Immune System: Innate vs Adaptive Immunity
What is an immunogen?
Something (antigen) that is capable of evoking an immune response such as the production of antibodies.
What does it mean if the constant fragments for the heavy chains of antibodies are different, but the variable region remains the same?
The immunoglobin will have the same specificity.
Damage-Associated Molecular Patterns (DAMPs)
"Normal" endogenous substances that are in the wrong place. One of the 2 molecular patterns recognized as non-self in the innate immune system. Example = the presence in the cytoplasm of proteins that normally reside in the cell nucleus, indicative of cell damage.
Lymphocytes - the key players of the adaptive response.
*B lymphocytes*: make antibodies which act as antigen receptors. Upon activation they differentiate into antibody-secreting cells known as *plasma cells*. *T lymphocytes*: express T cell receptors (TCRs) that bind antigen (in the form of peptides) and can be subdivided into: i. *T helper (Th) cells (CD4+)*: secrete numerous cytokines, activate dendritic cells and "help" B lymphocytes in producing antibodies. ii. *T cytotoxic (Tc) (CD8+) cells*:destroy virus-infected cells and tumor cells. iii. *T regulatory (Treg) cells*: regulate immune responses by controlling the activities of other immune cells including T cells.
(LO) Describe the effector functions of the various T lymphocyte subsets.
*Cytotoxic T Cells (CD8+)* • Reacts w/ antigenic peptides presented on MHC I (thus from inside the cell) • When costimulated by T helper cells, they become cytotoxic & kill infected cells (virus-infected, tumor) • Peptides derived from endogenous sources *Helper T Cells (CD4+)* • Reacts w/ antigenic peptides presented on MHC II of APC (thus from outside the cell, brought in via endocytosis) • Help to activate CD8+ T cell and B cells: 1. Helps Cytotoxic T cells become cytotoxic (TH1 subset) -OR- 2. Helps B cells make antibodies through cytokines & cell-cell interactions (TH2 subset) • They secrete cytokines and activate dendritic cells. • Peptides derived from exogenous sources *Regulatory T Cells (CD4+)* • CD4+, CD25+, MHC Class II restricted • Regulate the immune response: mostly inhibitory, prevents autoimmunity; help to control the immune response so that it does not run out of control. They regulate the actions of the other immune cells, including T cells.
(LO) Explain the differences between primary and secondary immune responses in the case of antibody production.
*Primary response*: make antibody *Secondary response*: memory - antibody pre-made; ready for attack • The secondary response has a shorter lag time. It is able to produce antibodies much more quickly than the primary response. • The plateau period is also longer in secondary response, and the decline is more gradual. • Antibody titer is higher in the secondary response (10-100x). • IgG is the major antibody class in secondary response, while IgM is the major antibody class in primary response. • Binding affinity in antibodies in the secondary response is much higher than that of antibodies in the primary response. "Antibody maturation"
What are the distinguishing features of the adaptive immune system response?
*Specificity*: Response is directed only against the stimulating antigen *Adaptability*: Responses can be made against an immense variety of antigens, even those that are not naturally occurring *Self/non-self discrimination*: Responses are made against foreign ("non-self") antigens and not usually against "self" antigens *Memory*: Ability to recall previous contact with a foreign antigen and to respond in a "learned" way by initiating a rapid and vigorous response following re-exposure to the antigen Invoked during the secondary immune response, but established after the primary immune response *Permits vaccines to work!*
Type I interferons (IFN) (alpha & beta)
1) Anti-viral system that exists in most cell types: has sensor molecules that can detect viruses (ex: double stranded DNA). When detected, the cells release Type I IFNs in the local environment. 2) IFNs act on neighboring cells: • Activate anti-viral states in other cells • Shut off protein synthesis (through phosphorylation of translation initiation factor) • Activate RNAse (degrades viral DNA) • Become better NK targets
(LO S19) Explain the clonal selection model of adaptive immunity.
1) Pre-existing lymphocytes (B & T) undergo numerous antigen receptor mutations: somatic gene recombination. As a result, each have their own, specific antigen receptor. 2) Antigen binds to its own specific receptor, activating that lymphocyte. 3) Clones with that antigen binding site replicate 4) An antigen-specific immune response occurs
(LO) Describe the kinetics of the antibody response.
