Micro ch 15

• protection provided by immune responses that mature throughout life
• involved B cells and T cells

the primary participants in the adaptive immune responses

• the first response to a particular antigen
• As a result of initial encounter, adaptive immune system "remembers" the mechanism that proved effective against specific antigen

refers to the stronger antigen-specific immune response that results when an antigen is encountered again later in life (after a primary repsonse)

• humoral immunity
• CMI (cell-mediated immunity) or cellular immunity
• *both are powerful and, if misdirected, can damage the body's own tissues

• works to eliminate extracellular antigens
• Ex:  bacteria, toxins, or viruses in bloodstream or in tissue fluids

deals with antigens residing within a host cell, such as a virus infecting a cell

• b lymphocytes
• responsible for humoral immunity
• develop in bone marrow
• programmed to make antibodies
• *In response to extracellular antigens, B cells may be triggered to proliferate and then differentiate into plasma cells

function as factories that produce Y-shaped proteins called antibodies

• Y shaped proteins
• bind to antigens, highly specific
• protect host by both direct and indirect mechanisms
• Have 2 functional regions: 2 identical arms & the stem

• Arm bind to specific molecules
• the amino acid sequence of the end of the arms varies among antibodies, providing the basis for their specificity

• function as a "red flag"
• tagging antigen bound by antibodies and enlisting other immune system components to eliminate molecule

• Direct effort is due to their ability to bind antigens. Simply by binding, coat antigen & prevent it from attaching to host cell
• Indirect protective effect is "red flag" tagging for elimination

a membrane-bound version of specific antibody the B cell is programmed to make

• B-cell surface has numerous copies of BCR
• If naive B cell encounters an antigen that it's BCR binds, cell is triggered to multiply
• Some of resulting clones eventually differentiate, becoming plasma cells
• *Before it can multiply, however, generally needs to be activated by another type of lymphocyte - a T_H cell- which also must recognize antigen and confirm danger

• T lymphocytes - are cell mediated immunity
• name reflects they mature in thymus
• 2 subsets help eliminate antigen: cytotoxic T cells and helper T cells
• Both have multiple copies of surface molecule T-cell receptor
• Also includes 3rd T-cell subset: regulatory T cells

Type of lymphocyte programmed to destroy infected or cancerous "self" cells

Type of lymphocyte programmed to activate B cells and macrophages, and assist other parts of the adaptive immune response

• functionally analogous to BCR
• allows cell to bind a specific antigen
• However, unlike BCR, does not recognize free antigen
• Instead, the antigen must be presented by one of body's own cells

• help prevent the immune system from mounting a response against "self" molecules
• failure to do this results in autoimmune diseases

• Dendritic cells are responsible for T-cell activation
• *recall T cell part of innate immunity. Once activated, T cell proliferates and then differentiates to form effector T cells, armed to perform distinct protective roles

• Effector helper T cells
• help orchestrate various responses of humoral and cell-mediated immunity
• Activate B cells and macrophages
• produce cytokines that direct and support T cells

• respond to intracellular antigens
• when they find antigen, induce the "self" cell that harbor it to undergo apoptosis

• collection of tissues and organs that bring the population of B cells and T cells into contact with antigens
• Each lymphocyte recognizes only one or a few different antigens

• lymphatic vessels
• where flow of lymphatic system takes place
• Carries lymph

a fluid that forms as a result of the body's circulatory system

• sites where lymphocytes gather to contact the various antigens
• Ex: lymph nodes, spleen, tonsils, adenoids, and appendix

• tissues in the intestinal walls that inspect samples of intestinal contents
• Have specialized epithelial cells (M cells) which transfer material from intestinal lumen to Peyer's patches
• Dendritic cells in and near patches also reach throu epithelial layer and grab intestinal stuff to present to lymphocytes

• Mucosa-associated lymphoid tissue
• Lymphoid tissue present in the mucosa of the respiratory, gastrointestinal and genitourinary tracts
• Includes Peter's patches

• the immune response that prevents microbes from invading the body via mucous membranes
• Involves MALT

• skin-associated lymphoid tissue
• Lymphoid tissues under the skin

• include the bone marrow and thymus
• Bone marrow is where hematopoietic stem cells reside.
• B cells and T cell originate in bone marrow, but ONLY B cells mature there
• Immature T cells migrate to thymus and mature there
• Once mature, lymphocytes gather in secondary lymphoid organs and await to encounter antigen

used when referring specifically to an antigen that elicits an immune response in a given situation

