1. Host Defenses Against Pathogens
Innate immune responses:
Occur early after infection
Are not specific for the invading pathogen
Do not induce memory
Include cytokines (esp. interferon) and natural killer cells
Adaptive immune responses
Require time to develop
Are specific for the invading pathogen
Give rise to immunological memory, making vaccination possible
Two arms: B cells (humoral immunity) and T cells (cellular immunity)

3. Cytokines and Chemokines
The cytokines are a family of >30 signaling proteins
They are secreted by many cells and have important regulatory roles
They play a very important role in regulating the immune system
They are components of both the innate and adaptive systems
They include the IFNs, many interleukins, TNF, among others
Most are about 30 kDa in size
The chemokines are a family of >30 small proteins, aa in length
Some are constitutive, others are induced
Some are proinflammatory
They attract leukocytes and serve to maintain, e.g., lymph nodes, to attract immune cells to sites of inflammation, and other roles

4. Interferons
There are two classes of interferons, which use different receptors
IFNs a and b use the same receptor and are called Type I IFNs
These are secreted by most cells
IFN g uses a different receptor
It is secreted by T-cells and is called immune IFN
Type I and II IFNs have overlapping but nonidentical effects
IFNs induce the transcription of many genes
They regulate the immune system
They induce the anti-viral state in which cells are resistant to viruses
They are extremely important for the control of viral infections
In the absence of IFN, most viral infections are much, much more serious

10. Effects of IFNs
IFNs induce the antiviral state in which viral RNA cannot be translated
The inducer of Type I IFNs is usually double-stranded RNA
Double-stranded RNA is also required for the activity of the induced enzymes RNase L and PKR
Thus, dsRNA plays a pivotal role in IFN action
IFN has toxic effects and tight regulation of its action is necessary
IFNs are also powerful regulators of the adaptive system
They activate many types of immune cells
They upregulate production of MHC and of other proteins required for function of the adaptive system

12. Natural Killer Cells
NK cells are a first line of defense against viral infection
They increase in activity in the first 2-3 days after infection and then decline
They kill virus-infected cells, probably because these cells display too little class I MHC
A deficiency in NK cells results in more serious viral infections

13. Complement
The complement system consists of >20 blood proteins
It is activated by a proteolytic cascade
It is a component of both the innate and adaptive immune systems
It can interact with antibody to kill viruses or infected cells
It can also kill pathogens in the absence of antibody
One group of effector molecules inserts into membranes to kill cells or viruses
Other effectors control pathogens in other ways
Complement is a potentially destructive system and its activity must be carefully regulated

14. Apoptosis
Apoptosis is a cell suicide pathway in which mitochrondria cease to function, DNA is degraded, and the cell fragments into small pieces
Apoptosis is non-inflammatory
Many events can trigger apoptosis, including stress of viral infection, withdrawal of growth factors, or a deregulated cell cycle
CTLs kill target cells by inducing apoptosis
Proteases called caspases are key players in the apoptotic pathway
By undergoing apoptosis, an infected cell prevents further production of virus

16. The Adaptive Immune System--CTLs
The cellular arm of the adaptive immune system consists of CTLs (cytotoxic T lymphocytes) that kill infected cells
Most CTLs express CD8 and respond to antigen presented by Class I MHC (major histocompatibility complex) molecules
CTLs recognize the antigen-MHC I complex by means of a T-cell receptor that they express on their surface
Activation of CTLs requires exposure to cognate antigen and a second signal, usually supplied by T-helper cells
Upon activation, CTLs express IFN-g and other proteins and begin to divide; they are programmed to undergo apoptosis once the cognate antigen is withdrawn
Upon activation, memory T-cells are formed that persist and that are programmed to respond rapidly upon renewed exposure to antigen

17. T-Helper Cells
TH cells express CD4 and recognize antigen presented by Class II MHC
Whereas MHC Class I is expressed by most cells in the body, Class II is expressed primarily by T-cells, B-cells, and other cells of the immune system
TH cells secrete cytokines that help CTLs or B-cells to become activated
A spectrum of TH cells exists that secrete different assortments of cytokines and that preferentially help CTLs or B-cells
The effector cells of the adaptive immune system require at least two different inputs to become activated, thus subjecting this potentially harmful system to greater control

