Microbiology Chapter 17: Adaptive Immunity

Difference between PAMPs and antigens?

-PAMPs are molecule structures found on numerous pathogens whereas -Antigens are unique to a specific pathogen

Causative agent of chicken pox?

Varicella-zoster virus

antigen got its name?

antibody generator -sometimes referred to as immunogens

MHC II

In contrast, MHC II molecules are only found on macrophages, dendritic cells, and B cells; they present abnormal or nonself pathogen antigens for the initial activation of T cells.

Inactivated Vaccines

Inactivated vaccines contain whole pathogens that have been killed or inactivated with heat, chemicals, or radiation. For inactivated vaccines to be effective, the inactivation process must not affect the structure of key antigens on the pathogen. Because the pathogen is killed or inactive, inactivated vaccines do not produce an active infection, and the resulting immune response is weaker and less comprehensive than that provoked by a live attenuated vaccine. Typically the response involves only humoral immunity, and the pathogen cannot be transmitted to other individuals. In addition, inactivated vaccines usually require higher doses and multiple boosters, possibly causing inflammatory reactions at the site of injection. Despite these disadvantages, inactivated vaccines do have the advantages of long-term storage stability and ease of transport. Also, there is no risk of causing severe active infections. However, inactivated vaccines are not without their side effects. Table lists examples of inactivated vaccines.

MHC I

MHC I molecules are found on all nucleated cells; they present normal self-antigens as well as abnormal or nonself pathogens to the effector T cells involved in cellular immunity.

epitopes

the part of an antigen molecule to which an antibody attaches itself -a single antigen may possess several different epitopes & different antibodies may bind to different epitopes on the same antigen

what molecular class (macromolecule) do antigens belong to?

they may belong to any number of classes, including carbohydrates, lipids, nucleic acids, proteins, and any combination of these molecules -in general, more complex molecules are more effective as antigens; such as proteins (capable of stimulating both humoral and cellular immunity); whereas, carbs are less complex/effective and can only stimulate humoral immunity; lipids/nucleic acids least antigenic

Adaptive Immunity: Overview

*2 arms of adaptive immunity -(1) Humoral immunity; antibodies are immune facilitators & Clonal selection to activate appropriate B cells -(2)Cell-mediated Immunity; antigen presentation & clonal section to activate appropriate T cells *Cytokines are chemical messengers of the immune system *Antigens are immune response triggers *Immune memory as defining feature of adaptive immunity -secondary responses are very, very fast and very, very effective *Humoral Immunity -fights antigens OUTSIDE cells; EX: bacteria, protozoa, helminths, and toxins -produces plasma cells that secrete protein antibodies that combat antigens -B cells are lymphocytes that are created and mature in the red bone marrow; recognize antigens with B cell receptors (BCR) & Make antibodies & Named for bursa of Fabricius in birds -IMAGE: structure of antibody (Y); two antigen-binding sites; light chain on outside and disulfide bridges connecting two light to two heave; heavy chain on inside; variable region on distal part of constant region & constant region on proximal part *cell mediated immunity -fights antigens INSIDE cells and help fight other infections; EX: viruses, intracellular bacteria & cancers -produces cytotoxic T lymphocytes that destroy host-infected cells -T cells are lymphocytes that are created in red bone marrow mature in the thymus; recognize antigens with T cell receptors (TCR) & Make cytokines & Named for thymus

T Cell-Independent Activation of B cells

*Activation of B cells without the cooperation of helper T cells is referred to as T cell-independent activation and occurs when BCRs interact with T-independent antigens. T-independent antigens (e.g., polysaccharide capsules, lipopolysaccharide) have repetitive epitope units within their structure, and this repetition allows for the cross-linkage of multiple BCRs, providing the first signal for activation (Figure). Because T cells are not involved, the second signal has to come from other sources, such as interactions of toll-like receptors with PAMPs or interactions with factors from the complement system. Once a B cell is activated, it undergoes clonal proliferation and daughter cells differentiate into plasma cells. Plasma cells are antibody factories that secrete large quantities of antibodies. After differentiation, the surface BCRs disappear and the plasma cell secretes pentameric IgM molecules that have the same antigen specificity as the BCRs (Figure). The T cell-independent response is short-lived and does not result in the production of memory B cells. Thus it will not result in a secondary response to subsequent exposures to T-independent antigens.

Antigen Presenting Cells (APCs)

*All APCs have MHC II *APC: -B cells -Innate immunity phagocytes; EX: macrophages, neutrophils, dendritic cells, mast cells

Antigen-Antibody Binding -def *Define -agglutination -opsonization -neutralization -activation of complement -antibody-dependent cell-mediated cytotoxicity (ADCC)

*An antigen-antibody complex forms when antibodies bind to antigens -strength of the bond is the affinity -protects the host by tagging cells/molecules for destruction by phagocytes and other cells; EX: agglutination, opsonization, neutralization, antibody-dependent cell-mediated cytotoxicity (ADCC) -activation of the complement system *Protective mechanism of binding antibodies to antigens -agglutination = reduces number of infectious units to be dealt with -opsonization = coating antigen with antibody enhances phagocytosis -neutralization = blocks adhesion of bacteria and viruses; blocks attachment of toxin -activation of complement = causes inflammation and cell lysis -antibody-dependent cell-mediated cytotoxicity (ADCC) = antibodies cause destruction by macrophages

Cell-Mediated Immunity

*Antigen presenting cells (APC) *T-helper cells [T(subH) cells] *Extracellular killing -cytotoxic T cells [T(subC) cells or CTL] -Natural killer cells (NK cels) -ADCC (antibody-dependent cell-mediated cytotoxicity) *Clonal section and expansion of T cells -Immunological memory

Antigens

*Antigens: antibody generators -substances that cause the production of antibodies -usually components of invading microbes or foreign substances -antibodies interact with epitopes, or antigenic determinants on the antigen

Clonal Selection of B Cells with T-Dependent Antigen

*B cells act as an APC -Inactive B cells have B cell receptors (BCR) that bind to protein antigens -B cells internalize and process protein antigens -antigen fragments are displayed on MHC class II molecules *All APC present protein antigens on MHC II: -T helper cell contacts the displayed antigen fragment and releases cytokines that activate more and more B & T cells -B & T cells undergo proliferation (clonal expansion) *Clonal selection and expansion differentiates B cells into -antibody-producing plasma cells for secondary immune responses -clonal deletion eliminates any harmful B cells (self-reacting) *ONLY B CELLS SPECIFIC FOR THE CURRENT ANTIGEN ARE ACTIVATED!! *STEPS -1. B cell receptors recognize and attach to protein antigen -2. protein antigen is internalized into the B cell -3. antigen fragments are presented on MHC II on the surface of the B cell -4. T helper cell that recognizes this antigen fragment is activated and releases cytokines, activating B cell -5. Activated B cell begins clonal expansion, producing an army of antibody-producing plasma cells and memory cells

Clonal Selection of B cells

*B cells activated in 2 ways -1. Direct activation by T-independent antigen -2. Activation by T-dependent antigen though MHC II and T(subH) cells *T-independent antigen -polysaccharide and lipopolysaccharide antigens -directly activate B cells without the help of T(subH) cells -provoke a weak immune response -no memory *T-dependent antigen -protein antigens -antigen that requires T(subH) cells to activate B cells -B cells act as an APC and present to T(subH) cells

Humoral Immunity Responses

*B cells combat EXTRACELLULAR pathogens -mature in the bone marrow -migrate from the bone marrow to the lymphatic system -attach to antigens via B-cell receptors (BCRs); 1st step in activating T-independent immunity; similar to Ig proteins

Vaccines

*Chinese children inhaling smallpox scabs?! *Turkish children having smallpox scabs needled into them?! -YES!! -Variolation = inoculation of smallpox into the skin *Jenner improved the process of inocculating cowpox to prevent smallpox -pasteur later termed it vaccination (vacca = cow) *vaccine: suspension of a microbe or fractions of a microbe that induce immunological memory

*Cytokines -define *Define these: -interleukins -chemokines -interferons (IFN) -tumor necrosis factor (TNF) -hematopoietic cytokines -overproduction?