• *Antigens include an enormous variety of materials, from invading microbes and their products to plan pollens
• But all fall into 2 categories:
• T-dependent antigens
• T-independent antigens

• The responding B cell requires assistance from the T_H cell in order to become activated
• characteristically have a protein component

• can activate B cells without T_H cell help
• include lipopolysaccharide (LPS) and molecules with repeating subunits, such as carbs

• term used interchangeably with immunogenic to describe the ability of an antigen to elicit an immune response
• Various antigen differ in effectiveness to stimulate immune response. Proteins generally induce strong response as lipids often do not

• discrete regions of an antigen molecule recognized by the adaptive immune system
• Some are stretches of 10 or so amino acids where as others are 3D shapes

• the two identical arms of antibody
• bind antigen

the stem of the antibody

• *recall all antibodies have same basic Y-shaped structure, called antibody monomer
• Consists of 2 copies of a high-molecular weight polypeptide chain, called the heavy chain, and two copies of a lower molecular-weight polypeptide chain, called the light chain
• (See pg 360)

• Amino acids in the chains fold into domains, referred to as immunoglobulin domains:
• light chains have two domains each
• Most heavy chains have 4

• by a disulfide bond
• the fork of the Y is a flexible stretch called the hinge region where one or more disulfide bonds link the two heavy chains

• the portion at the ends of the Fab regions (the top sections of the arms)
• accounts for the antigen-binding specificity

• part of the variable region
• the portion that attaches to a specific epitope (btwn the 2 fingers of the top portion of arms)
• fit needs to be precise, as interaction depends on numerous non-covalent bonds to keep molecules together
• Is reversible

• includes the entire Fc region, as well as part of two fab region (the lower 2 sections of arms)
• Allows other components of immune system to recognize the otherwise diverse antibody molecules

• IgM
• IgG
• IgA
• IgD
• IgE
• All have same basic monomeric structure, but each class has different constant portion of heavy chain

• Neutralization
• Opsonization
• Complement system activation
• Immobilization and prevention of adherence
• Cross-linking
• Antibody-dependent cellular cytotoxicity

• Toxins/viruses must bind specific molecules on cell surface before they can damage cell
• If they are covered in antibodies, can't attach to cells and is said to be neutralized

Phagocytic cells have receptors for F_c region of IgG, making it easier for phagocyte to engulf antibody-coated antigens

• Antigen-antibody complexes can trigger complement system
• When multiple molecules of certain antibody classes bond to cell surface, a specific complement system protein attaches to their F_c regions, initiating the cascade

• Binding of antibodies to flagella interferes with microbe's ability to move
• binding to pili prevents it from attaching to surfaces

• The 2 arms of antibody can bind separate but identical antigen molecules, linking them
• Overall effect is that large antigen-antibody complexes form, creating big "mouthfuls" of antigens for phagocytic cells to engulf

• (ADCC) 
• When multiple IgG molecules bind to a virally infected cell or a tumor cell, becomes target for destruction by natural killer cells (NK)

NK cells attach to F_c regions of IgG and once attached, kills the target cell by delivering compounds directly to it

• 970,000 daltons in cellular weight
• Structure is a pentamer (pentagon), large size prevents it from crossing from bloodstream into tissues, so primary role is control of bloodstream infections

• Accounts for 5% to 13% of circulating antibodies
• Half-life in serum is 10 days
• Is first class produced during primary response 
• Is principal class produced in response to some T-independent antigens
• Direct protection by neutralizing, immobilizing, preventing adherence to cell surfaces, and cross-linking
• Binding leads to activation of complement system

• 146,000 daltons in cellular weight
• Structure is typical Y antibody
• Accounts for 80% - 85% of total serum immunoglobulin (as serum is liquid part of blood)
• Most abundant class in blood and tissue fluids
• Provides longest term protection as half life is 21 days
• Transports across placenta & protects fetus; long 1/2 life extends protection through first several months after birth
• Provides direct protection by neutralizing, immobilizing, preventing adherence, and cross-linking
• Binding facilitates phagocytosis, leads to activation of complement system, and allows antibody-dependent cellular cytotoxicity

• 160,000 molecular weight
• Accounts for 10-13% of antibodies in serum
• However, most IgA is secretory IgA

• Secretory IgA
• *recall monomeric for accounts for 10-13%. Most IgA is secreted form, a dimer called sIgA
• 390,000 molecular weight
• Most abundant class produced, but majority secreted into mucus, tears, and saliva providing mucosal immunity

