Adaptive/specific immunity Consists of antigen-specific defense mechanisms, immunological memory, and self/nonself antigen recognition. Adaptive immune cells include T-cells and B-cells. Cellular/cell-mediated immunity Direct cell-to-cell attack mechanisms; activation of phagocytes, antigen-specific cytotoxic T-cells, and the release of various cytokines in response to an antigen. Humoral/antibody-mediated immunity Indirect attack mechanisms; Antibodies produced by plasma cells stimulate multiple forms of attack. Innate/nonspecific immunity Consists of anatomical barriers (skin, hair, mucous membranes), chemical barriers (temperature, pH), phagocytes, and inflammatory responses. Innate immune cells include natural killer cells, mast cells, eosinophils, basophils, and the phagocytotic cells such as macrophages, neutrophils, and dendritic cells. Natural active immunity Naturally acquired active immunity occurs when a person is exposed to a live pathogen, and develops a primary immune response, which leads to immunological memory. This type of immunity is "natural" because it is not induced by deliberate exposure. Artificial active immunity Active immunity acquired by vaccination. When the vaccine is given, the body’s immune system detects this weakened or dead germ or germ part and reacts just as if a new full-blown infection occurred. It begins making antibodies against the vaccine material. These antibodies remain in the body and are ready to react if the same infectious organism attacks. In a sense, the vaccine tricks the body into thinking it is under assault, and the immune system makes weapons that will provide a defense when the real infection becomes a threat. Natural passive immunity This is a form of temporary immunity that results from acquiring antibodies from another person. The only natural way for this to happen is when a fetus acquires antibodies from the mother through the placenta before birth, or for a baby through breast-feeding after birth. Artificial passive immunity This is a form of temporary immunity that results from the injection of pre-formed antibody solution when a patient is incapable of producing antibodies fast enough to combat a disease. This solution specific to a pathogen is obtained from humans, horses, and other animals. This immune serum is used as emergency treatments against snakebites, tetanus, rabies, etc. Pathogen Anything that can cause disease; includes bacteria, viruses, fungi, parasites. First line of defense • Skin: Composed of keratin, a tough protein that a few pathogens can penetrate. Also, with the exception of axillary and pubic areas, it is too dry and poor in nutrients to support much microbial growth. Even the microbes that do adhere to the epidermis are continually cast off along with the exfoliation dead keratinocytes. Our skin also provides chemical mechanisms such as dermicidin, an antibacterial peptide found in our sweat. Peptides such as defensins are produced by keratinocytes, neutrophils, and macrophages to help destroy bacteria, viruses, and fungi. All of these actions are



enhanced by the presence of vitamin D (calcitriol), which indicates the benefits of sun exposure for one’s resistance to infection. • Mucous membrane: Lines all body cavities that are open to the outside environment. Mucus serves to trap pathogens and prevent further entry. • Enzymes: Found in tear, stomach acid, and saliva. The pH helps to destroy bacteria by destroying its cell walls. Acid mantle Part of our first line of defense; the acid mantle is a thin film of lactic and fatty acids on the epidermis that inhibits bacterial growth. This slightly acidic Second line of defense Nonspecific; WBCs destroy pathogens if they penetrate the first line of defense. Third line of defense Specific; B-cells respond to antigens by producing antibodies that carry out humoral immunity. T-cells regulate the immune response of other cells, directly attack cells carrying specific antigens, and carry out cell-mediated immunity. Cytokine Small proteins produced mainly by WBCs; play roles in cellular communication, inflammation and immune responses. Cytokines include interleukins, interferons, colony-stimulating factors, chemotactic factors, etc. Neutrophil Respond to bacterial infections by means of phagocytosis and respiratory burst. Respiratory burst is a series of reactions that result when a neutrophil detects bacteria in the immediate area, its lysosomes migrating to the cell surface and discharge their enzymes into the ECF. These enzymes then cause the neutrophil to rapidly absorb oxygen and reduce the oxygen molecules to superoxide anions, which meet with hydrogen ions to form hydrogen peroxide. Another lysosomal enzyme produces hypochlorite from chloride ions in the ECF. Superoxide, hydrogen peroxide, and hypochlorite ions are extremely toxic and form a chemical killing zone around the neutrophil that destroys far more bacteria than the neutrophil can destroy by phagocytosis alone. Eosinophil Found especially in the mucous membranes standing guard against parasites and allergens. They become concentrated in sites of allergy, inflammation, and parasitic infection. Eosinophils also produce superoxide and hydrogen peroxide to kill parasites. They also secrete enzymes that degrade and limit the action of histamine and other inflammatory chemicals that, unchecked, could cause tissue damage. Basophil Secrete chemicals that aid the mobility and action of other leukocytes. Leukotrienes are chemicals that activate and attract other neutrophils and eosinophils. Histamine is a vasodilator, which increases blood flow and speeds the delivery of leukocytes to the area. Heparin is an anticoagulant and inhibits the formation of blood clots that would impede leukocyte mobility. Mast Cell Similar to basophils; mast cells are filled with basophil granules. They are numerously found in connective tissue and release histamine among other substances during inflammatory and allergic reactions.



