Immunology Final Flashcards
Be able to describe where (the anatomical location) and from what cell type a naïve B cell acquires cognate antigen.
In the secondary lymphoid tissue from the FDC
Describe the molecules that comprise the BCR (Heavy and light chains, Ig alpha/beta).
heavy chain on bottom then light chains we have light chains on further right and variable heavy inside
The strength of BCR signaling depends on what factor?
BCR cross linking
1) Antigen -> multivalent will send strong signal on BCR.
2) BCR -> affinity high affinity BCR engagement of BCR can be done with lower amount of antigen. Can detect small amount of antigen and low affinity BCR may not send signal at all. IMPORTANT IF WE THINK ABOUT DIFF BETWEEN MEMORY AND PRIMARY HUMORAL RESPONSES. Memory B cell has more sensitive BCR versus a naïve b cell. They can detect lower amounts of antigen so that they will be activated sooner.
Characteristics of thymus independent antigens
signals generated are sufficient to activate the B cell in the absence of additional signals. dense clustering of b cell receptors and co receptors which produces sufficient signaling to stimulate b cell proliferation. these antigens do not require help from t cells
they are repetitive, high density, cross link bars, elicit primarily low affinity IgM…IgM activate complement
Thymus-independent antigens induce IgM synthesis by B cells without cooperation by T cells. INDUCE IGM
Role of follicular dendritic cells (FDCs) in B cell responses. Positive selection of B cells
Provide survival signals to immature B cells, heavy and light chain rearrangement, negative selection non self reaction, leave bone marrow need surveil signal from FDC.
store intact antigen, interrogated by mature b cells.
Antigen repository for activation of naïve B cells
know that antigen is not phagocytosed, remains on FDC surface for months to years
Linked recognition
a process by which a B cell is optimally activated by a helper T cell that responds to the same, or physically associated, antigen but not necessarily the same epitope.
There are two waves of B cell proliferation/antibody production in a primary humoral response
explain the timecourse/characteristics of these waves
primary focus
Primary focus of clonal expansion. this cellular proliferation lasts several days and gives rise to diving B lymphoblasts secreting IgM. Antibody leaves the node in the efferent lymph and is delivered to the blood, which rapidly carries it to the site of infection
cognate pairs of mutually activated antigen specific b and tfh cells move from the boundary region to the medullary cords, where they proliferate to form large clones of identical cognate pairs
response.
Primary response reflects that initially IgM is produced quickly (3 days) T dependent responses first wave – represents b cells in medullary cords b cell that meets with tfh reconifnzes the same antigen but diff epitopes. They can come together and form stable assocaitation. Travel to medullary cords and the B cell expands and some become plasma cells that produce IgM. (low affinity)
Switching of cosntatnt heay region to igQ or ige , ceontroblasts become centrocytes compete for antigen with germinal center reaction we see maturation. Decline represents death of short lived plasma cells. Some anitbodies remain (long lived plasma cells) this period is a period of memory)
And the switching where the infection has been cleared with high level antibody = protective humoral immunity. This period is important because you possibly have given it to someone else and you are contiously being exposed to pathogen because you have high level of antibody.
If reexposed with memory response and dramatic expansion of antibody is switching because it is high affinity peak represents memory B cells. Memory b cells will go through second germinal center reaction and they will produce more antibody the first time and higher affinity. Protective immunity and immunological memory. Acquire more memory more plasma and each time there is subsequent germinal center reaction.
Secondary focus of clonal expansion
produces a germinal center source of high quality antibody. 2nd priority antibody quality. create antibody of same specificity remaining b and t cell pairs will go back and form germinal center reaction. differentiate to give plasma cells secreting antigen specific IgM. mitotic division
How do rare pathogen specific B cells find rare Tfh cells specific for the same pathogen? Why is this important for effective humoral responses?
they screen the antigens teh b cells put on the mhc class ii …….
What types of cells are found at a primary focus?
conjugate b and t cell pair. b lymphoblasts differentiate into plasma cells.
Where in the lymph node is the primary focus?
medullary cords
What type of antibody is produced there? primary focus
B lymphoblasts that secrete IgM and differentiate int plasma cells
Where in the lymph node is the secondary focus?
primary follicle
What structure does the secondary focus form?
germinal center is formed by the expanding population of antigen specific b cells, and this is where b cells undergo affinity natural and isotope switching of their antibodies
What types of antibodies are produced there? secondary
B cell expansion, antigen specific b cells
Describe the events that occur in the germinal center.