• Half life is 6 days
• Also found in breast milk, protecting infant intestine tract
• Protects by neutralizing, immobilizing, and preventing attachment

• 184,000 molecular weight
• typical Y structure
• <1% of all serum immunoglobulins
• Half life 3 days
• involved in development and maturation of antibody response
• Functions in blood not well understood

• 188,000 molecular weight
• typical Y structue
• <0.01% , barely detectable in blood
• Half life is 2 days
• Binds to the F_c region to mast cells and basophils
• Bound IgE allows cells to detect parasites & other antigens & respond by releasing granule contents
• Involved in many allergic reactions; unfortunately, basophils and mast cells also release chemicals when IgE binds to normally harmless materials such as foods, dust, pollen... leading to immediate reactions

• theory that describes how the immune system is capable of making an array of antibody specificities
• Each B cell is programmed to make only a single specificity of antibody
• When antigen is introduced, only B cells capable of making appropriate antibody can bind to antigen
• Critical theme in adaptive immune response, pertaining to both B cells and T cells

• When an antigen enters a secondary lymphoid organ, only the lymphocytes that specifically recognize that antigen will respond
• the antigen receptor they carry on their surface governs this recognition
• Lymphocytes may be immature, naive, activated, effector, or memory cells

These have not fully developed their antigen-specific receptors

These have antigen receptors, but have not yet encountered the antigen to which they are programmed to respond

• These are able to proliferate
• have bound antigen via their antigen receptor and have received the required accessory signals from another cell, confirming that the antigen merits a response

• Are descendants of activated lymphocytes, armed with ability to produce specific cytokines or other protective substances
• Plasma cells are effector B cells
• T_c cells are effector cytotoxic T cells
• T_H cells are effector helper T cells

• long-lived descendants of activated lymphocytes
• can quickly become activated when antigen is encountered again
• responsible for speed and effectiveness of secondary response

• recall most antigens are T-dependent
• meaning B cells that recognize them require help from T_H cells

• Naive B cells gather in secondary lymphoid organs to encounter antigens
• When B cell's antigen receptor binds to a T-depend antigen, B cell takes antigen in by endocytosis, enclosing within an endosome. There, antigen is degraded into peptide fragments & delivered to structures called MHC class II molecules

These molecules move the peptide fragments to the B-cell surface and "present" them for inspection by T_H cells

Process by which pieces of antigen are presented on B-cell surface for T_H cells to inspect

• Scans naive B cells in secondary lymphoid organs to determine if any have encountered any antigen they recognize
• If T_H antigen receptor binds one of the peptide fragments presented by B cell, then that T cell activates the B cell by delivering cytokines to B cell & initiating process of clonal expansion of that particular B cell

• That B cell may become anergic (unresponsive to future exposure to antigen)
• Results in tolerance to that antigen

• Takes about 10 - 14 days for substantial amounts of antibodies to accumulate
• During delay, person may experience s/s of infection
• Immune system is actively responding though

• Form of natural selection among proliferating B cells
• As activated B cells multiply, spontaneous mutation commonly occur in certain regions of antibody genes
• Some result in slight changes in antigen-binding site of antibody ( and therefore B-cell receptor)
• B cells that bind antigen for longest duration are most likely to proliferate

• All B cells are initially programmed to differentiate into plasma cells that secrete IgM
• Cytokines produced by T_H cells induce some activated B cells to switch that genetic program, causing them to differentiate into plasma cells that secrete other antibody classes
• B cells in lymph nodes most commonly switch to IgG production
• B cells in mucosa generally switch to IgA production
• *After class switching, some B cells become memory B cells

• significantly faster and more effective than primary- repeat invaders generally are eliminated before they cause noticeable harm
• Vaccination takes advantage of this naturally occurring phenomenon 
• Memory B cells are responsible

• Responsible for efficiency of 2nd response
• There are more cells - memory B cells & memory T helper cells - that can respond to specific antigen
• Memory B cells are able to scavenge even low concentrations of antigen cause receptors have been fine tuned through affinity maturation

• T-indep antigens can activate B cells without aid of T_H cells
• One type of T-indep antigens are polysaccharides & others have numerous identical evenly spaced epitopes
• Because of the arrangement of epitopes, clusters of B-cell receptors bind to antigen simultaneously, leading to activation of that B cell w/o involvement of helper T cells

