Innate Immunity (Module 2) Flashcards
What is inflammation?
Complex biological response to pathogens, trauma, or chronic illness that is characterized by redness, heat, swelling, pain, and loss of function.
Is inflammation always an indication of infection?
Often yes, but there are also many chronic disease states where inflammation is the result such as arthritis.
What protein fragments released during the complement cascade increase inflammation?
Examples are C3a, C4a, and C5a.
Is inflammation caused by pathogens?
Not directly, but inflammation is a result of the innate immune system preventing damage by that pathogen.
What are the symptoms of inflammation?
Redness, heat, swelling, pain, and loss of function each correlate to a phase of acute inflammation.
What does the cytokine, IL-1 (Interleukin-1) do when released in response to a pathogen?
Interleukin-1 (IL-1) causes capillaries in the immediate area to dilate which triggers endothelial cells to separate and become leaky. This allows blood (plasma, RBC, WBC, and platelets) to pass through into the area of tissue injury from the blood vessel (vasculature).
This creates redness, heat and swelling in the tissue which is not its normal state. The increased fluid pressure on nerve endings causes pain and loss of function.
Phagocytes migrate in from blood vessels and engulf and remove the pathogen.
What are the stages of inflammation?
Table 2-6
Vascular Permeability - vasculature dilates in response to IL-1, hyperemia (blood rushes in), transudation (passage of fluid through membranes) and fibrin plug formation results.
Emigration of Neutrophils - Neutrophils migrate through capillary endothelium to infection site and attach.
Emigration of Macrophages - Monocytes and macrophages travel to the site of infection (4-24 hrs)
Cellular Proliferation and Repair - Cells begin to repair in area (~18 hrs and peak at 48-72 hrs)
What is phagocytosis?
Process where cells internalize particulates, pathogens, dying cells and debris through endocytosis.
What are phagocytes? Name two common phagocytes.
Cells that specialize in phagocytosis.
Macrophages and neutrophils are two of the most efficient cells at removing pathogens via phagocytosis.
What two myeloid cells circulate in the body looking for an infection on a continuous basis as part of the innate immune function?
macrophages and neutrophils
They look for non-self and remove it.
What are the precursor cells for macrophages?
Monocytes
In a normal healthy individual are 3-11% of the total circulating WBC population.
What happens to the monocytes in the blood circulation?
The monocytes then leave the blood and reside in the various body tissues where they change to macrophages but each tissue has a specific name for their macrophages, e.g. in the liver – Kupffer cells, central nervous system - microglial cells.
What do the various macrophages do in the body tissues?
Act as the clean-up crew. Remove anything that is non-self or dying.
Most abundant cell in the body - more than red blood cells and skin.
What is the most abundant white blood cell circulating in a normal healthy individual?
Neutrophils
What word is used to describe neutrophils nucleus’ appearance?
Polymorphonuclear
How do neutrophils get though blood vessels to the area of infection?
Squeeze through blood vessels to infection site by diapedesis.
Neutrophils are ___________ lived than macrophages
shorter
True / False. Neutrophils are programmed to die.
True
What happens to neutrophils after they have engulfed pahtogens?
- Neutrophils will undergo programmed cell death, apoptosis, as a means of containing and preventing infection.
- Macrophages will consume the dead or dying neutrophils (your pus!).
What body part holds reserves of neutrophils?
Large reserves are maintained within the bone marrow and are released in times of infection.
What happens to the neutrophil population circulating in the blood during an infection?
Neutrophil population will increase above the normal reference range 50-70%.
How do macrophages recognize pathogens? (at least one way)
On the surface of macrophages are many receptors that are specific for particular components of pathogens. These receptors on the pathogens are shared among a variety of pathogens so it is still non-specific and part of the innate immunity.
In response to a receptor signal, macrophages release cytokines.
Name some examples of macrophage receptors
Table 2-7
Toll-like Receptor 4 (TLR4) - specific for the bacterial lipopolysaccharide present in gram negative bacterium cell walls.
Complement Receptor 1 (CR1) - binds to C3b
Complement Receptor 3 (CR3) - binds to iC3 fragments
Complement Receptor 4 (CR4) - binds to iC3 fragments
What are the first four of the eight phases of phagocytosis?
First four - extravasation - migration out of blood vessels into infected tissue.