*Cytokines are chemical messengers of the immune -Interleukins: cytokines between leukocytes -Chemokines: induce migration of leukocytes -Interferons: (IFN): interfere with viral infections of host cells -Tumor necrosis factor (TNF): involved in the inflammation of autoimmune diseases -Hematopoietic cytokines: control stem cells that develop into red and white blood cells -overproduction of cytokines can lead to exaggerated immune responses (potentially fatal)

Activation of Cytotoxic T cells

*Cytotoxic T cells (also referred to as cytotoxic T lymphocytes, or CTLs) are activated by APCs in a three-step process similar to that of helper T cells. *The key difference is that the activation of cytotoxic T cells involves recognition of an antigen presented with MHC I (as opposed to MHC II) and interaction of CD8 (as opposed to CD4) with the receptor complex. *After the successful co-recognition of foreign epitope and self-antigen, the production of cytokines by the APC and the cytotoxic T cell activate clonal proliferation and differentiation. Activated cytotoxic T cells can differentiate into effector cytotoxic T cells that target pathogens for destruction or memory cells that are ready to respond to subsequent exposures. *As noted, proliferation and differentiation of cytotoxic T cells is also stimulated by cytokines secreted from TH1 cells activated by the same foreign epitope. The co-stimulation that comes from these TH1 cells is provided by secreted cytokines. Although it is possible for activation of cytotoxic T cells to occur without stimulation from TH1 cells, the activation is not as effective or long-lasting.

Inactivated Viruses

*Description -Whole pathogen killed or inactivated with heat, chemicals or radiation *Advantages -Ease of storage and transport; no risk of severe active infection *Disadvantages -Weaker immunity (humoral only) -Higher doses and more boosters required *Examples -Cholera, hepatitis A, influenza, plague, rabies

Live Attenuated Vaccines

*Description -weakened strain of whole pathogen *Advantages -cellular and humoral immunity; long-lasting immunity; transmission of contacts *Disadvantages -difficult to store and transport; risk of infection in immunocompromised; risk of reversion *Examples -chickenpox, german measles, measles, mumps, tuberculosis, typhoid fever, yellow fever

Extracellular killing by NK cells

*Extracellular cell-mediated killing *kill cells without MHC class I -kill virus-infected, if infection reduces MHC I expression -kill tumor cells, if cancer reduces MHC I expression -kill eukaryotic microbes (no MHC I) *NK releases perforin and granzyme that induce apoptosis in the infected cell

Memory helper T cells

*Function -"Remember" a specific pathogen and mount a strong, rapid secondary response upon re-exposure

T(subH)17 cells

*Function -Stimulate immunity to specific infections such as chronic mucocutaneous infections

T(subH) 2 cells

*Functions -stimulate B cell activation and differentiation into plasma cells and memory B cells -direct antibody class in switching B cells

T(subH)1 cells

*Functions: -stimulate cytotoxic T cells and produce memory cytotoxic T cells -stimulate macrophages and neutrophils (PMNs) for more effective intracellular killing of pathogens -stimulate NK cells to kill more effectively

Clonal selection and expansion of T cells with T-dependent antigen

*clonal selection and expansion differentiates T cells into -active T(subH) cells and T(subC) cells for primary immune responses -long-lived memory T(subH) cells for secondary immune responses -clonal deletion eliminates any harmful T cells(self-reacting) *ONLY T CELLS SPECIFIC FOR THE CURRENT ANTIGEN ARE ACTIVATED

Haptens

*essentially free epitopes that are not part of the complex 3D structure of a larger antigen antigens too small to provoke immune responses; attach to carrier molecules (incomplete antigens)

Activation of Helper T Cells -HOW? -STEPS?

*Helper T cells can only be activated by APCs presenting processed foreign epitopes in association with MHC II. -1. The first step in the activation process is TCR recognition of the specific foreign epitope presented within the MHC II antigen-binding cleft. -2. The second step involves the interaction of CD4 on the helper T cell with a region of the MHC II molecule separate from the antigen-binding cleft. This second interaction anchors the MHC II-TCR complex and ensures that the helper T cell is recognizing both the foreign ("nonself") epitope and "self" antigen of the APC; both recognitions are required for activation of the cell. -3. In the third step, the APC and T cell secrete cytokines that activate the helper T cell. The activated helper T cell then proliferates, dividing by mitosis to produce clonal naïve helper T cells that differentiate into subtypes with different functions (Figure).

T-Dependent antigens

*Humoral = antibody-mediated immune system; control of freely circulating pathogens -Extracellular protein antigens -(1) A-B cell binds to the T-dependent antigen for which it is specific. HELP IS REQUIRED FROM A T(subH) CELL!! -(2) The B cell, WITH HELP FROM A T(subH) CELL, differentiates into a plasma cell --memory cells: some T and B cells differentiate into memory cells that respond rapidly to any secondary encounter with an antigen. -(3) Plasma cells proliferate and produce antibodies against the antigen. *Cellular =(cell-mediated) immune system; control of intracellular pathogens -intracellular antigens are expressed on the surface of an APC, a cell infected by a virus of a bacterium, or a parasite -(1) A T cell binds to MHC-antigen complexes on the surface of the infected cell, activating the T cell (with its cytokine receptors) --cytokines active T helper cell --cytokines activate macrophage -(2) Activation of macrophage (enhanced phagocytic activity) --cytokines for the T(subH) cell transform B cells into antibody-producing plasma cells -(3) CTLP becomes an activated cytotoxic T lymphocyte (CTL) able to induce apoptosis of the target cell --lysed target cell

T(subH cells) aka Helper T cells

*IMAGE STEPS -1. APC encounters an ingests a microbe. Antigens are enzymatically processed, combine with MHC class II molecules, and are displayed on the surface of the APC -2. TCR on the surface of a T helper cell binds to the MHC II-antigen complex. The T helper cell is activated and produces cytokines. -3. The activated T helper cell proliferates and activates B cells, activates cytotoxic T cells, and become memory cells *TCRs on the T(subH) cell recognize and bind to the protein antigen fragment and MHC II on APC *APC of the T(subH) secrete a costimulatory molecule, activating the T(subH) cell *T(subH) cells produce cytokines and differentiate into -T(subH)1 cells -T(subH)2 cells -T(subH)17 cells -T(subREG) cells -memory helper cells