Natural killer (NK) cell NK cells continuously patrol the body “on the lookout” for pathogens or diseased host cells. They directly attack and destroy bacteria, cells of transplanted organs and tissues, cells infected with viruses, and cancer cells. Upon recognition of an enemy cell, the NK cell binds to it and releases proteins called perforins, which polymerize in a ring and create a hole in its plasma membrane. The hole allows for a rapid inflow of water and sodium. If this is not enough to kill the enemy cell, the NK cell also secretes granzymes (protein-degrading enzymes) through the hole made by the perforins, ultimately inducing apoptosis of the enemy cell. Naive lymphocytes Naive lymphocytes are not yet “battle-tested” or exposed to an antigen. A naive T-cell is a T-cell that has differentiated in the bone marrow, and has successfully undergone negative and positive selection (tests for self-tolerance) in the thymus (T-cell “school”). Among these are the naive forms of helper T cells (CD4+) and cytotoxic T cells (CD8+). A naive B cell is a B-cell that has not been exposed to an antigen. Once exposed, it either becomes a memory B-cell or a plasma cell that produces antibodies specific to the antigen that was originally bound. Regulatory T-cell Important in preventing autoimmune disease; TR cells limit the immune response by inhibiting mitosis and cytokine secretion by other T-cells. Helper T-cell Can’t kill, but can activate the cells that do and help call the shots for the adaptive immune response. TH cells have receptors that will only bind and respond to one specific combination of MHC-II proteins. Upon binding, T-cell activation! Cytotoxic T-cell The “effectors”! The heroes of cellular immune response! … They directly attack the foreign cells. When a TC cell recognizes an MHC-I protein on a diseased cell, it delivers a lethal hit of chemicals that will destroy it, and goes off in search of other enemy cells. These chemicals include perforin and granzymes (like NK cells!), interferons (inhibit viral replication and call and activate macrophages), and tumor necrosis factors, which kill cancer cells. Major histocompatibility complex (MHC) A family of genes on chromosome 6 that contain the genetic code for MHC proteins, proteins on APCs’ surfaces. MHC proteins act as “identification tags” that signify and label every cell in your body as belonging to you and not foreign. MHC-I protein Present on surfaces of all nucleated cells. MHC-I proteins mainly present epitopes to cytotoxic T-cells. MHC-II protein Present on surfaces of APCs (B-cells, dendritic cells, macrophages, etc.) MHC-II proteins mainly present epitopes to helper T-cells. Antigen-presenting cell (APC) Although the function of T-cells is to recognize and attack foreign antigens, they usually cannot recognize such antigens on their own and therefore require the help of APCs. Dendritic cells, macrophages, and B-cells function as APCs. Antigen presenting cells use MHC proteins to present pieces (epitopes of antigens) of foreign molecules to our T-cells. Once a T-cell is presented with the antigen, it can coordinate a full-scale counterattack on the invaders.