- Adherence - Cytokines cause Weibel-palade bodies (selectins in endothelial cells) to express on the surface as P and E selectins. Glycolipids and glycoproteins on the leukocyte surface then stick to the selectin molecules on the endothelial surface and are guided to the inflamed tissue.
- Locomotion - phagocyte crawls along the surface of endothelium via expressed P and E selectins.
- Diapedesis - Leukocytes (mostly neutrophils) squeeze through the tissue by diapedesis. It forms pseudopods to make it through.
- Chemotaxis - leukocytes are drawn towards the area of pathogen invasion based on the chemical gradient created in the area of inflammation.
In chemotaxis _______ (one example given in text) draws leukocytes to the area of inflammation.
CXCL8
What are the last four of the eight phases of phagocytosis?
- Ingestion - adherence to pathogen
- Increased metabolism - hydrogen peroxide created by hexose monophosphate shunt pathway.
- Degranulation - fusion of intracellular (cytotoxic) granules with pathogen.
- Digestion - pathogen destroyed by enzymatic action in the fused vesicle within the phagocyte.
What does hydrogen peroxide do to bacteria?
Hydrogren peroxide aids in killing bacteria.
What is innate immunity?
It is a series of non-specific defenses against invading pathogens.
What are the main characteristics of innate immunity? (5)
Table 2-1
Prevention - innate immunity acts to prevent infection and removes the pathogen before the individual is even aware.
Non-specific - Protein and cells in the innate immune system remove many varieties of pathogens, and does not target any specific pathogen itself.
Present from birth - you are born with the protein and cells of the innate immune system to fight infection.
Immediate response - Fights as soon as pathogens are discovered and recognized they are “non-self”. Many components of innate immunity are within the various tissues of the body.
No memory - does not possess capability to form memory. Does not adapt to a specific pathogen.
What outer barrier does the body have that is very effective to block pathogens?
Humans have a tough skin barrier that is resistant to most of the challenges the external environment introduces.
What internal barrier does the body have?
Mucus membranes which line the body cavities such as the digestive, respiratory, and reproductive tracts.
What type of cells form these barriers and how does their arrangement assist in providing protection?
Epithelial cells line the human bodies internal and external barriers (skin and mucus membranes). The cell junctions prevent any pathogens from gaining access to our bodies if the skin remains intact (i.e. not cut).
How does the skin provide mechanical protection?
The epidermis of the skin is composed of many layers of epithelium cells; the outer cells can be sloughed off without creating any type of damage or risk to the underlying cells underneath. New cells continue to grow to renew the skins cell layers.
In this way, pathogens are sloughed off with the skin and then to create an infection.
What chemical characteristics of the skin prevent infection from pathogens (5)?
Commensal Organisms - normal flora competes with pathogens for resources
Sebaceous Glands - contains lactic acid and fatty acids which inhibit pathogen growth
Low pH - Many pathogens do not optimally grow in acidic pH
Lysozyme - secreted in tears, degrades cell wall of bacteria
Defensins - Antimicrobial peptides of 35-40 amino acids that mediate killing of microbes
Why is it important to regularly bath and wash your hands?
To remove pathogens on the outer skin surface and slough them off with the top outer epidermis layer.
What makes mucus an efficient first defense against pathogen growth?
- Mucus contains many chemical compounds that inhibit pathogen growth, e.g. glycoprotein, proteoglycans, and enzymes.
- Creates a barrier between the pathogen and the epithelium of the mucus membranes and traps them due to its stickiness.
- Goblet cells in the trachea of the respiratory tract secrete mucus and the nearby ciliated epithelial cells then “beat” the trapped pathogen so that colonization and infection cannot occur.
Name examples of the physical and chemical barriers for the respiratory system? (table 2-3)
Physical includes: - Nose hair - Cilia in upper respiratory tract - Coughing and sneezing Chemical includes: - Mucus
Name examples of the physical and chemical barriers for the gastrointestinal system? (table 2-3)
Physical includes: - Defecation - Vomiting Chemical includes: - Saliva - Lysozyme - Acid pH in stomach - Alkaline pH in intestine
Name examples of the physical and chemical barriers for the urinary system? (table 2-3)
Physical includes:
- Urination
Chemical includes:
Name examples of the physical and chemical barriers for the reproductive system? (table 2-3)
Physical includes:
Chemical includes:
- Acidic vaginal secretion
- Spermine in semen
What are acute phase proteins?
