What is the sole function of the B cell arm of the adaptive immune system?
What is the role of the Abs?
bind tightly to pathogens
The most efficient antibodies are those that do what 2 things?
produced early in infection,
bind antigen with high affinity
the onset of antibody production is delayed for about a week after onset of infection. Why?
B cells typically do not differentiate into plasma cells unless they have received T cell help
it takes time for B cells to undergo isotype switching and affinity maturation
Why is isotype switching and affinity maturation important?
they produce high affinity antibodies that direct the proper effector mechanisms for most efficient clearance of the pathogen
the effectiveness of the antibodies produced increases over the course of the response.
The high affinity Abs are retained how? why?
retained in the form of memory B cells that provide long-lived immunity to re-infection.
following secondary exposure to a pathogen, the B cell response should be what?
very efficient because high-affinity B cells of the proper isotype have already been clonally expanded and can be quickly reactivated following re-infection.
B cell activation requires what?
this clustering/aggregation of BCRs results in signaling to the inside of the cell. How is it done?
upon binding to antigen (protein or carbohydrate), the surface IgM molecules (BCRs) become physically crosslinked to each other and are drawn into the localized area of contact with the antigen;
What is the BCR composed of?
a single antibody molecule (the isotype that is produced by that B cell) that is associated with two protein chains: the immunoglobulin alpha and Beta chains (Ig-a and Ig-B)
the Ig-a and Ig-B chains serve as what of the B cell receptor. What is this analogous to on the T cell?
the signal transduction unit
analogous to the CD3 complex expressed by T cells
How does the signal transduction unit (Ig-a / Ig-B chains) of the BCR initiate intracellular signaling pathways?
the cytoplasmic tails of Ig-a and Ig-B have immunoreceptor tyrosine-based activation motifs (ITAMs)
- ITAMs become clustered (due to receptor crosslinking),
- tyrosine residues within these motifs become phosphorylated,
- tyrosine kinases are activated,
- intracellular signaling pathways are initiated
What is the B cell co-receptor?
a complex of at least 3 proteins
- complement receptor 2 (CR2 or CD21) which binds to complement components that are bound to the surface of a pathogen;
- CD19, which acts as the signaling chain of the co-receptor;
- CD81 (or TAPA-1) whose function is unknown (likely involved in signal transduction)
What acts as the signaling chain of the co-receptor?
What is the result when the B cell co-receptor is engaged?
cytoplasmic tail of CD19 becomes phosphorylated, allowing it to bind to intracellular signaling molecules which generate signals that synergize with those generated by the BCR complex,
resulting in a 1,000-10,000-fold increase in signaling
T/F signaling through the BCR in combination with signaling through the B cell co-receptor will induce activation of the naïve B cell
false, signaling through the BCR in combination with signaling through the B cell co-receptor is generally still insufficient to induce activation of the naïve B cell
How is a naive B cell activated?
signaling through BCR along with B cell co-receptor
a second signal of activation derived from helper T cells are also required
many antigens require help from what to elicit B cell responses? What type of antigens are these referred to?
an antigen-activated effector CD4+ T cell (helper T cell)
referred to as thymus-dependent antigens (TD antigens)
some antigens can activate B cells in the absence of T cell help; such antigens are referred to as what?
bacterial cell walls and capsules contain (or are composed of) what?
complex polysaccharides, lipopolysaccharides, and proteoglycans that are chemically and antigenically distinct from any antigens derived from mammalian cells
Why are the bacterial macromolecules (complex polysaccharides, lipopolysaccharides, and proteoglycans) major targets of Ab response?
often characterized by repetitive epitopes and serve as major targets of the antibody responses produced against extracellular bacterial pathogens
For TI antigens, what is the reason no T cell help occur?
The bacterial and capsule components cannot be processed and presented to T cells bc they are non-protein
for thymus-independent antigens, the need for T cell help can be overcome in two different ways. name them
TI-1 antigens have an intrinsic capacity for inducing B cells to proliferate
TI-2 antigens are typically composed of repetitive carbohydrate or protein epitopes present at high density on the surface of a microorganism
What provides the intrinsic capacity for TI-1 antigens to induce B cells to proliferate?