1. *Lag phase*: time between initial exposure and detection of antibodies (flat on graph) 2. *Exponential phase*: increase of antibodies in the circulation. Occurs rapidly due to rising number of plasma cells (positive slope on graph) 3. *Steady-state (plateau) phase*: rate of antibody synthesis equals the rate of degradation (graph is flat) 4. *Declining phase*: antibody synthesis is reduced as the immunogen is eliminated (slope declines)
Complement system: Classical Pathway
Activated by antibodies
Complement system: Lectin Pathway
Activated by mannose-binding lectin (MBL): MBLs bind to pathogens, activating the cascade.
Complement system: Alternative Pathway
Activated by microbes
(LO) Describe the roles of complement components in the innate immune response.
Complements are plasma proteins with anti-microbial properties that are activated in response to an infection. • Complement works to *induce inflammation*, *opsonize pathogens*, or *lyse pathogens*. It is an *enzymatic cascade* that begins once a pathogen enters the body and is recognized by complement. • Activated complement can use chemotaxis to draw the attention of the rest of the immune system (attract macrophages and neutrophils). • They *opsonize pathogens*, coating them with molecules that promote their uptake by phagocytosis through macrophages and neutrophils • They *kill directly pathogens/infected cells* by inducing lysis. This occurs by forming a membrane attack complex (MAC) that will puncture the membrane of the pathogen, causing cell death.
What if you had a mutation of TLR downstream signaling molecules?
Decreased resistance to the microbes, as the immune system wouldn't be activated properly (pro-inflammatory genes would not be expressed).
(LO) Describe the general features of *adaptive immunity*.
Immunity that is *learned* through exposure to a foreign substance or pathogen (antigen). It is specific for the particular antigen and is enhanced by repeated exposure, thus it *improves over time* and has immunological *memory*. • No physical components • Biochemical components: antibodies & cytokines • Cells: B&T lymphocytes and dendritic cells
(LO S19) Explain how antigen receptor diversity is generated for B and T cells.
In the bone marrow (B cells) or thymus (T cells), multiple V, D and J DNA gene segments that encode the *variable region* are randomly recombined to create new combinations in developing lymphocytes -> the imprecise joining of segments creates diversity.
Pathogen-Associated Molecular Patterns (PAMPs)
Molecules that are unique to microbes. One of the 2 molecular patterns recognized as non-self in the innate immune system. Example = components of the bacterial cell wall.
What is immunity?
Resistance or protection against infectious agents (e.g. bacteria, fungi, viruses).
What is an immune response?
The combined repertoire of cellular and molecular events that occur during exposure to foreign substances.
(LO) Describe the general features of *innate immunity*.
The part of your immune system that you are *born with*. It is not specific to any pathogen (antigen) and thus, not improved by repeated exposure (*no memory*). The body's first line of defense; holds pathogens "at bay" until the adaptive immune system can ramp up. • Physical components: skin, endothelium & epithelium, coughing, sneezing, crying, urination, and normal flora • Biochemical components: complement, lysozyme, pH, interferons • Cells: NK cells & phagocytes (neutrophils, monocytes, macrophages, dendritic cells)
What is immunology?
The study of the cellular and molecular events that occur during the host response to a foreign substance.
(LO) Describe the properties and functions of IgG
• *Principal Ig of serum* (~80%) • 4 subclasses in humans • Longest half life of all Igs (>20 days) • *Only antibody that crosses placenta* (IgG1 & 3); enters fetal circulation and may provide immunity for up to 1 year • Opsonic activity--facilitates uptake of pathogens by macrophages and neutrophils • Activates complement • Neutralizes toxins and viruses
What is inflammation?
• A tissue reaction that rapidly delivers mediators of host defense to a location of need (such as site of infection) • Initiated by: - complement - cytokines (small cell-signaling proteins) - other means, phagocytes are important (neutrophils, macrophages, dendritic cells) • Increases vascular permeability which permits: - influx of innate immune molecules - change in receptors - movement of WBCs from capillaries to tissues (esp. neutrophils) • Increases lymph flow - cells & pathogens to lymph nodes to initiate adaptive response • Once adaptive response starts, helps recruit effector cells
(LO Steph) Explain the clonal selection model of adaptive immunity.
• At any time, the body is filled with "clones" of naive B and T cells, each with different antigenic specificities on their surface. (B cells have immunoglobulins, Ig on their surface; T cells have T Cell Receptors, TCR). • Once an antigen binds to the antigenic specific receptors on a cell of the adaptive immune system (naive B or T cell), that cell with that specific antibody will replicate and produce many cells capable of producing that same antibody. These plasma cells then pump out the antibody in order to defeat the infection. (This is true for B cells) T cells will become activated and will develop either into helper or cytotoxic T cells. • Some of these selected cells are set aside to remember the pathogen in case it is encountered in the future.
