Innate Immunity II Flashcards by Joel Glotfelty

As with many or most immune cells, NK cells can be stimulated for growth and activation by

Cytokines

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Which type of cytokine stimulates growth and activation of NK cells?

IL-12, Type I interferon

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What are the two important substances contained in the granules of NK cells?

Perforin and granzymes

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Facilitates the entry into target cells of other substances from the NK cell

Perforin

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Enzymes that enter the cytoplasm of target cells and initiate signaling cascades leading to cell death by apoptosis

Granzymes

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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

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NK cells can also kill cells with

Intracellular microbes

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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

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Form a surveillance and antigen-capture network in epithelia and subepithelial tissues and in a number of other organs

Dendritic Cells

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The majority of DCs are called “conventional” DCs, and these include the

Langerhans cells in the skin

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Their primary function is to recognize and/or capture antigen, either microbes or free antigens

Conventional DCs

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Have a strong array of TLRs and other pattern-recognition receptors

Conventional DCs

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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

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Set off antigen-specific T cell responses and serving as a key link to the adaptive immune response

Conventional DCs

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A second, more rare, but critical type of dendritic cell is the

Plasmactytoid dendritic cell (pDC)

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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)

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pDCs have high levels of TLRs

3, 7, and 9

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In response, the pDCs turn on very strong production of the anti-viral family of

Type I interfurons (especially IFN-α, and IFN-β)

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These IFNs (in contrast to gamma interferon; IFN-γ) have 2 main effects: (1) they have a direct

Anti-viral effects

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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

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Primarily associated with immunity to multi-cellular parasites and to allergy and asthma, but they are also important for innate immunity

Mast Cells

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They are present in the skin and mucosal epithelium, where they are often found adjacent to the microvasculature and nerves

Mast Cells

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The mast cells have numerous cytoplasmic granules containing inflammatory mediators including

Histamine

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Mast cells also produce lipid mediators, such as

Prostaglandins and cytokines

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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

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