Anatomical and Physiological Barriers of Immune System

Anatomical and physiological barriers are the first defence barrier of immune system. These barriers stop the entry of pathogen in the body tissue. It is present on the outer surface and also in different opening part of body.

Anatomical barriers are mainly skin, hair, mucous membrane and epithelial lining. Skin is the outer covering of body. It is made up of dead keratinized epithelial cells. These cells are shed continuously and remove the attached bacteria from the surface.

The skin also contains structural proteins such as keratin and filaggrin. Filaggrin helps in aggregation of keratin. It gives mechanical strength to skin and also reduces water loss from body.

Mucous membrane is present in respiratory tract, digestive tract and urogenital tract. These places do not have hard skin. So the epithelial cells are closely arranged and they secrete sticky mucus. This mucus traps microbes, dust particles and other foreign materials.

In respiratory tract, the removal of microbes is done by cilia. Cilia are hair like structure present on epithelial cell. They beat in one direction and push the mucus towards mouth. This is called mucociliary escalator. Then mucus is swallowed or removed by coughing and sneezing.

Some physical washing process also protect the body. Tears, sweat, saliva, urination and defecation remove microorganisms from body surface. In this way microbes are flushed out before they attach strongly.

Physiological barriers are chemical and functional barriers. These barriers make unsuitable condition for growth of microbes. The skin secretes sebum. Sebum keeps the skin moist and makes the surface slightly acidic. This acidic pH inhibits many bacteria.

Gastric acid is present in stomach. It has very low pH, about 1 to 2. It denatures the microbial proteins and kills most of the microbes entering with food and water.

Some body secretions contain antimicrobial enzymes. Saliva, tears, sweat, mucus and breast milk contain lysozyme. Lysozyme breaks the bacterial cell wall. Mainly it acts on peptidoglycan layer and destroys bacteria.

Some proteins also act as physiological barrier. Lactoferrin and transferrin bind iron. As a result, bacteria do not get iron for their growth. Bile acids also damage lipid membrane of microbes and act like antiseptic substance.

Biological barrier is formed by normal microorganisms of body. These are called commensal microbiota. They are present on skin, intestine and genitourinary tract. They compete with pathogens for space and nutrients. In this way harmful bacteria cannot easily grow there.

Role of Anatomical and Physiological Barriers in Innate Immunity

The following are the role of anatomical and physiological barriers in innate immunity–

• Physical barrier– Skin is the first covering of body. It blocks the entry of pathogen. Mucous membrane also cover the inner opening part. The epithelial cells are closely arranged and microbes cannot enter easily.
• Shedding action– Dead keratinized cells of skin are shed continuously. During this process attached bacteria are also removed from surface. It reduces microbial number on skin.
• Mucus trapping– Mucus is sticky secretion of mucous membrane. It traps dust, bacteria, virus and other foreign particles. The trapped microbes cannot attach with epithelial cell.
• Ciliary movement– Cilia are hair like structure in respiratory tract. They move the mucus upward toward mouth. This is called mucociliary escalator. Then mucus is swallowed or expelled.
• Reflex removal– Coughing and sneezing remove microbes from respiratory tract. Urination removes microbes from urinary tract. Defecation also removes microbes from intestinal tract.
• Acid action– Gastric acid is present in stomach. It has very low pH. It denatures microbial protein and kills many microbes entering with food. Acidic skin also inhibits bacterial growth.
• Lysozyme action– Lysozyme is present in tears, saliva, mucus, sweat and breast milk. It breaks the peptidoglycan layer of bacterial cell wall. So bacterial cell becomes damaged.
• Defensin action– Defensins are antimicrobial peptides. They act on microbial membrane. It forms pore in membrane and causes loss of cell contents.
• Iron binding– Lactoferrin and transferrin bind free iron. Iron is needed for growth of many bacteria. So bacteria cannot multiply properly when iron is not available.
• Decoy effect– Tamm-Horsfall protein or uromodulin is present in urine. It binds with fimbriae of uropathogenic bacteria like Escherichia coli. Then bacteria clump and are removed with urine.
• Normal flora– Commensal microbiota live on skin, gut and genitourinary tract. They use space and nutrients. So pathogen do not get enough place and food for growth.
• Antimicrobial product– Some normal flora produce bacteriocins and free fatty acids. These substances inhibit the growth of pathogenic bacteria. This is a biological barrier.
• Immune detection– Epithelial cells contain pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are one type of these receptors. They recognize microbial pattern.
• Signal release– After detection of pathogen, epithelial cells release cytokines and chemokines. These chemicals call macrophages, neutrophils and other immune cells at infected site.

