a. The world is full of infectious agents that cause disease at every opportunity.

b. We fight infections against all potential pathogens through nonspecific defenses, especially the acute inflammatory response.

c. We also fight infections through specific defenses against particular organisms or viruses via the immune system, which has a molecular memory with regard to foreign molecules it has encountered.

d. The first line of defense against infection is mechanical and chemical.

e. Mammals are covered with skin, which has a water-resistant surface made of tough, dead cells that are constantly being rubbed off and replaced.

f. Skin cells are sealed together by tight junctions, and form an impenetrable barrier to microorganisms, as well as one that prevents dehydration.

g. Sebaceous glands, or oil glands, produce an oily sebum rich in waxes, fats, free fatty acids, and cholesterol, which inhibit the growth of fungi and bacteria on the skin (Figure 48.1).

h. In general, infectious agents only get through the skin when it is broken.

i. The nasal passages, mouth, and bronchi, have ciliated epithelia covered with mucus that traps viruses and microorganisms.

j. Mucous secretions and tears contain hydrolytic enzymes that attack bacteria and viruses.

k. Bacterial cell walls and mureins are described in Section 29.5.

l. Pathogens that surmount the first line of defense encounter white blood cells called phagocytes in the lymphatic system, lungs, and other spaces (Figure 48.2).

m. Phagocytes engulf foreign cells and viruses and digest them with enzymes.

a. Acute inflammation, such as that caused by a cut through the skin, is characterized by redness, swelling, pain, and heat (Figure 48.3).

b. Acute inflammation fights invaders and restores damaged tissues after an injury.

c. Inflammation is usually a type of prophylaxis (protection) but it can occasionally provoke anaphylaxis that entails labored breathing, shock, and even death (Section 48.13).

d. Acute inflammation involves dilation of arterioles (vasodilation) and constriction of venules (vasoconstriction), so that blood accumulates in the injured region (Section 45.5), causing redness.

e. Inflammation causes capillaries to become more permeable so that blood plasma exudes into the surrounding tissues, causing swelling.

f. Some substances in the exudate affect nerve endings, causing pain.

g. Inflammation depends on specialized leucocytes (Figure 48.4), which reside in connective tissues and lymphoid tissues and migrate through the lymphatics and blood.

h. Lymphocytes, the key cells of the immune system, are relatively small.

i. Monocytes are medium-sized phagocytes that may wander among tissue cells and become enlarged into macrophages.

j. The reticuloendothelial system is a series of macrophages that stay fixed in place, lining the cavities of lymph nodes, bone marrow, liver, and spleen, where they actively engulf foreign debris.

k. Granulocytes (polymorphonuclear leucocytes (PMNs)) are cells with distinctively staining cytoplasmic granules and distinctively formed nuclei.

a. Acute inflammation begins when an injury stimulates two events simultaneously, as shown in Figure 48.5.

b. Injuries expose blood to connective tissue molecules, and this activates a plasma protein called Hageman factor which, in turn, initiates three reaction cascades.

c. A cascade (Section 41.4) is a series of reactions that amplify a small initial stimulus into a large final effect.

d. Injuries also stimulate mast cells to expel the contents of their vesicles, mostly histamine.

e. The smooth muscle and endothelial cells, which have histamine receptors, then cause capillaries and arterioles to dilate and become more permeable, while venules constrict, and plasma exudes into the tissue.

f. Leucocytes are attracted into the tissue by chemotaxis; neutrophils arrive, followed by macrophages and lymphocytes (Figure 48.6).

g. During inflammation, leucocytes communicate with one another through local chemical mediators (paracrine communication).

h. Lymphocytes produce proteins that attract and keep monocytes in the tissue and that activate lysosomes of macrophages to phagocytize invaders.

i. Macrophages release interleukin-1, which induces the release of more histamine from mast cells, stimulates the breakdown of muscle proteins (causing weakness), and sets the body's thermostat higher, producing fever.

j. Fever is a nonspecific defense, as a higher body temperature can inhibit the growth of pathogens.

k. Paracrine communication is covered in Section 41.5.

