Innate Immune Response

Immunity to pathogens is divided into innate and adaptive immune responses. The innate immune response is the 1st line of defense against a variety of pathogens, including bacteria, fungi, viruses, and parasites. In essentially the same form, the innate type of immunity is present in all multicellular organisms. The innate immune response is activated within minutes to hours after exposure to an infection, which curtails microbe invasion at the initial stages. The pathogen has specific components recognized by pattern recognition receptors (PRRs). After identification of a microbial invasion, noncellular components (including the complement system and cytokines) act in concert with cellular elements to achieve cell recruitment, direct microbial killing, or phagocytosis induction. The steps all aim to eliminate the pathogen. Antimicrobial mechanisms in phagocytosis include acidification and respiratory/oxidative burst. The process terminates with destruction of the threat while maintaining immunologic homeostasis. The defense is also important in activating the adaptive immune system.

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Overview

Immune system

The immune system provides defense (immunity) against invading pathogens ranging from viruses to parasites; components are interconnected by blood and lymphatic circulation.

Two lines of overlapping defense:

  • Innate immunity (nonspecific) 
  • Adaptive immunity (based on specific antigen recognition):
    • Cell-mediated immunity: adaptive response in cells/tissues involving the T cells
    • Humoral immunity: adaptive response in fluids (“humoral”) involving B cells and immunoglobulins

Innate versus adaptive immunity

Table: Innate versus adaptive immunity
Innate immunityAdaptive immunity
GeneticsGermline encodedGene rearrangements involved in lymphocyte development
Immune responseNonspecificHighly specific
Timing of responseImmediate (minutes to hours)Develops over a longer period of time
Memory responseNoneResponds quickly upon recognition of antigen with memory response
Recognition of pathogenPattern recognition receptors (PRRs) such as toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs)
  • Memory cells (T and B cells)
  • Activated B cells
Components
  • Anatomical barriers (e.g., skin)
  • Chemical and biological barriers (e.g., gastric acid, vaginal flora)
  • Cells (e.g., granulocytes)
  • Secreted proteins:
    • Enzymes (e.g., lysozyme)
    • Other PRRs (e.g., antimicrobial peptides (AMPs))
    • Cytokines*
    • Complement* system
  • Cell-mediated immunity: T cells
  • Humoral immunity: B cells, immunoglobulins
*Mediators with roles in adaptive immunity

Components of the Innate Immune System

Innate immune response

  • Barriers:
    • 1st line of defense (mechanical, chemical, and biological)
    • Define and line surfaces of the body
    • Secrete substances to remove and reduce pathogens
  • Microbe detection: The 1st step is pathogen recognition:
    • Pattern recognition patterns (PRRs): proteins distinguishing self from foreign material and recognizing components specific to microbes:
      • Pathogen-associated molecular patterns (PAMPs): structures conserved among microbial species
      • Damage-associated molecular patterns (DAMPs) (also known as alarmins): endogenous molecules released from damaged cells
    • According to the location of PRR and PAMP interaction, PRRs can be associated with cells as transmembrane or intracellular receptors:
      • Toll-like receptors (TLRs)
      • Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs)  
      • NOD-like receptors (NLRs)
      • C-type lectin receptors (CLRs) 
    • Secreted and circulating PRRs are involved when the interaction occurs in body fluids (bloodstream and interstitial fluids):
      • Antimicrobial peptides (AMPs)
      • Collectins
      • Lectins
      • Pentraxins
      • Antimicrobial oligosaccharides
  • Several processes trigger a breach in barriers → inflammation:
    • Occurs in response to infection or injury
    • Results in the cardinal signs (swelling, redness, heat, and pain) 
    • Once the pathogen is identified via PRRs, proteins are secreted: 
      • Cytokines (functions include recruitment, cell-to-cell communication, and antiviral, antibacterial, and antifungal actions)
      • Chemokines (cell migration)
      • Complement system (“complements” or assists in eliminating microbes)
      • Some PRRs (e.g., AMPs) are also involved in pathogen elimination.
  • Cellular response: Various cells (e.g., phagocytes) are recruited and participate in the microbial killing.
  • The immune response is terminated when a need no longer exists (homeostasis).