Types of Anatomical Barriers

Different types of anatomical barriers are mentioned below-

1. Skin– Skin is the main outer barrier of body. It prevents the entry of pathogen into deeper tissue. It is made up of dead epithelial cells and dense keratin layer.
   • Stratum corneum– It is the outermost layer of skin. It contains dead keratinocytes called corneocytes. These cells are tightly joined by desmosomes and present in lipid rich matrix.
   • Filaggrin– Filaggrin is a structural protein of skin. It helps in aggregation of keratin. It gives mechanical strength and prevents excess water loss.
   • Tight junction– Tight junctions are present between epithelial cells. It seals the space between cells. It is formed by proteins like claudins and occludins.
   • Shedding– The outer dead cells of skin are shed continuously. During this process attached bacteria are also removed from skin surface.
2. Mucous membrane– Mucous membrane is present in eyes, respiratory tract, digestive tract and urogenital tract. These are soft epithelial lining. It acts as internal boundary of body.
   • Mucus– Mucus is a thick and sticky secretion. It traps dust, microbes and other foreign particles. So pathogen cannot reach deeper tissue easily.
   • Epithelial lining– The epithelial cells are closely arranged. It forms a continuous covering. It blocks the entry of microbes through the tract.
3. Endothelial barrier– Endothelial cells line the blood vessels and lymph vessels. In some area these cells are very tightly packed and form special internal barrier.
   • Blood-brain barrier– Blood-brain barrier protects brain and spinal cord. It prevents entry of many microbes into central nervous system (CNS).
4. Mechanical barrier– Some anatomical structures remove or filter microbes by physical action. These barriers mainly trap, sweep or wash out the pathogen.
   • Protective structure– Eyelids, eyelashes and nasal hairs act as mechanical filter. They trap dust particles and microbes.
   • Mucociliary escalator– It is present in respiratory tract. The epithelial cells contain hair like cilia. These cilia move mucus upward and remove trapped pathogen by coughing or swallowing.
   • Flushing action– Tears, sweat, urination and defecation wash away microbes from body surface and internal tract.
5. Genetic barrier– Genetic barrier depends on genetic makeup of person. Some pathogens need specific receptor for attachment and entry. If the receptor is absent, infection is not formed.
   • CCR5 mutation– In CCR5-delta-32 mutation, functional CCR5 co-receptor is absent. So HIV-1 cannot enter immune cells properly. This gives natural resistance against HIV-1.

Structure and Protective Functions of the Skin

The following are the structure and protective functions of skin–

• Keratin layer– Skin is the outer superficial barrier of body. It is made up of tightly arranged dead epithelial cells. These cells contain dense keratin. It makes the skin hard, dry and difficult for pathogen to enter.
• Stratum corneum– The outer part of skin is called stratum corneum. It contains dead keratinized cells. This layer is dry and not suitable for bacterial growth. So most microbes cannot multiply there.
• Cell shedding– Dead cells of skin are removed continuously from surface. This is called shedding or sloughing. During this process attached bacteria and other microbes are also removed with it.
• Surface condition– Skin surface is dry, salty and acidic. This condition is not favourable for many pathogen. It inhibits growth and survival of bacteria and fungi.
• Sebum secretion– Sebaceous glands produce sebum. It is oily secretion of skin. It locks moisture and protects the skin from drying. It also forms an oily protective covering on skin surface.
• Commensal microbes– Normal skin bacteria live on skin surface. They act as biological barrier. Propionibacterium acnes uses sebum and produces oleic acid. This maintains acidic condition and restrict harmful pathogen.
• Sweat secretion– Sweat is secreted by sweat glands. It washes away microbes from skin surface. It also contains toxic lipids which inhibit microbial growth.
• Lysozyme action– Sweat contains lysozyme. It is antimicrobial enzyme. It breaks bacterial cell wall and destroys bacteria. Mainly it acts on peptidoglycan layer.

