Check point questions - up to final Flashcards
what 3 major cell types found in the thymus play a role in T-cell development
Thymic epithelial cells (cTECs and mTECs)
macrophages
dendritic cells
what is the function of thymic epithelial cells in T-cell development
cTECs: provide signals for positive selection at DP stage - make sure TCR’s have the affinity for the MHC I or II molecule on APC presenting the antigen
mTECs: role in negative selection at SP stage - SP T-cells in the medulla that bind MHC presenting self-antigens on the surface of mTECs or CDs die by apoptosis
what is the function of thymocytes in T-cell development
- the developing T-cells themselves
- interact with TECs and other cells
what is the function of dendritic cells in T-cell development
- Found predominantly in the thymic medulla
- present self-antigens to developing T-cells during the negative selection process
why are individuals who lack the IL-7 receptor unable to produce functioning T cells
- the IL-7 receptor is important for T cell commitment in the double -ve stage
- IL-7 functions as a signalling protein required for TCR gene rearrangement
IL-7 provides anti-apoptotic signal (survival)
explain the role of Notch1 in T-cell development and its importance in lymphoid progenitor cell commitment to thymocyte development
- required for T-cell lineage commitment when CLP enters the thymus
- suppresses alternative fates (B-cell differentiation)
- turned off during B-selection (at DN4) as a consequence of pre-TCR signalling
what checkpoints can occur as part of the T cell development process
- TCR-B rearrangement: occurs at DN3 stage, Tests whether the TCRβ chain can pair with a surrogate α-chain to form a functional pre-TCR complex.
- TCR-a rearrangement: occurs at DP stage, tests the ability of the complete αβTCR to interact with self-MHC molecules presented by thymic epithelial cells. (positive and negative selection)
why don’t all 3 T cell development checkpoints need to be passed by a developing T cell
- yd T cells do not rearrange the β-chain of the TCR (skip pre BCR checkpoint)
- some specialized T-cell subsets recognize unconventional antigens or ligands might not strictly require positive selection
- Some γδ T cells and Treg cells may tolerate self-reactivity because they recognize stressed or altered self-antigens or directly suppressing immune responses
why do developing thymocytes need to use the pre-Ta chain to progress through the B-chain checkpoint?
- the pre-Tα chain serves as a surrogate partner for the newly rearranged TCRβ chain
- promotes allelic exclusion to ensure each T cell expresses a single, unique TCRβ chain
what are the 3 possible fates of double positive thymocytes continuing their development in the thymus?
- T-cell has no affinity for MHC on cTEC - leads to death by neglect (apoptosis)
- T-cell has moderate affinity for MHC on cTEC - leads to positive selection/maturation so SP thymocyte (what we want!!)
- T-cell has high affinity for MHC on cTEC - leads to negative selection (apoptosis)
which signal in differentiating progenitor cells is required to commit differentiation to B-cell development
signals from the TFs E2A, FOX01, EBF and PAX5
what are the critical checkpoints of B cell development
- pre-BCR testing
- central tolerance (-ve selection 1)
- peripheral tolerance (-ve selection 2)
what is the composition of the surrogate light chain and how does it resemble an immunoglobulin light chain
composition = y5 + VpreB
- pairs with a successfully rearranged Ig heavy chain, forming the pre-BCR complex
why is allelic exclusion of an immunoglobulin heavy chain that has not recombined necessary to normal B-cell function
- necessary to ensure that each B cell expresses a single, unique B-cell receptor (BCR) with a specific antigen-binding site
- maintains specificity and functionality of the adaptive immune system
compare and contrast the 3 possible fates of negative selection of self-reactive immature B cells
- Clonal Deletion (Apoptosis): Self-reactive B cells that strongly bind to self-antigens undergo apoptosis
- Receptor Editing: additional light chain rearrangements give immature B cells in bone marrow additional chances to replace auto reactive BCR with non reactive BCR
- Anergy (Functional Inactivation): Anergic B cells are functionally inactivated and cannot respond to their antigen even if they encounter it again
define the process of peripheral tolerance that occurs in B-cell development in the spleen
in SLO’s (such as the spleen) peripheral tolerance ensures that self-reactive B cells are either deleted, inactivated, or prevented from responding to self-antigens
what is the role of T cell priming in an adaptive immune response
- priming is the first contact that antigen-specific naive T cells have with an antigen
- happens in SLO’s by interactions between APCs and naïve T cells
both macrophages and DCs are capable of phagocytosis and processing antigens. why are macrophages not a major contributor to T-cell activation?