Extracellular killing by CTL

*IMAGE STEPS -1. a normal cell will not trigger a response by a cytotoxic T lymphocyte (CTL), but a virus-infected or cancer cell produces abnormal endogenous antigens -2. the abnormal antigen is presented on the cell surface with MHC I molecules. Binding of T(subH)1 cell promotes secretions of cytokines -3. the cytokines activate a precursor, CTL, which produces a clone of CTLs. -4. The CTL induces destruction of the virus-infected cell by apoptosis *intracellular cell-mediated killing *activated into cytotoxic T lymphocyte (CTL) with the help of T(subH) cell and cytokines *CTLs recognize and kill self cells altered by infection/cancer -carrying non-self antigens + MHC class I on their surface *CTL releases perforin and granzyme that induce apoptosis in the infected cell *Perforin protein causes pore to form in the plasma membrane like the complement MAC *Granzyme proteins induce apoptosis *apoptosis is programmed cell death -normal cell process to recycle cells -also prevents the spread of virus from infected cells into other cells -cells destroy their genome, causing the membrane to bulge outward via blebbing -phagocytes clean everything up

Big Picture: Immunity

*Innate immunity = rapid responses to a broad range of microbes; PRIMITIVE -External defenses = skin, mucous membranes, secretions -Internal defenses = phagocytes, antimicrobial proteins, inflammatory response, NK cells -Adaptive immunity = slower responses to specific microbes; ADVANCED; humoral immunity (antibodies) & cell-mediated immunity (cytotoxic cells) *Two branches of immune system -(1) innate immunity: nonspecific responses present before exposure to an agent; inflammation response & fever -(2) Adaptive immunity: develops after exposure to an agent and has memory; Humoral immunity uses B cells to produce antibodies to bind targets & Cell-mediated uses cytotoxic cells to directly destroy targets

Development of vaccines

*Less profitable than medicine!! -viagra makes a ton of money -saving children's lives with 3 shots, not so much *Trends in vaccine development -develop vaccines without the use of animals as hosts; cell culturing (EX: influenza vaccines in chicken eggs) saves $$ -recombinant vaccines from plants as a renewable source of vaccine -oral vaccines for mucosal infections; cholera, polio, rotavirus, adenovirus -redressing chronic diseases where vaccine development failed; malaria, gonorrhea, syphilis -development of vaccines that favor cellular immunity and not humoral

Adaptive Immunity: 4 Types

*Natural Immunity = is acquired through normal life experiences of a human and is not induced -Active Immunity (memory) = is the consequence of a person developing his or her immune response to a microbe. EX: infection -Passive Immunity (no memory) = is the consequence of one person receiving preformed immunity made by another person. EX: maternal antibody from breastfeeding *Artificial Immunity = is that produced purposefully through medical procedures (also called immunization) -Active Immunity (memory) = is the consequence of a person developing his or her immune response to a microbe. EX: vaccination -Passive Immunity (no memory) = is the consequence of one person receiving preformed immunity made by another person. EX: Immune globulin therapy

B Cell Production and Maturation -how produced? -STEPS of maturation

*Like T cells, B cells are formed from multipotent hematopoietic stem cells (HSCs) in the bone marrow and follow a pathway through lymphoid stem cell and lymphoblast (see [link]). *Unlike T cells, however, lymphoblasts destined to become B cells do not leave the bone marrow and travel to the thymus for maturation. Rather, eventual B cells continue to mature in the bone marrow. -1. The first step of B cell maturation is an assessment of the functionality of their antigen-binding receptors. This occurs through positive selection for B cells with normal functional receptors. -2. A mechanism of negative selection is then used to eliminate self-reacting B cells and minimize the risk of autoimmunity. Negative selection of self-reacting B cells can involve elimination by apoptosis, editing or modification of the receptors so they are no longer self-reactive, or induction of anergy in the B cell. -3. Immature B cells that pass the selection in the bone marrow then travel to the spleen for their final stages of maturation. There they become naïve mature B cells, i.e., mature B cells that have not yet been activated.

B-Cell Receptors

*Like T cells, B cells possess antigen-specific receptors with diverse specificities. *Although they rely on T cells for optimum function, B cells can be activated without help from T cells. *B-cell receptors (BCRs) for naïve mature B cells are membrane-bound monomeric forms of IgD and IgM. They have two identical heavy chains and two identical light chains connected by disulfide bonds into a basic "Y" shape (Figure). The trunk of the Y-shaped molecule, the constant region of the two heavy chains, spans the B cell membrane. The two antigen-binding sites exposed to the exterior of the B cell are involved in the binding of specific pathogen epitopes to initiate the activation process. *In order to be prepared to react to a wide range of microbial epitopes, B cells, like T cells, use genetic rearrangement of hundreds of gene segments to provide the necessary diversity of receptor specificities. *The variable region of the BCR heavy chain is made up of V, D, and J segments, similar to the β chain of the TCR. *One important difference between BCRs and TCRs is the way they can interact with antigenic epitopes. Whereas TCRs can only interact with antigenic epitopes that are presented within the antigen-binding cleft of MHC I or MHC II, BCRs do not require antigen presentation with MHC; they can interact with epitopes on free antigens or with epitopes displayed on the surface of intact pathogens. Another important difference is that TCRs only recognize protein epitopes, whereas BCRs can recognize epitopes associated with different molecular classes (e.g., proteins, polysaccharides, lipopolysaccharides). *Activation of B cells occurs through different mechanisms depending on the molecular class of the antigen. Activation of a B cell by a protein antigen requires the B cell to function as an APC, presenting the protein epitopes with MHC II to helper T cells. Because of their dependence on T cells for activation of B cells, protein antigens are classified as T-dependent antigens. In contrast, polysaccharides, lipopolysaccharides, and other nonprotein antigens are considered T-independent antigens because they can activate B cells without antigen processing and presentation to T cells.

Antigen Presentation with MHC I Molecules

*MHC I molecules, found on all normal, healthy, nucleated cells, signal to the immune system that the cell is a normal "self" cell. In a healthy cell, proteins normally found in the cytoplasm are degraded by proteasomes (enzyme complexes responsible for degradation and processing of proteins) and processed into self-antigen epitopes; these self-antigen epitopes bind within the MHC I antigen-binding cleft and are then presented on the cell surface. Immune cells, such as NK cells, recognize these self-antigens and do not target the cell for destruction. However, if a cell becomes infected with an intracellular pathogen (e.g., a virus), protein antigens specific to the pathogen are processed in the proteasomes and bind with MHC I molecules for presentation on the cell surface. This presentation of pathogen-specific antigens with MHC I signals that the infected cell must be targeted for destruction along with the pathogen. Before elimination of infected cells can begin, APCs must first activate the T cells involved in cellular immunity. If an intracellular pathogen directly infects the cytoplasm of an APC, then the processing and presentation of antigens can occur as described (in proteasomes and on the cell surface with MHC I). However, if the intracellular pathogen does not directly infect APCs, an alternative strategy called cross-presentation is utilized. In cross-presentation, antigens are brought into the APC by mechanisms normally leading to presentation with MHC II (i.e., through phagocytosis), but the antigen is presented on an MHC I molecule for CD8 T cells. The exact mechanisms by which cross-presentation occur are not yet well understood, but it appears that cross-presentation is primarily a function of dendritic cells and not macrophages or B cells.