• Different from B cells in that T cells never produce antibodies
• Instead, effector T cell directly interact with other cells - target cells - to cause distinct changes in those cells

• Has two polypeptide chains (set of either alpha and beta or gamma and delta), each with variable and constant region
• See pg 369

• T-Cell receptor
• *Recall T cells have multiple copies of T-cell receptor on surface that recognizes specific epitope
• Receptor does not interact with free antigen, must be presented by another host cell
• Host cell does this partly by degrading antigen & presenting peptides of antigens proteins via MHC molecules
• When T cell recognizes antigen, actually recognizing both peptide & MHC molecule

• Major histocompatibility complex molecules
• 2 types: MHC class I and class II
• Both shaped like elongated bun and hold peptide lengthwise, like bun holds hot dog

MHC class I molecules present endogenous antigens (antigens made within cell)

MHC class II molecules present exogenous antigens (antigens taken up by cell)

*All nucleated cells produce MHC class I, but only specialized cell types make class II

Referred to as APCs (antigen-presenting cells)

Includes dendritic cells, B cells and macrophages

Cytotoxic T cells (T_C) recognize antigen presented on MHC class I molecules & respond to endogenous antigens

Helper T cells (T_H) recognize antigen presented on MHC class II molecules & respond to exogenous antigens

• *As cytotoxic and helper T cells are identical microscopically, scientists distinguish them based on presence of surface proteins called CD markers
• Most Cytotoxic T cells have CD8 marker
• Most Helper T cells carry CD4 marker

• dendritic cells play crucial role in activation
• Immature dendritic cells reside in peripheral tissues, particularly under skin & mucosa, gathering materials
• They use both phagocytosis and Pinocytosis 
• En route to secondary lymphoid organs, dendritic cells mature into form that presents antigen to naive T cells
• Cells that detected pathogens produce co-stimulatory molecules

• Surface proteins produced by dendritic cells that detected pathogens
• function as emergency lights for T cell, communicating danger

If the T cells recognize antigen presented by dendritic cells DISPLAYING costimulatory molecules, can become activated T cell

If T cell recognize antigen presented by dendritic cell NOT DISPLAYING co-stimulatory molecules, become anergic (can't respond) and eventually undergo apoptosis

• Induce apoptosis in infected "self" cells
• also destroy cancerous "self" cells
• T_c cells distinguish infected/cancerous cells from normal by proteins produced in nucleus of cell. These are inspected by T cells through MHC class I molecules
• Is protein not recognized as self, cell will be targeted for lethal effector functions of T_c cells
• T cell will also release cytokines that alert neighboring cells

• they orchestrate the immune response
• activate B cells and macrophages and T cells

• T_H cells activate cells that present peptides they recognize on MHC class II
• Various cytokines are released, depending on subset of responding T_H cell
• Macrophages and B cells present peptides from exogenous proteins in the groove of MHC class II molecules

Direct immune system to an appropriate response

A vaccine composed of a polysaccharide antigen covalently attached to a large protein molecule, thereby converting what would be a T-independent antigen into a T-dependant antigen

• a molecule that binds to a B-cell receptor yet does not normally elicit antibody production
• Ex is how people develop allergies to penicillin

• recall they lack antigen specific receptors
• induce apoptosis in antibody-bound "self" cells - they can do this because they have F_c receptors for IgG on surface (recall Fc is red flag)
• Attach and delivers perforin and protease containing granules directly into cell
• They can also initiate apoptosis in stressed "self" cell that lacks MHC class I molecules

• 3 segments, one each from DNA regions called:
• V - variable  (40 different segments)
• D - Diversity (25 )
• J - Joining    (6)

• occurs when nucleotides get deleted or added btwn sections
• changes reading frame of encoded protein

• refers to specific groups of light chains and heavy chains that make up antibody molecule
• Both acquire diversity through gene rearrangement and imprecise joining

• Once B cells is developed antigen receptor, it passes through rigorous checkpoints in bone marrow
• Most important is negative selection, which eliminates any B cell that binds "self"
• Most B cells fail and induced to undergo apoptosis
• If cell weren't eliminated, immune system may attack "self" by mistake

• Fate of developing T cells rests on 2 phases of trials = pos & neg selection
• Positive only permits those T cells that recognize MHC to develop further
• If passes positive, must then go through neg = T cell that recognize "self" peptides presented on MHC are eliminated
• Pos & neg selection so strict, over 95% developing T cells undergo apoptosis in thymus