1. Animal Immune Systems
Chapter 43

2. Innate Vs. Adaptive Immunity
43.1 The innate immune system acts against a diversity of foreign pathogens.
Acquired
Specific
“Remembers”
Slower
Natural
Nonspecific
Rapid
Genetic
The immune system consists of two parts that work in different ways and interact with each other to protect against infection.
Innate, or natural, immunity provides protection in a nonspecific manner against all kinds of infection. This form of immunity is present in plants, fungi, and animals and is an evolutionarily early form of immunity.
Adaptive, or acquired, immunity, is specific to a given pathogen. This form of immunity “remembers” past infections. Subsequent encounters with the same pathogen generate a stronger response from the host.

3. Physical Barriers The skin is a physical barrier:
Organisms have a physical barrier surrounding them that protects against infection. Examples include the cell wall of bacteria, the bark of trees, the cuticle of leaves, the exoskeleton of insects, the scales of fish, the shells of eggs, and the skin of mammals.
At times this barrier can be breached.
The skin is a physical barrier:
pH of 3-5 from oil/sweat glands;
enzymes called lysozymes,
symbiotic bacteria, etc.

4. Skin Mucous membranes also act as physical barriers:
RT has cilia, mucus
Saliva, tears have antibacterial enzymes
Stomach has low pH
Symbiotic bacteria in skin and mm
In humans, the physical barrier against microorganisms is the skin. It has two layers, the outer epidermis and the inner dermis.
The epidermis consists of several layers of cells covered with the protein keratin.
The dermis consists of connective tissue, hair follicles, blood and lymphatic vessels, and glands.
Like the skin, the mucous membranes of the respiratory, gastrointestinal, and genitourinary tracts act as physical barriers. However, they have additional protective mechanisms.
Parts of the respiratory tract have cilia, hairlike projections that sweep mucus along with trapped particles and microorganisms out of the body.
Saliva and tears contain enzymes that help to protect against bacteria.
The stomach, with its low pH and enzymes that break down food, is inhospitable to many microorganisms.
Nonpathogenic organisms in the skin and mucous membranes in some cases provide protection against harmful pathogens by competing with them for food and space. They may also maintain health in other ways, such as by aiding digestion. We live in a mutualistic relationship with these microorganisms.

5. Development of White Blood Cells
Bone Marrow
The innate immune system has numerous cells in addition to those in the skin and mucous membranes, found in different locations in the body and having different mechanisms of action. These cells are white blood cells, or leukocytes. They arise by differentiation from stem cells in the bone marrow.
3 types
3 types Ab

6. Phagocytosis
Phagocytes: immune cells that engulf and destroy foreign cells (with lysozyme); I.e. macrophages, neutrophils, dendritic cells
Phagocytes are immune cells that engulf and destroy foreign cells or particles. The engulfing of a cell or particle by another cell is called phagocytosis.
A phagocyte encounters a cell or particle that it recognizes as foreign and binds to it.
The phagocyte extends its plasma membrane completely around the cell or particle until it is within a separate compartment inside the phagocyte.
In some cases, the compartment merges with a lysosome. Enzymes within the lysosome digest the foreign cell or particle.
Phagocytosis can also trigger a respiratory burst, a process that generates reactive oxygen species (superoxide radicals and hydrogen peroxide) and reactive nitrogen species (nitrogen oxide and nitrogen dioxide). These molecules directly damage pathogens.

7. Types of Phagocytic Cells
Macrophages: “big eaters”; patrol the body
Neutrophils: abundant in blood; first to an infection
Dendritic cells: skin and mm
There are three major types of phagocytic cell: macrophages, dendritic cells, and neutrophils. In each case, their names give clues to their morphology.
Macrophages are large cells that patrol the body.
Dendritic cells have long cellular projections reminiscent of the dendrites of neurons. These cells are typically part of the natural defenses found in the skin and mucous membranes.
Neutrophils are members of a group of cells called granulocytes because of the presence of granules in their cytoplasm. The granules of neutrophils take up both acidic and basic dyes, so their staining pattern is considered neutral. Neutrophils are very abundant in the blood and are often the first cells to respond to infection.