- DCs are the primary initiators of T-cell activation due to their role in antigen presentation, high expression of co-stimulatory molecules, and efficient migration to lymph nodes
- Macrophages are more involved in effector functions such as clearing pathogens and modulating immune responses, rather than in initiating new T-cell responses from naïve T cells
explain the process of T cell migration into SLOs
- binding of L-selectin to GlyCAM-1 and CD34 allows T-cell rolling on endothelium
- LFA-1 is activated by CCR7 signalling in response to CCL21 or CCL19 on endothelial cell surface
- activated LFA-1 binds to ICAM-1
lymphocyte enters lymph node via diapedesis
what costimulatory interaction is required between T cell and APCs
CD28 on the T-cell binds B7 on the APC
describe the role of TH1 cells
- release IFN-y
- amplify host responses to intracellular pathogens through classical activation of macrophages
describe the role of TH2 cells
- release IL4, 5 and 13
- coordinate type 2 responses by recruiting eosinophils, mast cells and basophils
- target helminth’s and parasites + repair tissue injury
describe the role of TH17 cells
- release IL 17 and 22 to produce the production of AMPs by epithelial cells
- coordinate type 3 responses by recruiting neutrophils
- target extracellular bacteria and fungi
describe the role of CTLs
induce apoptosis in infected target cells while sparing neighbouring uninfected cells
kill by releasing perforin, granzymes and granulysin
summarize the extrinsic pathway of apoptosis that CTLs use on target cells
- the Fas ligand binds and trimerizes Fas
- clustering of death domains allows Fas to recruit FADD
- FADD recruits and activates pro-caspase 8
- activated cascade 8 cleaves pro-caspase 3 which cleaves I-CAD
- CAD enters the nucleus and cleaves DNA
summarize the intrinsic pathway of apoptosis that CTLs use on target cells
- mitochondria release cytochrome C which binds to Apaf-1
- this assembles into an apoptosome which activates pro-caspase 9 which then activates pro-caspase 3
-pro-caspase 3 cleaves I-CAD then CAD enters the nucleus and cleaves DNA
explain the role of Tregs in peripheral tolerance
- bind to DC then release TGF-B and IL10
- inhibit the activation of other T cells
- target self and microbiome-derived pathogens
explain the interactions that must occur on the surface of a B cell that recognizes a thymus-dependent antigen for activation to take place
- BCR binds and internalizes one epitope on the antigen
- CD40 on B cell binds CD40L on helper T cell - signal for survival and proliferation
- MHC II on B cell presens a different epitope of the same antigen and presents it to TCR of helper T cell
how are B cells that recognize TI-1 activated
- multivalent pathogen with repeating epitopes binds dimerized BCR signalling and TLR on B cell surface
how are B cells that recognize TI-2 activated
- multivalent antigen binds to BCR and cause cross-linking
- CR2 on co receptor on B cell recognizes C3d on pathogen
what signals are provided by TH cells to activate B cells recognizing TD antigens
- CD40:CD40L = signal for survival and proliferation
- IL-21 = proliferation and differentiation
- cytokines = isotype switching
characteristics of primary foci in B-cell differentiation
- clusters of proliferating B cells that form early during the B-cell differentiation process
- no TFH interaction
- form in the medullary cords of lymph nodes or the red pulp of the spleen (outside the follicle)
- composed of proliferating plasmoblasts
- produce low-affinity IgM
- role in early neutralization
characteristics of secondary foci in B-cell differentiation
- clusters of plasma cells that form later (after the germinal center reaction) in B cell differentiation
- remain inside the follicle
- close association with TFH
- Consist of B cells in germinal centers
- produce high affinity class-switched antibodies (IgE, IgA, IgG)
- role in pathogen clearance
why is it important that centrocytes undergo a second round of selection within germinal centers
- Ensuring affinity maturation by selecting B cells that produce high-affinity antibodies.
- Preventing autoimmunity by eliminating self-reactive B cells.
- Optimizing the immune response by retaining only the most effective B cells.
