Innate Immune Response Notes


Innate Immunity

The innate immune system is a crucial part of the immune response, providing a rapid reaction to invading microbes while the adaptive immune system develops a specific response. Key characteristics include:

  • Present at birth.

  • Limited diversity for antigen recognition.

  • Attacks microbes with the same vigor upon repeated exposure (no memory).

  • Acts fast, within minutes to hours after infection.

  • No memory is generated; the response is not enhanced by repeated exposure.

Lines of Protection Mechanisms

The body has several lines of defense:

  1. 1st line: Non-specific defenses including skin, mucous membranes, and chemicals.

  2. 2nd line: Non-specific defenses including phagocytosis, complement, interferon, inflammation, and fever.

  3. 3rd line: Specific defenses including lymphocytes and antibodies.

Innate Immune Components/Barriers

The innate immune system includes:

  • Physical (anatomic) barriers

  • Physiologic barriers

  • Biological barriers

  • Innate cellular response

  • Inflammation

Physical (Anatomic) Barriers

  • Skin: Most pathogens cannot invade intact skin. The skin's acidic pH retards the growth of pathogenic organisms.

  • Respiratory tract: Cilia remove microbes. Saliva and mucous contain antimicrobial enzymes and chemicals.

  • GI tract: Mucous membrane with properties similar to the respiratory tract, but pathogens must survive the stomach's acidic pH.

  • Sticky mucus entraps foreign material.

Skin & Mucus Membranes

  • Skin: Stratified epithelium with keratin in outer layers.

  • Respiratory system: Columnar epithelium with cilia and mucus-producing cells.

Physiologic Barriers

  • Temperature: Many microbial pathogens cannot survive much past human body temperature.

  • pH: Acidic pH of the stomach and skin impedes the growth of many pathogens.

  • **Chemical:

    • Lysozyme: Breaks down bacterial cell wall peptidoglycan, found in tears, saliva, breast milk, and mucus.

    • Defensins: Form pores in bacteria and fungi, found within phagocytes.

    • Interferons: Including IFN-α and IFN-β, which are anti-viral.

Chemical Components

  • Lysozyme destroys peptidoglycan in bacterial cell walls, leading to lysis.

Biological Barriers

  • Blinking, sneezing, coughing reflexes expel foreign particles.

  • Flushing action of saliva, tears, and urine washes away microbes.

  • Sweat and sebaceous secretions inhibit microorganisms.

  • Normal bacterial flora competes with pathogens for attachment sites and nutrients and produces bacteriocins and acids.

External Defenses: Barriers

  • Damage to surface barriers (cuts, wounds, smoking, pollutants, etc.) can suppress this line of defense, allowing entry of foreign organisms into internal tissues and causing infection.

Innate Cellular Response

  • Phagocytic cells (monocytes/macrophages, neutrophils, and dendritic cells) are the first line of defense against invading pathogens.

  • They recognize pathogens via shared molecules not expressed on host cells.

  • Receptors of the innate immune system are called pattern recognition receptors (PRRs).

  • PRRs recognize pathogen-associated molecular patterns (PAMPs).

  • These receptors are present intrinsically, encoded in germline genes, and are not generated through somatic recombination.

  • The innate immune system can recognize <1,000 patterns, versus the adaptive immune system which can recognize over 1 billion specific sequences.

  • Toll-like receptors (TLRs) are a key type of PRR.

Cells of Innate Immunity

  • Neutrophils: Circulating phagocytes, short-lived, rapid response.

  • Eosinophils: Circulating phagocytes.

  • Monocytes/Macrophages: Monocytes circulate in blood, become macrophages in tissues, provide prolonged defense, produce cytokines, phagocytose pathogens, and clear dead tissue.

  • Dendritic cells (DCs): Found in all tissues, antigen processing and presentation, initiate inflammatory and adaptive immune responses.

  • Mast cells: Located in skin and mucosa, activated by innate TLRs and antibody-dependent (IgE) mechanisms.

  • Natural killer cells (NK cells): Located in blood and periphery, directly lyse cells, secrete IFN-γ.

Killing Mechanisms

  1. NK cells make close contact with the target cell and release granule contents on the surface, leading to pore formation, entry through pores, activation of apoptosis, and lysis.

  2. Antibody-dependent cell-mediated cytotoxicity (ADCC): IgG antibodies bind to target cells, and the Fc part of IgG binds to Fc receptors on NK cells, directing them to kill the target cell. NK cells use similar mechanisms as T cytotoxic cells (Tc) but are not antigen-specific and do not generate memory.

Innate Immunity: Cellular Defense Mechanisms: Phagocytes

  • Two main types: polymorphonuclear cells (neutrophils, eosinophils) and mononuclear cells (monocytes → macrophages).

  • Target particles in extracellular tissues or tissue fluids.

  • The process of engulfment is termed phagocytosis and intracellular killing.

N.B. Eosinophils

  • Cytoplasmic granules contain enzymes and toxic molecules active against parasites.

  • Release of these molecules allows extracellular killing of parasites too large to be phagocytosed (e.g., helminthes).

Phagocytosis

  • Chemotaxis of phagocytic cells into the area of antigen entry.

  • Ingestion and digestion of particulate debris, microorganisms, host cellular debris, and activated clotting factors.