8. Granulocytes Granulocytes: WBC with granule staining patterns
Neutrophils: in blood, first to an infection
Eosinophils & Basophils: defend against parasitic infections; contribute to allergies
Mast cells: release histamine contributing to allergies and inflammation
Natural killer cells: only recognize/kill infected or abnormal host cells
The innate immune system contains several other cells in addition to phagocytic cells.
Two types of granulocyte, eosinophils and basophils, defend against parasitic infections but also contribute to allergies.
Mast cells release histamine, an important contributor to allergic reactions and inflammation.
Natural killer cells do not recognize foreign cells, but instead recognize and kill host cells that are infected by a virus or have become cancerous or otherwise abnormal.

9. Recognizing foreign from self
Phagocytes detect surface molecules that are present on pathogen cells but not on host cells
Detect evoluntionarily conserved surface molecules shared by many microorganisms.
Toll-like receptors (TLR) on our own phagocytes cells bind to pathogen surface molecules.
This binding is a signal to the phagocyte to engulf its target and release cytokines (chemical messengers that recruit other immune cells to site of injury or infection).
Phagocytes attack foreign cells that they encounter but leave host cells alone. They are able to recognize pathogens by detecting specific surface molecules that are present on pathogens but not on the body’s own cells.
Toll-like receptors (TLRs) are a family of transmembrane receptors present on phagocytes that recognize and bind to molecules on the surface of microorganisms. As a result, they provide one of the earliest signals that an infection is present. TLRs detect a wide range of microorganisms by recognizing evolutionarily conserved surface molecules shared by many microorganisms.
Binding of the TLR to surface molecules on the pathogen is a signal to the phagocyte to engulf and destroy its target. In addition, phagocytes send a message to the rest of the immune system when a foreign molecule binds to the TLR. Phagocytes release chemical messengers called cytokines that recruit other immune cells to the site of injury or infection. Cytokines, like hormones, provide long-distance communication between cells.

10. Inflammation
Local, nonspecific reaction to an injury to prevent spread of pathogens
Mast cells release histamine
Increase in blood flow, blood vessel permeability
Recruitment of phagocytes
Redness, swelling, edema, heat, pain
Immune cells release cytokines, which recruit other immune cells to injury
While there are generally some immune cells already present at the site of tissue injury or infection, many more must be recruited to fight infection successfully. That recruitment happens as part of a process called inflammation. Inflammation is characterized by four classic signs, described by their Latin names: rubor (redness), calor (heat), dolor (pain), and tumor (swelling).
The process begins following tissue injury or infection:
Certain cells in the tissue, such as dendritic and mast cells, are activated and release cytokines and other chemical messengers.
Some of these chemical messengers recruit additional white blood cells to the site of infection or injury. Others make it easier for white blood cells to reach this site quickly.
For example, histamine is released by mast cells and basophils.
Histamine acts directly on blood vessels to cause vasodilation, increasing blood flow to the site of infection or injury. Vasodilation causes the characteristic redness and heat of inflammation.
Histamine increases the permeability of the blood vessel wall. Fluid leaks out of the blood vessel, carrying white blood cells into the damaged tissue. The increased fluid in the tissue surrounding the blood vessels is visible as swelling.
Some chemical messengers act directly on nerve fibers, causing pain.

11. Extravasation
Extravasation: when phagocytes move from a blood vessel to the site of the infection
Phagocytes can move from a blood vessel to the site of infection. This process is called extravasation.
The phagocyte travels along the vessel wall in a rolling motion, grabbing weakly onto the wall as glycoproteins on the phagocyte surface bind transiently to proteins on the endothelial cells.
Stronger interactions put a brake on this rolling motion and allow the phagocyte to adhere more firmly to the vessel wall.
As it nears the site of infection, the phagocyte encounters and binds to cytokines.
The phagocyte changes shape and moves in between cells lining the blood vessel and into the surrounding tissue.
Several proteins play key roles in inflammation.
Some, like C-reactive protein (CRP), bind to a pathogen to facilitate uptake by a phagocyte. This process is called opsonization.
A change in blood protein levels is a marker for the initial phase of the disease, known as the acute phase response.