Cells of the innate immune system

  • Many subsets of cells involved in the innate response develop from hematopoietic stem cells (HSCs) in the bone marrow (a primary lymphoid organ):
    • HSCs → common myeloid progenitor → gives rise to:
      • Granulocytes: professional phagocytes (neutrophils, monocytes, macrophages), eosinophils, basophils, and mast cells
      • Megakaryocytes → platelets
    • HSCs → common lymphoid progenitor → lymphocytes (generally undergo activation and proliferation in secondary lymphoid organs):
      • B cells and T cells: adaptive immunity
      • Natural killer (NK) cells: mostly innate immune response
      • Natural killer T (NKT) cells: bridge innate and adaptive immunity
  • Individually, the cells have varying functions and targets in the immune response.
  • Crucial roles:
    • Phagocytosis: Microbes or damaged particles are engulfed and digested.
    • Antigen presentation: performed by dendritic cells, macrophages, and B cells, which facilitate antigen recognition by adaptive immunity
Stem cells differentiate into 2 pathways

Stem cells differentiate into 2 pathways:
Myeloid pathways produce erythrocytes, platelets, and cells of the innate immune response. Lymphoid pathways produce the cells of adaptive response and natural killer cells.

Image by Lecturio.

Barriers

Mechanical barrier

Epithelial cells line body surfaces and are heavily exposed to antigens.

  • Skin keratinocytes: 
    • Express mannose-binding receptors: mediate the killing of Candida
    • Regular shedding and sweat secretion: limits the adhesion and invasion of microorganisms
  • Respiratory, GI, and genitourinary tracts: 
    • Mucus, a ciliated layer, and sloughing: reduce the adherence of microbes in the respiratory tract
    • GI tract peristalsis and urine flow: limits pathogen attachment

Chemical barrier

  • Skin and stomach: produce hydrochloric acid to kill bacteria
  • Saliva and tears produce lysozyme: breaks up bacterial peptidoglycan in the cell wall
  • The respiratory and GI tracts produce defensins: positively charged peptides creating holes/channels in the walls of bacteria, fungi, and viruses
  • Paneth cells (base of intestinal crypts): secrete AMPs, defensin, and lysozyme
  • Surfactant in the alveoli: binds to the microbe surface and facilitates phagocytosis

Biological barrier

Includes:

  • Microbiome (commensal organisms living in and on the body):
    • Nonpathogenic, coagulase-negative Staphylococci: inhibit the growth of Staphylococcus aureus by secreting antimicrobial peptides
    • Dysbiosis: a change in the microbiome composition of the GI tract (seen with antibiotic use), which can lead to Clostridioides difficile infection
  • IgA and IgG

Cell-associated PRRs

Cell-associated PRRs are expressed in various immune cells and can be intracellular (endolysosomal/cytoplasmic) or transmembrane.

TLRs

  • Detect a range of human pathogens
  • 10 well-defined TLRs in humans (11th is identified)
  • TLRs recognize a particular microbial building block (e.g., an amino acid sequence of endotoxin or peptidoglycan):
    • Transcription factors are activated.
    • The process leads to the synthesis of proinflammatory cytokines and cell surface molecules, ultimately resulting in a rapid innate immune response.
  • TLR1, TLR2, TLR4, TLR5, and TLR6 recognize microbial cell wall components:
    • TLR4 identifies lipopolysaccharide (LPS) in the outer membrane of gram-negative bacteria (involved in septic shock).
    • TLR4 binds to viral envelope proteins.
    • TLR5 recognizes flagellin from flagellated bacteria.
    • TLR1, TLR2, and TLR6 recognize lipoproteins.
  • TLR3, TLR7, TLR8, TLR9, and TLR10 are cytoplasmic:
    • Recognize nucleic acids derived from organisms
    • Endogenous nucleic acids → implicated in autoimmunity
  • TLR3, TLR4, TLR7, TLR8, and TLR9:
    • Trigger type-1 interferon (IFN) production (e.g., IFN-α, IFN-β)
    • Antiviral activity