Mucous Membranes and Mucus Secretion

The following are the role of mucous membranes and mucus secretion–

• Location– Mucous membranes are present where hard skin is absent. It is present in respiratory tract, gastrointestinal tract, genitourinary tract, eyes and ears. It forms continuous epithelial lining over these soft tissue.
• Epithelial barrier– The epithelial cells of mucous membrane are closely arranged. It acts as internal covering of body. It prevents direct entry of pathogen into deeper tissue.
• Mucus secretion– Goblet cells and other epithelial cells secrete mucus. Mucus is thick, sticky and viscous material. It covers the epithelial surface.
• Trapping action– Mucus traps bacteria, virus, dust and other foreign particles. So microbes cannot attach with epithelial cells easily. It is a mechanical barrier of mucosal surface.
• Ciliary movement– In respiratory tract, epithelial cells contain hair like cilia. These cilia beat in coordinated manner. It moves the contaminated mucus upward toward mouth.
• Mucociliary escalator– This movement of mucus by cilia is called mucociliary escalator. The mucus containing microbes is coughed out or swallowed. After swallowing, microbes are destroyed by gastric acid in stomach.
• Lysozyme action– Mucus contains lysozyme. It breaks bacterial cell wall. Mainly it acts on peptidoglycan layer and bacteria become damaged.
• Lactoferrin action– Lactoferrin is present in mucosal secretion. It binds free iron. So bacteria do not get iron for growth and multiplication.
• Lactoperoxidase action– Lactoperoxidase is oxidizing enzyme in secretion. It helps in destruction of bacteria and virus. It increases chemical defence of mucous membrane.
• Defensin action– Epithelial cells secrete defensins and other antimicrobial peptides. These peptides damage microbial membrane. So bacteria, fungi and some virus are inhibited.
• Immune cells– Mucous membrane contain immune cells like intraepithelial lymphocytes. These cells stay near epithelial layer. They help to detect and remove pathogen at entry site.
• Immune sensing– Epithelial cells have pattern recognition receptors (PRRs). These receptors detect microbial particles in mucus layer. After detection, epithelial cells release cytokines and start inflammatory response.

Mechanism of Anatomical Barriers of the Immune System

The following are the mechanism of anatomical barriers of immune system–

• Mechanical sealing– Skin forms the outer physical barrier of body. It is made up of dead keratinized epithelial cells. These cells are called corneocytes. They are tightly joined by desmosomes and present in lipid rich matrix. So pathogen cannot enter easily.
• Keratin strength– Keratin makes the skin hard and strong. Filaggrin helps in aggregation of keratin filament. It gives mechanical strength to skin and prevents water loss. Due to this skin surface becomes dry and unsuitable for many microbes.
• Tight junction– Tight junctions seal the space between epithelial cells. It is made up of proteins like claudins and occludins. These junctions are present in skin and mucosal lining. It prevents entry of pathogen, allergen and toxin into deeper tissue.
• Mucus trapping– Mucous membrane secretes mucus in internal tract. Mucus is thick, sticky and viscous. It traps bacteria, virus, dust and other particles before they attach to host tissue. This is a physical trapping mechanism.
• Coarse filtration– Nasal hairs and cerumen or ear wax act as coarse filter. They trap dust, pollutant and microbes from outside environment. So foreign particles cannot enter easily into deeper part.
• Ciliary movement– Respiratory epithelial cells contain hair like cilia. These cilia beat in one direction. It moves pathogen containing mucus upward from lower airway. This is called mucociliary escalator. Then mucus is swallowed or expelled.
• Cell shedding– Outer layer of skin or stratum corneum sheds dead cells continuously. During this shedding, attached microbes are removed from body surface. This process is called desquamation.
• Reflex expulsion– Coughing and sneezing remove foreign particles from respiratory tract. It expel trapped pathogen from airway with force. So microbes cannot reach fragile alveolar space easily.
• Fluid flushing– Tears, sweat and urine wash away microbes from eye, skin and urinary tract. Bowel movement also removes pathogen from gastrointestinal tract. In this way microbes are flushed out before colonization.