12. The complement System Complement system:
Consists of circulating proteins that activate one another
Activation results in the formation of a membrane attack complex (MAC) that:
Lyses bacteria/other cells
Produces proteins that enhance phagocytosis
Generates cytokines
In addition to individual proteins, there is an entire system of proteins circulating in the blood that participates in innate immune function. Collectively, these proteins make up the complement system.
The complement system consists of more than 25 proteins that circulate in the blood in an inactive form.
The system is activated when these proteins bind to molecules specific to microorganisms or to antibodies.
Activation in turn sets off a biochemical cascade in which the product of one reaction is the enzyme that catalyzes the next. Such sequential activation leads to amplification of the response.
Activation of the complement system has three effects:
The most dramatic is breaking open cells, or lysis. Complement proteins form a membrane attack complex (MAC) that makes holes in bacterial cells.
The complement system targets pathogens for phagocytosis by coating bacteria with a protein that phagocytes recognize (opsonization).
Activated proteins attract other components of the immune system.
Complement deficiencies are a rare form of immunodeficiency, any disease in which part of the immune system does not function properly. Their effects depend on which component of the complement system is lacking. For example, one type of complement deficiency makes individuals vulnerable to bacterial infections because fewer pathogens undergo cell lysis and opsonization.

13. Organs of the Immune System
43.2 The adaptive immune system includes B cells that produce antibodies against specific pathogens
Adaptive Immunity: acquired or developed
Specific responses to specific microbes
Based on having prior exposure to pathogen or vaccination; memory
Diversity
Recognition of foreign versus self
Bone marrow: where B lymphocytes or B cells are made/mature
Thymus: where T lymphocytes or T cells mature
Liver, spleen, lymph nodes: where mature lymphocytes are found
Like the innate immune system, the adaptive immune system can react to diverse pathogens and has the capacity to distinguish self from non-self. However, it also has two additional features not present in the innate immune system: specificity and memory.
While many cells and tissues play a role in adaptive immunity, two types of cell are particularly important: B lymphocytes, or B cells, and T lymphocytes, or T cells.
In mammals, B cells mature in the bone marrow.
T cells mature in the thymus, an organ of the immune system located just behind the sternum, or breastbone.
B and T cells circulate in blood and lymphatic vessels. They also can be found in the spleen, liver, and lymph nodes.
One of the hallmarks of adaptive immunity is the ability to target specific pathogens. The specificity of the adaptive immune system is in part the result of antibodies produced by B cells. An antibody is a large protein that carries sugar molecules attached to some amino acids. An antibody binds to foreign molecules that occur naturally on or in microorganisms and participate in normal cellular functions. Such a molecule is termed an antigen, which is a molecule that binds to and leads to the production of antibodies.
Antibodies can be found on the surface of B cells or free in the blood or tissues. Collectively, antibodies make up a significant portion of the proteins present in the blood.

14. CELLS OF ADAPTIVE IMMUNITY
Specificity:
Due to antibodies produced by B cells
Response to an antigen: foreign body
2 Halves of Adaptive Immunity:
Humoural immunity (antibodies or Ig)
Works in blood/fluids
Uses B cells
Works by releasing antibodies from plasma cells
Works mainly on bacteria
Cell-Mediated Immunity
Works in viral-infected cells, early cancer
Uses cytotoxic T cells
Like the innate immune system, the adaptive immune system can react to diverse pathogens and has the capacity to distinguish self from non-self. However, it also has two additional features not present in the innate immune system: specificity and memory.
While many cells and tissues play a role in adaptive immunity, two types of cell are particularly important: B lymphocytes, or B cells, and T lymphocytes, or T cells.
In mammals, B cells mature in the bone marrow.
T cells mature in the thymus, an organ of the immune system located just behind the sternum, or breastbone.
B and T cells circulate in blood and lymphatic vessels. They also can be found in the spleen, liver, and lymph nodes.
One of the hallmarks of adaptive immunity is the ability to target specific pathogens. The specificity of the adaptive immune system is in part the result of antibodies produced by B cells. An antibody is a large protein that carries sugar molecules attached to some amino acids. An antibody binds to foreign molecules that occur naturally on or in microorganisms and participate in normal cellular functions. Such a molecule is termed an antigen, which is a molecule that binds to and leads to the production of antibodies.
Antibodies can be found on the surface of B cells or free in the blood or tissues. Collectively, antibodies make up a significant portion of the proteins present in the blood. Ab 14

