The Body Defenses Chapter 12
Immunity is the body’s ability to resist or eliminate potentially harmful foreign materials or abnormal cells. • The immune system plays a key role in this. – It defends against invading pathogens, removes “worn-out” cells, and identifies and destroys abnormal or mutant cells. – Inappropriate immune responses lead to allergies or autoimmune responses. – The primary pathogens are bacteria and viruses. Bacteria are non-nucleated, single-celled micro-organisms. Viruses are not cellular, consisting of a nucleic acid enclosed by a protein coat. Virulent forms of either can cause disease (pathogenic)
Leukocytes are the effectors of the immune system. There are five types. – – – • • • Neutrophils are highly mobile phagocytes. Eosinophils secrete chemicals that fight parasites. Basophils release histamine and heparin. Monocytes change into macrophages. B lymphocytes change into plasma cells that make antibodies. T lymphocytes are responsible for cell-mediated immunity. Most leukocytes arise from stem cells in the bone marrow. Lymphocytes arise from lymphocyte colonies in lymphoid tissue. Lymphoid tissue include the bone marrow, lymph nodes, spleen, tonsils, adenoids, appendix, and Peyer’s patches in the digestive tract. Pathogens in lymph are filtered by lymph nodes. Lymphocytes serve as macrophages there. The spleen performs a similar role on the blood. The thymus and bone marrow process T and B lymphocytes respectively.
Immune responses are either innate and nonspecific or adaptive and specific. • They differ in the timing and selectivity of the defense mechanism. • Innate, nonspecific, responses work immediately when the body is exposed to a threatening agent. They nonselectively defend against foreign invaders. They provide a first line of defense, with rapid but limited responses. • Adaptive, or acquired, immunity specifically targets foreign material to which the body has already been exposed. The body has had an opportunity to prepare for attack. This takes more time. • Neutrophils and macrophages are important in innate defense, along with several plasma proteins. • The responding phagocytic cells are covered with toll–like receptors. They recognize and bind to pathogenic markers. Other chemicals are secreted by the phagocytes of the adaptive immune system.
Innate immunity defenses include inflammation, interferon, natural killer cells, and the complement system. • Inflammation is a nonspecific response to foreign invasion or tissue damage. • Neutrophils and macrophages, phagocytic specialists, play a major role. Plasma proteins contribute. • Inflammation attempts to: – isolate, destroy, and inactivate the invaders. – remove debris. – prepare for subsequent healing and repair.
Inflammation responses are a series of events. • • • Resident macrophages defend against invasive bacteria during the first hour. Arterioles, serving the invaded area, dilate. Histamine is released to increase capillary permeability in the area. Plasma proteins can leave the blood and enter the area. The leakage of plasma proteins and fluid from the blood causes localized edema in the injured area. The fluid accumulation causes swelling, redness, and increased temperature in the area. The swelling causes pain. Fibrin formation walls off the area from surrounding tissues. Neutrophils or monocytes emigrate from the blood into the area. They adhere to the inside surface of capillaries by margination. They enter the interstitial spaces by diapedesis. They are guided to the areas where they are needed by chemotaxis.
Within a few hours of the beginning of the inflammatory response, there is leukocyte proliferation. • • • Neutrophil numbers may increase four or five times. Monocytes increase at a slower rate, forming macrophages. Bacteria are marked for destruction by opsonins. This allows phagocytes to distinguish among normal and foreign/abnormal cells. The opsonins are antibodies and one of the activated proteins of the complement system. Leukocytes destroy bacteria by phagocytosis. There is mediation of the inflammatory response by phagocyte-secreted chemicals. These chemicals include: nitric oxide (fron macrophages) lactoferrin (from neutrophils) histamine (increasing capillary permeability) kinins (formed from kininogens) endogenous pyrogen (induces fever development) leukocyte endogenous mediator (decreases plasma iron) acute-phase proteins from the liver
Finally the inflammatory process repairs tissues. – The repair can be perfect. Cell division replaces lost cells, replacing the injured area with the same kind of cells. – Scar tissue replaces nonregenerative tissues such as nerve and muscle. • Salicylates and glucocorticoid drugs suppress the inflammatory response. – Salicylates decrease histamine release. They also reduce fever by inhibiting the production of prostaglandins. – Glucocorticoids suppress most aspects of the inflammatory response.