Types of Physiological Barriers

Different types of physiological barriers are mentioned below-

1. Acidic pH– Low pH acts as important physiological barrier. It stops growth of many microbes and also kills some pathogen.
   • Gastric acid– Stomach secretes hydrochloric acid (HCl). It maintains pH about 1 to 2. It denatures microbial proteins and destroys many ingested pathogen.
   • Skin acid– Skin surface is slightly acidic. It is due to fatty acids like oleic acid and other secretion. This condition inhibits harmful bacteria.
   • Vaginal acid– Vaginal tissue maintains acidic condition due to lactate. It prevents growth of many pathogenic microbes.
2. Fever– Fever is increase in body temperature during infection. It is produced by action of inflammatory cytokines on hypothalamus. High temperature inhibits pathogen multiplication and also increases activity of immune cells.
3. Antimicrobial enzyme– Some body fluids contain enzymes which destroy microbes.
   • Lysozyme– Lysozyme is present in tears, saliva, sweat and mucus. It breaks bacterial peptidoglycan cell wall. So bacterial cell becomes weak and destroyed.
   • Digestive enzyme– Digestive proteins like pancreatin and peptidase are present in gastrointestinal tract. They degrade microbial proteins and reduce survival of microbes.
4. Iron binding– This barrier is based on removal of free iron. Iron is needed for bacterial metabolism and multiplication.
   • Lactoferrin– Lactoferrin is present in mucosal fluids and breast milk. It binds free iron and makes it unavailable for microbes.
   • Transferrin– Transferrin is present in blood. It also binds iron. So iron dependent pathogens cannot grow properly.
5. Antimicrobial peptides– Antimicrobial peptides (AMPs) are secreted by epithelial cells and innate immune cells. They are broad acting defensive peptides.
   • Defensins– Defensins damage microbial membrane. It forms pore in lipid membrane and causes leakage of cell contents.
   • Cathelicidin– Cathelicidin such as LL-37 acts against bacteria, fungi and some viruses. It attacks membrane and causes lysis of microbes.
6. Decoy protein– Some soluble proteins act as false receptor. They bind pathogen and prevent their attachment with host tissue.
   • Uromodulin– Tamm-Horsfall protein (THP) or uromodulin is present in urine. It binds fimbriae of uropathogenic bacteria like Escherichia coli. Then bacteria are trapped and removed during urination.
7. Bile acid– Bile acids are secreted by liver into small intestine. They act like natural antiseptic surfactant. It disrupts lipid bilayer of microbial membrane.
8. Pulmonary collectin– These barriers protect alveolar space of lungs.
   • SP-A and SP-D– Surfactant protein A (SP-A) and surfactant protein D (SP-D) bind carbohydrate on respiratory pathogen. It causes agglutination of bacteria or virus. Then alveolar macrophages remove them easily.
9. Soluble recognition protein– Some proteins present in blood and mucosal fluid detect microbial molecules.
   • CRP– C-reactive protein (CRP) binds foreign microbial surface and helps in opsonization.
   • Fibrinogen– Fibrinogen helps in trapping and marking microbes during infection.
   • LBP– Lipopolysaccharide-binding protein (LBP) binds bacterial lipopolysaccharide (LPS) and helps in immune recognition.
10. Intracellular sensor– Barrier cells contain internal defense sensors. They detect microbial DNA or RNA inside the cell.
    • TLRs– Toll-like receptors (TLRs) recognize microbial pattern and start immune signaling.
    • STING pathway– STING pathway detects foreign DNA inside cell. It helps in production of antiviral interferons.
    • Inflammasome– Inflammasomes detect danger signal and produce inflammatory response. It may also cause pyroptosis, where infected cell dies and pathogen niche is removed.

Role of Body Temperature and Fever

The following are the role of body temperature and fever in innate immune response-

• Fever initiation– Fever is a systemic immune response. It starts when immune cells like macrophages detect pathogen. Then inflammatory cytokines like TNF-alpha, IL-1 and IL-6 are released.
• Hypothalamus action– These cytokines act on hypothalamus of brain. Hypothalamus produces prostaglandin E2 (PGE2). It raises body temperature by increasing heat production and reducing heat loss.
• Vasoconstriction– During fever, blood vessels of skin become narrow. This is called vasoconstriction. Heat loss from body surface becomes low. So body temperature rises.
• Microbial inhibition– High body temperature is not suitable for many microbes. It goes above their optimum growth temperature. So bacterial and viral multiplication becomes slow.
• Immune cell activity– Fever increases metabolic and enzymatic reaction of body. Phagocytes become more active. Lymphocytes multiply faster. Antibody and cytokine production also increases.
• Heat shock protein– Fever induces heat shock proteins in body cells. These proteins are recognized by intraepithelial T-lymphocytes. Then more inflammatory cytokines are produced for fighting with pathogen.
• Tissue repair– Fever increases general metabolic rate. Due to this tissue repair becomes faster. Healing process after infection or injury is supported by fever.
• Hyperpyrexia– Very high fever is harmful. When body temperature becomes 41.5°C (106.7°F) or more, it is called hyperpyrexia. It can denature body enzymes and cause cellular damage.

Role of pH in Host Defense

The following are the role of pH in host defense-

• Skin pH– Skin has acidic surface. The pH is about 4.5 to 5.5. It is maintained by sweat, sebum and natural moisturizing factors. This acidic surface do not allow many harmful microbes to grow.
• Skin protection– Low pH inhibits pathogen like Staphylococcus aureus. It also helps normal antimicrobial substance of skin. When pH is proper, skin barrier remain active.
• Gastric pH– Stomach has very low pH due to hydrochloric acid (HCl). The pH is about 1 to 2. It is very harmful for ingested microbes. Microbial protein become denatured and many microbes are killed.
• Vaginal pH– In vagina, normal bacteria like Lactobacillus use glycogen. Then lactate is formed. This makes acidic condition. Many pathogenic bacteria and fungi cannot grow in this condition.
• Urine pH– Urine is slightly acidic. It acts as chemical barrier in urinary tract. It restricts growth of microbes and helps in protection of urogenital tract.
• High pH effect– If acidic pH is lost, barrier becomes weak. In atopic dermatitis, skin pH becomes almost neutral. Then antimicrobial peptides work less and Staphylococcus aureus colonize easily.