TI-1 antigens bind to BCR, but also engage other receptors on the surface of B cells whose stimulation promotes proliferation and differentiation
at high [ ], TI-1 antigens can activate almost any B cell, regardless of the BCR specificity (non-specific activation)
antigens that cause such polyclonal activation of B cells are known as B cell mitogens; an example of a B cell mitogen is lipopolysaccharide (LPS), which is a common component of Gram-negative bacteria
•• the concentration of antigen required to polyclonally activate B cells is much higher than is normally encountered during a natural infection; during an infection, the B cell mitogen concentration is sufficient to activate only those B cells that have been engaged through their BCRs by their specific antigen, and therefore, only antigen-specific B cells will be activated
without the participation of cytokine signals produced by helper T cells, what Abs are produced? and what 2 functions are disabled?
primarily IgM antibodies are produced (very little class-switching)
no affinity maturation
No differentiation to memory cells
What is polyclonal activation? What antigens cause it?
at high concentrations, TI-1 antigens can activate almost any B cell, regardless of the BCR specificity (non-specific activation)
B cell mitogens
During polyclonal activation of B cells, how are only antigen-specific B cells activated?
the concentration of antigen required to polyclonally activate B cells is much higher than is normally encountered during a natural infection;
during an infection, the B cell mitogen concentration is sufficient to activate only those B cells that have been engaged through their BCRs by their specific antigen
How do TI-2 antigens typically carry out their function?
probably act by crosslinking BCRs and B cell co- receptors to the extent that no additional signals are needed to activate the B cell
When does a response to TI-2 antigens usually observed?
•• responses to TI-2 antigens are usually observed about 48 hours after encounter with antigen
typical TI-2 antigens are what? What is the responding B cell?
bacterial cell wall polysaccharides,
the responding B cells are B1 B cells (a minority subset of B cells);
why do infants make poor antibody responses to polysaccharide antigens?
B1 B cells usually become functional at about 5 years of age
What Abs can be induced by TI-2 antigens? Why are they important?
both IgM and IgG antibodies
these Abs are an important part of the early B cell response to some common bacterial infections
although responses to TI-2 antigens may play an important role in early containment of some bacterial infections, these responses have 3 profound limitations: name them
1) there is no significant isotype switching,
2) no affinity maturation takes place
3) no immunological memory is provided
the bulk of the pathogen-specific antibody produced during immune responses comes from what?
B cells stimulated by T-dependent antigens
activation of B cells stimulated by TD antigens occurs where? Why is this an easy place for this action?
in secondary lymphoid tissues
where B cells, specific antigen, and effector CD4+ T cells (helper T cells) all come together
while T cells enter secondary lymphoid tissues via what route and specific process? antigen enters the 2 ̊ lymphoid tissues via route?
the circulation (diapedesis thru HEV)
the lymph to the node nearest the infected tissue
What carries the antigen in the lymph? What happens when it gets there?
DCs or by itself
antigen becomes trapped in the lymph node and some of it is processed and presented by professional APCs
Where do naïve CD4+ T cells bearing a TCR specific for presented peptide antigens (bound to MHC class II) will become activated to form what?
in the T cell zones
effector T cells
B cells pass through the T cell zone and when their cognate antigen is present, they can become activated if they do what?
if they productively present peptide antigen to an effector CD4+ T cell (the helper cell supplies the 2nd signal of activation
the B cell receptor has two distinct roles in B cell activation: name them
1) binding to cognate antigen (1st signal of activation),
2) internalizing the antigen so that it can be processed and peptides presented on MHC class II molecules on the B cell surface
a B cell that receives the 2nd signal of activation from an effector CD4+ cell will form what?
a primary focus of dividing lymphoblasts within the T cell zone of the 2 ̊ lymphoid tissue
some B lymphoblasts move into the medullary cords and differentiate _____ under the influence of what molecules?
directly into plasma cells
the TH2 cytokines IL-5 and IL-6
B cells that differentiate directly into plasma cells from the influence of Th2 cytokines IL-5 and IL-6, secrete what Ig predominantly?
other lymphoblasts from the primary focus will migrate to the primary follicles as what?
conjugates with their effector helper T cells
What are centroblasts?
rapidly dividing cells that are very metabolically active which have migrated to the primary follicles as conjugates with their effector helper T cells
as the numbers of centroblasts rapidly expands, the follicle changes and becomes dominated by what?
the germinal center
What is a germinal center? When do they appear?
contains the newly formed B cells and are responsible for the characteristic swelling of lymph nodes (lymphadenopathy) draining an infection
germinal centers appear approximately one week after the start of infection
What happens to the helper T cells that migrated to the lymphoid follicle along with the B lymphoblasts?
they proliferate and are intermingled with the centrocytes
after a few days, how would you describe the vast majority of lymphocytes within the germinal center? the B cells (which are not specific for the antigen) that were present in the follicle before entry of the of the activated B cell-T cell conjugates are pushed to the outside of the germinal center
clones derived from one or a few of the founder pairs of antigen-activated B and T cells
What happens to the B cells (which are not specific for the antigen) that were present in the follicle before entry of the of the activated B cell-T cell conjugates?
pushed to the outside of the germinal center
What is the role of the helper T cell for non-protein determinants?