Major Histocompatibility Complex

*MHC genes encode molecules on the surface of host cells -Class I MHC are on the membrane of all nucleated animal cells; identify "self" from "non-self" (cancerous, infected, transplanted cells); "Non-self" cells killed (cell-mediated immunity) -Class II MHC are on the surface of antigen-presenting cells (APC)

IgE

*Monomer *2 binding sites (valence of 2) *0.002% of serum antibodies *On mast cells, basophils and in blood *Cause the release of histamines when bound to antigen *Lysis of parasitic worms -least abundant in serum -Fc region of IgE binds to basophils and mast cells -Fab region of the bound IgE then interacts with specific antigen epitopes, causing the cells to release potent pro-inflammatory mediators -the inflammatory reaction resulting from the activation of mast cells and basophils aids in the defense against parasites but this rxn is also central to allergic rxns

IgA

*Monomer *2-4 binding sites (valence of 2-4) *13% of serum antibodies *Mucous membranes, saliva, tears, and breast milk *Prevent microbial attachment to mucous membranes -one of the important functions of secretory IgA is to trap pathogens in mucus so that they can later be eliminated from the body

IgG

*Monomer (very small) *2 binding sites (valence of 2) *80% of serum antibodies *In the blood, lymph, and intestine *Cross the placenta; trigger complement enhance phagocytosis; neutralize toxins and viruses; protect the fetus -occurs in large numbers during the secondary immune response -most versitile

IgD

*Monomer 2 binding sites (valence of 2) *0.02% of serum antibodies *Structure similar to IgG *In blood, lymph and on B cells *No well-defined functions; assists in the immune response on B cells -membrane-bound monomer, found on surface of B cells, where it serves as an antigen-binding receptor -IgD is not secreted by cells, and only trace amounts are detected in serum, which are likely to come from degradation of old B cells and the release of IgD molecules from their cytoplasmic membranes

Safety of vaccines

*On rare occasions, vaccines can cause the disease *No medical or scientific proof of MMR vaccines being linked to autism *Safest and most effective means of preventing infectious disease in children *Concerns about antigenic overload/side effects -in 2015, there were 4,606 proven bad rxns in the US -in 2015, $225 million in compensation

Differentiation of Cytotoxic T Cells

*Once activated, cytotoxic T cells serve as the effector cells of cellular immunity, recognizing and kill cells infected with intracellular pathogens through a mechanism very similar to that of NK cells. *However, whereas NK cells recognize nonspecific signals of cell stress or abnormality, cytotoxic T cells recognize infected cells through antigen presentation of pathogen-specific epitopes associated with MHC I. *Once an infected cell is recognized, the TCR of the cytotoxic T cell binds to the epitope and releases perforin and granzymes that destroy the infected cell (Figure). Perforin is a protein that creates pores in the target cell, and granzymes are proteases that enter the pores and induce apoptosis. This mechanism of programmed cell death is a controlled and efficient means of destroying and removing infected cells without releasing the pathogens inside to infect neighboring cells, as might occur if the infected cells were simply lysed.

IgM

*Pentamer (5 monomers held with a j chain) *10 binding sites (valence of 10) *6% of serum antibodies *In the blood *Cause clumping of cells and viruses (10 binding sites) *first response to an infection; short-lived -Pathogen-specific IgM = a 'Valuable diagnostic marker during active or recent infections b/c IgM is the first antibody produced and secreted by B cells during primary immune responses

Innate & Adaptive Immunity Meet

*Phagocytes are the ultimate effector of immunity -garbage disposals of the body *Adaptive immunity uses various systems to help phagocytes do phagocytosis

Antigen Presentation with MHC II Molecules

*STEPS: -1. a bacterium is engulfed by phagocytosis into a dendritic cell and is encased in a phagosome -2. lysosomes fuse with the phagosome (form phagolysosome) and digest the bacterium -3. Immunodominant epitopes are associated with MHC II and presented on the cell surface

Antibodies

*Secreted proteins called immunoglobulins (g) *Valence is the number of anti-binding sites on an antibody -EX: bivalent antibodies have 2 binding sites *4 protein chains form a Y-shape molecule -2 identical chains and 2 heavy chains joined by disulfide bonds -Variable (v) regions are at the ends of each arms; bind epitopes -constant [F(subC] region is identical for a particular Ig class *5 classes of Ig (IgM, IgG, IgA, IgE, IgD)

T cells

*T cells are grouped by their clusters of differentiation (CD) proteins on their surface *CLASS *HELPER T CELLS -Surface CD molecule:CD4 -Activation: APCs presenting antigens associated with MHC II -Functions: Orchestrate humoral and cellular immunity; involved in the activation of macrophages and NK cells *REGULATORY T CELLS -Surface CD molecule: CD4 -Activation: APCs presenting antigens associated iwth MHC II -Functions: Involved in peripheral tolerance and prevention of autoimmune responses *CYTOTOXIC T CELLS -Surface CD molecule: CD8 -Activation: APCs infected nucleated cells presenting antigens associated with MHC I -Functions: Destroy cells infected with intracellular pathogens

Cell-mediated immunity responses

*T cells combat INTRACELLULAR pathogens and help fight other infections -mature in the thymus; thymic selection eliminates immature T cells -migrate from the thymus to lymphatic system -attach to antigens via T-cell receptors (TCRs); 1st step in activating T-dependent immunity; similar to Ig proteins

Maturation of T lymphocytes

*The maturation of thymocytes within the thymus can be divided into tree critical steps of positive and negative selection, collectively referred to as thymic selection. -1. The first step of thymic selection occurs in the cortex of the thymus and involves the development of a functional T-cell receptor (TCR) that is required for activation by APCs. Thymocytes with defective TCRs are removed by negative selection through the induction of apoptosis (programmed controlled cell death). -2. The second step of thymic selection also occurs in the cortex and involves the positive selection of thymocytes that will interact appropriately with MHC molecules. Thymocytes that can interact appropriately with MHC molecules receive a positive stimulation that moves them further through the process of maturation, whereas thymocytes that do not interact appropriately are not stimulated and are eliminated by apoptosis. -3.The third and final step of thymic selection occurs in both the cortex and medulla and involves negative selection to remove self-reacting thymocytes, those that react to self-antigens, by apoptosis. This final step is sometimes referred to as central tolerance because it prevents self-reacting T cells from reaching the bloodstream and potentially causing autoimmune disease, which occurs when the immune system attacks healthy "self" cells.

Principles and Effects of Vaccination

*Vaccines provoke a primary immune response -T-dependent antigens -leads to the formation of antibodies and memory cells *Pre-stages a rapid, intense secondary response *Herd immunity: immunity in most of the population -outbreaks are sporadic due to the lack of susceptible individuals

T-independent antigens

*humoral = antibody-mediated immune system; control of freely circulating pathogens -Extracellular polysaccharide or lipopolysaccharide antigens -(1) A-B cell binds to the T-antigen for which it is specific. NO HELP REQUIRED -(2) The B cell, WITHOUT HELP, differentiates into a plasma cell. Some B cells become memory cells -(3) Plasma cells proliferate and produce antibodies against the Antigen

Adaptive Immunity

*know graph of primary vs secondary responses *Adaptive immunity: defenses that target a specific pathogen -acquired through infection or vaccination -uses B & T lymphocytes -Primary response: 1st time the immune system combats a particular foreign substance -secondary response: later interactions with the same foreign substance; faster and more effective due to "immunological memory"

Extracellular killing by ADCC

*protozoans and helminths are too large to be phagocytized *Antibody-dependent cell-mediated cytotoxicity (ADCC) -protozoan or helminth target cell is coated with antibodies -immune system cells attach to the Fc regions of antibodies -target cell is lysed by the immune system cell