l. The mass of necrotic cells, tissue debris, blood clots, partially digested bacteria, and leucocytes that accumulate around an inflammation is called purulent exudate, or pus.

m. An abscess is a localized mass of pus surrounded by inflamed tissue.

a. Injuries that cause inflammation also typically tear blood vessels and start an autonomic response that causes arterioles to constrict.

b. At the same time, a blood clotting reaction begins, as temporary platelet plugs are made to stop leakage from vessels.

c. Cascades as biological amplifiers are covered in Section 41.4.

d. The protein fibrin makes blood clots after a long cascade of activations (Figure 48.7).

e. This long chain of clotting reactions is subject to mistakes; several types of hemophilia in humans are genetic deficiencies that cause errors in the clotting proteins.

f. Blood drawn for analysis or transfusion is kept from clotting by small amounts of anticoagulants, such as citrate or heparin; the anticoagulant rat poison warfarin causes internal bleeding.

g. A blood clot that breaks loose becomes an embolus that may lodge in a narrow vessel, block blood flow, and cause damaged tissue, a heart attack, or a stroke.

h. Normal functions depend on a balance between clotting reactions and fibrinolysis reactions that prevent clotting and break up formed clots.

i. Hageman factor initiates a second inflammatory cascade in a series of about 20 plasma proteins known collectively as complement (Figure 48.8).

j. Complement proteins can either lyse bacteria by forming a membrane attack complex in the bacterial cell membrane, allowing the cytoplasm to leak out, or coat bacteria, making them more attractive to phagocytes.

k. A third, short cascade produces peptides called kinins, (Figure 48.9), which increase vascular permeability and vasodilation, and stimulate mast cells to release more histamine.

l. An active ingredient in wasp venom is a kinin (Figure 48.9).

a. The immune system of vertebrates is a backup to the nonspecific mechanisms of inflammation and mechanical and chemical barriers to infection.

b. An animal's immune system can recognize and destroy foreign particles (e.g. viruses, bacteria) that enter the body.

c. The technique of vaccination or immunization was first developed by Edward Jenner, using smallpox.

d. Louis Pasteur, who first worked with cholera bacteria, generalized the technique of using a vaccine, a preparation of weakened or inactivated bacteria that can be injected into the body to confer immunity.

e. For example, a rabbit injected with diphtheria vaccine will begin producing blood serum that forms a fluffy complex with live diphtheria cells that are later introduced into its bloodstream.

f. This antiserum or immune serum contains new blood proteins called antibodies that recognize and attack the diphtheria cells.

g. The vaccine that induced the formation of antibodies is called an antigen.

h. Antigens and antibodies have complementary shapes and bind to each other with specificity (Figure 48.10).

i. Most antigens are proteins or polysaccharides and must have a minimum molecular weight of about 5,000.

j. The titer of antibody in a serum is an indication of the antibody's concentration or biological activity, and is measured by diluting the serum serially (Figure 48.11) until reaching the most diluted tube where complex still forms.

k. In the rabbit example, the titer of antibody in the rabbit's serum rises for a while after innoculation, then falls (Figure 48.12) during a primary response.

l. A second injection of vaccine elicits a secondary response with a much higher and longer-lasting titer.

m. The fact that the immune system can elicit secondary responses shows that it has a memory, which resides in certain specific cells to be addressed later.

a. The immune system resides in scattered organs and patches of tissue where immunocytes produce two closely related events, the humoral and the cell-mediated responses to foreign materials.

b. Lymphocytes grow and mature in primary lymphoid tissues, in the bone marrow and thymus gland (Figure 48.13).

c. Lymphocytes differentiate into several types that can be distinguished by their surface proteins.

d. In secondary lymphoid tissues (e.g. spleen, lymph nodes, tonsils, adenoids, and Peyer's patches around the intestine), immunocytes meet antigens and interact with each other to produce antibodies.

e. As lymph nodes filter lymph from nearby tissues and vascular spaces, they become hard and sensitive with inflammation as they trap and inactivate materials whose antigens are foreign.

a. Antibodies are Y-shaped molecules called immunoglobulins that all have the same general structure: two light (L) chains and two heavy (H) chains held together by disulfide bonds.