15. Antibody Structure Specificity of antibody:
Antibodies have a distinctive structure that reflects their specificity for a given antigen. Here, the simplest antibody molecule is a Y-shaped protein made up of four polypeptide chains—two identical light (L) chains and two identical heavy (H) chains, so called because of their relative molecular weights. Covalent disulfide bonds hold the four chains together.
The light and heavy chains are further subdivided into variable (V) and constant (C) regions. Within the variable regions of the L and H chains are regions that are even more variable, called hypervariable regions. Together, these hypervariable regions interact in a specific manner with a portion of the antigen called the epitope. Each of the billions of different antibodies has a distinct set of hypervariable regions that recognizes a unique epitope.
Binding of antibodies to antigens is the first step in recognition and removal of microorganisms. Binding alone is sometimes enough to disable a microorganism. In these cases, binding can lead to precipitation of the antibody–antigen complex. More often, the microorganism is destroyed by a different component of the immune system, such as a phagocyte or the complement system.
How does antibody activate these other components? If broken at the hinge region, an antibody yields two Fab fragments and one Fc fragment. (The letters “ab” stand for “antigen-binding”; “c” stands for “crystallizing.”) Each Fab fragment has an antigen-recognition site. The Fc fragment activates the complement system and binds to cell-surface receptors of other cells of the immune system.
Specificity of antibody:
Hypervariable region of Ab binds to epitope region of antigen
Ab-antigen combination is easy target for phagocytosis or MAC
Antibodies:
Found on surface of B cells
Free in blood or tissues

16. Classes of Antibodies
Antibodies: class of blood proteins also known as immunoglobulins (Ig)
Mammals produce 5 types of Ab or immunoglobulins (Ig)
IgG: most abundant; crosses placenta and confers maternal immunity
IgM: forst circulating Ab to appear; indicates current infection
IgD: foiund on surface of B cells
IgA: secreted by saliva, tears
IgE: involved in allergies & inflammation; causes release of histamine
Antibodies are members of a family of proteins with common structural features. As a group, they are called immunoglobulins (Ig). There are five classes of immunogloblulin—IgG, IgM, IgA, IgD, and IgE—each with a different function. These classes are defined by their heavy chains, which differ in the amino acid sequences of their constant regions. There are also two types of light chain. These two types of light chain occur in all five classes of antibody, but any given antibody contains only one type of light chain.
IgG is by far the most abundant of the five antibody classes. IgG circulates in the blood and is particularly effective against bacteria and viruses. In addition, IgG is the only class of antibody that can cross the placenta because of the presence of receptors on placental cells for the Fc portion of IgG. The ability of IgG to cross the placenta provides protection to the developing fetus.
IgM is typically a pentamer. It is particularly important in the early response to infection and is very efficient in activating the complement system and stimulating an immune response.
IgA is usually a dimer consisting of two antibody molecules linked by a joining chain. It is the major antibody on mucosal surfaces, such as those of the respiratory, gastrointestinal, and genitourinary tracts. It helps to protect mucous membranes from infection. It is also present in secretions, including tears, saliva, and breast milk.
IgD and IgE, like IgG, are monomers. IgD is typically found on the surface of B cells. This immunoglobulin helps initiate inflammation. IgE plays a central role in allergies, asthma, and other immediate hypersensitivity reactions, which are characterized by a heightened or an inappropriate immune response to common antigens.
The five classes of antibody are also called isotypes. B cells can change the class of antibody they make, a process known as isotype or class switching.