Immunological memory

*secondary (memory) response occurs after the second exposure to an antigen -more rapid, lasts many days, greater in magnitude -memory cells produced in response to the initial exposure are activated by the secondary exposure -antibody titer is the relative amount of antibody in the serum; reflects intensity of humoral response; IgM is produced first, followed later by IgG

Antigen-Presenting Cells (APCs)

-All nucleated cells in the body have mechanisms for processing and presenting antigens in association with MHC molecules. This signals the immune system, indicating whether the cell is normal and healthy or infected with an intracellular pathogen. -However, only macrophages, dendritic cells, and B cells have the ability to present antigens specifically for the purpose of activating T cells; for this reason, these types of cells are sometimes referred to as antigen-presenting cells (APCs). -While all APCs play a similar role in adaptive immunity, there are some important differences to consider. -Macrophages and dendritic cells are phagocytes that ingest and kill pathogens that penetrate the first-line barriers (i.e., skin and mucous membranes). -B cells, on the other hand, do not function as phagocytes but play a primary role in the production and secretion of antibodies. -In addition, whereas macrophages and dendritic cells recognize pathogens through nonspecific receptor interactions (e.g., PAMPs, toll-like receptors, and receptors for opsonizing complement or antibody), B cells interact with foreign pathogens or their free antigens using antigen-specific immunoglobulin as receptors (monomeric IgD and IgM). -When the immunoglobulin receptors bind to an antigen, the B cell internalizes the antigen by endocytosis before processing and presenting the antigen to T cells.

Major Histocompatibility Complex (MHC)

-As discussed in Cellular Defenses, major histocompatibility complex (MHC) molecules are expressed on the surface of healthy cells, identifying them as normal and "self" to natural killer (NK) cells. MHC molecules also play an important role in the presentation of foreign antigens, which is a critical step in the activation of T cells and thus an important mechanism of the adaptive immune system -The major histocompatibility complex (MHC) is a collection of genes coding for MHC molecules found on the surface of all nucleated cells of the body. In humans, the MHC genes are also referred to as human leukocyte antigen (HLA) genes. Mature red blood cells, which lack a nucleus, are the only cells that do not express MHC molecules on their surface. -There are two classes of MHC molecules involved in adaptive immunity, MHC I and MHC II

B Lymphocytes (B cells)

-Bone marrow -produce antibodies (type of glycoproteins) aka immunoglobulins --Defense vs. Extracellular pathogens/toxins -Humoral Immunity

Cytotoxic T cells

-Class = cytotoxic T cells -Surface CD molecules = CD8 -Activation = APCs presenting antigens associated with MHC I -Function = Destroy cells infected with intracellular pathogens

Helper T cells

-Class = helper T cell -Surface Molecule = CD4 -Activation = APCs presenting antigens associated with MHC II -Functions = orchestrate humoral and cellular immunity; involved in the activation of macrophages and NK cells

T lymphocytes (T cells)

-Thymus -destroy cells infected w/ intracellular pathogens -cell-mediated immunity

Humoral Immunity

-antibodies -antigen-antibody binding -MHC and antigen presentation -clonal selection and expansion of B cells

Types of Vaccines

1. *Live attenuated Vaccines -chicken pox, measles, mumps, rubella -weakened pathogen; long-term lab culturing cause nature to select for loss of unnecessary pathogenic traits; closely mimic an actual infection; confers lifelong cellular and humoral immunity (up to 95%) 2. *Inactivated killed vaccines -rabies, polio, influenza -killed/inactivated chemically -safer (weaker) than live vaccines... -but require repeated booster doses -induce humoral immunity 3. *Subunit vaccines -whooping cough, pneumococcal pneumonia and meningococcal meningitis -use antigenic fragments ("subunits") to stimulate an immune response -some are recombinant vaccines; clones pathogen gene in harmless host; virus-like particle vaccines (hepB and HPV) have cloned viral capsid gene in harmless host -toxoids; EX: tetanus and diphtheria; inactivated toxins used as vaccine instead of microbe; alternative to older antitoxins (serum containing antibodies against the toxin or chemically inactivated toxin) 4. *Conjugated Vaccines -Haemophilus influenza B -used for diseases in children with poor immune responses to capsular polysaccharides (T-independent antigens) -conjugate a protein toxoid to the polysaccharide for T-dependent immune response 5. *DNA vaccines -West Nile virus in horses -not currently approved in humans -injected naked DNA (plasmid + cloned microbe gene causes host cells to produce the microbe protein antigen -protein antigens carried to the red bone marrow stimulate humoral and cellular immunity

conjugate vaccines

A conjugate vaccine is a type of subunit vaccine that consists of a protein conjugated to a capsule polysaccharide. Conjugate vaccines have been developed to enhance the efficacy of subunit vaccines against pathogens that have protective polysaccharide capsules that help them evade phagocytosis, causing invasive infections that can lead to meningitis and other serious conditions. The subunit vaccines against these pathogens introduce T-independent capsular polysaccharide antigens that result in the production of antibodies that can opsonize the capsule and thus combat the infection; however, children under the age of two years do not respond effectively to these vaccines. Children do respond effectively when vaccinated with the conjugate vaccine, in which a protein with T-dependent antigens is conjugated to the capsule polysaccharide. The conjugated protein-polysaccharide antigen stimulates production of antibodies against both the protein and the capsule polysaccharide. Table lists examples of conjugate vaccines.

Agglutination

Agglutination or aggregation involves the cross-linking of pathogens by antibodies to create large aggregates (Figure). IgG has two Fab antigen-binding sites, which can bind to two separate pathogen cells, clumping them together. When multiple IgG antibodies are involved, large aggregates can develop; these aggregates are easier for the kidneys and spleen to filter from the blood and easier for phagocytes to ingest for destruction. The pentameric structure of IgM provides ten Fab binding sites per molecule, making it the most efficient antibody for agglutination.

Classes of T cells

All T cells produce cluster of differentiation (CD) molecules, cell surface glycoproteins that can be used to identify and distinguish between the various types of white blood cells. Although T cells can produce a variety of CD molecules, CD4 and CD8 are the two most important used for differentiation of the classes. Helper T cells and regulatory T cells are characterized by the expression of CD4 on their surface, whereas cytotoxic T cells are characterized by the expression of CD8. Classes of T cells can also be distinguished by the specific MHC molecules and APCs with which they interact for activation. Helper T cells and regulatory T cells can only be activated by APCs presenting antigens associated with MHC II. In contrast, cytotoxic T cells recognize antigens presented in association with MHC I, either by APCs or by nucleated cells infected with an intracellular pathogen. The different classes of T cells also play different functional roles in the immune system. Helper T cells serve as the central orchestrators that help activate and direct functions of humoral and cellular immunity. In addition, helper T cells enhance the pathogen-killing functions of macrophages and NK cells of innate immunity. In contrast, the primary role of regulatory T cells is to prevent undesirable and potentially damaging immune responses. Their role in peripheral tolerance, for example, protects against autoimmune disorders, as discussed earlier. Finally, cytotoxic T cells are the primary effector cells for cellular immunity. They recognize and target cells that have been infected by intracellular pathogens, destroying infected cells along with the pathogens inside.

active immunity vs passive immunity

All forms of adaptive immunity can be described as either active or passive. Active immunity refers to the activation of an individual's own adaptive immune defenses, whereas passive immunity refers to the transfer of adaptive immune defenses from another individual or animal. Active and passive immunity can be further subdivided based on whether the protection is acquired naturally or artificially.

complement activation through complement cascade

Another important function of antibodies is activation of the complement cascade. As discussed in the previous chapter, the complement system is an important component of the innate defenses, promoting the inflammatory response, recruiting phagocytes to site of infection, enhancing phagocytosis by opsonization, and killing gram-negative bacterial pathogens with the membrane attack complex (MAC). Complement activation can occur through three different pathways (see [link]), but the most efficient is the classical pathway, which requires the initial binding of IgG or IgM antibodies to the surface of a pathogen cell, allowing for recruitment and activation of the C1 complex.

artificial active immunity

Artificial active immunity is the foundation for vaccination. It involves the activation of adaptive immunity through the deliberate exposure of an individual to weakened or inactivated pathogens, or preparations consisting of key pathogen antigens.