(LO) Describe the mechanisms of *innate immunity*.
• Epithelial surfaces like the skin, lungs, reproductive tract, and GI tract protect the host through physical barriers (tight junctions) that have antimicrobial properties (low gut pH, antibacterial peptides/enzymes, flow of fluid, motion of cilia). • The complement system involves a large number of circulating plasma proteins with anti-microbial properties which are activated in response to infection. It also acts as a chemical signal to trigger immune response to that area. • In the tissues and circulation, immune cells like macrophages, neutrophils, dendritic cells kill microbes and *initiate an inflammatory response*. NOTE: innate system can work with & be augmented by adaptive components AND most cells in the body perform innate immune functions.
(LO) Describe the properties and functions of IgM
• Exists as *pentamer* (10 binding sites) in serum • On surface of naive B cells, expressed as monomer • *Predominant antibody during first week of infection* • *Strong activator of complement* • Extra constant domain • Does not cross placenta (Note: elevated levels of IgM in fetus is indicative of perinatal infection)
(LO) Describe the properties and functions of IgE
• Extremely low concentration in serum • Induced in response to parasitic infections (such as worms) • Important in allergic reactions (binds to Fc receptors on mast cells, basophils, & eosinophils) -- antigen encounter leads to release of inflammatory signals
(LO) Describe the properties and functions of IgA
• Most abundant Ig in the body • Exists as monomer (in serum), dimer (secretory) • *Predominant form of Ig in sero-mucus secretions* such as breast milk, colostrum, tears, saliva • *Protects exposed mucosal regions* from pathogenic organisms • Is transferred in breast milk to gut of newborn infant where it provides protection against newly-encountered bacteria. • Functions mainly as a neutralizing antibody
(LO) Explain how the innate immune system recognizes "non-self".
• PAMPs: Pathogen-Associated Molecular Patterns (molecules that are found on nonself, i.e. bacteria) are recognized by *Toll-like Receptors (TLRs)* and *NOD-like Recepters (NLRs)*. TLRs and NLRs (as well as other stimuli) induce the inflammatory response and activate cells, increasing the killing capacity of phagocyte, cytokines, and virus resistance. • *TLRs recognize functional groups that are on the surface of the pathogen*, such as peptidoglycan that is in the cell wall of bacteria. Other examples are lipoproteins and lipopolysaccharides (LPS). TLRs can also recognize elements inside the cell, but they must do it in an endosome because they sit on the plasma membrane (membrane-bound sac inside the cytoplasm of the cell). • *NLRs recognize patterns within the cytosol of the cell.* There are at least 23 genes of these in humans. They typically interact with microbial ligands inside the cell, activating the NLRs and producing signals that will enhance inflammation. NOTE: if a pathogen has made it into your cytoplasm, it's a big deal! The response from the NLRs is thus huge. • In complement system, complement proteins assembly a membrane attack complex (MAC) that punctures the cell membrane. In human cells, CD59 binds to the complex and prevents binding of C9, which forms the pore. Thus, *complement MACs cannot lyse human cells.* • Interferons (IFN) are secreted once the anti-viral system in most body cells detect an infection. Interferons can act on the same cell or neighboring cells. This will shut off protein synthesis and activating RNAse to digest RNA, effectively preventing the virus from replicating and infecting other cells.
(LO Steph) Explain how antigen receptor diversity is generated for B and T cells.
• There are too many combinations for there to be a single gene for every known pathogen. Instead, there are many possible combinations of genes that can create the variable regions of antibody and T-cell receptors. The variable region of the antibody or receptor is what recognizes the antigen. • There are many genes for each DNA segment. For a heavy chain, a V segment, a D segment, and a J segment are randomly selected. The light chain is similarly assembled. • The genes rearrange during B cell formation. After development RNA splicing will remove extra genes. • The gene rearrangement, variable heavy and light chains make for a huge amount of diversity in these antigenic receptors. • Once a functional immunoglobin is produced, the other loci is shut off (one of each chromosome). This ensures that the cell will only present one type of receptor, and produce one kind of antibody (maintain specificity).
What are macrophages?
• Tissue-resident (derived from monocytes) in connective tissues, mucosal tissues, liver, etc. • Long-lived and present at the outset of infection • Initiate responses and serve many other roles, including direct killing of microbes and facilitating adaptive immunity