17. Clonal Selection
Clonal selection is the basis for antibody specificity:
An antigen binds to 1 or a few B cells on the basis of the fit with its cell-surface Ab receptor
Leads to B cell differentiation into plasma and memory cells
Clonal selection is the basis for antibody specificity.
Every individual has a very large pool of B cells, each with a different antibody on its cell surface. Collectively, these antibodies recognize a great diversity of antigens, but each individual antibody can recognize only one antigen or a few antigens.
An antigen interacts with the B cell, or a small set of B cells, that has the best fit between the antigen and the membrane-bound antibody.
Binding leads the B cell to divide and differentiate into two types of cell:
Plasma cells secrete antibodies.
Memory cells are long-lived cells that contain membrane-bound antibody having the same specificity as the parent cell.
Specific Ab
Specific memory
B cells
B Cell clones

18. Primary and Secondary Responses
Primary response:
Long lag period
Short response
Less anitbodies
Secondary response
Quicker
More energetic
Provides basis for immunity
Clonal selection explains immunological memory.
Primary response: The first encounter with an antigen leads to a primary response. In this response, there is a short lag before antibody is produced. The lag is the time required for B cells to divide and form plasma cells. The plasma cells secrete antibodies, typically IgM. The level of IgM in the blood increases, peaks, and then declines.
Secondary response: On re-exposure to the same antigen, even months or years after the first exposure, there is a secondary response. The secondary response is quicker, stronger, and longer than the primary response. During this response, the antibodies are released by memory B cells. These cells respond more quickly to antigen exposure than naïve B cells. In addition, the pool of memory B cells is larger than the pool of naïve B cells for a given antigen, explaining why the secondary response produces more antibodies for a longer period of time.
Vaccines provide future protection from an infection. An antigen from a pathogen is deliberately given to a patient in a vaccine to induce a primary response but not the disease.

19. Antibody Diversity
Antibody diversity is generated by genomic rearrangement, where individual gene segments are joined to form functional genes.
In 1965, American biologists William Dreyer and J. Claude Bennett suggested a novel hypothesis to explain antibody diversity. They proposed that a single antibody is made by separate gene segments that are brought together by recombination. According to this model, many copies of each gene segment are present, each slightly different from the others. Only one copy of each gene segment ends up in the final, recombined antibody gene.
It wasn’t until 10 years later that direct experimental evidence showed this hypothesis to be true. In 1976, Japanese immunologists Nobumichi Hozumi and Susumu Tonegawa tested the Dreyer and Bennett hypothesis.
Using mice as a model system, they isolated DNA from embryonic cells (before recombination was thought to occur) and from adult B cell tumor lines that produce one type of antibody (after recombination was thought to occur). DNA was cut by restriction enzymes.
The fragments were separated on a gel and transferred to a filter paper. A light chain (containing both V and C regions) was used as a radioactive probe to determine the size and positions of the V and C regions.
Hozumi and Tonegawa found that the V and C regions were far apart in the DNA of embryonic cells and close together in adult cells, suggesting that the gene segments were brought together during B cell differentiation.

20. Genomic Rearrangement
As a B cell differentiates, different gene segments are joined in a process called genomic rearrangement that produces a specific antibody.
For H chains, there are multiple V (variable), D (diversity), J (joining), and C (constant) gene segments. During B cell differentiation, the DNA in this region undergoes recombination so that just one of each of these segments makes part of a functional H chain gene, and the intervening DNA is deleted. The assembled VDJ segment encodes the variable portion, and the C segment encodes the constant region.
L chain genes also contain multiple copies of gene segments, except they do not have a D gene segment. The VJ segment encodes the variable portion and the C segment encodes the constant region. The result of this process is that each B cell encodes a single H chain and a single L chain, and each B cell expresses a unique antibody.
We generally think of DNA as being a stable blueprint present in identical copies in all of the cells in our bodies. B cells are an exception. As a result of genomic rearrangement, the DNA in each mature B cell is different from the DNA in every other mature B cell and different from the DNA in other cells in the body.