Description of different TLRs

Table: Different TLRs
Toll-like receptorLocalizationLigandOrigin of the ligand
TLR1Plasma membraneTriacyl lipoproteinBacteria
TLR2LipoproteinBacteria, viruses, parasites
TLR3EndolysosomedsRNAViruses
TLR4Plasma membraneLPSBacteria, viruses
TLR5FlagellinBacteria
TLR6Diacyl lipoproteinBacteria, viruses
TLR7, TLR8EndolysosomessRNAViruses, bacteria
TLR9CpG-DNAViruses, bacteria, protozoa
TLR10UnknownInfluenza virus, Listeria monocytogenes
dsRNA: double-stranded RNA
LPS: lipopolysaccharide
ssRNA: single-stranded RNA
CpG: cytosine-phosphate-guanine
Pattern recognition receptors

Pattern recognition receptors (PRRs):
Phagocytic cells contain PRRs capable of recognizing various pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) (shown as green structures), which are a group of PRRs, recognize different microbial components, including lipopeptide, flagellin, or peptidoglycan. The PRRs can be found on the plasma membrane or intracellularly.
When a PRR recognizes a PAMP, a signal is sent to the nucleus which activates genes involved in phagocytosis, cellular proliferation, enhanced intracellular killing, and the production and secretion of antiviral interferons and proinflammatory cytokines.

Image: “Pattern recognition receptors” by Nina Parker et al. License: CC BY 4.0

RLRs

  • Located intracellularly (cytoplasmic sensors): recognize the cytoplasm-invading pathogens
  • RIG-I
  • Recognize viral nucleic acids 
  • Activated RLRs increase the synthesis of IFN-α and IFN-β, which increases the response to virus infection.

NLRs

  • Located intracellularly (cytoplasmic sensors): recognize the cytoplasm-invading pathogens
  • Nucleotide-binding oligomerization domain (NOD)
  • Recognize the structures of bacterial peptidoglycans and muramyl dipeptides
  • Involved in host defense against viruses, parasites, fungi, and intracellular bacteria (e.g., Listeria
  • Caspase 1 activation: ↑ proinflammatory cytokines, facilitates pyroptosis or inflammatory cell death
  • Act synergistically with TLRs

CLRs

  • Expressed on the cell surface with an associated transmembrane domain
  • Recognize carbohydrates on microorganisms such as bacteria and fungi:
    • Bacteria and yeasts have mannan on the surface (polysaccharides not found in humans).
    • Mannan-binding lectin (MBL) (also known as mannose-binding protein): 
      • Found in dendritic cells and macrophages binding mannose in microbes
      • Activates complement
      • Opsonin-enhancing phagocytosis
    • Dectin-1: recognizes β-glucan in the fungal cell wall (e.g., Candida)
  • Also responsible for recognizing endogenous proteins from necrotic host cells

Secreted and Circulating PRR

Secreted and circulating PRRs include many proteins (e.g., AMP, lectins, collectins).

AMPs

  • Secreted PRRs: short, positively charged peptides with natural antimicrobial activity 
  • Exhibit activity against bacteria, fungi, viruses, and protozoa
  • Found primarily: 
    • Within granules of neutrophils 
    • In secretions from epithelial cells covering skin and mucosal surfaces
  • Major functions:
    • Cationic AMPs are electrostatically attracted to the negatively charged bacterial surface (with phospholipids).
    • Interaction between peptides and the microbial membrane leads to:
      • Disruption and permeabilization of the microbial membrane
      • Bacterial death
    • AMPs disrupt cellular processes:
      • DNA/RNA/protein synthesis 
      • Enzymatic activity
      • Cell-wall synthesis
    • Immunomodulatory activities:
      • Stimulation of chemotaxis 
      • Regulation of excessive proinflammatory response (e.g., TLR activity, cytokine production) to avoid harm to the host
      • Regulation of commensal microorganisms by restricting colonization and providing defense against opportunistic bacteria