Interferon transiently inhibits the multiplication of viruses in most cells. It interferes with viral replication. – It triggers the production of virus-blocking enzymes by potential host cells. The enzymes remain inactive unless cells are attacked by viruses. – Interferon is released nonspecifically from any cell infected by a virus. It can induce immunity against many different viruses in many other cells. – It can bind to and forewarn neighboring cells to viral attack. Interferon slows cell division. It has anticancer effects. • Natural killer cells destroy virus-infected cells and cancer cells on first exposure to them. – They lyse cell membranes upon first exposure to these cells. NK cells provide an immediate, nonspecific defense.
Complement punches holes in micro-organisms. • • • The complement system consists of plasma proteins produced by the liver. This is a nonspecific response. It is activated by exposure to particular carbohydrate chains on the surface of microbes and to antibodies produced by specific foreign invaders. The powerful complement cascade reinforces other general inflammatory tactics. C 1 of this cascade actives C 2 and so forth. C 5 through C 9 assemble into the membrane attack complex. This attacks the surface membrane of micro-organisms. Complement proteins have additional functions such as serving as chemotaxins and acting as opsonins.
Adaptive immune responses are antibody-mediated (humoral) immunity and cell-mediated immunity. • B cells differentiate and mature in the bone marrow. • The thymus gland processes T cells that migrate from the bone marrow. • B and T cells take up residence in lymphocyte colonies. There they produce new B and T cells. They occupy different lymphoid tissues. • Thymosin is a hormone that maintains T cell lineage. • An antigen induces an immune response against itself. Their presence allows B and T cells to distinguish between foreign invaders (antigenic) and normal cells.
B cells carry out antibodymediated immunity. • A given lymphocyte has receptors on its surface to recognize one unique antigen. The TLRs of innate effector cells recognize generic traits of all microbes. • Antigens stimulate B cells to convert into plasma cells • that produce antibodies. A plasma cell produces antibody molecules that can combine with a specific kind of antigen. All antibodies eventually enter the blood or lymph. • The antibody (immunoglobulin) subclasses are: – Ig. M - serves as the B cell surface receptor for antigen attachment – Ig. G - the most abundant antibody produced in large amounts – Ig. E - protects against parasitic worms and is the antibody mediator for common allergic responses – Ig. A - found in the secretions of the digestive, respiratory, and genitourinary systems – Ig. D - on the surface of many B cells with uncertain function
Antibodies are Y-shaped molecules. • • • All five classes are composed of five, interlinked polypeptide chains. Two are long, heavy chains and two are short, light chains arranged in the shape of a Y. They are classified according to properties of their tail regions. Characteristics of the arm regions of the Y determine the specificity of the antibody. Properties of the tail portion (heavy chains) determine the functional properties of the antibody. An antigen-binding site is on the tip of each arm. These antigen-binding sites are unique for each antibody and are responsible for the large variety of antibody molecules. The tail of each antibody is constant for all members of each class. The tail contains binding sites for particular mediators of antibody-induced activities.
Antibodies amplify innate immune responses to promote antigen destruction. • Antibodies can physically hinder antigens. • By neutralization they prevent harmful chemicals from interacting with susceptible cells. • They can bind to foreign cells by agglutination. • Amplification augments the immune response. Antibodies mark or identify foreign material, targeting it for destruction. This is followed by: • activation of the complement system; This sets of a cascade leading to the formation of the membrane attack complex. This is activated by an antibody. • enhancement of phagocytosis; • stimulation of killer cells; • Occasionally an exaggerated antigen-antibody response cause tissue damage. This is an immune complex disease.
Activated B-cell clones multiply and differentiate into plasma cells or memory cells. • Most are transformed into plasma cells. They produce and secrete Ig. G antibodies. Each antibody combines with an antigen, marking it for destruction. • During initial contact with a microbial antigen, the antibody response is delayed. Plasma cells are formed. It reaches its peak a a couple of weeks by the primary response. After this peak, antibody concentration decreases. • A small percentage of the B lymphocytes become memory cells. The remain dormant and expand a specific clone. Upon reexposure to the same antigen, they are more ready for immediate action than the original lymphocytes of the clone. • This secondary response is quicker, more potent, and longerlasting. This can be induced by disease or vaccination.
The large variety of B cells arises from the reshuffling of a small set of gene fragments. – Each different combination gives rise to a unique B cell clone. – The antibody genes of already-formed B cells are highly prone to mutation, further contributing to variation. • Active immunity results from exposure to an antigen. Passive immunity is from the transfer of preformed antibodies. – One example of passive immunity is the transfer of Ig. G antibodies from mother to fetus. – Passive immunity gives immediate protection. – Serum sickness is one drawback to receiving preformed antibodies.
