Innate Immunity II Flashcards
As with many or most immune cells, NK cells can be stimulated for growth and activation by
Cytokines
Which type of cytokine stimulates growth and activation of NK cells?
IL-12, Type I interferon
What are the two important substances contained in the granules of NK cells?
Perforin and granzymes
Facilitates the entry into target cells of other substances from the NK cell
Perforin
Enzymes that enter the cytoplasm of target cells and initiate signaling cascades leading to cell death by apoptosis
Granzymes
Thus, NK cells have several primary roles: in the early phases of a viral infection, before there are virus-specific CTLs, NK cells can
Kill virus-infected cells
NK cells can also kill cells with
Intracellular microbes
Released by activated NK cells activates macrophages for more efficient phagocytosis and killing of bacteria or intracellular targets such as cells carrying intracellular pathogens, such as Listeria monocytogenes
IFN-γ
Form a surveillance and antigen-capture network in epithelia and subepithelial tissues and in a number of other organs
Dendritic Cells
The majority of DCs are called “conventional” DCs, and these include the
Langerhans cells in the skin
Their primary function is to recognize and/or capture antigen, either microbes or free antigens
Conventional DCs
Have a strong array of TLRs and other pattern-recognition receptors
Conventional DCs
After recognizing and capturing antigens, DCs have which 2 major effects?
- ) Produce pro-inflammatory cytokines
2. ) Travel to lymph nodes to present antigen to T cells
Set off antigen-specific T cell responses and serving as a key link to the adaptive immune response
Conventional DCs
A second, more rare, but critical type of dendritic cell is the
Plasmactytoid dendritic cell (pDC)
These cells specifically have high levels of TLR 3, 7 and 9 in the endosome, whereby they can respond with great sensitivity to single- and double-stranded RNA, and also to DNA, which are characteristic of viruses
Plasmactytoid dendritic cell (pDC)
pDCs have high levels of TLRs
3, 7, and 9
In response, the pDCs turn on very strong production of the anti-viral family of
Type I interfurons (especially IFN-α, and IFN-β)
These IFNs (in contrast to gamma interferon; IFN-γ) have 2 main effects: (1) they have a direct
Anti-viral effects
Also, these Type I interferons modulate a host of cellular reactions by cells of the immune system, making the Type I IFNs an important link between
Innate and adaptive immunity
Primarily associated with immunity to multi-cellular parasites and to allergy and asthma, but they are also important for innate immunity
Mast Cells
They are present in the skin and mucosal epithelium, where they are often found adjacent to the microvasculature and nerves
Mast Cells
The mast cells have numerous cytoplasmic granules containing inflammatory mediators including
Histamine
Mast cells also produce lipid mediators, such as
Prostaglandins and cytokines
Mast cells contain a number of pathogen recognition receptors, including most
TLRs
Mast cells contain a number of pathogen recognition receptors, including most TLRs, which can be stimulated by their ligands in vitro to induce
Degranulation and cytokine release
The location of mast cells, and the presence of important PRRs suggests an important role in
Innate immunity
Recognition molecules critical to innate immunity are also found in the serum and in tissues, and help
Tag or destroy molecules
Recognition molecules bind to microbes, acting as
Opsonins
This enhances their recognition by cellular receptors on macrophages, neutrophils and dendritic cells because these cells have receptors for these
Opsonins
May initiate or promote inflammatory responses that attract phagocytes, and/or they may participate directly in killing of pathogens
Soluble recognition molecules
Perhaps the best known and most important soluble recognition and effector molecules are those of the
Complement system
This system is composed of roughly 20 proteins in normal human serum, most of which are produced in the liver
Complement proteins
Functions in defense against pathogens, and functions in homeostasis, particularly recognizing damaged or apoptotic cells or their components and helping dispose of them without triggering inflammation
Complement system
Functions to opsonize (coat) and tag microbes for phagocytosis and killing
Complement system
The complement system mobilizes and recruits phagocytes to the site of
Infection
In some cases, the complement system functions to directly kill
Pathogens
What are the three pathways to trigger the cascade of reactions of the complement system?