The helper T cell that provides the second signal of activation to a B cell that has already encountered its cognate antigenic determinant does not need recognize the same antigenic determinant as the B cell
What occurs in centrocytes during the germinal center reaction?
the activation and proliferation phase that results from B cell activation is followed by what process?
somatic hypermuttion (affinity maturation) is initiated by what? takes place where?
initiated by cytokines produced by the helper T
it takes place in the centroblasts dividing within the germinal center
the population of centrocytes within the germinal center expresses immunoglobulin that has a range of affinities for the antigen. What allows this?
somatic hypermutation (affinity maturation) gives rise to non-dividing centrocytes that have mutated surface immunoglobulin that either has lower, higher, or similar affinity for the antigen than that of the original unmutated B cell receptor
What signal from what cell is required by the centrocyte to avoid apoptosis?
the survival signal is delivered by helper T cells in the form of the CD40L (which binds to CD40 on the centrocyte)
What must a centrocyte do in order to engage a helper T cell?
it must have successfully competed with other centrocytes for antigen that it then internalized, processed, and presented peptides to the cognate helper T cell
How does a B cell receive the survival signal (CD40L) to be positively selected for?
B cells bind to antigen that has been trapped on the surface of follicular dendritic cells (FDCs),
those B cells bearing higher affinity surface Ig will out-compete those B cells that have lower affinity Ig for binding to antigen (and for subsequent interaction with a helper T cell),
those centrocytes that have lower affinity BCR undergo what?
removed from the germinal center by tingible body macrophages
T/F somatic hypermutation can also give rise to self-reactive B cells within the germinal center
Describe peripheral tolerance wrt B cells
when a centrocyte acquires a mutated BCR that is self-reactive, it should no longer have specificity for the original antigen and will be unable to compete for binding to antigen trapped on the surface of FDCs; these cells will be unable to receive survival signals and will not be positively selected, and they will die
What are follicular dendritic cells (FDCs) ?
the characteristic stromal cell of primary lymphoid follicles;
these cells pick up antigen, but they do not internalize it, but instead display it on their surface for long periods of time.
How can FDCs interact with many B cells simultaneously?
FDCs cells have a dense network of antigen-loaded dendrites
What are 2 important distinctions of FDCs from DCs?
FDCs are not derived from a hematopoietic stem cell
they do not express MHC class II molecules
What cells can supply survival signals to centrocytes that have high affinity for antigen?
helper T cells => CD40L
What receptors do FDCs express? what are they used for?
FDCs express Fc receptors and complement receptors on their surface
to capture immune complexes that are then displayed on their surface for long periods,
providing a source of intact antigen for B cells to sample
What are iccosomes (immune-complex coated bodies)? what is their role?
bundles of membrane coated with immune complexes that bud off of FDCs
can be bound, internalized, and processed by B cells for presentation to helper T cells
How and where does isotype switching occur?
takes place in B cells within the germinal center
signals are provided by the effector T cells that are also proliferating within the germinal center
What is the difference between Th1 and Th2 wrt class switching to isotypes of Abs for opsonization?
Th2=> weakly opsonizing and IgA and IgE
What is the fate of B cells that survive the selection process in the germinal center?
proliferate and begin to differentiate into plasma cells
leave the 2 ̊ lymphoid tissue and migrate to the bone marrow or Peyer’s patches in the gut (IgA producers)
The differences between resting B cells and plasma cells is what? (ppt)
At the height of the adaptive immune response, differentiation is almost exclusively to what?
in the later stages of a successful immune response, B cells within the germinal center begin to differentiate primarily what?
memory B cells
once a pathogen-specific B cell has been identified and has been signaled to proliferate, isotype switching allows the immune system to do what?
diversify the effector mechanisms of B cells derived from the original antigen-specific B cell clone
Why is isotype switching important for Ab-mediated effector mechanisms?
isotype switching maintains the antigen- specificity of the antibody while altering the constant region of the heavy chain (the Fc region)
the Fc regions of antibody molecules have three critical functions: name them
1) delivery of the antibody to anatomical sites within the body that would otherwise be inaccessible,
2) some isotypes of antibody have ligands in their Fc region that bind the complement component C1 which initiates the classical complement cascade
3) recruitment of non-specific effector cells (macrophages, NK cells, mast cells, granulocytes) into the immune response (in short, they form a bridge between the innate and acquired arms of the immune response)
In what ways are different isotypes of Abs identified?