- Acute phase proteins are a series of serum proteins that rapidly change in concentration due to inflammation.
- Produced in the liver by hepatocytes in response to cytokines, which are released in inflamed tissue.
- Quantity of these proteins fluctuate depending on their associated activity.
What does the acute phase protein ‘Alpha 1-Antitrypsin’ do?
Alpha 1-Antitrypsin - binds free neutrophil enzymes to prevent damage to surrounding cells.
What does C-reactive protein CRP (acute phase protein) do?
C-Reactive Protein:
Stimulates the complement cascade.
Rapidly increases (100 - 1000xs) during trauma or inflammation.
What does the complement proteins do (acute phase proteins)?
Complement Proteins, group of plasma proteins that:
- Lyse bacteria
- Encourage pathogen phagocytosis
- Draws phagocytes to area where pathogen is (i.e. chemotaxis)
- Increases inflammation (which further leads to pathogen removal).
What does the acute phase protein ‘Fibrinogen’ do?
Fibrinogen:
Traps pathogens in a clot to prevent their spread, and seals off” area of trauma to allow healing to occur.
What does the acute phase protein ‘Haptoglobin’ do?
Haptoglobin:
Binds free hemoglobin from hemolyzed red cells.
Rapids increase (2-10x’s) during infection/inflammation.
What does the acute phase protein ‘Interferons’ do?
Interferons create an antiviral environment to prevent viral replication.
What does the acute phase protein ‘Mannose Binding Lectin’ do?
Mannose Binding Lectin:
Binds to mannose and other sugars on pathogens surface, to stimulate the complement cascade.
Natural killer cells are what type of cell.
Granular Lymphocytes.
What do natural killers cells do? How do they do it?
- Kill tumor cells
- Kill virally infected cells.
This is done by releasing cytotoxic granules. They also signal to other cells through secretion of cytokines - which affects those cells function/activity.
Are natural killers cells ready to defend the body and why?
Natural killers cells circulate in a partially activated state so that they are quick to respond to a viral invasion.
Natural killers cells do not require previous experience with the virus to remove it.
Why don’t natural killers cells circulate in a fully activated state in the blood?
Natural killer cells could damage normal healthy cells if they were fully activated all the time.
What activates the natural killer cell?
Normally a healthy cell displays a self-antigen on their surface to tell the immune system that they are supposed to be there. But once a cell gets a virus, the self-antigens are mutated and become viral antigens. The natural killer cell recognizes these non-self antigens on the cell surface, bind to the cell via its receptors, which signals the NK cell to become fully activated.
Once a natural killer cell is activated how does it kill the virally infected cell?
The NK cell secretes perforin from its cytotoxic granules which causes holes in the membrane of the virally infected cell. This process leads to apoptosis of infected cell and prevention of viral spread.
After natural killer cells attack some virally infected cells what happens to the surrounding tissue to protect it?
Interferons (IFN’s), molecules, released by cells to mediate protection from viruses. There are three type of interferons:
Type 1
- IFN-alpha - interferes with viral replication and signals to uninfected cells to resist viral invasion.
- IFN-beta - same as above.
Type 2
- IFN-gamma - Activates macrophages and induces proliferation of natural killer cells.
What is the complement cascade (in general)?
A series of plasma proteins that act in a cascade of reactions to attack extracellular pathogens such as bacteria.
Can the complement system remove intracellular pathogens such as viruses?
No, because viruses only invade and replicate within host cells. BUT - instead the complement system results in other helpful outcomes to fight infection.
What are the main outcomes of the complement system? (4)
Inflammation
Chemotaxis
Opsonization
Pathogen Death
What are the inactive form of the complement cascade proteins called? Where are they found?
Zymogens
Found within circulation ready to respond wherever needed.
Approximately how many different complement cascade proteins are there?
Over 30 proteins in the compliment cascade.
What are the three recognized pathways of the complement cascade?
Alternate
Lectin
Classical Pathways
What is the most abundant and important protein of the complement cascade?
C3
What does C3 Convertase cleave?
C3 into
C3a, an anaphylatoxin.
C3b, an opsonin.
What is an anaphylatoxin?
Anaphylatoxin are fragments of complement proteins that result in increased inflammation (e.g. C3a, C4a and C5a)
What is inflammation?