T-cell activation • Antigen recognition: T-cell activation begins when a TC or TH cell recognizes and binds to the epitope of the MHC protein of the APC. (TC cells only recognize MHC-I proteins and TH cells only recognize MHC-II proteins). • Costimulation: Before the response can go any further, the T-cell must bind to another protein on the same APC in order to “double-check” that an immune response is really necessary. • Clonal selection: Successful costimulation activates clonal selection, when the T-cell undergoes repeated mitosis and produces a large number of effector cells (TC or TH) or memory cells (TM). • Attack: TC cells attack and destroy abnormal cells with lethal hits. TH cells secrete cytokines and interleukins that stimulate multiple forms of attack such as increased leukopoiesis. Tumor necrosis factor (TNF) A type of cytokine secreted by TC cells that activate macrophages and kills cancer cells. Lethal hit Performed by TC cells. TC cells release perforins and granzymes by exocytosis. Perforins create pores through which granzymes can enter the target cell, stimulating apoptosis. Memory T-cell After clonal selection, some T-cells become TM cells. These cells are long-lived and much more numerous than naive T-cells. Aside from their abundance, they also require fewer steps to be activated and therefore respond to antigens a lot faster. Upon reexposure to the same antigen later in life, TM mount a quick attack called the T-cell recall response. This response allows for the destroying of the pathogen so quickly that no noticeable symptoms of illness occur. B-cell Unlike T-cells, B-cells cannot directly attack infected cells. Instead, B-cells produce antibodies that can hijack invaders as they travel in the blood. When they come across invaders, B-cells are stimulated into action and produce plasma cells and memory B-cells. Each plasma cell is an antibody factory; they are abundant in rough endoplasmic reticulum. Plasma cell A fully differentiated B-cell; has tons of rough endoplasmic reticulum to produce a single type of antibody. B-cell activation Antigen recognition: An immunocompetent B-cell has thousands of surface receptors for one antigen. B-cell activation begins when an antigen binds to several of these receptors, links them together, and is taken into the cell by receptor-mediated endocytosis. Antigen presentation: Remember, B-cells act as APCs. After the B-cell internalizes the antigen and displays the processed epitope on some of its MHC-II proteins on its surface, helper T-cells bind to it and secrete interleukins that activate the B-cell into clonal selection. Clonal selection: B-cell mitosis gives rise to a battalion of identical B-cells programmed against that specific initial antigen. Differentiation: Some cells of the clone become memory B-cells but most become plasma cells. The memory B-cells made here can lie in wait for years, ready to respond very rapidly in the bud any reinfection caused by the same antigen. Memory B-cells are found mainly in the germinal centers of lymph nodes and they mount a very rapid second/anamnestic response is reexposed to the same antigen.



Monocyte Leukocytes that emigrate from the blood into the connective tissues to transform into macrophages. Interferon S.O.S.! When certain cells, especially leukocytes are infected with viruses, they secrete proteins called interferons. Interferons are like “dying words” that alert and warn neighboring cells to protect them from the same oncoming infection. They bind to surface receptors on neighboring cells and activate second-messenger systems within so that they can be ready. Interferons also activate NK cells and macrophages to destroy infected cells. Antigen (Ag) is any molecule that triggers an immune response. Some antigens are free molecules such as venoms and toxins; and others are components of plasma membranes and cell walls. Small universal molecules such as glucose and amino acids are not antigenic; if they were our immune systems would constantly attack these molecules that are essential to our very survival. Their uniqueness allows the body to distinguish its own molecules from those of any other individual or organism. The immune system learned to distinguish self-antigens and nonself-antigens before birth.

Epitope Only certain regions of an antigen molecule can stimulate immune responses. An epitope is the part of an antigen to which an antibody attaches itself. Antibody A blood protein produced by the immune system in response to and counteracting a specific antigen. Antibody structure Antibodies are also called immunoglobulins. Immunoglobulins (Igs) are glycoprotein molecules produced by plasma cells. The basic structure of an antibody, the antibody monomer, is composed of 4 polypeptides linked by disulfide (-s-s-) bonds. The two heavy chains are about 400 amino acids long and the two light chains are about half that long. Each heavy chain has a hinge region where the antibody is bent, giving the monomer a T or Y shape. All four chains have a variable (V) region that gives the antibody its uniqueness. The rest of each chain is the constant (C) region, which has the same amino acid sequence in all antibodies of a given person. This region determines the mechanism of the antibody’s action.



Immunoglobulin ( Igs) A.k.a. antibodies! Immunoglobulins are glycoprotein molecules formed by plasma cells. Critical part of the immune response as they recognize and bind to antigens and aid in their destruction. IgA Found as a dimer in mucus, tears, milk, saliva, and intestinal secretions. It prevents pathogens from adhering to epithelia and penetrating underlying tissues. Also provides some passive immunity to the newborn (milk). IgD Found as a monomer as a transmembrane protein of B-cells, functions in activation of B-cells by antigens. IgE Found as a monomer as a transmembrane protein of basophils and mast cells. Stimulates them to release histamine. Important in immediate hypersensitivity reactions and attracting eosinophils to sites of parasitic infections. IgG Found as a monomer, constituting about 80% of circulating antibodies in blood plasma. Includes anti-D antibodies of Rh blood group. Small enough to pass through placenta to fetus to provide passive immunity. Triggers the complement system. IgM Monomer IgMs are transmembrane proteins of B-cells serving as antigen receptors. Pentamer IgMs are found in blood plasma and lymph and it is the predominant antibody produced in the primary immune response; has very strong agglutinating properties due to its many antigenbinding sites. Once antibodies are released by plasma cells, they can use four mechanisms to render antigens harmless: • Neutralization: Only certain regions of an antigen are pathogenic. Antibodies recognize these toxic regions and mask/cover them. • Complement fixation: IgM and IgG antibodies bind to enemy cells and change shape, exposing their complement-binding sites. This leads to complement proteins binding to the enemy’s cell surface, causing inflammation, phagocytosis, and cytolysis.