Blood groups are a form of passive immunity. • • The ABO blood types are named by the presence of antigens on the surface of erythrocytes: A, B, AB (both antigens), or O (neither antigen). The ABO antibody makeup in a person is the opposite, by letter, to the antigen content: – – • • antibody A in blood type B antibody B in blood type A both antibodies in blood type O neither antibody in blood type AB By the transfusion reaction, if the antigen of the donor and antibody of the recipient match, by letter, the donated red cells can agglutinate in the blood of the recipient. For example, the donation of blood type A (antigen) to a person with blood type B (antibody A) can produce agglutination in the blood of the recipient. Blood type O is the universal donor (no ABO antigens). Blood type AB is the universal recipient (no ABO antibodies)
There are other blood-group systems. • A person with the Rh factor is Rh-positive. • A person without the Rh factor is Rh-negative. • An Rh negative person can produce anti-Rh antibodies when first exposed to the Rh factor. This can occur when an Rh-negative mother develops antibodies against the erythrocytes of an Rh-positive fetus. This condition is called the hemolytic disease of the newborn. • There about 12 minor human erythrocyte antigen systems.
Lymphocytes respond only to antigens presented to them by antigen-presenting cells. • Macrophages can be an antigen-presenting cells. They cluster around an appropriate B-cell clone, making the introduction. • Phagocytosis occurs, processing the raw antigen intracellularly and presenting the processed antigen, exposing it to the outer surface of the macrophage’s plasma membrane. • As a macrophage engulfs and ingests a microbe, it ingests it into antigenic peptides. Each binds to an MHC molecule. • The MHC transports the bound antigen to the cell surface, presenting it to passing lymphocytes. • Antigen-presenting macrophages secrete interleukin. This chemical mediator enhances the differentiation and proliferation of the now-activated B cell clone. Dendritic cells are antigenpresenting cells. Helper T cells help B cells.
T lymphocytes carry out cellmediated immunity. • They do not secrete antibodies. They bind directly to targets. T type killer cells release chemicals that destroy these targeted cells. • T cells are clonal and antigen specific. They acquire receptors for this specificity in the thymus. • T cells are activated foreign attack only when on the surface of a cell that carries foreign and self antigens. Both must be on a cell’s surface for T cell binding. • T cells learn to recognize foreign antigens only in combination with a person’s own tissue antigens. There is a dual antigen requirement. • A few days is required before T cells are activated to launch a cell-mediated attack.
The two types of T cells are cytotoxic and helper. Helper cells are the most numerous T cells. • • • Cytotoxic T cells secrete chemicals that destroy target cells. Most frequently they destroy cells infected with viruses. There is a clone of these cells specific for a particular virus. These T cells bind to the viral antigens and self-antigens on the surfaces of the viral- infected cells. The cytotoxic T cells release chemicals that destroy the attacked cell before the virus can enter the nucleus and start to replicate. Cytotoxic T cells also destroy targeted cells by releasing perforins. The exception to this is nerve cells. Viruses are released from the destroyed cells. They are destroyed in the extracellular fluid by phagocytic cells. Cell division replaces the lost body cells with healthy cells.
Helper T cells secrete chemicals that amplify the activity of other immune cells. • Cytokines are chemicals (with the exception of antibodies) secreted by helper T cells. They spur other immune cells to help ward off the invader. Examples of cytokines include the B-cell growth factor, interleukin 2, chemotaxins, and macrophagemigration inhibition factor. • There are two subsets of helper T cells that augment different patterns of immune responses by secreting different types of cytokines.
The immune system is normally tolerant of self-antigens. • Tolerance refers to preventing the immune system from attacking the person’s own tissues. There at least five different mechanisms. • By clonal deletion there is a triggering of the apoptosis of immature cells that would react with the body’s own proteins. • By clonal anergy a lymphocyte must receive two specific signals at the same time for activation. A single signal from a selfantigen turns off a compatible T cell, rendering the cell unresponsive to further exposure to the antigen. • By receptor editing, a B cell with a receptor for one of the body’s own antigens changes its receptor to a nonself version if it encounters a self antigen. • B antigen sequestering self molecules are hidden from the immune system. • A few tissues have immune privlege.
Autoimmune diseases arise from a loss of tolerance of selfantigens. There are several causes. • The exposure of normally inaccessible antigens induces an immune attack against them. • Normal self-antigens can be modified. • There is an exposure of the immune system to a foreign antigen almost structurally identical to a selfantigen. • Some may be related to pregnancy, arising from lingering fetal cells in the mother’s body after the pregnancy.