Types of AMPs

  • Defensins:
    • Short peptides with 3 disulfide bonds (protect from protease activity)
    • α-defensins: 
      • Found in neutrophilic granules and intestinal Paneth cells
      • Able to kill microbes directly or indirectly through entrapment in nets
    • β-defensins: 
      • Extensively found in epithelial surfaces (e.g., respiratory tract, GI tract)
      • Trauma or infection increases the production
  • Cathelicidins:
    • LL-37: C-terminal peptide of cathelicidin antimicrobial peptide (CAMP) from neutrophils and epithelial cells induced by vitamin D
    • Play a role in wound healing, angiogenesis, and removal of dead cells
    • Neutralizing activity against LPS
  • Other AMPs:
    • AMPs expressed in the eye: 
      • C-terminal fragments of keratin 
      • Lysozyme 
      • Lactoferrin 
      • Lipocalin 
    • AMPs expressed in the urinary tract: 
      • Lipocalin 2: defends against uropathogenic Escherichia coli 
      • Uromodulin: a protein binding the pili of bacteria, limiting bacterial attachment, and facilitating flushing away by urine
    • Hepcidin:
      • Regulates iron metabolism (dietary iron absorption and distribution)
      • Relevant action against iron-dependent organisms such as malaria, tuberculosis, and HIV-1

Antibacterial oligosaccharides

  • Found in human milk: provides newborn protection
  • Biofilms utilized by bacteria (for protection) are broken down by oligosaccharides.

Lectins

  • Proteins binding to microbial carbohydrates and triggering the lectin complement pathway
  • Examples:
    • Galectin: disrupts bacterial membrane, inhibits influenza virus replication, and brings on cell apoptosis
    • MBL: identifies mannose residues and opsonizes; activates the complement pathway

Collectins

  • A family of lectins with collagen-like proteins 
  • Bind to carbohydrate or lipid microbial molecules
  • Functions: 
    • Complement activation
    • Opsonization
    • Microbial lysis
  • Members of the family include:
    • C1q
    • MBL: a collectin and acute-phase reactant produced by the liver 
    • Surfactant proteins A and D:
      • Produced by alveolar type II cells 
      • Major component of lung surfactant (keeps alveoli open)

Pentraxins

  • Characterized by the C-terminal pentraxin domain with 5 subunits
  • Function: activates the classical pathway of complement with microbial lysis and opsonization
  • The family of proteins includes:
    • CRP: a classic, acute-phase reactant (secreted with TLR activation or as the effect of proinflammatory cytokines)
    • Serum amyloid P (SAP) component: implicated in amyloid deposition disorders such as amyloidosis and Alzheimer disease
    • Pentraxin 3 (PTX 3)

Complement

Immune responses follow the recognition of pathogen molecules. The complement system is 1 response activated in the cascading fashion to destroy microbes.

Complement system

  • A major component of both innate and adaptive immunity
  • Consists of nearly 60 plasma and membrane proteins with activation occurring in both immune cells and extracellular space. 
  • C1q: 
    • A circulating, cell-associated PRR
    • Part of C1: the 1st component of the complement system
    • When bound by an antibody (fixed to a microbe, immune complex, or damaged tissue) → the complement cascade is triggered
  • Activated via different pathways

Activation pathways

Complement activation is through distinctive pathways (all start with a different initiating molecule), but all produce C3b (the central molecule of the complement cascade):