- Supporting long-term immunity by generating high-quality memory B cells
how does the activity of TH cells drive isotype/class switching
- the cytokine they secrete will determine which isotype is produced
what are the properties and functions of IgM
- low affinity
- not class switched
- rapid first phase of B cell response to primary infection
- primarily in blood
- activate complement
- form pentamer
what are the properties and functions of IgD
- co-expressed with IgM during maturation
- no known function
what are the properties and functions of IgG
- class switching
- found in blood and extracellular fluid
- transported across placenta
- high affinity
- diffusion into extracellular sites
- participate in opsonization, neutralization, sensitization and compliment activation
what are the properties and functions of IgE
- class switching
- sensitization of type 2 immune cells (mast cells)
- high affinity
what are the properties and functions of IgA
- class switching
- diffuse into secretions at mucosal epithelial surfaces
- high affinity
- diffuse into extravascular space
- involved in neutralization
what are the different properties of ILC subsets in terms of their immune function
cytotoxic ILCs: release IFN-y to target viruses
Group 1 ILCs: release IFN-y to target intracellular bacteria
Group 2 ILCs: release IL-13 and IL-5 to target helminths (parasites)
Group 3 ILCs: release IL-17 and IL-22 to target extracellular bacteria
how does immunological memory work to prevent and fight disease
- established after an initial infection or vaccination and involves both humoral immunity
- the adaptive ability to recognize previously encountered pathogens upon re-exposure
migration pattern and function of central memory T cells
recirculate between blood, T cell zones of SLO and lymph
migration pattern and function of effector memory T cells
recirculate between non lymphoid tissues, lymph, lymph nodes and blood
some remain in blood circulation and migrate only through spleen
migration pattern and function of resident memory T cells
do not recirculate - are confined to a single tissue
differentiate between the primary and secondary immune response
Primary = naive B cells involved, longer lag time and onset time, IgM with lower affinity
Secondary = memory B cells involved, shorter lag time and onset time, IgG with higher affinity
what is the purpose of negative signalling in naive B cells through activation of FcyRIIIB1
- FcyRIIB1 is an inhibitory receptor on the surface of naive B cells
- interacts with Fc component of IgG
- regulatory mechanism to prevent overactivation of the immune system and ensure self-tolerance
- delivers inhibitory signals to B cells when bound to immune complexes
why are mucins effective as a defense against infection at mucosal surfaces
- thick and sticky consistency allows it to trap pathogens
- antimicrobial properties
- retains sIgA and AMPs to neutralize pathogens
- neutralize microbial toxins
how is antigen capture and delivery to SLO’s different at an open wound than mucosal surfaces
Mucosal surface
- capture antigen in M cells found in the epithelium
- mucus provides a physical barrier to trap pathogens
- Antigen-bound sIgA neutralizes pathogens
- priming in MALT
- Mucosal DCs often induce Tregs for tolerance to commensals and dietary antigens
- Local mucosal immunity (sIgA, Th17, Th2 responses)
Open wound
- Exposed to external pathogens and tissue damage; barrier breached
- capture antigen by phagocytosis, opsonization, neutralization and
- delivery to SLO’s by lymphatic drainage, antigen presentation and pro-inflammatory cytokines
- Systemic immunity (IgG, cytotoxic T cells)
explain the process of antigen delivery to mucosa-associated lymphoid tissue driven by M cells
- M cells are embedded in the epithelial lining of mucosal tissues, primarily in the follicle-associated epithelium (FAE) overlying MALT
- they are specialized for transcytosis of microbes into the MALT
- sub-epithelial dome below M cells is rich in DCs which capture and process antigens delivered by M cells
would you predict that an organism that is deficient in the production of NOD2 would be more or less susceptible to infection in mucosal tissue?
- Deficiency in NOD2 impairs mucosal immunity by weakening antimicrobial defenses, disrupting barrier integrity, and compromising immune regulation.
- the organism would be more susceptible to infections in mucosal tissues, particularly those caused by bacteria exploiting weak epithelial defenses.
how do DCs provide oral tolerance for an organism
- Gut DCs promote oral tolerance by inducing Tregs which work to inhibit pro-inflammatory T cells to prevent unnecessary immune responses to harmless pathogens found in food
- Gut DCs present antigens to CD4 T cells which stimulate B cells to secrete IgA
name the innate immune cells that play a role in mucosal immunity and describe their functions
Type A IEL’s: function like effector T cells (TCR activation leads to release of perforin granzymes and FasL)
Type B IEL’s: function like NK cells (act independently of TCR activation through NKG2D)
ILC’s: respond to microbes that breach the epithelium - release cytokines
Intestinal macrophages: promote PGE2 repair
Gut DC’s: promote oral tolerance by inducing Tregs and IgA production
explain the role of antibodies in mucosal immunity (mostly IgA)
- bind and neutralize pathogens on gut surface or internalized in exosomes
- export toxins from the lamina propria while being secreted
- bind to Dectin-1 on M cells to allow transport of antigen to DC’s
what is immunodeficiency
- immune system’s ability to respond to infections or other challenges is impaired
- results in susceptibility to infection
how does inherited immunodeficiency differ from acquired?