Genes called MHC produce MHC molecules. These self-antigens are plasma membrane glycoproteins. • They vary from one person to another. Their natural function is to direct the responses of T cells. • MHC molecules on cells block T cell binding. • Cytotoxic T cells do not bind to MHC self-antigens in the absence of a foreign antigen. Therefore, normal body cells are protected from lethal immune attack. • T cells become active only when they match a given MHCforeign peptide combination. • Cytotoxic T cells can respond to foreign antigens only in association with class 1 MHC glycoproteins. • Class II MHC glycoproteins, recognized by helper T cells, are confined to the surface of a few special types of immune cells. • T cells do bind with MHC antigens present on the surface of transplanted cells, accounting for their rejection.
By immune surveillance the T cell system recognizes and destroys newly arisen, potentially cancerous tumor cells. • A tumor consists of a clone of cells identical to the original mutated cell. A benign tumor does not infiltrate surrounding tissues. • Malignant tumors are invasive and cancerous. Their cells tend to metastasize. If these cells spread throughout the body, they cannot be removed surgically. • Untreated cancer is eventually fatal. • Most genetic mutations do not lead to cancer.
Immune surveillance depends on the interplay of cytotoxic T cells, NK cells, and macrophages plus interferon. They attack and destroy cancer cells. • NK cells are the first line of defense against cancer. • Cytotoxic T cells probably defend against virus-induced cancers. • Macrophages clear away the remains of dead cells and engulf and destroy cancer cells intracellularly. • Some cancer cells can avoid these immune mechanisms. Some cancer cells have counter-productive blocking antibodies that interfere with T cell function. • The immune system is regulated by the endocrine and nervous systems by negative feedback loops. • For example, cortisol mobilizes the body’s store of metabolic fuel. Lymphocytes and macrophages are responsive to blood-borne signals.
Abnormal functioning of the immune system can lead to immune diseases. • Immune deficiency diseases result from insufficient immune responses. The immune system does not respond adequately to foreign invasion. • For example, in severe combined immunodeficiency both B and T cells are lacking. • In HIV a virus invades and incapacitates helper T cells. • Inappropriate adaptive immune attacks cause reactions the harm the body. They include autoimmune responses, in which the immune system turns against the body. Another example is immune complex diseases, which damage tissues by violent reactions. • The third example is allergies.
An allergy is the acquisition of an inappropriate specific immune reactivity (hypersensitivity) to a normally harmless environmental substance. • Hypersensitivity can be immediate (within about 20 minutes after exposure to an allergen) or delayed, occurring a day or so after exposure. The difference is due to different mediators involved. • Triggers for hypersensitivity include pollen grains, bee stings, penicillin, certain foods, molds, dust, feathers, and animal fur. • Allergens bind to and elicit the synthesis of Ig. E antibodies. Their tail portions are attached to mast cells and basophils. These cells produce and store inflammatory chemicals such as histamine. • Chemical mediators include histamine, SRS-A, and eosinophil chemotactic factor
Other facts on allergies include: • Symptoms of immediate hypersensitivity vary. Usually the reaction is localized to the body site where the Ig. E-bearing cells first contact the allergen. Examples include hay fever, asthma, and the hives. • Antihistamines block some of these reactions. Adrenergic drugs and cortisol are often used. • Anaphylactic shock occurs when large amounts of chemical mediators enter the blood. Circulatory failure and bronchiolar constriction occur. • Immediate hypersensitivity is similar to the responses elicited from parasitic worms. • Delayed hypersensitivity is a T cell-mediated immune response. Allergens from poison ivy can produce this.
The most obvious external defense is the skin. • • • The skin is a barrier for the passage of most materials into the body. It consists of an outer protective epidermis and an inner connective tissue dermis. The epidermis consists of numerous layers of epidermal cells. It lacks a blood supply and has an outer, protective keratinized layer. The dermis has an abundance of blood vessels and specialized nerve endings. The blood vessels are involved in temperature regulation. Exocrine glands of the skin include sweat glands and sebaceous glands. Sweat glands are involved in temperature regulation for the body. The sebum from sebaceous glands protects the body surface. The hypodermis is a subcutaenous layer. It is mainly adipose tissue.
Specialized cells in the epidermis produce keratin and melanin. • They participate in immune defense. • Melanocytes produce the pigment melanin. It absorbs harmful UV rays. • Keratinocytes secrete the protective protein, keratin. • Langerhans cells are antigen-presenting cells. • Granstein cells inhibit skin-activated immune responses. • The skin synthesizes vitamin D.
Protective measures in body cavities include: • Secretions in the oral cavity (saliva) and the p. H of the stomach are examples of protective measures in the digestive system. • The genitourinary system protects through mucous secretions and its p. H. • The respiratory system has nasal hairs, adenoids, the mucous escalator, and alveolar macrophages for protection.