-Once triggered, converge to a common pathway
Classical, alternative, and lectin pathways
The “classical pathway”, so-called because it was the first pathway recognized and described, is initiated by
Antibody binding to pathogen
Because it involves antigen-specific antibodies, it is often considered part of adaptive immunity
Classical pathway
The alternative and lectin pathways do not depend on pathogen-specific
Antibodies
The 3 pathways differ primarily in their early events, but then connect through the critical protein
C3
Is always going on, because it begins with the spontaneous hydrolysis of complement protein C3, which is present in high concentrations in serum (and in tissue)
Alternative tissue
The C3 products are
C3a and C3b
Highly reactive (and very short-lived), and can react with and covalently bind to bacterial or fungal polysaccharides or proteins
C3b
If no targets of active C3b are nearby, the reactive group on C3b quickly hydrolyzes and the C3b becomes
Inactive
However, C3b bound to cells binds another serum protein called
Factor B
Cleaved by a plasma protease to form a “Bb” fragment, so there is now a C3bBb complex on the bacterial surface
Factor B
This creates a powerful amplification of both the amount of protease activity to activate C3, and also to “decorate” or tag the bacteria or other targets with a lot of complement, particularly
C3b
With multiple C3b molecules attached, the cells become targets for
Phagocytes
Opsinizes pathogens
C3b
Some membrane-bound C3bBb complexes can bind a 2nd molecule of C3b, changing its proteolytic specificity so it becomes a
C5 convertase
Can cleave C5, producing the fragments C5b and C5a
C5 convertase
The larger C5b piece can stick to the cell surface and recruit components (C6, 7, 8 and 9; this is known as the
Membrane attack complex (MAC)
This forms a pore in some cells, and may be capable of lysing some cells, particularly bacteria of the
Neisseria genus (species of which can cause meningitis or gonorrhea)
The cleavage of both C3 and then C5 (and C4 in the other pathways) releases the smaller, soluble protein fragments
C5a and C3b
In response, many inflammatory cells chemotax toward the site of infection, and may be activated for
Inflammation
The fragments can also cause degranulation of mast cells, releasing “inflammatory mediators”, including
Histamine and leukotrines
Have critical effects in acute inflammation
Leukotrines
If complement is extensively activated in the bloodstream, large amounts of C3a/C5a are produced, and a large number of mast cells will be stimulated
Degranulate
These may release sufficient inflammatory mediators to produce systemic vasodilation, loss of blood pressure, and shock, i.e., anaphylaxis, so that these fragments are called
Anaphylatoxins
Takes advantage of the fact that carbohydrates on the surface of healthy human cells may differ from those on pathogens
Lectin pathway
The best known example of the initiation of the Lectin pathway is when
Mannan-Binding Lectin (MBL) recognizes terminal glycolipids and glycoproteins on bacteria or fungi
After MBL binds to the bacterial (or fungal) sugar on the bacterium, it recruits specific proteases (“MBL-associated serine proteases”; MASPs) that then cleave proteins
C4 and C2
This produces cell-bound
C4b2a, a second C3 “convertase”
Cleaves C3 to C3b and C3a
C4b2a
Some of the C3b can join bind to the C4b2a to form a C5 convertase, analogous to that of the alternative pathway, leading to the same outcomes as from the
Alternative pathway
As mentioned above, the “classical pathway” relies on an antigen-specific antibody that recognizes and binds to an antigen of the pathogen. The bound antibody is then recognized by
Complement C1
Subunits of complement C1 cleave C4 and C2, creating
C3 convertase
Some of cleaved C3b binds to C4bC2a to form the
C5 convertase
An example of extending the older complement system of innate immunity and coupling it to antibodies, produced by the B cells of adaptive responses
Classical pathway
Because of the requirement for pathogen-specific antibodies, this pathway is generally engaged only on repeated or prolonged encounter with a pathogen, when specific antibodies have been produced
Classical Pathway
Can produce increased susceptibility to bacterial infections, particularly early in life
C3 deficiency
Variable from asymptomatic to increased susceptibility to bacterial infection. Can be associated with systemic lupus erythematosus
C2 and C4 deficiency
Increased susceptibility to Neisseria
C9 deficiency
Increased complement activation → Reduced levels of C3 (“depletion”) → increased infection.
Factor I or Factor H deficiency
Complement also serves an important role in helping to clear complexes of
Antigen and antibody
Have complement receptors and bind circulating immune complexes
Erythrocytes
The complexes bound to red cells are phagocytosed and destroyed by macrophages in the
Liver and spleen
Alternatively, if the complexes reach lymph nodes and are trapped by dendritic cells, this is a potent stimulus to an
Immune response
Persons genetically defective in early components of complement (C1 through C3) have an elevated frequency of
Autoimmune disease
Antibody-antigen complexes (“immune complexes”) lodged in tissue create damage by
Complement activation
A major target of such damage, since it filters these complexes from blood
The kidney
In autoimmune disease, because a component of the body is the antigen, immune complexes are
Continuously formed
Ongoing or very high level deposition of an antigen-antibody complex, can lead to high levels of complement recognition and activation, leading to cellular damage, thereby contributing to life-threatening
Kidney Damage
There are other soluble recognition and effector molecules. One important family is the
Pentraxins
Include some of the proteins that are produced during inflammation, called acute-phase proteins, or acute-phase reactants
Pentraxins
What are two examples of pentraxins?
C-reactive protein (CRP) and serum amyloid protein (SAP)
These can activate complement C1, feeding into the complement pathway
CRP and SAP
In addition, these proteins, particular CRP sometimes serve diagnostically as important “biomarkers” for
Inflammation
Proteins that act as signals with the immune system (and some also during development and other processes)
Cytokines
In the pro-inflammatory pathways, the major cytokines are
TNF-α, IL-1, and IL-6
During viral infections, the main signal released are
Type I and Type III interferons
The major outcomes of activating the components of innate immunity are either an
Inflammatory response or an immune response
Includes the recruitment of leukocytes, and the phagocytosis and killing of microbes by activated phagocytes, as well as stimulating elements of adaptive immunity to both produce a stronger response and initiate immunological memory
Inflammatory Response
Depends on the production of Type I and Type III interferons (primarily IFN-αs and IFN-β) by cells infected by virus
Antiviral response
Is NOT a Type I IFN, does not have a major role in the antiviral response, is produced under different conditions and has distinct biological activities
Gamma interferon, IFN-γ
Can activate almost all nucleated cells
Type I IFNs
Primarily promote antiviral responses on epithelial cells of mucosal tissue, which are a common sites of virus invasion
Type III IFNs
All nucleated mammalian cells can respond to viruses through their various
PRRs