Artificial passive immunity

Artificial passive immunity refers to the transfer of antibodies produced by a donor (human or animal) to another individual. This transfer of antibodies may be done as a prophylactic measure (i.e., to prevent disease after exposure to a pathogen) or as a strategy for treating an active infection. For example, artificial passive immunity is commonly used for post-exposure prophylaxis against rabies, hepatitis A, hepatitis B, and chickenpox (in high risk individuals). Active infections treated by artificial passive immunity include cytomegalovirus infections in immunocompromised patients and Ebola virus infections. In 1995, eight patients in the Democratic Republic of the Congo with active Ebola infections were treated with blood transfusions from patients who were recovering from Ebola. Only one of the eight patients died (a 12.5% mortality rate), which was much lower than the expected 80% mortality rate for Ebola in untreated patients.1 Artificial passive immunity is also used for the treatment of diseases caused by bacterial toxins, including tetanus, botulism, and diphtheria.

Regulatory T cells

Class = regulatory T cells -Surface CD molecules = CD4 -Activation = APC presenting antigens associated with MHCII -Functions = involved in peripheral tolerance and prevention of autoimmune responses

DNA vaccines

DNA vaccines represent a relatively new and promising approach to vaccination. A DNA vaccine is produced by incorporating genes for antigens into a recombinant plasmid vaccine. Introduction of the DNA vaccine into a patient leads to uptake of the recombinant plasmid by some of the patient's cells, followed by transcription and translation of antigens and presentation of these antigens with MHC I to activate adaptive immunity. This results in the stimulation of both humoral and cellular immunity without the risk of active disease associated with live attenuated vaccines. Although most DNA vaccines for humans are still in development, it is likely that they will become more prevalent in the near future as researchers are working on engineering DNA vaccines that will activate adaptive immunity against several different pathogens at once. First-generation DNA vaccines tested in the 1990s looked promising in animal models but were disappointing when tested in human subjects. Poor cellular uptake of the DNA plasmids was one of the major problems impacting their efficacy. Trials of second-generation DNA vaccines have been more promising thanks to new techniques for enhancing cellular uptake and optimizing antigens. DNA vaccines for various cancers and viral pathogens such as HIV, HPV, and hepatitis B and C are currently in development. Some DNA vaccines are already in use. In 2005, a DNA vaccine against West Nile virus was approved for use in horses in the United States. Canada has also approved a DNA vaccine to protect fish from infectious hematopoietic necrosis virus.4 A DNA vaccine against Japanese encephalitis virus was approved for use in humans in 2010 in Australia.5

Conjugate Vaccines

Description -Capsule polysaccharide conjugated to protein Advantages -T-dependent responses to capsule -Better response in young kids Disadvantages -Costly to produce -No protection against antigenic variation -May interfere with other vaccines Examples -Meningitis -(Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis)

Subunit Vaccines

Description -Immunogenic antigens Advantages -Lower risk of side effects Disadvantages -Limited longevity; multiple doses required; no protection against antigenic variation Examples -Anthrax, hepB, influenza, meningitis, papillomavirus, pneumococcal pneumonia, whooping cough

Toxoid Vaccines

Description -Inactivated bacterial toxin Advantages -Humoral immunity to neutralize toxin Disadvantages -Does not prevent infection Examples -Botulism, diphtheria, pertussis, tetanus

peripheral tolerance

Despite central tolerance, some self-reactive T cells generally escape the thymus and enter the peripheral bloodstream. Therefore, a second line of defense called peripheral tolerance is needed to protect against autoimmune disease. Peripheral tolerance involves mechanisms of anergy and inhibition of self-reactive T cells by regulatory T cells. Anergy refers to a state of nonresponsiveness to antigen stimulation. In the case of self-reactive T cells that escape the thymus, lack of an essential co-stimulatory signal required for activation causes anergy and prevents autoimmune activation. Regulatory T cells participate in peripheral tolerance by inhibiting the activation and function of self-reactive T cells and by secreting anti-inflammatory cytokines.

T cell Receptors

For both helper T cells and cytotoxic T cells, activation is a complex process that requires the interactions of multiple molecules and exposure to cytokines. The T-cell receptor (TCR) is involved in the first step of pathogen epitope recognition during the activation process. The TCR comes from the same receptor family as the antibodies IgD and IgM, the antigen receptors on the B cell membrane surface, and thus shares common structural elements. Similar to antibodies, the TCR has a variable region and a constant region, and the variable region provides the antigen-binding site (Figure). However, the structure of TCR is smaller and less complex than the immunoglobulin molecules ([link]). Whereas immunoglobulins have four peptide chains and Y-shaped structures, the TCR consists of just two peptide chains (α and β chains), both of which span the cytoplasmic membrane of the T cell. TCRs are epitope-specific, and it has been estimated that 25 million T cells with unique epitope-binding TCRs are required to protect an individual against a wide range of microbial pathogens. Because the human genome only contains about 25,000 genes, we know that each specific TCR cannot be encoded by its own set of genes. This raises the question of how such a vast population of T cells with millions of specific TCRs can be achieved. The answer is a process called genetic rearrangement, which occurs in the thymus during the first step of thymic selection. The genes that code for the variable regions of the TCR are divided into distinct gene segments called variable (V), diversity (D), and joining (J) segments. The genes segments associated with the α chain of the TCR consist 70 or more different Vα segments and 61 different Jα segments. The gene segments associated with the β chain of the TCR consist of 52 different Vβ segments, two different Dβ segments, and 13 different Jβ segments. During the development of the functional TCR in the thymus, genetic rearrangement in a T cell brings together one Vα segment and one Jα segment to code for the variable region of the α chain. Similarly, genetic rearrangement brings one of the Vβ segments together with one of the Dβ segments and one of thetJβ segments to code for the variable region of the β chain. All the possible combinations of rearrangements between different segments of V, D, and J provide the genetic diversity required to produce millions of TCRs with unique epitope-specific variable regions.

primary and secondary immune response on a graph

LOOK AT PIC

toxoid vaccines

Like subunit vaccines, toxoid vaccines do not introduce a whole pathogen to the patient; they contain inactivated bacterial toxins, called toxoids. Toxoid vaccines are used to prevent diseases in which bacterial toxins play an important role in pathogenesis. These vaccines activate humoral immunity that neutralizes the toxins. Table lists examples of toxoid vaccines.