inherited: caused by genetic mutations, present from birth, examples = SCID and XLA
acquired: caused by external factors, develops later in life, examples = HIV/AIDS
how does a deficiency in the innate immune system lead to disease
- defects in the complement cascade lead to decreased destruction of diseased cells and decreased opsonization
- decrease in phagocytes lead to accumulation of pathogens
- decrease in ROS needed for killing pathogens
how does a combined deficiency in lymphocyte development or action lead to disease
- impairs B and T cell functions due to inherited mutation
- causes susceptibility to recurrent infections
- can’t maintain self-tolerance
how does a deficiency in T-cell action lead to disease
- less helper T-cells impairs B cell function of clearing extracellular pathogens
- less effector T cells impairs clearance of infected cells
how does a deficiency in B-cell action lead to disease
- cannot clear extracellular pathogens due to lack of antibodies being produced
how does HIV cause AIDS
- HIV attacks CD4+ T cells - destruction of these cells and the depletion of the immune system leads to immune deficiency
- gp120 protein on the HIV surface recognizes the proteins CD4 (helper T), CCR5 and CXCR4 receptors
what are primary ways that pathogens evade the immune system defenses
- antigenic variation: Pathogens can alter their surface antigens to evade recognition
- antigenic shift: sudden major change in the viral genome involving the reassortment of genetic material from different virus strains
- antigenic drift: slowly accumulated mutation that results in minor alterations in the structure of the virus’s surface proteins
- viral latency: viruses enter a latent or dormant state in the host, evading immune detection for long periods
how does genetic variation allow pathogens to evade the immune system
memory cells won’t be able to recognize these variations upon a second exposure
how do pathogens hide from the immune system
latency
what are the different types of hypersensitivity reactions
type 1: immediate - IgE mediated
type 2: cytotoxic - IgG/IgM mediated
type 3: immune complex - immune complex mediated
type 4: delayed type - T cell mediated (helper and effector)
how does type 1 hypersensitivity occur
- 1st exposure to allergen causes sensitization - class switching to produce IgE
- 2nd exposure to allergen causes effector mechanism - cross-linking of Ig bound to high-affinity receptors on mast cells
what factors are responsible for type II hypersensitivity reactions
- occurs when IgG recognize cell surface molecules and bind to them, leading to destruction of cells
how does type III hypersensitivity reaction occur
- occurs when immune complexes (antigen-antibody complexes) form in the bloodstream and deposit in tissues
- activate the complement system (classical pathway)
- C5a binds to and sensitizes mast cells (anaphylatoxin)
- FcyRIII on mast cells is activated and their contents are released
- causes local inflammation and blood vessel occlusion
what is delayed-type hypersensitivity
- occurs when T cells recognize an antigen and release cytokines, triggering an inflammatory response
- takes 24-72 hours to develop
- inflammation results from the activation of macrophages and other immune cells, leading to tissue damage
what is the relationship between self-tolerance and autoimmunity
- lack of self-tolerance leads to autoimmunity because the immune system cannot distinguish self from non-self
how do genetic and environmental factors affect the progression of autoimmune diseases
genetic: MHC polymorphisms, non-MHC mutations (such as genetic defects in transcription factors)
environmental: infections, chemical exposure, physical trauma
explain why many autoimmune diseases are caused by the production and action of autoantibodies
- autoantibodies are self-reactive Igs which react to self-antigens
- production occurs when the immune system loses its ability to distinguish between self and non-self antigens, a breakdown in self-tolerance
when is a normal adaptive immune response to a pathogen capable of inducing an autoimmune response
- molecular mimicry: similarities between foreign and self-antigens favour autoreactive T- or B-cell activation
- genetic predisposition
what are some strategies to treat autoimmune diseases
- corticosteroids: inhibit dendritic cells, monocytes and macrophages from secreting cytokines and prevent phagocytosis
- NSAIDs: inhibit COX1/2 to inhibit production of prostaglandins (PGE2)
- Anti-TNF-a: blocks activity of TNF-a which suppresses the immune system
compare and contrast the direct and independent pathways of allorecognition
Direct: donor cell alloAg recognized by donor DCs and migrate to SLO’s - activate recipient T cells - effector T cells migrate to graft - graft rejection
Indirect: donor cell alloAg recognized by recipient DCs and migrate to SLO’s - activate recipient T cells - effector T cells migrate to graft - graft rejection
explain how cyclosporine A functions to block T-cell activation
- inhibits the enzyme calcineurin by blocking Ca2+ release
- NFAT can no longer function to promote the expression of IL-2 genes
how do vaccines prevent disease
- train the immune system to recognize and respond to antigens without causing sickness
- introduce antigens prompting the immune system to produce specific antibodies and activate memory cells
- if the body encounters the pathogen in the future, these memory cells enable a faster and stronger immune response
what are the different types of viral and bacterial vaccines
live attenuated
killed pathogen
inactivated toxoid
subunit/conjugate
RNA/DNA vaccine
what are the strategies to make attenuated vaccines
- pathogenic virus is isolated from a patient and grown in cultured human cells
- cultured virus is used to infect monkey cells
- the virus acquires many mutations to allow it to grow in monkey cells
- virus no longer grows well in human cells but is still perceived as antigen, so it can be used as a vaccine
what are the criteria for a safe and effective vaccine
- gives sustained protection
- induces neutralizing antibodies
- protects against illness resulting from exposure to live pathogen
- induces protective T cells
- doesn’t cause illness or death
what is the role of an adjuvant vaccine
enhance immunogenicity by promoting innate immunity (TLR’s, etc.)