Antimicrobial Substances in Body Secretions

Some of the important antimicrobial substances in body secretion are-

• Lysozyme– Lysozyme is a antimicrobial enzyme. It is present in tears, saliva, sweat, nasal secretion, mucus and breast milk. It breaks bacterial cell wall. Mainly it acts on peptidoglycan layer.
• Lactoferrin– Lactoferrin is iron binding protein. It is present in tears, saliva, bronchial secretion and breast milk. It bind free iron. So bacteria do not get iron for growth.
• Lactoperoxidase– Lactoperoxidase is present in saliva. It is oxidizing enzyme. It helps in killing of bacteria and virus in oral cavity.
• Antimicrobial peptides– Antimicrobial peptides (AMPs) are small protective peptides. They are secreted from epithelial cells. They damage the membrane of bacteria, fungi and some virus. The important examples are defensins, cathelicidin (LL-37), dermcidin, psoriasin (S100A7) and RNases.
• Gastric acid– Gastric acid is hydrochloric acid (HCl) of stomach. It has very low pH, about 1 to 2. It denatures microbial protein. Most of the microbes entering with food are destroyed.
• Digestive enzymes and bile acid– Pepsin, pancreatin and peptidase are present in digestive secretion. They break microbial protein. Bile acids damage lipid layer of microbes and control microbial growth in intestine.
• Sebum and fatty acids– Sebum is oily secretion of sebaceous gland. It contains toxic lipid substance. Normal skin bacteria act on sebum and form oleic acid. This makes skin surface acidic and prevents harmful bacteria.
• Lactic acid– Lactic acid or lactate is present in vaginal secretion. It is formed when normal bacteria use glycogen. This acidic condition prevents growth of many pathogen.

Role of Saliva, Tears, and Sweat in Immune Defense

The following are the role of saliva, tears and sweat in immune defense-

• Flushing action– Tears and sweat are secreted continuously. They wash away microbes from eye and skin surface. So pathogen get less time for attachment and colonization.
• Lysozyme action– Saliva, tears and sweat contain lysozyme. It is an antimicrobial enzyme. It breaks the bacterial cell wall and causes destruction of bacteria.
• Iron binding– Tears and saliva contain lactoferrin. Lactoferrin binds free iron. So bacteria do not get enough iron for growth and multiplication.
• Lactoperoxidase action– Saliva contains lactoperoxidase enzyme. It helps in degradation of bacteria and virus. It increases antimicrobial activity in oral cavity.
• Acidic protection– Sweat makes the skin surface slightly acidic. Low pH inhibits the growth of many microbes. It also helps in maintaining skin chemical barrier.
• Lipid protection– Sweat contains some toxic lipid substances. These lipids act against microbes on skin. They make the skin surface unsuitable for microbial growth.

Normal Microbiota as a Protective Barrier

Normal microbiota are the harmless microorganisms present on skin and mucosal surfaces. They act as biological barrier against pathogen. They prevent attachment, growth and multiplication of harmful microbes.

The following are the protective role of normal microbiota–

• Competition– Normal microbiota occupy the surface of skin, intestine, respiratory tract and genitourinary tract. So pathogen do not get proper place for attachment. They also use the nutrients present there. Some commensal bacteria like Corynebacterium bind free iron and reduce growth of pathogenic Staphylococcus.
• Acid formation– Some normal flora produce acidic substances from host material. Propionibacterium acnes uses skin sebum and produces oleic acid. Vaginal Lactobacillus uses glycogen and produces lactate. This low pH prevents growth of many pathogenic bacteria.
• Antimicrobial toxin– Many commensal bacteria secrete antimicrobial substances. Bacteriocins are peptide like substance produced by bacteria. They kill or inhibit other harmful bacteria. Lugdunin is produced by nasal commensal bacteria and it can destroy pathogenic Staphylococcus aureus.
• Hydrogen peroxide– Some normal microbiota produce hydrogen peroxide (H₂O₂) as metabolic product. It forms oxidative condition. This condition is harmful for many pathogens and stops their growth.
• Biofilm prevention– Some commensal bacteria prevent colonization of pathogen. Staphylococcus epidermidis present in nasal cavity secretes serine protease enzyme. This enzyme prevents Staphylococcus aureus from attachment and formation of biofilm.
• Free fatty acid– Some beneficial bacteria use host secretion and form toxic fatty acids. Corynebacterium accolens uses lipase enzyme and breaks skin triacylglycerol. It forms free fatty acids which have antibacterial action.
• Immune priming– Normal microbiota continuously interact with host immune system. Their signals keep innate immune cells ready. Alveolar macrophages, natural killer (NK) cells and some T-lymphocytes become active and prepared. So respiratory and intestinal pathogen are removed more quickly.