21. Helper T and Cytotoxic T Cells
43.3 The adaptive immune system includes helper and cytotoxic T cells that attack pathogens , foreign cells, and diseased cells.
Helper T cells:
Central role between humoural and cell-mediated immunity
Hold entire adaptive immune system together
Turns on phagocytosis, B cells, cytotoxic T cells, secrete cytokines
Surface marker CD4
HIV virus kills helper T cells
B cells and their antibodies have limitations.
B cells on their own can make antibodies only against some antigens; for other antigens, they require the assistance of other cells.
B cells are sometimes ineffective against pathogens that take up residence inside a cell, as do the bacteria that cause tuberculosis.
To handle these and other kinds of pathogens, there is another part of the adaptive immune system, which depends on the second type of lymphocyte—the T cell. T cells do not secrete antibodies. Instead, they participate in cell-mediated immunity, where cells, not antibodies, recognize and act against pathogens.
T cells originate in the bone marrow but mature in the thymus. A mature T cell has T cell receptor (TCR) on the plasma membrane, a protein receptor that recognizes and binds to the antigen.
There are two major subpopulations of T cells: helper T cells and cytotoxic T cells.
Helper T cells help other cells of the immune system by secreting cytokines.
Cytotoxic T cells can kill other cells.
These two types of T cell are distinguished by the presence of different glycoproteins on their surface—CD4 on helper T cells and CD8 on cytotoxic T cells.
Cell-Mediated Immunity
Works in viral-infected cells, early cancer
Uses cytotoxic T cells
Have CD8 surface markers

22. T Cell Receptor (TCR) If TCR binds to MHC II antigen
Have T cell receptor (TCR) on its plasma membrane
Recognizes and binds to antigen
Binding of TCR to antigen triggers T cell to divide into clones
Results in a pool of T cells specific for a given antigen
NOTE: TCRs only recognize antigens that have an association with proteins called major histocompatibility complex (MHC) on their surface
If TCR binds to MHC I antigen
How T cells are like B cells:
Each T cell has just one type of TCR on its surface.
Binding of TCR to an antigen triggers the T cell to divide into clones, resulting in a pool of T cells that are each specific for a given antigen.
The diversity of TCRs among different T cells results from genomic rearrangement of V, D, J, and C gene segments.
How T cells are not like B cells:
TCRs are composed of two polypeptide chains.
TCRs are always membrane bound on the T cell surface, never secreted.
TCRs only recognize antigen in association with proteins of the major histocompatibility complex, or MHC, proteins that appear on the surface of most mammalian cells.
Once activated, T cells divide to form multiple helper or cytotoxic T cells. Some cells of each type are memory cells that provide long-lasting immunity following an initial infection, as in the case of B cells.
T cells can sometimes be activated too strongly, causing a delayed hypersensitivity reaction. For example, if you touch poison ivy, your skin will turn red and start itching only after a delay of several hours or days. Delayed hypersensitivity reactions are initiated when helper T cells release cytokines that attract macrophages to the site of exposure, which is typically the skin.

23. Activation of T Helper Cells
T cells require two signals to become activated.
An antigen, which indicates the presence of foreign cells or particles.
An MHC protein. T cells interact only with antigens that are bound to molecules of the MHC on the surface of host cells.
The MHC is a cluster of genes present in all mammals that encode proteins on the surface of cells. The MHC is composed of many genes with a high rate of polymorphism, meaning that there is a lot of variability in the gene sequence (and consequently the protein sequence) among individuals. In humans and mice, the genes are divided into three classes:
Class I genes are expressed on the surface of all nucleated cells.
Class II genes are expressed on the surface of macrophages, dendritic cells, and B cells.
Class III genes encode several proteins of the complement system and proteins involved in inflammation.
When an antigen enters the immune system,
it may be recognized by an antibody directly or be taken up by antigen-presenting cells. These cells include macrophages, dendritic cells, and B cells.
An antigen-presenting cell takes up the antigen and returns portions of it to the cell surface bound to an MHC class II protein.
Helper T cells recognize processed antigen along with MHC class II molecules by their T cell receptors.
The helper T cells release cytokines that activate other parts of the immune system, including macrophages, B cells, and cytotoxic T cells.