What types of cells are involved (I can think of three)?
centroblasts , AID induced by tfh..cytokines and cd40L induce . express mutated/switched cell surface Ig. increases IgE and increases affinity. centrocyytes perform this
Centroblasts
Proliferation: Centroblasts (proliferating B cells)- directed by Tfh ( cytokines, CD40L), upregulate AID = iso switch, somatic hypermutation
Competition for survival: Centrocytes
are no longer proliferating, Ig is a range of affinities, undergo affinity maturation (Centrocyte with high affinity acquires antigen from FDC, presents to Tfh to receive CD40L survival signal)
Two types of cells produced by germinal center reaction
plasma cells (IL 10) or memory B cells (IL 4) depending on the cytokines secreted by their cognate Tfh
At what point during the course of an infection are B cells more likely to differentiate into plasma cells
at the height of the adaptive immune response, the main need is for large quantities of antibodies to find infection, the centrocytes leave germinal center and differentiate under influence of IL 10 to produce plasma cells
At what point during the course of an infection are B cells more likely to differentiate into memory b cells
as the infection subsides and under the influence of IL 4 the centrocytes turn into long lived memory b cells that now possess isotope switching, high affinity antigen receptors.
Describe the role of the Tfh cell in various stages of the humoral response (medullary cord B cells, centroblasts, centrocytes). Especially focus on the role of CD40L.
tfh provides the critical survival signal, they have linked recognition of t and b cells. in the primary focus before the GC the cytokines and CD40L drive b cell proliferation and differeitanteion to plasma cells (IgM)
role of tfh on humoral response during germinal center reaction
centroblasts cytokines and cd40L AID induced
competition for antigen. must become effector cell to either differentiate into plasma or b cell. promote survival of centrocytes and present to TFH cells. promotion and inducing AID will lead to somatic hypermutation and isotope switching CD40L is a potent activator of B cells and is able to induce proliferation and, in combination with cytokines, isotype switching and differentiation of B cells.
What enzyme is only expressed in germinal centers?
AID- essential for both somatic hypermutation and isotope switching
In what types of infections are IgG most useful?
CD40L and Cytokines control isotype switching in B cells. In humans IFN gamma induces production of opsonizing antibody (IgG1 and IgG3) while IL-4 induces production of IgE.
IgG - bacterial and viral
in waht types of infections are IgE most useful?
allergic reactions
What signal guides isotype switching in germinal center B cells?
AID
Which isotypes protect the blood, lymph, and extracellular spaces of the body?
IgM, IgG and monomeric IgA
Which isotypes are especially good at: Activating complement, neutralization, activating granulocytes, protecting mucosal surfaces?
IgM…mucosal surfaces = dimeric IgA
The anatomical location of mast cells provides protection throughout the body. Describe the locations of mast cells and how they protect against invading pathogens.
Mast cells are found in most tissues of the body, particularly in locations that are in close contact with the external environment, such as skin, airways, and intestines and blood. Mast cells can modulate host innate immune responses through the release of granular and secreted mediators (reviewed in [1], [2]). The release of histamine and other vasoactive mediators increases vascular permeability and local blood flow, and can act on smooth muscle to increase the expulsion of mucosal parasites.
Describe bacterial exotoxins
released when the bacterium dies. they cause disease by disrupting normal function of human cells.
What type of immune response is most effective against these molecules… bacterial exotoxins
antigen antibody mediated immunity … acquired
How are vaccines formulated to generate this type of immune response
neutralizing antibodies are made against receptor binding chain of the bacteria , high affinity neturalizing IgG cover up the binding site in the toxins module
what are toxoids?
antibodies that bind to the receptor binding polypeptide can be sufficient to neutralize a taxon and the vaccines and tetanus work on this principle. they are modified toxin molecules, in which the toxic chain has been denatured to remove its toxicity .. ELICIT NEUT ANTIBODY
Fc epsilon-R I
High affinity IgE receptor. this is specific to myeloid cells…mast cells - tissue resident.. activation of esonophils mucosal surfaces and basophils circulation
Fc receptor that is expressed on granulocytes when cross linked it will cause the granulocyte to release granules. High affinity receptors levels of IgE quite low, it is bound to granulocytes (sensitization)
Fc gamma-R I
High affinity Fc receptor for IgG, constitutive on macrophages, DCs, monocytes, induced on neutrophils and eosinophils -> myeloid cells. facilitates uptake and destruction of pathogens..after pathogen has been tethered to the phagocyte, interactions between antibody Fc regions and the fc gamma RI send signals that induce the phagocyte to engulf the antibody coated pathogen …becomes full engullfed
Major phagocytic receptor, macrophages express this when they see opsonized IgE will release this.
Fc gamma receptor IIB
inhibitory factor and beat ITIMS, which associate with intracellular proteins that develop inhibitory signals.