Mechanism of Physiological Barriers of the Immune System

The following are the mechanism of physiological barriers of immune system–

• Low pH action– It is based on acidic condition of body secretion. Gastric acid of stomach has pH about 1 to 2. It denatures microbial protein and changes the membrane potential of microbes. Skin and vagina also maintain mild acidic condition. So harmful microbes cannot grow properly.
• Enzymatic hydrolysis– Lysozyme is present in tears, saliva and mucus. It hydrolyses β(1→4) glycosidic bond of bacterial peptidoglycan. So bacterial cell wall is broken down. Pancreatin and peptidase also degrade microbial structure in digestive tract.
• Nutrient starvation– This mechanism is based on binding of essential nutrient. Lactoferrin and transferrin bind free ferric iron (Fe³⁺). Lactoferrin is present in mucosal fluid and breast milk. Transferrin is present in blood. So iron dependent pathogen do not get iron for metabolism and replication.
• Membrane disruption– Antimicrobial peptides (AMPs) act on microbial membrane. Defensins and cathelicidins are cationic peptides. They enter into lipid bilayer and form pores. Then microbial cell contents come out and cell lysis occurs. Bile acids also act as antiseptic surfactant and damage microbial lipid membrane.
• Decoy inhibition– Some soluble proteins act as false receptor. Tamm-Horsfall protein (THP) or uromodulin is present in urine. It has oligomannose rich N-glycans. It binds with fimbriae of uropathogenic bacteria. Then bacteria are clumped and removed with urine instead of attachment with host tissue.
• Opsonization and complement– C-reactive protein (CRP), fibrinogen, surfactant protein A (SP-A) and surfactant protein D (SP-D) bind on microbial surface. They act as opsonins and mark pathogen for phagocytosis. They can also activate complement system. Then membrane attack complex (MAC) is formed and microbial membrane is perforated.
• Fever action– Fever is formed by endogenous pyrogens like IL-1β, IL-6 and TNF-α. These act through prostaglandin E2 (PGE2) and increase body temperature set point. High temperature is not suitable for many pathogen. It also increases enzymatic reaction, antiviral gene expression and immune cell multiplication.
• Intracellular sensing– Barrier cells contain internal sensors for pathogen DNA and danger signal. STING pathway detects foreign DNA and produces type I interferons. Inflammasome activates caspase-1, forms inflammatory cytokines and causes pyroptosis. In this process infected cell dies and intracellular pathogen niche is removed.

Factors Affecting Barrier Function

The following are the factors affecting barrier function–

• Genetic mutation– Genetic defect directly affects the barrier. Mutation in filaggrin (FLG) gene reduces water holding capacity of skin and acidic pH is not maintained. In CFTR gene mutation, mucus becomes thick and dehydrated and mucociliary escalator is affected. Defect in tight junction gene like CLDN1 also damages epithelial seal.
• Physical trauma– Cuts, wounds and burns destroy the normal skin and mucous membrane barrier. Pathogens enter easily through damaged surface. Repeated scratching also damages tight junctions and increases barrier permeability.
• Inflammatory cytokines– Some cytokines reduce the production of barrier proteins. IL-4, IL-13, IL-17 and IFN-γ down regulate claudin-1 and claudin-23. So tight junction becomes weak and barrier disruption occurs.
• Microbial infection– Some bacteria and viruses directly damage the barrier. Staphylococcus aureus produces proteins and superantigens which disturb tight junction and increase inflammation. Chronic viral infection like EBV, CMV, HCV and HTLV-1 can damage exocrine glands and reduce saliva and tear secretion.
• Environmental trigger– Mold, allergen, dust and pollutants affect the weak barrier. These substances enter through vulnerable surface and start local inflammation. This inflammation again damages the barrier function.
• Age and hormone– Ageing reduces the strength of barrier. Claudin-1 expression becomes low and skin becomes dry, thick and weak. Low estrogen also causes mucosal dryness and makes the immune barrier less protective.
• Drug effect– Some medicines reduce barrier function. Long use of topical corticosteroids decreases claudin-1 and claudin-4 expression. So skin barrier becomes thin, weak and less protective.