24. Activation of Cytotoxic T cells
Cytotoxic T cells also recognize antigen displayed by host cells, but in this case the antigen is presented in association with MHC class I molecules. Because class I molecules are present on virtually all cells, cytotoxic T cells recognize and kill any host cell that becomes abnormal in some way.
For example, a virus-infected cell often expresses viral antigens and MHC class I molecules on its surface. Cytotoxic T cells recognize the antigen and MHC class I molecules and kill the cell.
Tumor cells express novel antigens along with MHC class I proteins, and may also be eliminated in some cases by cytotoxic T cells.

25. Selection of T cells
Of the possible T cell receptors that are generated by genomic rearrangement, only some are useful: those that react with the host’s own MHC molecules. In addition, useful T cell receptors must not react with molecules normally present in or on cells of the host.
A sorting process is therefore necessary so that only some T cells mature and others are eliminated.
As T cells mature in the thymus, they interact with cells of the epithelium of the thymus.
Those that recognize self MHC molecules on epithelium cells are positively selected and continue to mature.
Those that react too strongly to self antigens in association with MHC are negatively selected and eliminated through cell death.
The result of this sorting process is twofold:
T cells become MHC restricted, so helper T cells interact with foreign antigen plus MHC class II proteins and cytotoxic T cells interact with foreign antigen plus MHC class I proteins.
T cells exhibit tolerance—they do not respond to self antigens. Those antigens present as T cells mature are labeled as self and do not elicit a response; those not present are non-self and, if encountered, do elicit a response.
The ability to distinguish self from non-self is critical. Failure leads to autoimmune diseases, in which the immune system becomes active against antigens of the host. Autoimmune diseases can be debilitating as T cells or antibodies attack cells and organs of the host.

26. Antigenic Drift
43.4 Some pathogens have evolved mechanisms that enable them to evade the immune system.
The flu (influenza) is caused by an RNA virus that can change its surface proteins through antigenic drift and antigenic shift
Antigenic Drift:
Allows a population of viruses to evolve over time; gradual
Evades memory T and B cells that remember past infectins
The flu—its full name is influenza—is caused by an RNA virus that infects mammals and birds. It is notable for causing seasonal outbreaks, or epidemics. The flu causes hundreds of thousands of deaths each year, and millions of deaths during pandemics.
Cells infected by viruses secrete cytokines that bring macrophages, T cells, and B cells to the site of infection. These cytokines, produced in abundance, lead to many of the symptoms commonly associated with the flu. For example, the cytokine interleukin-1 produces fever.
Part of the success of the virus lies in its ability to spread easily. Part lies in the virus’s ability to evade the immune system. There are three major types of flu virus—called A, B, and C—and many different strains. Once in the cell, the virus replicates its genome and makes more virus particles. However, replication is prone to error, so there is a high rate of mutation that leads to changes in the amino acid sequences of antigens present on the viral surface.
This process is called antigenic drift. It allows a population of viruses to evolve over time and evade memory T and B cells that remember past infections.

27. QUICK CHECK
How does T cell activation differ from B cell activation?

28. ANSWER
T cells are activated when their surface T cell receptors bind to an antigen with an MHC molecule.
B cells are activated when their surface antibodies bind to a free antigen.

29. Antigenic Shift Antigenic Shift:
Sudden change in cell-surface proteins
Co-infected with 2 or more different flu strains
Antigenic drift leads to a gradual change of the virus over time. The flu virus is also capable of sudden changes by a process known as antigenic shift. The viral genome consists of eight linear RNA strands. If a single cell is co-infected with two or more different flu strains, the RNA strands can reassort to generate a new strain.
Antigenic drift and shift make it difficult to predict from year to year which strains will be most prevalent and therefore what vaccine will be most effective.