Inhibitory receptor – when engaged will send inhibitory signal to cell that expresses it on a naïve b cell. Prevents or inhibits naïve b cell responses during a secondary response. B cell will be getting a specific signal in BCR and inihibitory signal with this receptor so it doesn’t expand or differentiate.
Fc gamma-R III
activating receptor for IgG and is the only Fc receptor expressed by NK cells. they have been studied in the context of killing by NK cells. antibody dependent cell mediated cytotoxicity is the way in which the therapeutic anti cd20 monoclonal antibody eliminates types of b cell tumor. this has a low affinity for Fc. they ae used for IgG activation and cancer, autoimmunity and transplantation
macrophage naeutroophil eosinophil nk cells
Expressed on NK cells and the ADCC. Virus infected cell , viral proteins will be produced. These will be expressed on surface of infected host cell. Antibodies will recognize the foreign vira protein and the effector mechanism is phagocytic cell or NK cells can use this receptor to bind to the Fc regions on this virus infected cell. It will form a stable pairing and NK cells will secrete its cytotoxic variable into this. Good example of adapted immunity makes for mores specific killing of virus infected cell. Recognition mechanism is different.
FcRn
IgG receptor diverts the IgG away from the lysosomes and takes it to the basolateral surface of the cell, where the basic pH of the extracellular fluid induced the receptor to release IgG. this transport receptor is FcRn. this is the brambell receptor. two molecules bind to the Fc region of one IgG molecules. this selectivity protects IgG from the processes of degradation to which other plasma proteins are subject
Transcytosis of IgG. Carrying a molecule across a cell layer. This will be carrying IgG across placenta -> mothers blood stream into fetal blood stream.
Describe the type of passive immunity that an infant receives form its mother.
the transfer of preformed IgG from mother to child in breast milk is passive transfer of immunity. another is intravenous immunoglobulin given to pattens with genetic defects.
Why are infants especially susceptible to infection from the age of 3-12 months?
IgG levels are lowest in infants aged 3-12 months , and this is when they are most susceptible to infection. can take longer to attain immune competence after birth.
Describe the role of FcεRI in parasitic infection. What cell types are involved in killing parasites?
binds to IgE antibodies. IgE is secreted un small amounts by plasma cells and become attached to the surfaces of mast cells resident in tissue, activated eosinophils at mucosal surfaces, and circulation basophils, where these cells are ready to bind to pathogens and antigens. IgE is specialized in causing physical ejection of pathogens and toxic substances. this receptor carries a variety of IgE molecules that are specific of different antigens. mast cells with large granules are deposited that contain histamine and other molecules that contribute to inflammation. cross link generates signals to release granules. increase permeability of flood and vasodilation recruits cells and proteins to defend the site of infection.
Mast cell that is sensitized with parasitic IgE. After humoral response initiated after . Binding to Fc episolon receptor 1further exposure will cause them to degranulate and degranulation involves release of multiple molecules and most potent is histamines. Histamine in parasite responses induces parastalsis in the GI tract that will expel in the tract, vomiting. Induce mucosal and reduce parasites trhough sneezing and blowing nose. Recreuit more granulocytes to site of parasitic infection. To get IgE it is all mediated by the CD4 TH2 response. Humoral response afain parasite needed for the sesnsitization. IL 4 AND IL5 are major players. IL 4 drives IgE isotype switching. IL5 activates granulocytes. Lower levels tend to induce Th2. In general TH2 is what you see with parasitic infection.
Describe how the humoral response enhances the ability of phagocytes to fight infection. (Mention FcγRI)
facilitate the uptake and degradation of pathogens by phagocytes. in adaptive immune response, antibodies made against surface antigens will coat the pathogen tith their Fc regions pointing outward and free to bind the Fc RI expressed on myeloid cell surfaces. this induces the phagocyte engulfing of pathogens
For what type of bacteria is this antibody effector function critical (See asplenia case study)?
they must be osponised for efficient phagocytosis … ecanpuulation is harder, they must be opsonized because they are resistant to phagocytosis, resistant to complement fixation
Describe how the humoral response enhances the ability of NK cells to fight infection. (Mention FcγRIII, ADCC).
NK cells can recognize and kill humans cells that have been coated with IgG1 and IgG3 antibodies. the antibody dependent cell mediated cytotoxicity (ADCC) signals from FC RIII activated the NK cell to kill the tumor cell. the ADCC can kill healthy B cells that express CD20. NK cells are major contributors to the innate immune response to infection, in which they use mechanisms other than ADCC. in the primary adaptive immune, ADCC will only come into play as a mechanism of NK cell killing once pathogen specific IgG antibodies are available.
