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Where do activated B cells undergo intense proliferation and differentiation?
PRR (pattern recognition receptors) include...
Difference between naïve lymphocytes and effector lymphocytes?
Naive lymphocytes are inactive and reside in the 2* lymphoid tissue until they meet THEIR SPECIFIC ANTIGEN and differentiate into effector T-lymphocytes which will now act on that antigen
Examples of opsonins include...
C-3b, Surfactant protein (SP-A), mannose-binding lectin, and C-reactive protein
Where is MHC I expressed?
All NUCLEATED cells
Which antibody is secreted into mucosal surfaces/mother's milk?
Affinity maturation is an outcome of...?
Total strength of antibody + 2 identical antigens
Antigen processing for M. tuberculosis occurs in...?
MHC and CD_ matchup
- MHC I = CD8 (cyto)
- MHC II = CD4 (helper)
How do co-receptors (CD4/8) aid in T-cell signaling initiation?
Recruit non-receptor kinase Lck
f(x) homologue of VpreB:λ5 is....
Allelic exclusion is shown in...
- Heavy/light chain rearrangement during B cell development
- β chain rearrangement during T cell development
- α chain rearrangement during T cell development (delayed)
What regulated graft rejection?
alloreactive T-cells (react to non-self MHC of same species)
Describe the affinity hypothesis
T cell must be weakly attracted to a self antigen presented on an MHC molecule to be positively selected, but will be negatively selected if the affinity is too great
Describe the circulation of lymphocytes
- Constant recirculation through lymph and re-entering 2* lymphoid tissues UNITL antigen is encountered or lymphocyte dies
- antigen encountered: proliferates and differentiates
- dies: new lymphocyte takes its place (# remains constant)
Define homing of lymphocytes
- Regulated trafficking of lymphocytes to sites of antigenic or microbial invasion (via chemokines)
- T: CCR7 recognizes CCL19 and CCL21
- B: CXCR5 recognizes CXCL13
Describe the various outcomes of lymphocytes meeting antigen for the first time in the periphery (peripheral tolerance)
- deletion: strongly cross-linking antigen undergo apoptosis without receptor editing
- anergy: bind an abundant soluble antigen (only weakly cross-linking)
- T cell does not receive appropriate co-stimulation during antigen recognition
- Survival: Inflammation has induced costimulatory molecules on DC
- Thanks to these costimulatory molecules and cytokines the lymphocyte is successfully differentiated in an effector
- Why?: No inflammation = no costim = no PIP3K = no signal transduction
Describe the components of T-cell-mediated immunity
- Naive CD8 recognize pathogen peptides presented by MHC I
- Tcyto: recognize and kill infected cells
- Naive CD4 recognize pathogen peptides presented by MHC II
- TH1, TH2, TH17, TFH: activate their target cells
- TH1 - infected MO, B cell antibody production
- TH2 - B cell antibody production (esp IgE class switching)
- TH17 - Enahnce neutrophil response
- TFH - help isotype switching, antibody production
- Regulatory T-cells: limit extent of immune activation
What is the primary cell-mediated immune response?
- 1. T cell mediated toxicity
- 2. Macrophage activation by effector T cells
- 3. help B cells to trigger antibody production (first step in humoral immunity)
What is T cell priming?
- The activation/clonal expansion of a naïve T cell on its initial encounter with antigen
- DC most important in priming
- CD8 priming -> Tcyto
- CD4 priming -> various Thelper
(Re: graph) Why do the number of antigen-specific cells in efferent lymph start moderate, go to near-zero, then become very high over a period of days?
- Lymphocyte recognition is very effective
- Antigen in node "traps" all specific lymphocytes while they differentiate and proliferate, and will then leave the node (more than entered)
Describe lymphocyte entry into lymphoid tissues (chemokines and adhesion molecules)
- 1. rolling of lymphocytes along endothelial surface (selectins/addressins)
- 2. Activation of integrins on T cells (activated by chemokines)
- 3. Firm adhesion
- 4. Diapedesis (following chemokine gradients)
What classes of adhesion molecules are involved in lymphocyte entry into lymphoid tissue?
- Selectins: surface of T cells
- Vascular addressins: surface of endothelia
- Integrins: surface of T cells
- Ig superfamily: surface of manycells
Professional vs non-professionsal APCs
- Professional: DC, M0, B cells | MHC II | Costimulatory molecules
- Non-professional: nucleated cells | MHC I | no costimulatory molecules
What is the difference between presentation of antigen/MHC to T cells by DC, M0, and B cells?
- DC: activates T cells
- Drive the initial clonal expansion and differentiation of naïve T cells
- M0 and B cells: present to T cells to be activated themselves
- Interact mainly with already primed effector CD4 cells
What are the classes of DC?
- Conventional DC: present antigens to and and activateing naïve T cells in the adaptive immune response
- Plasmacytoid DC: produce interferon in the innate immune response
- Follicular DC: aid in somatic hypermutation of B cells
What are the different ways antigen processing can occur in DC? Which MHC are they presented on? What type of naïve T cell is activated?