30. Tuberculosis TB: tuberculosis: Called “Consumption”
Like the flu, tuberculosis is spread through small droplets dispersed in the air when a person with active disease coughs or sneezes. Also like the flu, the TB pathogen replicates inside host cells. But unlike the flu, TB is caused by a bacterium, not a virus. TB results from infection with Mycobacterium tuberculosis, a bacterium with several unusual properties. It is very small with a compact genome, lacks a plasma membrane outside of the cell wall, and replicates exceedingly slowly. M. tuberculosis takes about 16–20 hours to divide, compared to 20 minutes for the common intestinal bacterium and model organism E. coli.
TB is very common. It is estimated that about a third of the world’s population has TB. Symptoms are absent in most cases because the bacteria are in a dormant state, kept in check by the immune system. About 10% of cases are active, characterized by chronic cough, fever, night sweats, and the weight loss that gives TB its other name: consumption.
TB primarily affects the lungs.
The bacteria enter macrophages in the alveoli of the lungs, where they replicate.
The macrophages release cytokines, recruiting T and B cells to the site of infection.
These lymphocytes surround the infected macrophages, forming a structure called a granuloma. The granuloma helps to prevent the spread of the infection and aids in killing infected cells.
Many TB cases remain asymptomatic. However, the bacteria can sometimes overcome host defenses, especially if the immune system is compromised or suppressed, as in the case of co-infection with HIV. Treatment for active disease requires a long course of multiple antibiotics.
Diagnosis poses challenges, especially in the case of asymptomatic infections. The tuberculin skin test is performed by injecting protein from the bacteria under the skin and observing whether or not a reaction, in the form of a hard, raised area, occurs. A positive skin test is an example of a delayed hypersensitivity reaction caused by the recruitment of memory T cells to the site of inoculation.
TB: tuberculosis: Called “Consumption”
Caused by a bacterium
Grows very slowly and resides inside of cells; particularly macrophages in lungs
Very common; in 33% of world’s population
Symptoms dormant, kept in check by immune system
10% cases are active; chronic cough, fever, night sweats, weight ;loss

31. Malaria
Malaria: cause by single-celled eukaryote called Plasmodium falciparum
Devastating and common
Causes cyclical fevers and chills and can lead to coma and death
Transmitted to humans by bite of infected mosquito; spreads to human liver and RBC
Evades immune system by antigenic variation: expresses only 1 gene out of about 60 genes for its membrane proteins and changes which one it expresses
Malaria is caused by a single-celled eukaryote of the genus Plasmodium. Several species infect humans, but P. falciparum is the most common and most virulent. Malaria is both devastating and common: There are about 500 million cases and 2 million deaths every year, mostly in sub-Saharan Africa, and mostly of children. Malaria causes cyclical fevers and chills and can lead to coma and even death.
The malaria parasite is transmitted to humans by the bite of an infected mosquito. The parasite thus bypasses the natural protective barrier provided by the skin. The malaria parasite spreads to the liver and then to red blood cells, where it completes its life cycle. The progeny can be taken up again by mosquitoes.

32. Malaria Adaptations
The malaria parasite is able to evade our immune system.
It resides in liver cells and red blood cells, where it cannot be easily detected by macrophages, B cells, or T cells.
Infected red blood cells can be removed by the spleen, but the malaria parasite has evolved a way to avoid this filtering action:
The parasite expresses an adhesive protein that inserts itself on the surface of red blood cells.
This protein interacts with proteins on the surface of cells lining blood vessels, helping infected cells stick to blood vessel walls and keeping them in the circulatory system and out of the spleen.
The protein, PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1), could conceivably be a target for antibodies or TCRs. However, it is encoded by one of about 60 genes, each slightly different from the others. The parasite expresses just one of these genes at a time and can change which one is expressed, in a process called antigenic variation. The great and ever-changing diversity of this protein, both in a single parasite and in the population as a whole, makes it a moving target for the immune system.
Despite continuing research, there is no vaccine. Researchers hope that the sequence of the malaria genome, completed in 2002, will provide new targets for vaccine research. In the meantime, efforts to control malaria focus on measures to control mosquitoes, such as nets and insecticides, and on treatment with antibiotics.