  • Classical pathway (activity assessed by the CH50 test):
    • Triggered by antigen-binding antibodies (primarily IgG and IgM)
    • C1 is C1q in the complex with the 2 proteases: C1r and C1s (C1q + C1r + C1s):
      • The C1q subcomponent attaches to the Fc portion of the antibody.
      • C1r autoactivates and cleaves C1s.
    • C1s cleaves C4 and then C2 → fragments of C4 and C2 (C4b and C2b respectively) → C3 convertase (C4b2b)
    • C3 convertase cleaves C3 and produces C3b (acting as an opsonin) and C3a (acting as an anaphylatoxin).
    • C5 convertases (C4b2b3b) are formed from cleaved components.
    • C5 convertases → cleave C5 → C5a (an anaphylatoxin) and C5b (initiates the membrane attack complex (MAC))
  • Lectin pathway: 
    • Also known as the mannan- and mannose-binding pathway
    • Triggered by lectins (proteins recognizing repetitive patterns of carbohydrates (e.g., mannose, N-acetylglucosamine/GlcNAc))
    • MBL binds to mannose.
    • Leads to cleavage of C4 and C2 by MBL-associated serine proteases (MASPs) (similar to C1s and C1r) → C3 convertase (C4b2b)
    • The cascade proceeds as the classical pathway.
  • Alternative pathway:
    • Antibodies or lectins are not needed to activate.
    • Dependent on the constant presence of C3 at low levels in the circulation (“C3 tickover”)
    • Tickover occurs at a rate of 1% per hour in the blood, with C3 landing on healthy tissue or engaging with pathogens or debris:
      • On healthy tissue, C3 undergoes inactivation.
      • Without a target, C3 is removed from circulation. 
      • C3 becomes activated upon encountering pathogens or cell debris.
    • Activated C3 binds factor B → bound factor B is lysed by factor D → produces Ba (released) and Bb → forms C3 convertase (C3bBb) 
    • C3 convertase (C3bBb) is stabilized by properdin → C3bBbP
    • C3 convertase continues cleaving more C3 to C3b → amplification loop leads to large deposits of C3b on the target
    • C5 convertase is formed (C3bBb3b) and C5 is subsequently cleaved.
  • Effectors produced from activated pathways:  
    • Anaphylatoxins: C3a, C4a, and C5a (C5a also facilitates neutrophil chemotaxis)
    • Opsonin: C3b 
    • MAC: C5b to C5b-9 (cytolysis)
  • Inhibitors regulate complement activation of self cells:
    • Decay-accelerating factor (CD55)
    • C1 inhibitor (C1-INH)
Innate Immune Response

Complement initiation pathways lead to a common terminal pathway:
Grey boxes identify initiation pathways; complement components are identified along the arrows. The classical pathway is activated by antigen-antibody complexes (Ag-Ab complexes) recognized by C1q in complex with C1r and C1s. Proteases C1r and C1s cleave C4 and C2 to generate the classical pathway C3 convertase C4b2b. The lectin pathway is triggered by the binding of mannose-binding lectin (MBL) or ficolins to carbohydrates on the target membrane.
The MBL-associated serine proteases (MASPs) then cleave C4 and C2 generating the C3 convertase C4b2b. The alternative pathway is triggered when the low levels of C3b protein directly bind a microbe, foreign material, or damaged tissue. When C3b binds with factor B, C3bB is formed. Factor B is cleaved by factor D to form an alternative pathway C3-convertase (C3bBb). The convertase is stabilized by properdin. C3b opsonizes targets for phagocytosis and B-cell activation.
All 3 initiation pathways converge on C3 with distinct C3 convertases cleaving C3 to generate anaphylatoxin C3a and more C3b to form the C5 convertases (C4b2a3b and C3bBb3b). C5 convertase then cleaves C5 into C5a and C5b. The anaphylatoxins C3a, C4a, and C5a can attract/activate inflammatory cells and contract smooth muscle through receptors C3aR and C5aR. The membrane attack complex (MAC) forms when C5b binds C6, C7, C8, and multiple copies of C9. Membrane attack complex pores can cause cell death by osmotic flux.