- Receptor-mediated phagocytosis: MHC II | CD4
- Macropinocytosis: MHC II | CD4
- Viral infection: MHC I | CD8
- Cross presentation after 1 or 2: MHC I | CD8
- Transfer from incoming dendritic cell: MHC I | CD8
Describe the interactions between T cells and other immune cells
- Tnaive: require costimulation and Ag stimulation from DC for maturation
- Tcyto: only require Ag stimulation (no costim) to destroy infected cell
- TH1: requires Costimulation (CD40/CD40L) from macrophage to activate
- TFH: requires costimulation (CD40/CD40L) to activate B cell
What are the 3 signals involved in clonal expansion/differentiation of naïve T cells
- antigen specific signals: derived from specific peptide:MHC complex with TCR
- co-stimulatory signals: promote survival and expansion of T cells
- signals for T-cell differentiation: promote different subsets of effector T cells (Varies w/ cytokines)
- *IL-2 plays key role in proliferation
Describe anergy vs normal development in a T cell. Incl. mechanism
- Anergy: T cells are stimulated with antigen in absence of costimulation
- Prevents self-reactive T cell from undergoing clonal expansion
- GRAIL (gene related to anergy in lymphocytes) ubiquitinates CD3, causing degredation and then inability to be activated
- This is prevented by CD28 signalling
Why do CD8 cells require more signaling to activate than CD4 cells? Describe that extra signaling
- Because the actions are so destructive, additional co-stimulatory activity is needed (two ways)
- 1. In some viral infections DC can directly CD8 after intrinsically increasing co-stim activity
- 2. Most viral infections TH17 CD4 cells that recognize the same antigen provide additional signaling when bound to the same APC (probably DC)
- increasing co-stim activity of DC AND producing IL-2 for CD8 proliferation
General function of T helper cells (think that picture)
- T naïve ----DC---->Effector T (priming)
- TH1: activate macrophages
- TH17: Require for activation of Tcyto cells
- TFH: provide B cell help in follicle
- Treg: regulation
Why is apoptosis preferable to necrosis?
- Apoptosis: cell begins to condense and stops all activity, shrinks but retains cell membrane integrity, trapping pathogens
- Necrosis: cell stops all activity, but is easily lysed and pathogens escape, able to re-infect
What are the effector proteins found in Tcyto cytoxic granules and what are their functions?
- Perforin: forms pores in membrane for delivery of cytotoxic granules
- Granzymes: family of serine proteases that trigger apoptosis
- Granulysin: antimicrobial activity, induces apoptosis in high [ ]
- Serglycin: acts as sscaffold in sorting/packing of perforin and granzymes
How do Tcells target only certain cells for destruction w/o damaging nearby cells?
- Tcyto reorient their secretory apparatus toward each cell and kill them one by one
- Specific recognition by TCR identifies which target cell to kill
- Polarized release of cytotoxic granules ensures neighboring cells are spared
Why must TH1 cells adhere to infected MO for extended periods of time?
- hours vs tcyto 5 mins
- TH1 cells must express CD40L and INF-y in order to activate MO.
- It takes time to produce protein expression, therefore the interaction will take longer to progress
What is the result of the humoral immune response? What are the three ways it contributes to immunity?
- Activation of B cells which produce Ab
- 1. Neutralization
- 2. Opsonization
- 3. Complement activation
What are the 2 functions of BCR
- Cross-linking BCRs signal to cell that antigen is bound
- Delivers bound antigen to intracellular sites to be degrades/presented on MHC II (recognized by Tfh which cause proliferation and differentiation)
If a microbial antigen directly activates B cell (without T cell help) what are the ramifications?
The B cell doesn't undergo somatic hypermutation therefor they only produce IgM (lower affinity and lower versatility)
Give examples of thymus-dependent and thymus-independent antigens
- Thymus-dependent: protein antigens (tend to have varied surface structures)
- Thymus-independent: LPS, DNA (tend to have uniform surface structure, very large)
- 2nd signal tends to come from TLR rather than Tcell OR extensive amounts of crosslinkings
Describe linked recognition
The epitopes that activate B cells and T cells should be FROM the same pathogen, but may not be identical epitopes
Diff between TI-1 and TI-2 antigens
- TI-1: cause proliferation of B cells regardless of antigen specificity (polyclonal)
- Antigen-specific antibody responses tend to be low
- TI-2: activate only mature B cells (monoclonal)
- long, repeating units
Describe the function of the secretory component of IgA?
- Prevents secretory IgA from binding to the IgA
- Binds to mucins, acting as glue to bind secreted IgA to mucous layer
- Protects the antibodies against cleavage by guy enzymes
Where are the Ig's found?
- IgG and IgM: blood
- IgG and monomeric IgA: extracellular fluid in tissues
- Dimeric IgA: secretions across epithelia, breast milk
- *note-fetus gets IgG from placental transport
- IgE: mast cells (allergic reactions)
How are immune complexes removed from circulation after complement or neutralization?
- Binding of C11 to immune complex leads to binding of C4b and C3b which trigger CR1 on erythrocytes
- Erythrocytes transport the bound complexes to the liver and spleen where macrophages remove and destroy them
Describe the 3 ways to kill virus-infected cells
- 1. Cytotoxic T cells: recognize virus-derived peptides on MHC I
- 2. NK cells: invariant receptors recognize ligands that are induced on abnormal cells without the need for antibody
- 3. NK cells recognize/destroy antibody-coated target cells via antibody-dependent-cell-mediated cytotoxicity (ADCC)