different isotypes of antibody direct different effector mechanisms which reflect their differing roles in immune clearance;
their roles are also reflected in their characteristic distribution in the tissues of the body
Blood and extracellular fluids are protected by
IgM, IgG, and IgA
T/F IgM is the first antibody produced by every B cell
How is IgM secreted and what is it's main function? limits?
it is secreted only in pentameric form
carried via the blood to sites of tissue damage and infection throughout the body
due to its pentameric structure, IgM can bind to microorganisms/particulate antigens with very high avidity
each IgM molecule has 10 antigen-binding sites
large size limits its ability to leave the circulation and move into inflammatory sites
Why can't IgM directly recruit phagocytes or other leukocytes for help in immune response?
since there are no Fc receptors for IgM expressed on phagocytes or other leukocytes, IgM cannot directly recruit these cells for participation in immune responses
T/F IgM can efficiently activate the complement cascade
What are the main Ig to control or prevent blood-borne infection (septicemia)?
IgM, IgG, IgA
How does IgM fight blood pathogens?
neutralize potential pathogens
What is the most abundant and important Ab isotype for infection control? Why?
1) it can fix complement
2) most phagocytes as well as NK cells have Fc receptors that recognize the Fc portion of IgG molecules,
- actively transported into extracellular spaces,
- longest half-life of any antibody isotype
What cells synthesize IgA? where are these cells primarily?
IgA is synthesized by plasma cells that reside primarily in secondary lymphoid tissues that line the mucosal surfaces of the body (MALT)
monomeric IgA helps to patrol what 3 areas?
the blood (less important),
mucosal surfaces of the body (most important)
What is the difference between monomeric and dimeric IgA wrt location of class switching?
monomeric igA => germinal center reaction
dimeric IgA => lymphoid tissues underlying mucosal surfaces
dimeric IgA helps to prevent infection by pathogens that gain access to the body via what route? give examples
(linings of the gastrointestinal tract, the eyes, the nose, the throat, the respiratory, the urinary and genital tracts, and the mammary glands)
What is the main difference between monomeric and dimeric IgA wrt receptor binding?
dimeric form of IgA binds to the poly- Ig receptor
What is the poly-Ig receptor?
a receptor on the basolateral surface of epithelial cells that binds to polymeric immunoglobulins, especially dimeric IgA, and transports them across the epithelium via transcytosis
the transport of molecules from one side of an epithelium to the other by endocytosis into vesicles within the epithelial cells at one face of the epithelium and release of the vesicles at the other
What is the portion of the poly-Ig receptor that binds the dimeric IgA molecule?
How is IgG actively transported from the blood into extracellular spaces? what function is this?
by an Fc receptor present on vascular endothelial cells
most of the IgG in a normal individual resides where and for how long?
extracellular spaces where it has a relatively long half-life and can help to protect tissues from infection
What receptor is responsible for transporting IgG across the placental barrier?
Brambell receptor (or FcRn) is also responsible for transporting IgG across the placental barrier into fetal circulation
T/F during pregnancy, the developing fetus is physically protected from infection by the mother
For the 9 months of life, what does a newborn use against common pathogens?
they depend on maternal antibodies to protect them against common pathogens
Why is maternal IgA vital to a newborns early health? how does it receive it?
babies are especially vulnerable to infectious agents that infect via mucosal surfaces,
colostrum and breast milk
What Ab is transferred to the developing fetus? How? What is the concentration of IgG at birth in the baby?
IgG via the brambell receptor across the placental barrier into the bloodstream of the fetus
[ ] is the same as the mother's
What are the 2 ways passive immunization can be achieved?
transfer of maternal antibodies
injecting antigen-specific antibodies into an individual to protect them against a particular pathogen or toxin
What is passive transfer of immunity?
the transfer of immunity to a non-immune individual by either natural means (IgG crossing placental barrier or breast milk) or by the injection of specific antibody, immune serum, or T cells
How does an Ab neutralize potential pathogens or toxins?
prevent binding of a pathogen (viral or bacterial) or toxin to its specific host cell receptor, thereby preventing infection or toxicity,
once neutralized, it is opsonized for phagocytic destruction
What is the binding event that signals the phagocyte to engulf the foreign material and destroy it? How is it done with different cells
Antibodies can directly mark pathogens for uptake and destruction by phagocytes;
macrophages and neutrophils have Fc receptors on their surface that can bind to antigen/antibody complexes via the Fc portion of the antibody molecule.