b. Both L and H chains have a constant (C) region, which is the same for immunoglobulins of the same class, and a variable (V) region, which is unique to each type of antibody.

c. The V regions of H and L chains join together to form an antigen-binding site, which is stereospecific for an antigen with a complementary shape.

d. Many different antigen-binding sites can be made by combining H and L chains randomly.

e. An immunoglobulin is directed not against a whole antigenic protein, but only a small, distinctively shaped portion called an epitope, or antigen determinant.

f. Blood serum and mucous secretions carry five classes of immunoglobulins (IgA, IgD, IgE, IgG, and IgM), which all have the same type of L chain but different H chains.

g. IgA is secreted in mucus and in milk, and is the main antibody in the intestinal tract.

h. The passive immunity that a baby obtains by nursing its mother and ingesting IgA is different from the active immunity that it produces by making its own antibodies.

i. IgD is a surface receptor on B-cells.

j. IgE binds to mast cells and is involved in allergic reactions.

k. IgG is the principal serum antibody and is the only type of Ig that can cross the placenta in mammals.

l. The first antibodies made in response to a new antigen are mostly IgM.

m. Antibodies in the blood or secreted in mucus or milk bind to complementary antigens and precipitate them into clumps that can be engulfed by phagocytes.

n. Concepts 48.1 covers the use of the terms antibody and antigen.

a. Self is defined as anything the body normally does not make antibodies against, and nonself is anything that elicits antibody formation.

b. A series of special proteins appear to be designed for making each animal's cells distinct.

c. These proteins are encoded by genes of the major histocompatibility complex (MHC).

d. Closely related people have similar or identical MHC genes and proteins, so one person's immune system may recognize the cells of another person as "self."

e. As the genetic differences between people increase, the likelihood of a successful tissue graft or transplant decreases.

f. Most MHC proteins belong to two classes that have distinct roles in immune responses (Figure 48.14).

g. As viruses proliferate within host cells (Figure 48.15), viral proteins appear in the plasma membrane, where they combine with class I MHC proteins and mark the cell as different (Figure 48.16), thus eliciting a response that causes the animal to kill its own cells.

h. Killing infected cells before they can produce more viruses is most effective, and this is a primary function of T-killer cells.

i. Suppression of tumors, which also appear to be foreign, is another important function of the immune system, though it fails when cancer cells succeed in spreading.

a. During development, animals make enormous numbers of lymphocytes that later differentiate into many distinct clones.

b. Each clone is programmed, or committed, to make antibodies with a single kind of antigen-binding site.

c. An antigen in the body selects clones that make complementary antibodies by stimulating some cells in each clone to proliferate and to make large amounts of their antibodies.

d. This clonal selection model for the activation of antibody-making cells is well confirmed (Figure 48.17).

e. Methods 48.1 covers monoclonal antibodies and hybridomas.

f. Returning to the rabbit example, many B-cells that are stimulated to proliferate will differentiate into plasma cells that live only a few days but produce large amounts of antibody.

g. Many lymphocytes differentiate into memory cells, which, in a molecular sense, remember their first encounter with antigens and later produce a rapid secondary response when presented with the same antigen.

h. These processes are governed by paracrine factors called interleukins and interferons (Figure 48.18).

i. Macrophages produce interleukin-1, which activates T-helper cells.

j. Macrophages then combine with T-helper cells, which start to make several proteins:

k. Gamma interferon is a nonspecific defense made in response to viral infection; virtually all cells in the body can make interferon if they become infected.

l. Interferons are specific to the type of animal that makes them, not to the virus that induces them.

a. Immunoglobulin chains are encoded by several gene segments, each encoding a portion of the whole polypeptide.

b. Mice and humans have three families of immunoglobulin genes (Figure 48.19): one for heavy chains and one for each of two classes of light chains called kappa and lambda.

c. Each family is a cluster of gene segments on one chromosome.

d. For example, an L chain is encoded by three groups of segments that produce three regions: a V region, a J (joining) region, and a C region (Figure 48.20).

