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)

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, 70-80 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

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

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

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

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

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

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

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

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

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.

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

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

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

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

Inhibition of Apoptosis by Adenoviruses

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)