  • An active, multi-step, sequential process involves:

    • Extension of pseudopodia to engulf attached material.

    • Fusion of pseudopodia to trap material in a phagosome.

    • Fusion of the phagosome with a lysosome to create a phagolysosome.

    • Digestion.

    • Exocytosis of digested contents.

Steps of Phagocytosis

  1. Chemotaxis: Phagocytes move towards microorganisms following chemoattractants.

  2. Attachment: Phagocytes have surface receptors that recognize and bind pathogen-associated molecular patterns (PAMPs).

  3. Engulfment: The phagocyte's cytoplasmic membrane surrounds the organism and encloses it in a vacuole called a phagosome.

  4. Fusion: Phagosomes fuse with lysosomes (containing enzymes and killing substances) to form phagolysosomes.

  5. Killing: Microorganisms are exposed to microbicidal proteins and oxidizing agents, leading to their death and digestion.

Intracellular Killing

  • Respiratory burst: Activates a membrane-bound oxidase that generates oxygen metabolites toxic to ingested microorganisms.

    • NADPH\text{NADPH}

    • Oxidase reduces oxygen to superoxide anion(O2−)\text{Oxidase reduces oxygen to superoxide anion}(\text{O}_{2}^{-})

    • Which generates hydroxyl radicals, hydrogen peroxide (H<em>2O</em>2)\text{Which generates hydroxyl radicals, hydrogen peroxide (H}<em>{2}\text{O}</em>{2})

    • These are microbicidal (oxygen-dependent).

  • Reactive nitrogen intermediates also play a role.

  • Lysosomal contents of phagocytes contain oxygen-independent degradative materials:

    • Lysozyme digests bacterial cell walls by cleaving peptidoglycan.

    • Defensins form channels in bacterial cell membranes.

    • Lactoferrin chelates iron.

    • Hydrolytic enzymes.

Evasion of Phagocytosis

  • Microorganisms may lack pattern molecules or may cover themselves with a thick capsule.

  • Attachment may occur if microorganisms are coated by a host protein (antibody, complement component, CRP), which is called opsonization.
    The phagocyte uses specific receptors for the host protein coating the microbe -> immune phagocytosis.

  • The substance which helped phagocytosis is called an opsonin.

Opsonization demonstrates how different components of the immune system can help each other.

N.B.

  1. Most phagocytosed material is killed and degraded. However, some material (e.g., TB bacilli) is resistant to lysosomal killing and remains unaltered within the phagosome, leading to granuloma formation.

  2. When large numbers of phagocytes die, pus accumulates (abscess).

Defects in phagocytosis increase susceptibility to serious infections. Chronic granulomatous disease (CGD) is an inherited deficiency in NADPH oxidase.

Cytokines Involved in Innate Immunity

  • Pro-inflammatory cytokines:

    • Interleukin (IL)-1, IL-6, and TNF-α:

      • Secreted by macrophages.

      • Cause fever, cachexia, production of acute phase proteins (e.g., C-Reactive Protein and complement components), and leukocytosis.

    • IL-12:

      • Secreted by macrophages.

      • Activates NK cells, leading to Type II Interferon (IFN-γ) production.

  • Type I Interferons (IFNs):

    • IFN-α:

      • Secreted by dendritic cells and macrophages.

      • Activates all cells, increases class I MHC expression, and activates NK cells.

    • IFN-β:

      • Secreted by fibroblasts.

      • Activates all cells, increases class I MHC expression, and activates NK cells.

Interferons

  • Three types: α, β & γ:

    • α & β (Type I): part of innate immunity, secreted by any virus-infected cell, interfere with virus replication in infected cells.

    • γ (Type II): part of adaptive & innate immunity, secreted by T lymphocytes & NK cells, interfere with virus replication in uninfected cells, and carries out other functions.

Therapeutic Use of Interferons (IFNs)

  • IFNs induce increases in the expression of class I and II MHC molecules and augment NK cell activity.

  • Interferon-α has antiviral activity and is used in the treatment of hepatitis B and C infections and within cancer therapy.

  • Interferon-β has a positive effect on young adults with multiple sclerosis.

  • Interferon-γ is used in the treatment of chronic granulomatous disease (CGD).

  • Side effects include headache, fever, chills, and fatigue.

Acute Phase Proteins

  • Present at low levels in normal serum, but their concentration rises dramatically shortly after the onset of infection in response to cytokines (e.g., IL-6).

    • Example: C-reactive protein

  • Act by binding to bacteria and facilitating elimination by effector mechanisms (e.g., activating the complement system or enhancing phagocytosis).

Complement

  • A group of proteins present in an inactive form can be activated by certain pathogens (and by antibody binding to pathogens).

  • Activation leads to the elimination of the organism.

  • Because it is a very powerful system, it is carefully controlled.

Inflammation

  • Release of granule contents occurs immediately after infection and leads to inflammation.

  • The goal of inflammation is to bring more leukocytes and plasma proteins to the area to supplement defense.

Inflammation Importance

  • Inflammatory fluid and cells enhance phagocytosis, restrict infection (formation of fibrin clot), limit tissue damage, and start tissue repair.

Conclusion

The innate immune system is often sufficient to destroy invading microbes. If it fails to clear infection rapidly, it activates the adaptive immune response, which takes over.