e. Since different gene segments are combined randomly in every differentiating B-cell, each animal acquires lymphocytes programmed to produce antibodies with many distinct antigen-binding sites, and capable of fighting every kind of pathogen.

a. Immunocytes are closely connected to the nervous system and are strongly influenced by hormonal controls.

b. The immune system thus becomes another set of sensors and effectors but is specialized for dealing with a special class of stimuli–foreign invaders that might be pathogens.

c. The physical bases for correlations between emotional well-being and a strong or weak immune system are being explored in neuroimmunology or psychoneuroimmunology studies.

d. The nervous system innervates key lymphoid tissues, such as the thymus gland, bone marrow, spleen, lymph nodes, among others.

e. Neuropeptides, such as vasoactive intestinal peptide and neuropeptide Y have been identified as the neurotransmitters in some of these sites.

f. These peptides may act as mediators between nervous and immune systems.

g. The implications of this are that there is a two-way communication system between immunocytes and the nervous system, as well as communication among immunocytes by means of neuropeptides.

h. Several hormones have strong effects on immune functions:

i. A clear nervous system-endocrine system regulatory circuit involving the adrenal cortex has been demonstrated (Figure 48.21).

j. Some immune responses can be conditioned, or learned, as demonstrated by Robert Adler and Nicholas Cohen, in research with rats (Sections 49.10).

k. Various nontraditional medical practices and pseudosciences that employ vague "mind-body" connections have been used to cure illnesses.

l. Massage techniques, yoga, visualization, meditation, prayer, herbal medicines, and dietary practices have been used to attempt to improve people's health and cure diseases.

a. The human immunodeficiency virus (HIV) causes acquired immune deficiency syndrome (AIDS).

b. The virus causing AIDS was identified around 1983 as a retrovirus–an RNA virus that produces a DNA copy of its genome, which integrates into the chromosome of its host (Figure 48.22).

c. The principal surface protein of a virion determines what cells the virus will attack, and the AIDS virus protein has a high affinity for proteins found mostly on T-helper cells, macrophages and other leucocytes, and some nervous system cells.

d. The provirus DNA copied into the host cell genome by the AIDS virus may lie dormant but eventually produces enough copies of virus to seriously deplete T-helper cells and effectively destroy the host's immune system.

e. No cure for AIDS has yet been discovered, though some treatments can hold certain symptoms in check for a while.

f. Recently, it has been shown that a deficiency of selenium, an essential trace element that is incorporated into certain proteins, is associated with HIV pathogenesis.

g. The AIDS virus is now thought to be transmitted only via direct contact with sexual fluids or blood.

a. The immune system can sometimes hurt the animal it is supposed to protect.

b. Some of the most common adverse effects are hypersensitivity reactions, including allergy.

c. Anaphylaxis, a type of hypersensitivity discovered in the early 1900s, involves reactions ranging from mild localized itching or hives to severe systemic reactions that involve skin rash, flushed skin, respiratory distress, vomiting, generalized shock, and even death.

d. These reactions all result from inflammation that is initiated by the release of histamine, which particularly affects the so-called shock tissues: The epithelium of breathing passages and the smooth muscle of the respiratory tree.

e. Allergic sensitivity is transferable, and this fact has been used in developing skin tests that involve injecting small amounts of allergins under the skin and checking for a localized reaction.

f. About 10—20 percent of humans have strong allergies to various substances.

g. Though allergic tendencies are inherited, the genetics is complex.

h. Complex-mediated hypersensitivity results from antigen-antibody complexes forming in certain tissues, passing through inflamed capillaries, and initiating blood-clotting and complement cascades (Figure 48.23).

i. An autoimmune disease results when the immune system reacts against normal body tissues.

j. This failure to distinguish "self" from "nonself" happens when molecules normally hidden from the immune system become exposed to it.

k. In rheumatoid arthritis, an infection or other disturbance allows antibodies to form against collagen and other connective tissues, resulting in antigen-antibody complexes that lead to local inflammation.

l. Lupus erythematosus is a disease that slowly causes lesions of the skin and internal organs and general wasting; it is apparently caused by antibodies that are made to intracellular proteins.

m. Figure 48.24 illustrates the structures of the most important proteins involved in immunity.