Failure of Anatomical and Physiological Barriers

The following are the failure of anatomical and physiological barriers–

• Skin failure– Atopic dermatitis is a chronic inflammatory skin disease. It occurs due to loss of function mutation in filaggrin (FLG) gene. Due to this, natural moisturizing factors become low. The skin becomes dry and dehydrated.
• pH failure– In atopic dermatitis, skin pH becomes high and acidity is lost. The antimicrobial peptides of skin do not work properly. So pathogen like Staphylococcus aureus colonizes the skin easily.
• Junction failure– Inflammation in skin decreases claudin-1 and claudin-23. These proteins are important for tight junctions. When tight junction is damaged, physical barrier of skin becomes weak.
• Mucociliary failure– Cystic fibrosis occurs due to mutation in CFTR gene. Chloride and bicarbonate ion transport is impaired. So mucus of lungs becomes thick, sticky and dehydrated.
• Mucus stasis– Thick mucus stops the action of mucociliary escalator. Inhaled particles and microbes remain trapped in lung. This stagnant mucus forms suitable condition for infection.
• Biofilm infection– In cystic fibrosis, bacteria like Pseudomonas aeruginosa grow in thick mucus. It forms chronic biofilm infection. Lung tissue damage occurs slowly.
• Secretory failure– Sjögren’s syndrome is also called autoimmune epithelitis. In this disease immune system attacks salivary gland and lacrimal gland. So saliva and tears become very low.
• Chemical loss– Due to low tear and saliva, lysozyme and lactoferrin also decrease. These are normal antimicrobial substances. Dry eye, dry mouth, dental decay and mucosal infection are commonly seen.
• Complement failure– Defect in complement system decreases innate immunity. Deficiency of early components like C1, C2 and C4 reduces clearance of immune complex. It may produce autoimmune manifestation.
• Lysis failure– Deficiency of terminal complement components like C5-C9 prevents direct lysis of bacteria. So recurrent meningococcal infection occurs. Mainly infection by Neisseria meningitidis is seen.
• Phagocyte failure– Chronic granulomatous disease occurs due to defect in NADPH oxidase enzyme complex. Phagocytes cannot produce oxidative burst. So engulfed pathogens are not killed properly.
• Abscess formation– In defective phagocyte killing, microbes survive inside tissue. Recurrent tissue abscesses are formed. This shows failure of cellular part of innate immune defence.

Clinical Significance of Anatomical and Physiological Barriers

The following are the clinical significance of anatomical and physiological barriers–

• Atopic dermatitis– Atopic dermatitis is also known as eczema. It occurs due to loss of function mutation in filaggrin gene. The skin becomes dry, dehydrated and pH becomes almost neutral. Tight junctions are disturbed and allergens enter easily. Pathogens like Staphylococcus aureus colonizes the skin and infection occurs.
• Cystic fibrosis– Cystic fibrosis occurs due to mutation in CFTR gene. Ion transport is not proper. So mucus becomes thick and dehydrated in respiratory and digestive tract. In lungs this thick mucus stops mucociliary escalator. Bacteria like Pseudomonas aeruginosa grow in this stagnant mucus and cause chronic lung infection.
• Sjögren’s syndrome– Sjögren’s syndrome is an autoimmune disease. In this disease tear gland and salivary gland are attacked by own immune system. Tears and saliva become low. So lysozyme and lactoferrin also become low. Dry eyes, oral candidiasis and rapid dental decay are seen.
• Urinary infection– Tamm-Horsfall protein (THP) or uromodulin is present in urine. It acts as decoy barrier. It binds uropathogenic bacteria like Escherichia coli and removes them with urine. Defect or deficiency of THP increases urinary tract infection (UTI) and chronic kidney disease.
• Respiratory weakness– Surfactant protein A (SP-A) and surfactant protein D (SP-D) protect the alveolar space of lungs. Deficiency of these proteins is seen in premature neonates, chronic smokers and COPD patients. So viral lung infection like RSV, Influenza and SARS-CoV-2 occurs more easily.
• Microbiome dysbiosis– Normal commensal microbiota are present on skin and mucosal surface. They compete with pathogen for nutrients and space. Long use of antibiotic destroys this normal flora. Then colonization resistance becomes low and respiratory or intestinal infection increases.
• MBL deficiency– Mannose-binding lectin (MBL) is a soluble blood protein. It works as opsonin and marks microbes for destruction. In inherited MBL deficiency, phagocytic clearance becomes weak. Patient becomes more susceptible to systemic infection and disseminated intravascular coagulation (DIC) may occur.
• Genetic resistance– Some genetic variation prevents virus entry into host cell. CCR5-delta-32 mutation is important example. In this mutation functional CCR5 co-receptor is absent. HIV-1 needs this receptor to enter immune cells. So HIV-1 infection does not occur easily.