Inflammation is a complex biological response
to pathogens, trauma, or chronic illness that is
characterized by redness, heat, swelling, pain,
and loss of function.
What is chemotaxis?
Chemotaxis is the movement of cells in
response to a chemical gradient.
What is opsonin?
Opsonin:
A molecule that “marks” a pathogen for
removal via phagocytosis (example: C3b).
What is opsonization?
Opsonization is the process by which pathogens
are marked for uptake by phagocytes.
What are phagocytes? (repeat question with another way of saying the answer).
Phagocytes are cells capable of engulfing and
ingesting particulates, pathogens, dying cells,
and debris (referred to as the process of
phagocytosis)
What pathway is first to respond to the pathogen?
Alternate pathway
Why is the alternate pathway the first to respond to a pathogen?
The alternate is activated simply by the pathogens presence.
What pathways follow the alternate pathway?
Lectin, than Classical
Which pathway can be activated by both the innate immune system and adaptive immune system?
Classical pathway - which is activated by both C-reactive protein (acute phase protein of innate immunity) and/or antibodies (adaptive immunity).
What complement protein do the alternate, lectin, and classical pathways all use? and outcomes ended with?
C3
Outcomes: Inflammation, chemotaxis, opsonization, and pathogen death.
What activates the alternate pathway?
The alternate pathway is activated by various components of a pathogen, such as: bacterial cell
wall, fungal cell wall, lipopolysaccharides, viral capsid, etc. The body is capable of recognizing that the
pathogen is non-self, and therefore initiates the alternate pathway as a means of its removal.
What happens to C3 in the alternate pathway?
C3 undergoes spontaneous process of hydrolysis.
C3 becomes iC3 (or C3 (H2O))
iC3 will then bind with factor B, which can get cleaved by factor D.
Result: iC3Bb bound to pathogen surface and a Ba fragment which is released.
iC3Bb will then continuously convert C3 into C3a and C3b. C3b will become
attached to the pathogen surface as an opsonin and C3a will act as an anaphylatoxin. This process will
occur over and over again, rapidly coating the pathogen and increasing inflammation in the area the
pathogen is invading.
What is another term for iC3Bb and what does it do in the alternate pathway?
C3 Convertase - a molecule that cleaves C3 into C3a and C3b.
How is the lectin pathway activated?
MBL (mannose binding lectin) binds to mannose containing carbohydrates on the surface of proteins. Then this protein is coupled with associated serine protease to become MBL-MASP (Mannose binding lection -associated serine protease). This protease will act on subsequent proteins and will meet up with the classical pathway at the C4 and C2 proteins.
How many different proteins make up the classical pathway?
9
C1 to C9
What are the three stages of the classical pathway?
- Recognition
- Activation
- Creation of the Membrane Attach Complex (MAC)
The complement protein C1 is composed of these three components and forms what?
C1 composed of C1q, C1r, and C1s which forms C1qrs.
In the classical pathway, what does C1qrs do?
C1qrs is a protease that cleaves C4 and C2 that are in close proximity to calcium ions.
C4 –> C4a (anaphylatoxin) and C4b which becomes bound to pathogen surface.
C2 –> C2a becomes bound to pathogen surface and C2b which is released.
What is different about C2a in the classical pathway?
C2a is the only “a” fragment that remains bound to the pathogen’s surface instead of becoming an anaphylatoxin.
What do C4b and C2a combine together make in the classical pathway?
C4b2a, a C3 Convertase
What does C3 convertase do in the classical pathway?
C3 Convertase acts on C3 in the vicinity and cleaves it into C3a, an anaphylatoxin and C3b, an opsonin.
How is C5 Convertase formed in the classical pathway?
If C3b is close enough in the area to C4b2a then it will combined with it forming C4b2a3b, a C5 Convertase. C5 Convertase cleaves C5 into C5a, an anaphylatoxin and C5b.
How is a MAC form and what does it stand for?
MAC = Membrane Attack Complex.
C5b from C5 Convertase (after cleaving C5) combines with C6, C7, C8 and C9 to form the Membrane Attack Complex (MAC).
What does the MAC, membrane attack complex do?
The membrane attach complex creates a pore on the pathogen surface, which disturbs the osmotic balance of the pathogen resulting in its cell death. After that cell lysis, the MAC can attach to other nearby pathogens and kill them too.