Live attenuated vaccines

Live attenuated vaccines expose an individual to a weakened strain of a pathogen with the goal of establishing a subclinical infection that will activate the adaptive immune defenses. Pathogens are attenuated to decrease their virulence using methods such as genetic manipulation (to eliminate key virulence factors) or long-term culturing in an unnatural host or environment (to promote mutations and decrease virulence). By establishing an active infection, live attenuated vaccines stimulate a more comprehensive immune response than some other types of vaccines. Live attenuated vaccines activate both cellular and humoral immunity and stimulate the development of memory for long-lasting immunity. In some cases, vaccination of one individual with a live attenuated pathogen can even lead to natural transmission of the attenuated pathogen to other individuals. This can cause the other individuals to also develop an active, subclinical infection that activates their adaptive immune defenses. Disadvantages associated with live attenuated vaccines include the challenges associated with long-term storage and transport as well as the potential for a patient to develop signs and symptoms of disease during the active infection (particularly in immunocompromised patients). There is also a risk of the attenuated pathogen reverting back to full virulence. Table lists examples live attenuated vaccines.

Natural active immunity

Natural active immunity is adaptive immunity that develops after natural exposure to a pathogen (Figure). Examples would include the lifelong immunity that develops after recovery from a chickenpox or measles infection (although an acute infection is not always necessary to activate adaptive immunity). The length of time that an individual is protected can vary substantially depending upon the pathogen and antigens involved. For example, activation of adaptive immunity by protein spike structures during an intracellular viral infection can activate lifelong immunity, whereas activation by carbohydrate capsule antigens during an extracellular bacterial infection may activate shorter-term immunity.

Natural passive immunity

Natural passive immunity involves the natural passage of antibodies from a mother to her child before and after birth. IgG is the only antibody class that can cross the placenta from mother's blood to the fetal blood supply. Placental transfer of IgG is an important passive immune defense for the infant, lasting up to six months after birth. Secretory IgA can also be transferred from mother to infant through breast milk.

Neutralization of pathogens

Neutralization involves the binding of certain antibodies (IgG, IgM, or IgA) to epitopes on the surface of pathogens or toxins, preventing their attachment to cells. For example, Secretory IgA can bind to specific pathogens and block initial attachment to intestinal mucosal cells. Similarly, specific antibodies can bind to certain toxins, blocking them from attaching to target cells and thus neutralizing their toxic effects. Viruses can be neutralized and prevented from infecting a cell by the same mechanism (Figure).

T Cell-Dependent Activation of B cells

T cell-dependent activation of B cells is more complex than T cell-independent activation, but the resulting immune response is stronger and develops memory. T cell-dependent activation can occur either in response to free protein antigens or to protein antigens associated with an intact pathogen. Interaction between the BCRs on a naïve mature B cell and a free protein antigen stimulate internalization of the antigen, whereas interaction with antigens associated with an intact pathogen initiates the extraction of the antigen from the pathogen before internalization. Once internalized inside the B cell, the protein antigen is processed and presented with MHC II. The presented antigen is then recognized by helper T cells specific to the same antigen. The TCR of the helper T cell recognizes the foreign antigen, and the T cell's CD4 molecule interacts with MHC II on the B cell. The coordination between B cells and helper T cells that are specific to the same antigen is referred to as linked recognition. Once activated by linked recognition, TH2 cells produce and secrete cytokines that activate the B cell and cause proliferation into clonal daughter cells. After several rounds of proliferation, additional cytokines provided by the TH2 cells stimulate the differentiation of activated B cell clones into memory B cells, which will quickly respond to subsequent exposures to the same protein epitope, and plasma cells that lose their membrane BCRs and initially secrete pentameric IgM (Figure). After initial secretion of IgM, cytokines secreted by TH2 cells stimulate the plasma cells to switch from IgM production to production of IgG, IgA, or IgE. This process, called class switching or isotype switching, allows plasma cells cloned from the same activated B cell to produce a variety of antibody classes with the same epitope specificity. Class switching is accomplished by genetic rearrangement of gene segments encoding the constant region, which determines an antibody's class. The variable region is not changed, so the new class of antibody retains the original epitope specificity.

Primary and Secondary Responses

T cell-dependent activation of B cells plays an important role in both the primary and secondary responses associated with adaptive immunity. With the first exposure to a protein antigen, a T cell-dependent primary antibody response occurs. The initial stage of the primary response is a lag period, or latent period, of approximately 10 days, during which no antibody can be detected in serum. This lag period is the time required for all of the steps of the primary response, including naïve mature B cell binding of antigen with BCRs, antigen processing and presentation, helper T cell activation, B cell activation, and clonal proliferation. The end of the lag period is characterized by a rise in IgM levels in the serum, as TH2 cells stimulate B cell differentiation into plasma cells. IgM levels reach their peak around 14 days after primary antigen exposure; at about this same time, TH2 stimulates antibody class switching, and IgM levels in serum begin to decline. Meanwhile, levels of IgG increase until they reach a peak about three weeks into the primary response (Figure). During the primary response, some of the cloned B cells are differentiated into memory B cells programmed to respond to subsequent exposures. This secondary response occurs more quickly and forcefully than the primary response. The lag period is decreased to only a few days and the production of IgG is significantly higher than observed for the primary response (Figure). In addition, the antibodies produced during the secondary response are more effective and bind with higher affinity to the targeted epitopes. Plasma cells produced during secondary responses live longer than those produced during the primary response, so levels of specific antibody remain elevated for a longer period of time.

T cell production & maturation

T cells, like all other white blood cells involved in innate and adaptive immunity, are formed from multipotent hematopoietic stem cells (HSCs) in the bone marrow (see [link]). However, unlike the white blood cells of innate immunity, eventual T cells differentiate first into lymphoid stem cells that then become small, immature lymphocytes, sometimes called lymphoblasts. The first steps of differentiation occur in the red marrow of bones (Figure), after which immature T lymphocytes enter the bloodstream and travel to the thymus for the final steps of maturation (Figure). Once in the thymus, the immature T lymphocytes are referred to as thymocytes. It is not completely understood what events specifically direct maturation of thymocytes into regulatory T cells. Current theories suggest the critical events may occur during the third step of thymic selection, when most self-reactive T cells are eliminated. Regulatory T cells may receive a unique signal that is below the threshold required to target them for negative selection and apoptosis. Consequently, these cells continue to mature and then exit the thymus, armed to inhibit the activation of self-reactive T cells. It has been estimated that the three steps of thymic selection eliminate 98% of thymocytes. The remaining 2% that exit the thymus migrate through the bloodstream and lymphatic system to sites of secondary lymphoid organs/tissues, such as the lymph nodes, spleen, and tonsils (Figure), where they await activation through the presentation of specific antigens by APCs. Until they are activated, they are known as mature naïve T cells.

Activated Helper T cells can differentiate into one of four distict subtypes. What are they?