Image: “Complement initiation pathways” by Girardi G. License: CC BY 4.0

Major functions

Ultimately, the complement pathways aim to eliminate microbes and cellular debris/apoptotic cells:

  • Anaphylatoxins (C3a–C5a) cause:
    • Chemotaxis (leading leukocytes to inflammatory sites)
    • Release of mediators (e.g., histamine from mast cells)
    • Activation of nonimmune cell types (including epithelial and endothelial cells)
    • Contraction of smooth muscles
    • Dilation of blood vessels and exudation of plasma/cells
  • Opsonization through identification of foreign materials and damaged self, which facilitates:
    • The immediate killing of the opsonized target
    • Transfer by erythrocytes to tissue macrophages in the liver or spleen
    • Activation of B cells (leading to antigen production and immunologic memory)
  • Cell lysis via the MAC eliminates targets:
    • Disruption of the integrity of cell membrane (via pore-forming proteins)
    • Bacterial cell lysis

Cytokines

Cytokines are soluble proteins released by different cells, which play overlapping roles in innate and adaptive immunity like the complement system.

Major cytokines

  • Target cell actions:
    • Autocrine (target cell is the same cell secreting the cytokine) 
    • Paracrine (nearby target cell)
    • Endocrine (cytokine is secreted into circulation to act on a distant target)
  • General overview of key functions:
    • Inflammatory cytokines in early response to infection (mediating fever and sepsis): 
      • Tumor necrosis factor (TNF)-ɑ
      • Interleukin-1 (IL-1) 
      • Interleukin-6 (IL-6)
    • Chemotaxis: interleukin-8 (IL-8)
    • T-cell proliferation and activation: interleukin-2 (IL-2)
    • Th2 differentiation and proliferation: interleukin-4 (IL-4)
    • B-cell class switching to IgE and IgG: IL-4
    • B-cell class switching to IgA: interleukin-5 (IL-5)
    • Antiinflammatory (attenuates the immune response): interleukin-10 (IL-10), transforming growth factor-β
    • Antiviral (DNA/RNA virus) activity: IFN-ɑ, IFN-β, IFN-ɣ
  • Notable sources:
    • Macrophages secrete: IL-1, IL-6, IL-8, interleukin-12 (IL-12), TNF-ɑ
    • All T cells secrete: IL-2, interleukin-3 (IL-3)
    • Th1 cells secrete: IFN-ɣ
    • Th2 cells secrete: IL-4, IL-5, IL-10

Description of cytokines

Table: Cytokines
CytokinesSourceFunction and activity
IL-1Monocytes, macrophages, B cells, fibroblasts, most epithelial cells
  • Fever, acute inflammation, sepsis
  • Upregulates adhesion molecules
  • Neutrophil recruitment
  • Osteoclast-activating factor
IL-2T cells
  • T cell activation and proliferation
  • NK cell proliferation and activation
IL-3T cells, NK cells, mast cellsHematopoiesis progenitor stimulation
IL-4T cells, mast cells, basophils
  • Th2 differentiation and proliferation
  • B-cell maturation and class switch to IgE and IgG
IL-5T cells, mast cells, eosinophils
  • Eosinophil growth and differentiation
  • B-cell growth, class switch to IgA
IL-6Monocytes, macrophages, B cells, fibroblasts, most epithelial cells
  • Fever, acute phase production
  • T- and B-cell growth
IL-7Bone marrow, thymic epithelial cellsDifferentiation of B cells, T cells, and NK cells
IL-8Monocytes, macrophages, T cells, neutrophils, fibroblasts, endothelial cells, epithelial cells
  • Major neutrophil chemotactic factor
  • Angiogenesis
IL-9T cells
  • Proliferation of mast cells
  • T-cell growth
IL-10Monocytes, macrophages, T cells, B cells, keratinocytes, mast cells
  • Antiinflammatory
  • Attenuation of immune response (↓ cytokines, inhibits T cells and NK cells)
IL-11Bone marrow stromal cells
  • Acute phase production
  • ↑ megakaryocyte formation and maturation
IL-12Activated macrophages, dendritic cells, neutrophils
  • Formation of Th1 cells
  • ↑ IFN-ɣ
IFN-ɣT cells, NK cells
  • Regulates activation of macrophages and NK cells
  • Activates macrophages → granuloma
TNF-ɑMonocytes, macrophages, mast cells, basophils, eosinophils, NK cells, B cells, T cells, fibroblasts, thymic epithelial cells
  • Proinflammatory
  • Capillary leak
  • WBC recruitment and cytotoxicity
  • Cachexia in cancer
Transforming growth factor-βMost cellsAntiinflammatory
Abbreviations:
IL: interleukin
IFN: interferon
NK: natural killer
Th2: type 2 T helper
TNF: tumor necrosis factor
WBC: white blood cell
Note: The list is not exhaustive, but important cytokines are included.

