INNATE IMMUNITY
Innate immunity: defences against infection prior to the attack by an antigen.
Includes physical, chemical, and cellular barriers
• Physical-skin, mucous membranes
• Chemical- acidity of stomach
• Specialized immune cells- Some white blood cell types (macrophages and
neutrophils) are activated to rapidly engulf and destroy extracellular
microbes through the process of phagocytosis.
Anatomical barriers
External barriers: Skin and mucous membranes (mucosal epithelia that line the
respiratory, gastrointestinal, and urogenital tracts)
The skin, the outermost physical barrier, consists of two distinct layers: a thin outer
layer, the epidermis, and a thicker layer, the dermis.
The epidermis contains several tiers of tightly packed epithelial cells; its outer layer
consists of mostly dead cells filled with a waterproofing protein called keratin.
The dermis is composed of connective tissue and contains blood vessels, hair
follicles, sebaceous glands, sweat glands, and scattered myeloid leukocytes such as
dendritic cells, macrophages, and mast cells.
A number of nonspecific physical and chemical defense mechanisms also contribute to
preventing the entry of pathogens through the epithelia of secretory tissues. For example,
the secretions of these tissues (mucus, urine, saliva, tears, and milk) wash away potential
invaders and also contain antibacterial and antiviral substances. Mucus, the viscous fluid
secreted by specialized cells of the mucosal epithelial layers, entraps foreign
microorganisms.
In the lower respiratory tract, cilia, hairlike protrusions of the cell membrane, cover the
epithelial cells. The synchronous movement of cilia propels mucus-entrapped
microorganisms from these tracts. Coughing is a mechanical response that helps us get rid
of excess mucus, with trapped microorganisms, that occurs in many respiratory infections.
The flow of urine sweeps many bacteria from the urinary tract.
With every meal, we ingest huge numbers of microorganisms, but they must run a gauntlet
of defenses in the gastrointestinal tract that begins with the antimicrobial compounds in
saliva (lysozyme, lactoferrin, secretory immunoglobulin A (sIgA), histatins, defensins,
cathelicidins, peroxidase, and statherin) and in the epithelia of the mouth and includes the
hostile mix of digestive enzymes and acid found in the stomach.
Similarly, the acidic pH of vaginal secretions is important in providing protection against
bacterial and fungal pathogens.
To provide strong defense at these barrier layers, epithelial cells secrete a broad spectrum
of proteins and peptides that provide protection against pathogens.
Among the antimicrobial proteins produced by the skin and other epithelia in humans,
several are enzymes and binding proteins that kill or inhibit growth of bacterial and fungal
cells.
Lysozyme is an enzyme found in saliva, tears, and fluids of the respiratory tract-cleaves the
peptidoglycan components of bacterial cell walls.
Lactoferrin and calprotectin are two proteins that bind and sequester metal ions needed
by bacteria and fungi, limiting their growth.
Among the many antibacterial agents produced by human skin, recent research has
identified psoriasin, a small protein of the S-100 family with potent antibacterial activity
against Escherichia coli, an enteric (intestinal) bacterial species.
Despite the strong defenses of our protective epithelial layers, some pathogens have
evolved strategies to penetrate these defenses, and epithelia may be disrupted by wounds,
abrasions, and insect bites that may transmit pathogens. Once pathogens penetrate
through the epithelial barrier layers into the tissue spaces of the body, an array of cellular
membrane receptors and soluble proteins that recognize microbial components play the
essential roles of detecting the pathogen and triggering effective defenses against it.
Phagocytic cells make up the next line of defense against pathogens that have penetrated
the epithelial cell barriers. Macrophages, neutrophils, and dendritic cells in tissues and
monocytes in the blood are the main cell types that carry out phagocytosis—the cellular
uptake (eating) of particulate materials such as bacteria—a key mechanism for eliminating
pathogens.
Through various cell surface receptors macrophages recognize microbes such as bacteria,
extend their plasma membrane to engulf them, and internalize them in phagosomes
(endosomes resulting from phagocytosis). Lysosomes then fuse with the phagosomes,
delivering agents that kill and degrade the microbes.
Neutrophils are a second major type of phagocyte, usually recruited to sites of infection.
Finally, dendritic cells also can bind and phagocytose microbes. Uptake and degradation of
microbes by dendritic cells play key roles in the initiation of adaptive immune responses.
In addition to triggering phagocytosis, various receptors on phagocytes recognize microbes
and activate the production of a variety of molecules that contribute in other ways to
eliminating infection
Phagocytes express on their surfaces a variety of receptors, some of which directly recognize
specific conserved molecular components on the surfaces of microbes, such as cell wall
components of bacteria and fungi.
These conserved motifs, usually present in many copies on the surface of a bacterium,
fungal cell, parasite, or virus particle, are called pathogen-associated molecular patterns
(PAMPs). Note that they can be expressed by microbes whether or not the microbes are
pathogenic; hence, some researchers have started to use the more general term microbe-
associated molecular patterns (MAMPs).
The receptors that recognize PAMPs are called pattern recognition receptors (PRRs).
Most PAMPs that induce phagocytosis are cell wall components, including complex
carbohydrates such as mannans and β-glucans, lipopolysaccharides (LPS), other lipid-
containing molecules, peptidoglycans, and surface proteins.
Activation of phagocytosis can also occur indirectly, by phagocyte recognition of soluble
proteins that have bound to microbial surfaces, thus enhancing phagocytosis, a process
called opsonization (from the Greek word for “to make tasty”). Many of these soluble
phagocytosis-enhancing proteins (called opsonins) also bind to conserved, repeating
components on the surfaces of microbes such as carbohydrate structures,
lipopolysaccharides, and viral proteins; hence, they are sometimes referred to as soluble
pattern-recognition proteins. Once bound to microbe surfaces, opsonins are recognized by
membrane opsonin receptors on phagocytes, activating phagocytosis
Macrophage phagocytosis of dead, dying, and aging cells
Collectively the components of dead/dying cells and damaged tissues that are
recognized by PRRs leading to their clearance are sometimes referred to as damage-
associated molecular patterns (DAMPs).
Apoptotic cells attract phagocytes by releasing the lipid mediator lysophosphatidic acid,
which functions as a chemoattractant. These dying cells facilitate their own
phagocytosis by expressing on their surfaces an array of molecules not expressed on
healthy cells, including phospholipids (such as phosphatidyl serine and
lysophosphatidyl choline), proteins (annexin I), and altered carbohydrates. These
DAMPs are recognized directly by phagocytic receptors
Toll-like receptors (TLRs) were the first family of PRRs to be discovered and are still the
best-characterized in terms of their structure, how they bind PAMPs and activate cells, and
the extensive and varied set of innate immune responses that they induce.
TLRs are membrane-spanning proteins that share a common structural element in their
extracellular region called leucine-rich repeats (LRRs); multiple LRRs make up the
horseshoe-shaped extracellular ligand-binding domain of the TLR polypeptide chain. When
TLRs bind their PAMP or DAMP ligands via their extracellular LRR domains, they are induced
to dimerize.
TLRs exist both on the plasma membrane and in the membranes of endosomes and
lysosomes. TLRs that recognize PAMPs on the outer surface of extracellular microbes are
found on the plasma membrane, where they can bind these PAMPs and induce responses.
In contrast, TLRs that recognize internal microbial components that have to be exposed by
the dismantling or degradation of endocytosed pathogens— nucleic acids in particular—are
found in endosomes and lysosomes.
In addition to microbial ligands, TLRs also recognize DAMPs, endogenous (self) components
released by dead/ dying cells or damaged tissues.