References

1. Cummings, R. D. (2025, February 3). 16] Facts About: Major Glycoprotein in Urine – Uromodulin/Tamm-Horsfall Protein (THP). National Center for Functional Glycomics (NCFG).
2. 20.1F: Fever – Medicine LibreTexts. (n.d.).
3. Ferraboschi, P., Ciceri, S., & Grisenti, P. (2021). Applications of lysozyme, an innate immune defense factor, as an alternative antibiotic. Antibiotics (Basel), 10(12), 1534. https://doi.org/10.3390/antibiotics10121534
4. OpenStax CNX. (n.d.). Barrier defenses and the innate immune response. In Anatomy and physiology II.
5. Duffy, S., & Duffy, S. (2023). Chapter 2: Innate immune barriers and components. In Basic concepts in applied immunology.
6. Chapter 2: Innate Immunity – PMC. (n.d.).
7. Khan, R., Petersen, F. C., & Shekhar, S. (2019). Commensal bacteria: An emerging player in defense against respiratory pathogens. Frontiers in Immunology, 10, 1203. https://doi.org/10.3389/fimmu.2019.01203
8. Commensal bacteria mediated defenses against pathogens – PMC. (n.d.).
9. Johns Hopkins Cystic Fibrosis Center. (2026). Effects of CF.
10. Epidermal tight junction barrier function is altered by skin inflammation, but not by filaggrin-deficient stratum corneum – PubMed. (n.d.).
11. Fever and the thermal regulation of immunity: The immune system feels the heat – PMC – NIH. (n.d.).
12. UF Medical Physiology Online. (n.d.). How does the immune system work? Exploring the 3 lines of defense. University of Florida.
13. Cleveland Clinic. (2023, October 20). Immune system function, conditions & disorders.
14. Immunostimulating commensal bacteria and their potential use as therapeutics – PMC. (n.d.).
15. Institute for Quality and Efficiency in Health Care (IQWiG). (2023, August 14). In brief: The innate and adaptive immune systems. InformedHealth.org.
16. Massive Bio. (2026, April 16). Innate immunity.
17. Aristizábal, B., & González, Á. (2013, July 18). Chapter 2: Innate immune system. In J. M. Anaya, Y. Shoenfeld, A. Rojas-Villarraga, et al. (Eds.), Autoimmunity: From bench to bedside. El Rosario University Press.
18. Khan Academy. (n.d.). Innate immunity (article) | Immune system.
19. Sabir, S., & Jan, A. (2025, December 1). Physiology, immune response. StatPearls Publishing.
20. Protective role of the lung collectins surfactant protein A and surfactant protein D in airway inflammation – PMC. (n.d.).
21. Watson, A., Madsen, J., & Clark, H. W. (2021). SP-A and SP-D: Dual functioning immune molecules with antiviral and immunomodulatory properties. Frontiers in Immunology, 11, 622598. https://doi.org/10.3389/fimmu.2020.622598
22. Lupus Foundation of America. (2013, July 11). Sjogren’s syndrome: What you need to know.
23. Sjögren’s syndrome and viral infections – PMC – NIH. (n.d.).
24. Cleveland Clinic. (2025, December 23). Sjögren’s syndrome: Symptoms & treatment.
25. Skin barrier defects in atopic dermatitis – PMC – NIH. (n.d.).
26. Skin barrier in atopic dermatitis: Beyond filaggrin – PMC – NIH. (n.d.).
27. Skin barrier in atopic dermatitis: Beyond filaggrin – PubMed. (n.d.).
28. Structural model of urinary uromodulin [Tamm – Horsfall protein ( THP… – ResearchGate. (n.d.).
29. Kishore, U., Greenhough, T. J., Waters, P., Shrive, A. K., Ghai, R., Kamran, M. F., López Bernal, A., Reid, K. B. M., Madan, T., & Chakraborty, T. (2006). Surfactant proteins SP-A and SP-D: Structure, function and receptors. Molecular Immunology, 43(9), 1293-1315. https://doi.org/10.1016/j.molimm.2005.08.004
30. Tamm-Horsfall protein protects against urinary tract infection by Proteus mirabilis – PMC. (n.d.).
31. Cell Signaling Technology. (2026). The innate immune response.
32. Kaiser, G. E. (2020, February). The innate immune system: Fever. The Community College of Baltimore County.
33. Cedzyński, M., & Świerzko, A. S. (2024). The role of pulmonary collectins, surfactant protein A (SP-A) and surfactant protein D (SP-D) in cancer. Cancers, 16(18), 3116. https://doi.org/10.3390/cancers16183116
34. Katsarou, S., Makris, M., Vakirlis, E., & Gregoriou, S. (2023). The role of tight junctions in atopic dermatitis: A systematic review. Journal of Clinical Medicine, 12(4), 1538. https://doi.org/10.3390/jcm12041538
35. The systemic architecture of host defense: A comprehensive treatise on anatomical, physiological, and biological barriers in human immunity. (n.d.).
36. The pulmonary collectins, SP-A and SP-D, orchestrate innate immunity in the lung – PMC. (n.d.).
37. Maslinska, M., & Kostyra-Grabczak, K. (2022). The role of virus infections in Sjögren’s syndrome. Frontiers in Immunology, 13, 823659. https://doi.org/10.3389/fimmu.2022.823659
38. Uromodulin (Tamm–Horsfall protein): Guardian of urinary and systemic homeostasis – PMC. (n.d.).
39. Dutta, S. S. (2021, March 11). What are the three lines of defense? News-Medical.Net.
40. AAT Bioquest. (2023, November 7). What are the components of the innate immune system?