each of the non-phagocytic innate immune cells what on their surface? when do they perform their effector function?
express Fc receptors on their surface,
when these Fc receptors bind to the appropriate antibody
Describe what makes a binding interaction a high avidity interaction wrt the Fc receptor
low affinity Fc receptors only bind to Ab that is bound to its specific antigen;
since the affinity of Fc:Fc receptor binding is low, unbound antibodies do not stay bound to the receptors for long periods;
however, when multiple antibodies are bound to an antigen, they can bind to multiple Fc receptors on the surface of an immune cell
What is a NK cell? what immune response is it important for?
• large granular lymphocyte-like cells that have important functions in innate immune responses
Where does the NK cell arise?
arise from the lymphoid progenitor in the bone marrow,
functionally very different from lymphocytes
T/F NK cells do not express antigen-specific receptors (B cell receptor or T cell receptor)
Describe how immunization, memory and antigen recognition help NK cell activity
• NK cell activity cannot be enhanced by immunization,
memory is not involved in their function
NK cells do not recognize specific antigens
NK cells are stimulated by what? What is their role specifically?
cytokines produced by macrophages
TNF-a and IL-12 act synergistically on NK cells to elicit production of IFN-y (an inflammatory cytokine)
How do NK cells play a role in the amplification of inflammatory reactions?
NK cells produce IFN-y which is a potent signal for upregulation of macrophage activity
NK cells IFN-y, IL-1, and GM-CSF, what is their role other than inflammatory amplification?
modulate macrophage activity and have other proinflammatory effects
What are the effectors of ADCC (antibody-dependent cell-mediated cytotoxicity)?
How does the NK cell carry out its function within ADCC?
NK cells express the FcyRIII receptor;
this receptor can bind to IgG that is bound to infected host cells;
this binding causes the NK cell to degranulate,
initiating apoptotic death of the infected host cell
How are NK cells a bridge between innate and acquired immunity?
they express no antigen-specific receptors,
but they can initiate killing of cells that have been recognized as infected by specific antibody molecules
T/F ADCC by NK cells is dependent of the MHC class I inhibitory signal
NK cells are programmed to kill host cells that do not express MHC class I
FasL expression helps NK cells do what?
helps NK cell trigger apoptosis in target cells that express Fas
When the NK cells release their granules to initiate killing. Give the steps of this
granules => 1)perforin (forms membrane-destabilizing pores) and 2) granzymes (gain access to cell interior because of perforin activity)
granzymes are proteases that can 3) initiate the caspase cascade that results in programmed cell death (apoptosis)
What are large granular cells that are found in large numbers in vascularized connective tissues (beneath the epithelial surfaces of the body)?
Tell where mast cells arise and what part of immune system
arise from the common myeloid precursor in the bone marrow
innate cells of the immune system
T/F mast cells do not make any antigen-specific receptor molecules
Mast cells are commonly involved with what Ig? How do they bind?
mast cells do express a high-affinity Fc receptor that binds to the Fc portion of IgE antibodies
Why is very little IgE found in the serum? What does this allow?
most of the IgE that is produced by B cells rapidly binds to FceRI receptors on mast cells
single mast cell can have a large number of IgE Abs bound to FcRI receptors on their surface that can have a different specificity
What is the role of mast cells?
initiate inflammatory responses in epithelial tissues in response to antigens that have previously initiated an antigen-specific IgE antibody response
•• parasite pathogens typically elicit what type of response
What induces the mast cell to release the contents of its granules?
crosslinking of antigen-specific IgE bound to FcRI receptors by specific antigen
What is the most notable mediator released by mast cells upon degranulation?
Describe the process of mast cell degranulation
degranulation causes a local increase in blood flow, vascular permeability, and fluid accumulation (including Ab molecules)
the site of local inflammation becomes populated with neutrophils, macrophages, eosinophils, and effector lymphocytes
fluid accumulation also leads to increase in lymph flow, which facilitates antigen delivery to lymphoid tissues
Mast cells are therefore an important part of the frontline of host defenses against what?
parasite pathogens that enter the body across epithelial barriers
What cells play a similar role to that of mast cells in hypersensitivity reactions?
basophils and eosinophils
eosinophils also play an important role in killing what? what receptor is important for this?
multicellular parasites that have been opsonized with IgE antibodies
IgE Fc receptor (FceRI)