Innate Immunity

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Innate Immune Response

The first line of defense comprises physical and chemical barriers that prevent pathogen entry into the body.

The second line of defense comprises the internal cells, complement system and other circulating proteins, and pathogen recognition receptors.

Some participants of the innate immune system also activate the adaptive arm of the immune system: – Some pathogen receptors trigger B and T cell responses of the adaptive system; the toll-like receptors are especially important. – Dendritic cells and macrophages present antigens to T cells, which then participate in the cellular response to pathogens; thus, dendritic cells and macrophages are called "Antigen presenting cells."

1st Line of Defense

Physical Barriers Keratinized squamous epithelia of the skin physically prohibits entry into the body.

Chemical Barriers Low surface pH of the skin, vagina, and stomach; this barrier in the skin is referred to as the acid mantle. Mucus creates another type of chemical barrier. It is secreted by goblet cells, and comprises antimicrobial lysozymes and sticky mucin that traps microbes and prevents binding to host cells.

When physical and chemical barriers are breached, internal defenses activate.

2nd Line of Defense - Internal

Cellular Defenses

Leukocytes Neutrophils and macrophages are phagocytic cells that engulf and destroy microbes; recall that they are early responders in the acute inflammatory response.

Eosinophils and mast cells, release pro-inflammatory molecules, such as histamine.

Natural killer cells Often considered a specialized lymphocyte; these cytotoxic cells are regulated via inhibitory and activating signals.

Healthy cells display MHC I, which inhibits the natural killer cell; also, the natural killer cell's activator receptor is unbound.

Virus-infected cells have diminished expression of MHC I molecules; also, NK activation receptor is stimulated, which results in destruction of the infected cell.

Dendritic cells Bind with antigen and trigger cytokine release; recall that cytokines mediate the inflammatory response.

Complement System

Destroys microbes via proteins C3a and C3b, which are inactive proteins that circulate in the blood. The products of C3 cleavage (C3a and C3b) have multifold functions.

Three pathways lead to C3 cleavage: Classical pathway: C1 is "fixed" to antibody-antigen complexes, which initiates a cascade of events that lead to C3 cleavage.

Alternative pathway: Triggered by spontaneously activated C3b.

Lectin pathway: Triggered when lectins, such as, mannose-binding lectin, binds microbial sugars and marks them for phagocytosis.

Effects of cleaved C3: C3a has pro-inflammatory effects; it recruits neutrophils and macrophages. C3b opsonizes microbes, which involves binding pathogens and marking them for phagocytosis. Membrane Attack Complexes (MAC): C3b combines with other complement proteins (C5b, C6, C7, C8, and C9) to form a pore in the membrane of the microbe; massive water influx through the MAC lyses the microbe.

Circulating proteins with antimicrobial effects

Defensins are positively charged peptides that insert pores into microbe membranes and trigger lysis. Defensins are particularly active in the GI and respiratory tracts (be aware that some authors include defensins as part of the first line immune defenses, too).

Interferons are antiviral proteins that inhibit virus replication and activate natural killer cells to enhance destruction of infected cells.

Acute-phase proteins promote opsonization and/or activate the complement system. The liver is a major source of these proteins, which include: C-reactive protein, serum amyloid A, and the collectins.

Some important examples of collectins are pulmonary surfactant proteins that fight pathogens in the lungs, and mannose-binding lectin, which, as we learned, can activate the complement system.

Pathogen recognition receptors (PRRs)

We address these individually, but be aware that they often coordinate to effectively eradicate pathogens.

Toll-like receptors sense a wide variety of pathogens, including bacteria, myocbacteria, viruses, and fungi. They are present in both cellular and endosomal membranes. Upon stimulation, they trigger the release of pro-inflammatory cytokines and interferons.

NOD-like receptors (Nucleotide-binding Oligomerization Domain-like) are cytosolic sensors that also respond to diverse stimuli: Some NOD-like receptors recognize bacterial wall peptidoglycans and trigger pro-inflammatory cytokine release. Some NOD-like receptors respond to microbial and non-microbial materials via inflammasomes, which are protein complexes that can trigger cell death and recruit pro-inflammatory cells.

RIG-like receptors trigger interferon release in response to viral RNA.

Cytosolic DNA sensors induce interferon release in response to DNA from damaged cells.

Innate Immunity

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