• Agglutination: Antibodies can cause agglutination; effective in mismatched blood transfusions and as a defense against bacteria. An antibody has 2 to 10 binding sites; thus, it can bind to antigen molecules on multiple enemy cells at once and stick them together, immobilizing them and prevent them from spreading through the tissues. • Precipitation: Similar process; antibodies link antigen molecules on the enemy cell (not whole cells) together which makes it easier for macrophages to carry out phagocytosis. Primary response The immune reaction after a person is exposed to a particular antigen for the first time. The appearance of protective antibodies is delayed for 3 to 6 days while naive B-cells multiply and differentiate into plasma cells to make the antibodies. As the plasma cells begin secreting the antibodies specific to that antigen, antibody titer begins to rise; IgM appears first, peaks in about 10 days, and soon declines. IgG levels rise as IgM declines, but even the IgG titer drops to a low level within a month. The primary response leaves the individual with immune memory of the antigen (during clonal selection, some became memory B-cells). Secondary response The immune reaction on the second/subsequent exposure to the same antigen; has a quicker response and lesser lag time than primary response. The quick reaction is due to the presence of memory Bcells that were specifically made according to the same antigen. These B-cells recognize and react rapidly due to prior knowledge on how to strategically fight against the antigen. Plasma cells form within hours so the IgG titer rises sharply; low levels of IgM are also secreted and quickly decline but IgG levels remain elevated for weeks to years conferring lasting protection. (This is humoral immunity; but humoral immunity does not last as long as cellular immunity). Antibody titer The antibody titer is a test that detects the presence and measures the amount of antibodies within a person's blood. The amount and diversity of antibodies correlates to the strength of the body's immune response. Booster shots Childhood vaccinations aim to induce an immune memory of a particular pathogen. However, like anything, it isn’t always perfect and the benefits can wear off. The memory B-cells produced for that particular pathogen may have either died off, or immune memory may have simply not taken place during the initial exposure. A booster shot is an additional dose of a vaccine needed periodically to “boost” the immune system. This may be because someone simply needs to restimulate his or her immune memory or an extra dose may help to maintain the highest level of protection by stimulating B-cell activation. We can test for immune memory after vaccinations by measuring the antibodies specific to that disease in the blood (antibody titer). Complement system A system of circulating proteins that assist antibodies in the destruction of pathogens. Coined “complement” because it “completes the actions of antibodies.” Complement protein Complement proteins are mainly synthesized by the liver and circulate in the blood in inactive form and are activated in the presence of pathogens. The inactive proteins are named with the letter C and a number such as C3. Activation splits them into fragments, which are identified by lower case letters after the number, for example C3a and C3b.



Activated complement proteins contribute to pathogen destruction by four methods: Inflammation, immune clearance, phagocytosis, and cytolysis. There are three routes in achieving these goals: the classical pathway, alternative pathway, and the lectin pathway. Classical pathway The classical pathway requires an antibody to get started; thus it is part of the adaptive immunity. The antibody binds to an antigen on the surface of a microbe and changes shape, exposing a pair of complement-binding sites. Complement C1 protein binds to these sites and sets of a reaction cascade. Like the cascade of blood coagulation, each step generates an enzyme that catalyzes the production of many more molecules at the next step; each step is an amplifying process so many molecules are the result from a small beginning. In the classical pathway, the cascade is called complement fixation (mentioned earlier). Alternative pathway The alternative pathway does not require an antibody to get started; thus is it part of the nonspecific immunity. Complement protein C3 slowly breaks down in the blood into C3a and C3b. C3b proteins bind directly to targets such as cancerous cells, viruses, bacteria, and yeasts. This too triggers a reaction cascade; this time with an autocatalytic effect in which C3b leads to the accelerated splitting of more C3 and production of even more C3b. Lectin pathway Lectins are plasma proteins that bind to carbohydrates. In the lectin pathway, a lectin binds to certain sugars of a microbial cell surface and sets off yet another reaction leading to C3b production. As you can see, the splitting of complement protein C3 into C3a and C3b is an intersection where all three pathways converge. These two C3 fragments then carry out these results of the complement system: • Inflammation: Complement protein C3a stimulates mast cells and basophils to secrete histamine and other inflammatory chemicals. It also activates and attracts neutrophils and macrophages (the two key cellular agents of pathogen destruction in inflammation). • Immune clearance: C3b binds pathogenic Ag-Ab complexes (antigen-antibody) to red blood cells. As these RBCs circulate through the liver and spleen, the macrophages residing in those organs then strip off and destroy the Ag-Ab complexes, leaving the RBCs unharmed. This way, foreign antigens from the bloodstream are cleared. • Phagocytosis: Bacteria, viruses, and other pathogens are phagocytized and digested by neutrophils and macrophages, BUT, these phagocytes cannot easily internalize “naked” microorganisms. C3b assists them by opsonization (opson- to prepare food). Opsonization is the process of C3b proteins coating pathogenic cells and serving as binding sites for macrophages. C3b proteins “butter up” pathogens to make them look more appetizing! • Cytolysis: In cytolysis (cyto- cell, lysis- breakdown), C3b splits another complement protein, C5, into C5a and C5b. C5b binds to the enemy cell and then attracts complement C6, C7, and C7. This conglomeration of proteins (now called C5b678), goes on to bind up to 17 molecules of complement C9 which ultimately forms a ring called the membrane attack complex. The complex forms a large, lethal hole in the target cell’s membrane. It can no longer maintain homeostasis; electrolytes (Na+, Ca+, K+) leak out, water flows rapidly in, and the cell ruptures!