24. Adaptive Immunity--B cells
The humoral immune response is carried out by B cells
B cells express anchored antibody on their surface
Upon exposure of the cell to an antigen recognized by the antibody, the cell can divide and produce plasma cells that secrete antibody
Activation of the B cell requires a second signal supplied by TH cells
After activation, memory cells are formed that persist and are capable of more rapid activation upon exposure to cognate antigen
Secreted antibodies are of 5 different kinds which have different functions in the immune response

28. Types of Secreted Antibodies
IgM is the earliest antibody secreted by a plasma cell. It is a sign of recent infection.
IgG is long lived and circulates in the blood for years. Many cells in the body are thus exposed to it. It is also transferred to the fetus of a pregnant woman and is responsible for maternal immunity.
IgA is secreted on mucosal surfaces and if effective against viruses that replicate in the respiratory tract or the intestinal tract
IgE is most effective against large parasites and is responsible for the symptoms of hay fever when it reacts against pollen grains, mites, dust particles, or other large objects
IgD is only expressed together with IgM. Its precise role in immunity is not clearly understood.

34. Control of the Immune System and Autoimmunity
T-cells are negatively selected during development if they recognize self
Activation of B-cells or T-cells requires two signals, exposure to the cognate antigen and cytokine stimulation from TH cells
An inflammatory response induced by infection is important for optimal signaling and activation
After activation the cells die off when the cognate antigen is no longer present in sufficiently high concentrations
Failure of these control mechanisms can result in autoimmunity, which can lead to very serious illness

35. Vaccines
The existence of memory in the adaptive immune system makes it possible to immunize people by vaccination
Vaccines may be attenuated viruses that infect but do not cause disease, inactivated viruses that cannot infect but which expose the person to the viral antigens, or subunit vaccines that contain only a subset of viral proteins
Attenuated vaccines usually are the most effective, but it can be difficult to balance sufficient attenuation so as not to cause disease in any individual with the necessity for sufficiently vigorous replication to induce immunity
Inactivated or subunit vaccines require that large amounts of protein be injected and it may be difficult to obtain an inflammatory response required for a vigorous response without overdoing it

36. Vaccines (con)
The take of live virus vaccines can be interfered with by concurrent infection with another virus, which is not a problem with inactivated virus vaccines
Live virus vaccines are less stable than inactivated vaccines
Inactivated virus vaccines require large amounts of material, multiple injections, and give less solid immunity
Some candidate inactivated virus vaccines have given unbalanced responses that resulted in potentiating more serious illness upon subsequent infection by the virus rather than in immunity to the virus

39. Many Vaccines Have Been Successful in Controlling Viruses
Smallpox has been eradicated
Poliovirus is on the verge of being eradicated
Good vaccines exits for mumps, measles, rubella, yellow fever, tick-borne encephalitis, and other viruses
However, it has not yet been possible to develop vaccines against some viruses, such as HIV and RSV
Although a good vaccine against measles exists, it has not been possible to eradicate the virus because infants in some developing countries become infected with the wild-type virus as soon as maternal immunity is lost

49. Inhibition of Apoptosis by Adenoviruses

53. Pathogens and the Immune System
The humoral system may have evolved to fight bacteria and the CTL system to fight viruses, but both are important for the control of any pathogen
Humans cannot live without an immune system but this is the result of a long process of coevolution
This coevolution required mutual adaptation
Pathogens that are too virulent for their reservoir host become attenuated (e.g., rabbit myxoma virus)
Pathogens that are effectively defeated by the immune system often evolve new tricks to get around it (e.g., counterdefenses evolved by herpes-, pox-, and adenoviruses)
Hosts that cannot control their pathogens are removed from the gene pool in favor of variants that can (e.g., rabbits and myxomavirus)