Microbial Killing

After pathogen recognition and recruitment of immune cells (with coordinated help from complements and cytokines), strategies are implemented to eliminate the microbes.

Pathogen elimination

  • Phagocytosis:
    • Phagocytes: macrophages, monocytes, neutrophils, dendritic cells
    • Attachment is either by recognition of PRR or mediated by opsonins. 
    • Engulfment of the pathogen in a vesicle follows
    • The phagocyte forms a pseudopod, which wraps around the pathogen and becomes a pinched-off membrane vesicle (phagosome). 
    • A phagolysosome is formed as the phagosome fuses with a lysosome.
    • Microbial killing mechanisms:
      • Acidification within the phagolysosome is bacteriostatic or bactericidal. 
      • ↓ pH activates pH-dependent, hydrolytic, lysosomal enzymes (digest the pathogen)
      • Antimicrobial peptides
      • Production of toxic nitrogen- and oxygen-derived species (respiratory or oxidative burst)
    • When the pathogen is destroyed, the phagocyte undergoes apoptosis (e.g., pus), or the waste is eliminated by exocytosis.
  • Other elimination strategies (if the pathogen is not engulfed):
    • Large pathogens (e.g., nematode) cannot be ingested:
      • Groups of cells (neutrophils, eosinophils, macrophages) surround the pathogen.
      • Defensins, lysosomal, and other toxic products are released (degranulation) to sufficiently eliminate the pathogen.
    • Immune cells kill the pathogens or infected cells (e.g., neutrophils release neutrophil extracellular traps (NETs), NK cells induce apoptosis).
Innate Immune Response

The stages of phagocytosis: engulfment of a pathogen, formation of a phagosome, digestion of the pathogenic particle in the phagolysosome, expulsion of undigested materials from the cell

Image: “The stages of phagocytosis” by Nina Parker et al. License: CC BY 4.0

Respiratory burst

  • Release of reactive oxygen species (ROS) from various cells (e.g., macrophages, neutrophils)
  • Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase complex reduces O₂ to an oxygen free radical (superoxide anion (O₂•)) and then to hydrogen peroxide (H₂O₂).
  • Neutrophils and monocytes (using myeloperoxidase) combine H₂O₂ with Cl → hypochlorite (HOCl•), which helps to destroy the bacteria
  • Myeloperoxidase contains a heme pigment, which produces a green color in secretions (e.g., mucus and sputum) or pus.
Innate Immune Response

Respiratory burst initiated by the NADPH-oxidase complex:
The phagocyte NADPH-oxidase complex is activated, reducing O2 to an oxygen free radical (superoxide anion (O2)) and then to H2O2. Neutrophils and monocytes (using myeloperoxidase) combine H2O2 with Cl to produce hypochlorite (HOCl•), which helps destroy the bacteria.

Image: “Respiratory burst initiated by NADPH oxidase complex” by Al Maruf A et al. License: CC BY 3.0