Pyrogens: Fever-inducing agents. Endogenous pyrogens: (endo- from inside) Caused by our WBCs and macrophages. Exogenous pyrogens: (exo- from outside) Caused by bacteria and viruses. When our neutrophils and macrophages fight pathogens, they secrete a variety of polypeptides called endogenous pyrogens. These stimulate neurons of the anterior hypothalamus to raise the set point for body temperature. Prostaglandin E2 is secreted by the hypothalamus. Aspirin and ibuprofen reduce fever by inhibiting prostaglandin synthesis! When the set point for our temperature rises, a person shivers to generate heat and the cutaneous arteries constriction to reduce heat loss. This is the effect of fever, or pyrexia. Fever is commonly regarded as an undesirable side effect of illness and efforts are constantly made to reduce fever, but it’s actually our defense mechanism against fighting illness and does us more good than harm!

Reye syndrome In children, chickenpox or influenza is sometimes followed by a serious disorder called Reye syndrome. This disease is characterized by the swelling of brain neurons and swelling of liver viscera. Neurons die from hypoxia and pressure of the swelling brain, which results in nausea, vomiting, disorientation, seizures, and coma. About 30% of victims die; survivors suffer mental retardation. Reye syndrome can be triggered by the use of aspirin to control fever. Hypersensitivity An excessive, harmful immune reaction to antigens. Hypersensitivity includes reactions to tissues transplanted from another person, abnormal reactions to one’s own tissues, or allergens.



Allergens Environmental antigens such as mold, dust, pollen, vaccines, bee/wasp venom, animal dander, toxins from poisonous plates, nuts, milk, eggs, shellfish. Some drugs such as penicillin are allergenic to some people. Hyperemia The most immediate requirement for dealing with tissue damage and response to pathogen contact is to get defense leukocytes to the site quickly and this is achieved by hyperemia, the increase of blood flow to a localized area by vasodilation. AIDS Acquired immunodeficiency syndrome: A group of conditions caused by HIV. Characterized by a low Tcell count, the person succumbs to opportunistic infections.



HIV structure/function The human immunodeficiency virus has an inner core consisting of a protein capsid that encloses two RNA molecules, two enzymes called reverse transcriptase, and other enzymes. The capsid is enclosed in another layer of viral proteins called the matrix. External to this is the viral envelope composed of phospholipids and glycoproteins derived from the host cell. Like other viruses, HIV can only be replicated by living host cells (person’s own). It invades other T-cells, dendritic cells, and macrophages. HIV binds to our cells and tricks them to internalize them; once inside our cells the reverse transcriptase uses its RNA as a template to synthesize DNA (the opposite of usual genetic transcription). Viruses that carry out this reverse transcription are called retroviruses. The new DNA is inserted into the host cell when it may lie dormant for years. When activated, it induces the host cell to replicate the “bad” DNA, thus producing new viruses.

SCID Severe combined immunodeficiency disease: A group of disorders caused by recessive alleles; results in the scarcity or absence of both T-cells and B-cells. Children with SCID are highly vulnerable to opportunistic infections and must live in protective enclosures. The most publicized case of SCID was David Vetter, a boy who spent his life in sterile plastic chambers before finally succumbing at age 12 to cancer triggered by a viral infection. Transplants of bone marrow or fetal thymus may offer hope to victims of SCID.