells, macrophages, and natural killer cells. These cells are organized into discrete structures called mucosal follicles or aggregates, which are distributed along the mucosal surfaces of the gastrointestinal tract, respiratory tract, urogenital tract, and other organs. Some examples of MALT are the tonsils, adenoids, Peyer`s patches, appendix, and bronchus-associated lymphoid tissue (BALT).

MALT functions as the first line of defense against pathogens that enter through the mucous membranes. The epithelial cells that line the mucous membranes express specialized molecules called M cells, which can capture antigens from the lumen and transport them to the underlying MALT. There, the antigens are presented to dendritic cells, which then activate B cells and T cells to initiate an immune response.

MALT also produces large amounts of immunoglobulin A (IgA), which is a type of antibody that is secreted into the mucus layer. IgA can bind to pathogens and prevent them from adhering to or invading the epithelial cells. IgA can also neutralize toxins and viruses and facilitate their clearance by mucus movement or phagocytosis.

MALT is also involved in the generation of immune tolerance to harmless antigens, such as food or commensal bacteria. This is achieved by inducing regulatory T cells (Tregs) or anergic B cells that suppress inflammatory responses and prevent autoimmune reactions.

MALT is therefore a crucial component of the mucosal immune system that protects the body from various pathogens while maintaining a balance between immunity and tolerance.

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