T(subH)1 cells T(subH)2 cell T(subH)17 cells Memory helper T cells

herd immunity

The four kinds of immunity just described result from an individual's adaptive immune system. For any given disease, an individual may be considered immune or susceptible depending on his or her ability to mount an effective immune response upon exposure. Thus, any given population is likely to have some individuals who are immune and other individuals who are susceptible. If a population has very few susceptible individuals, even those susceptible individuals will be protected by a phenomenon called herd immunity. Herd immunity has nothing to do with an individual's ability to mount an effective immune response; rather, it occurs because there are too few susceptible individuals in a population for the disease to spread effectively. Vaccination programs create herd immunity by greatly reducing the number of susceptible individuals in a population. Even if some individuals in the population are not vaccinated, as long as a certain percentage is immune (either naturally or artificially), the few susceptible individuals are unlikely to be exposed to the pathogen. However, because new individuals are constantly entering populations (for example, through birth or relocation), vaccination programs are necessary to maintain herd immunity.

Variolation and Vaccination

Thousands of years ago, it was first recognized that individuals who survived a smallpox infection were immune to subsequent infections. The practice of inoculating individuals to actively protect them from smallpox appears to have originated in the 10th century in China, when the practice of variolation was described (Figure). Variolation refers to the deliberate inoculation of individuals with infectious material from scabs or pustules of smallpox victims. Infectious materials were either injected into the skin or introduced through the nasal route. The infection that developed was usually milder than naturally acquired smallpox, and recovery from the milder infection provided protection against the more serious disease. Although the majority of individuals treated by variolation developed only mild infections, the practice was not without risks. More serious and sometimes fatal infections did occur, and because smallpox was contagious, infections resulting from variolation could lead to epidemics. Even so, the practice of variolation for smallpox prevention spread to other regions, including India, Africa, and Europe. Etching of a person administering something into the mouth of a younger person with an instrument while another person holds the younger person's head back. Variolation for smallpox originated in the Far East and the practice later spread to Europe and Africa. This Japanese relief depicts a patient receiving a smallpox variolation from the physician Ogata Shunsaku (1748-1810). Although variolation had been practiced for centuries, the English physician Edward Jenner (1749-1823) is generally credited with developing the modern process of vaccination. Jenner observed that milkmaids who developed cowpox, a disease similar to smallpox but milder, were immune to the more serious smallpox. This led Jenner to hypothesize that exposure to a less virulent pathogen could provide immune protection against a more virulent pathogen, providing a safer alternative to variolation. In 1796, Jenner tested his hypothesis by obtaining infectious samples from a milkmaid's active cowpox lesion and injecting the materials into a young boy (Figure). The boy developed a mild infection that included a low-grade fever, discomfort in his axillae (armpit) and loss of appetite. When the boy was later infected with infectious samples from smallpox lesions, he did not contract smallpox.3 This new approach was termed vaccination, a name deriving from the use of cowpox (Latin vacca meaning "cow") to protect against smallpox. Today, we know that Jenner's vaccine worked because the cowpox virus is genetically and antigenically related to the Variola viruses that caused smallpox. Exposure to cowpox antigens resulted in a primary response and the production of memory cells that identical or related epitopes of Variola virus upon a later exposure to smallpox. The success of Jenner's smallpox vaccination led other scientists to develop vaccines for other diseases. Perhaps the most notable was Louis Pasteur, who developed vaccines for rabies, cholera, and anthrax. During the 20th and 21st centuries, effective vaccines were developed to prevent a wide range of diseases caused by viruses (e.g., chickenpox and shingles, hepatitis, measles, mumps, polio, and yellow fever) and bacteria (e.g., diphtheria, pneumococcal pneumonia, tetanus, and whooping cough,)

- Superantigens and unregulated activation of T cells

When T cell activation is controlled and regulated, the result is a protective response that is effective in combating infections. However, if T cell activation is unregulated and excessive, the result can be a life-threatening. Certain bacterial and viral pathogens produce toxins known as superantigens (see Virulence Factors of Bacterial and Viral Pathogens) that can trigger such an unregulated response. Known bacterial superantigens include toxic shock syndrome toxin (TSST), staphylococcal enterotoxins, streptococcal pyrogenic toxins, streptococcal superantigen, and the streptococcal mitogenic exotoxin. Viruses known to produce superantigens include Epstein-Barr virus (human herpesvirus 4), cytomegalovirus (human herpesvirus 5), and others. The mechanism of T cell activation by superantigens involves their simultaneous binding to MHC II molecules of APCs and the variable region of the TCR β chain. This binding occurs outside of the antigen-binding cleft of MHC II, so the superantigen will bridge together and activate MHC II and TCR without specific foreign epitope recognition (Figure). The result is an excessive, uncontrolled release of cytokines, often called a cytokine storm, which stimulates an excessive inflammatory response. This can lead to a dangerous decrease in blood pressure, shock, multi-organ failure, and potentially, death.

Subunit vaccines

Whereas live attenuated and inactive vaccines expose an individual to a weakened or dead pathogen, subunit vaccines only expose the patient to the key antigens of a pathogen—not whole cells or viruses. Subunit vaccines can be produced either by chemically degrading a pathogen and isolating its key antigens or by producing the antigens through genetic engineering. Because these vaccines contain only the essential antigens of a pathogen, the risk of side effects is relatively low. Table lists examples of subunit vaccines.

Antibody-dependent cell-mediated cytotoxicity (ADCC)

Yet another important function of antibodies is antibody-dependent cell-mediated cytotoxicity (ADCC), which enhances killing of pathogens that are too large to be phagocytosed. This process is best characterized for natural killer cells (NK cells), as shown in Figure, but it can also involve macrophages and eosinophils. ADCC occurs when the Fab region of an IgG antibody binds to a large pathogen; Fc receptors on effector cells (e.g., NK cells) then bind to the Fc region of the antibody, bringing them into close proximity with the target pathogen. The effector cell then secretes powerful cytotoxins (e.g., perforin and granzymes) that kill the pathogen.

How to Haptens become antigenic? Name an example

for a hapten to become antigenic, it must first attach to a larger carrier molecule (usually a protein) to produce a conjugate antigen the hapten-specific antibodies produced in response to the conjugate antigen are then able to interact with unconjugated free hapten molecules. Haptens are not known to be associated with any specific pathogens, but they are responsible for some allergic responses. For example, the hapten urushiol, a molecule found in the oil of plants that cause poison ivy, causes an immune response that can result in a severe rash (called contact dermatitis). Similarly, the hapten penicillin can cause allergic reactions to drugs in the penicillin class.

vaccination

injection of a weakened or mild form of a pathogen to produce immunity For many diseases, prevention is the best form of treatment, and few strategies for disease prevention are as effective as vaccination. Vaccination is a form of artificial immunity. By artificially stimulating the adaptive immune defenses, a vaccine triggers memory cell production similar to that which would occur during a primary response. In so doing, the patient is able to mount a strong secondary response upon exposure to the pathogen—but without having to first suffer through an initial infection. In this section, we will explore several different kinds of artificial immunity along with various types of vaccines and the mechanisms by which they induce artificial immunity.

image of antibody parts

know parts -light chain -heavy chain -Fc region -Fab region -variable region -constant region -disulfide bonds -antigen-binding sites

Opsonization for phagocytosis

opsonization is the coating of a pathogen with molecules, such as complement factors, C-reactive protein, and serum amyloid A, to assist in phagocyte binding to facilitate phagocytosis. IgG antibodies also serve as excellent opsonins, binding their Fab sites to specific epitopes on the surface of pathogens. Phagocytic cells such as macrophages, dendritic cells, and neutrophils have receptors on their surfaces that recognize and bind to the Fc portion of the IgG molecules; thus, IgG helps such phagocytes attach to and engulf the pathogens they have bound (Figure).