Clinical Relevance

  • Hereditary angioedema: caused by deficiency or dysfunction of C1-INH, a protein regulating the classical pathway of complement activation. The condition is characterized by increased levels of bradykinin, which leads to enhanced vascular permeability. Symptoms include recurrent angioedemas (swelling of the face, lips, and tongue). The GI tract may also be involved (nausea, abdominal pain, and vomiting). Diagnosis involves measurement of complement levels (low levels of C4 and decreased levels/functionality of C1-INH). Treatment includes purified, human C1-INH, kallikrein inhibitors, and bradykinin inhibitors. ACE inhibitors are contraindicated.
  • C1q deficiency: a rare disorder characterized by either absent or defective C1q protein. The disorder is caused by mutations in 1 of the 3 genes encoding C1q and has an autosomal-recessive inheritance. In most cases, the disease is associated with systemic lupus erythematosus (SLE). Other clinical manifestations include chronic kidney disease, recurrent skin lesions, chronic infections, and alopecia. Treatment depends on the symptoms. Production of C1q can be restored by allogeneic HSC transplantation. 
  • Terminal complement deficiencies (C5–C9): a genetic condition affecting MAC function. In the United States, deficiencies commonly found involve C5, C6, or C8. Because cell lysis still proceeds with C5–C8, deficiency of C9 causes less severe defects. The deficiency will appear as a low/undetectable CH50 titer. Individuals with terminal complement deficiency are at risk for recurrent Neisseria infections.
  • Chronic granulomatous disease (CGD): a genetic condition characterized by granuloma formation and recurrent, severe bacterial and fungal infections. Defective NADPH oxidase (responsible for the respiratory burst) in neutrophils and macrophages leads to impaired phagocytosis. Infections commonly affect the lungs, skin, lymph nodes, and liver. Dihydrorhodamine (DHR) 123 (a neutrophil function test) is abnormal and genotyping confirms the diagnosis. 
  • Systemic lupus erythematosus: a chronic, autoimmune-inflammatory condition causing immune-complex deposition in organs resulting in systemic manifestations. Features include a malar rash, nondestructive arthritis, nephritis, serositis, cytopenias, thromboembolic disease, seizures, and/or psychosis. Diagnosis is based on clinical findings and tests (e.g., antinuclear antibodies, SLE-specific antibodies). Low C4 and C3 are noted in approximately 50% of cases because immune complexes activate the classical complement pathway. Management aims to control symptoms and prevent organ damage. Treatment options include corticosteroids, hydroxychloroquine, and immunosuppressants.

References

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  3. Haynes, B.F., & Soderberg, K.A., & Fauci, A.S. (2018). Introduction to the immune system. Jameson, J., & Fauci, A.S., & Kasper, D.L., & Hauser, S.L., & Longo, D.L., & Loscalzo, J. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192284326
  4. Johnston, R.B. An overview of the innate immune system. (2021). UptoDate. Retrieved July 7, 2021, from https://www.uptodate.com/contents/an-overview-of-the-innate-immune-system
  5. Liszewski, M.K., Atkinson, J.P. (2021). Inherited disorders of the complement system. UptoDate. Retrieved July 9, 2021, from https://www.uptodate.com/contents/inherited-disorders-of-the-complement-system
  6. Liszewski, M.K., Atkinson, J.P. (2021). Overview and clinical assessment of the complement system. Uptodate. Retrieved July 30, 2021, from https://www.uptodate.com/contents/overview-and-clinical-assessment-of-the-complement-system
  7. Mahlapuu, M., Håkansson, J., Ringstad, L., Björn, C. (2016). Antimicrobial Peptides: An Emerging Category of Therapeutic Agents. Front Cell Infect Microbiol, 27;6:194. https://pubmed.ncbi.nlm.nih.gov/28083516/ 
  8. Pier G.B. (2018). Molecular mechanisms of microbial pathogenesis. Jameson, J., & Fauci, A.S., & Kasper, D.L., & Hauser, S.L., & Longo, D.L., & Loscalzo, J.(Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=183880368
  9. Ryan K.J. (Ed.). (2017). Immune response to infection. Sherris Medical Microbiology, 7e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2268&sectionid=176081453
  10. Riedel, S., Hobden, J.A., Miller, S., Morse, S.A., Mietzner, T.A., Detrick, B., Mitchell, T.G., Sakanari, J.A., Hotez, P., Mejia, R. (Eds.). (2019). Immunology. Jawetz, Melnick, & Adelberg’s Medical Microbiology, 28e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2629&sectionid=217769996
  11. Smole U., Kratzer B., Pickl W.F. (2020). Soluble pattern recognition molecules: Guardians and regulators of homeostasis at airway mucosal surfaces. Eur J Immunol, 50(5):624-642. https://pubmed.ncbi.nlm.nih.gov/32246830/

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