revised: 9/27/04 AM. Chapter 2: Innate Immunity. Innate immunity is germline encode (you are born with it ready to go) It has made the self/nonself discrimination on an evolutionary time-scale It uses few receptors that recognize features common to many microorganisms
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revised: 9/27/04 AM
Chapter 2: Innate Immunity
Therefore, parts of it are always active or can be activated quickly
Innate immunity is the first line of defense. Without innate immunity nearly every microorganism would be pathogenic
Most surface epithelia are constantly exposed to microorganisms. Many microorganisms grow on these surfaces (e.g., skin, gut) or must cross an epithelial barrier (skin, gut, respiratory) to enter the body.
Lots of macrophages in the liver, lungs, spleen and near epithelial surfaces
phagocytes = neutrophils and macrophages
Mucus prevents attachment; tears, saliva wash away microorganisms
Skin provides a physical/chemical barrier to invasion (thick, tough, dry, acidic, toxic)
Also, macrophages may release toxic molecules including reactive oxygen species, nitric oxide and other (see figure 2.6)
Cytokine activate macrophage, dendritic cells and cause inflammation
Inflammation induced when macrophages bind bacteria products:
1. Delivers effector cells to the site of the infection and augments macrophages that are already there
2. Creates a barrier to the spread of the microorganisms (captures microorganisms, blood clot prevents microorganisms from entering the circulation)
3. Repairs the damage
The macrophages’ affects on endothelial cells (the cells that line the blood vessels and largely control inflammation by controlling the flow of cells and fluids out of the post-capillary venules) result form release of prostaglandins, leukotrienes and cytokines such as IL-1 and tumor necrosis factor-a (TNF).
Blood coagulation stops bleeding and prevents pathogens from entering the circulation.
Agents produced by phagocytes (macrophages and/or neutrophils) upon bacterial stimulation
Macrophages that bind bacterial products (and other stuff) release cytokines* that cause inflammation (heat, redness, swelling and pain).
This first delivers neutrophils and blood proteins (such as complement and immunoglobulins), then, hours later, other inflammatory cells (monocytes, as well as B and T cells) and more blood proteins to augment the macrophages already there.
Blood clots stop bleeding, trap microorganisms, keep microorganisms from entering the circulation
*including prostaglandins, leukotrienes, TNF (these have big effects on endothelial cells and affect trafficking of cells out of the blood and into the lymphatics).
The Complement System
Discovered as a heat-labile antibacterial substance in immune serum
non immune (normal) serum……………
heated* immune serum………………….
heated immune serum plusnon-immune serum………………….
*560C for 30 minutes or 600C for 5 minutes
Conclusion: Two components are needed for bacterial inactivation: a heat-stable immune component (antibody) and a heat-labile non immune component (complement). (there is something in normal serum that complements immune serum)
The complement system is comprised of many proteins that react with each other and with other compounds to
1. Opsonize (make stuff easily phagocytized)
2. Kill cells
3. Induce inflammationvasoactive, chemoattractant, phagocyte activator
Complement activation results in an enzyme cascade* that amplifies the response and thus requires tight regulation
*one enzyme activates a second enzyme and the second enzyme activate a third enzyme and ….
Three pathways to activate complement
C3 convertase is an enzyme that activates C3
C3 C3a +C3b
Several components are activated by cleavage into two pieces; a small piece designated with an “a” and a big piece designated with a “b.” For example, C3 C3a + C3b.C3 is inactive but C3a and C3b are both active.
Initiation of the classical pathway is with C1
C1 is activated by antibody ( this will be dealt with later) and can be activated by itself on the surface of certain bacteria
Binding of two of the C1q heads to the surface of a bacteria activate C1r to cleave and activate C1s
C3 C3a + C3b
C2 C2a + C2b
C4 C4a + C4b
C4b are C2b combined to form C4b2b
C4b2b is a C3 convertase (there are others)
Mannan-binding lectin (MBL) is similar to C1 but it binds to mannose then activates C4 and C2.
MB-lectin pathway is particularly important in children that do not have much antibody
C3b is quickly inactivated in solution but is stabilized when it binds to bacteria surfaces
The Alternative Pathway of Complement activation
For C3, there is spontaneous cleavage or tickover that occurs whether bacteria are presence or absent
C3b binds to factor B, factor B is cleaved by Factor D. The C3bBb is a C3 convertase so it makes more C3b
C3b is an opsonin
C3 convertase makes C3b. C3b binds to factor B; factor B is cleaved by Factor D. The resultant C3bBb is a C3 convertase.
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C4b2b and C3bBb are C3 convertases but if you add another C3b then:
C4b2b3b and C3b2Bb are C5 convertases
C5 C5a + C5b
Distribution and function of complement receptors
stimulates phagocytosis = opsonization
Activates cells by triggering intracellular signals
Sometimes complement-mediated opsonization requires activation of the phagocye
(C3a, C4a, C5a)
Anaphylactic shock can be caused by systemic distribution of anaphylatoxins and mast cell degranulation
anaphylotoxins cause mast cell degranulation
Terminal complement components and the formation of the membrane attack complex
Receptors of innate immunity
Induce production/activation of other signaling molecules (e.g., cause cytokine production and secretion)
MB lectin binds patterns of mannan
Scavenger receptor binds certain charged particles (anionic polymers)
LPS-binding protein (LBP) bind LPS and CD14 (see next slide)
Adjuvants are compounds that enhance the adaptive immune response when mixed with antigens. Some work by inducing expression of co-stimulators such as CD80/CD86
Co-stimulators CD80 and CD86 also known as B7.1 and B7 .2
Induced Innate Responses to Infection
Cytokines are proteins or peptides. They might act on the cell that made them, on neighbors or on distant cells
The same compounds are involved in adaptive immune responses (TH1) but probably more
Small chemoattractant proteins that stimulate migration and activation of lymphocytes and phagocytes
Q: How do chemokines, cytokines and other molecule affect cell migration (trafficking)?
A: By affecting expression of adhesion molecules
Adhesion Molecules Direct Trafficking (these are not receptors, why?)
Intercellular adhesion molecule (ICAM)
Extravasation (the whole process)
During the first 6 hours of an typical inflammatory response, mostly neutrophils leave the blood. After that, large numbers of monocytes (macrophages) and other mononuclear cells also enter the tissue.
Locally, TNF can cause inflammation
Systemically, high doses of TNF can cause septic shock and death
Chronic systemic TNF (sometimes associated with cancer or other diseases) can lead to cachexia
Systemic affects of Macrophage-produced cytokines
IL-6 induces synthesis of acute-phase proteins in the liver
These actions mostly prepare non-infected cells to resist infection
Ribonuclease activityProtein synthesis inhibition
Interferon- a and Interferon-b
Most cells can make IFN-a and IFN-b in response to virus [i.e., double stranded RNA (dsRNA)]
Q: why increase expression of MHC class I?
Later we will see that interferon-g is made by TH1 cells and activates macrophages
NK cells kill cells that have low levels of MHC class I on their surface
Natural killer (NK) cells
Q: why is that a good idea?
Q: why do interferons a and b attempt to increase MHC class I on virus-infected cells and increase NK activity?
Certain defense mechanism seem to fall between innate and adaptive immunity. They use an immunoglobulin or a TCR to bind antigens but they have limited repertoires that appears to be germline encoded. These include:
1. A subset of T cells called gd T cells (mostly in skin and near epithelial surfaces)
2. CD5+ B cells (i.e., B-1 B cells)(mostly in the peritoneum)
3. Natural antibodies