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Flashcards in IAHI [Week 1] Deck (130):

What 3 characteristics are common to all innate immune defenses?

1. They rely on mechanisms that exist BEFORE the infection
2. Capable of responding rapidly
3. React in the same way to repeat infections (compared to T/B cells that become "activated")


What are the 6 types of cells/specific macro-polypeptide that make up the innate immune system?

1. epithelial barriers
2. Macrophages/Neutrophils (Phagocytes)
3. Granulocytes = eosinophils, basophils, mast cells
4. Dendritic cells
5. Natural Killer cells
6. Complement system


What is the most common portal of microbe entry?

through [physical/chemical] epithelial barriers (skin, cilia, etc.)


What chemical barriers do epithelial cells secrete to provide dense against microbes? Which epithelial surface(s) has the most of these chemical barriers?

-antibiotic proteins: antimicrobial peptides = AMPs, defensins; low pH; mucus; lysozyme (eye); sebum; THP (protein in urethra to prevent UTIs)
-GI lumen/Vagina


How do AMPs work? What kind of cells secrete defensins?

AMPs (antimicrobial peptides) are small peptides that can form pores through the microbe PM to cause lysis
-PMNs (neutrophils) and epithelial cells [GI, vagina, etc.]


_____ flora protect against pathogen establishment. Explain the 4 ways they do this:

1. compete for resources with virulent pathogens
2. produce own antimicrobial substances
3. interact with immune cells, causing an immune response to be stronger (think adjuvent!)
4. In females, they secrete acid to produce a lower vaginal pH (Lactobacillus)


Describe a neutrophil.

-also referred to as polymorphonuclear cell (PMN)
-most abundant, circulating WBC [4500-11000]
-multi-lobed nucleus with small granules (primary/secondary)
-SHORT-LIVED (few hours)
-phagocytize microbes and kill them with MPO (myeloperoxidase) and NOX to produce free radicals; and iNOS for vasodilation


What is Chronic Granulomatous?

deficiency in PMN function; associated with chronic and severe bacterial/fungal infections


_____ are the first phagocytes to emigrate into an infected tissue.



What is purulent exudate?

pus; accumulates when there is rapid PMN death at infection site (b/c short-lived cells)


Describe briefly the mechanisms of MPO, NOX and iNOS.

MPO = fused phagocytized phagosome with lysosome (with MPO) to catalyze HOCL (reactive) from H2O2 and Cl-
NOX = production of superoxide (free radical)
iNOS = catalyze NO from arginine
[Neutrophils, Macrophages, etc.]


Describe macrophages.

-also known as Mø
-constantly phagocytosing until encounters microbe, then activated by producing IL-1/IL-6/TFN∂ and receptor signaling via PAMP to enhance phagocytosis/txn of enzymes (iNOS, NOX, MPO)
-present antigen on MHC II


Name the 4 reasons DCs are known as "sentinels" (soldier).

1. constantly sample environment (like Mø)
2. DCs migrate via lymphatics into draining lymph node (unlike Mø)
3. once in lymph node, come into greater contact with T and B cells for adaptive immune response
4. HIGH level of MHC II expression (due to increase surface area--dendrites) and expression of co-receptors CD40 (CD80, CD86)


Which type of leukocyte is best at pathogenic helminth defense? Why?

-granulocytes (especially eosinophils)
-helminths are too big to be phagocytosed


Describe an Eosinophil.

-lots of acidic (eosin) granules [red-stained]
-generally circulate at low levels (200/ul blood)
-activated by IgE


Describe a Basophil.

-lots of blue granules that stain basic dyes
-very low circulating levels (40/ul blood)
-non-phagocytic; release IL-4 (Th2 cytokine)


Describe a Mast Cell.

-tissue-resident cell, especially in mucosal epithelia
-involved in helminth infections and ALLERGIC RXNs
-granules contain HEPARIN and HISTAMINE


Granulocytes are phagocytotic. T/F



When granulocytes secrete their granules (like histamine), it is known as _______. Granulocytes are activated by Ag-bound ______ binding the ____ receptor.

-Fc[epsilon]RI (which causes subsequent release of IL)


Granulocyte activation depends on _______ to an antigen.

previous exposure (Ab response)


The _____ is the host-parasite interface and it is metabolically active. Proteases released by granulocytes can break this down.



Why are DCs ideal cell targets for vaccinations?

they present with more efficiency to T/B cells and can migrate into the lymph nodes


What is ADCC?

Antibody Directed Cytotoxicity = binding of immune cell to Fc region of an antibody, causing another immune signaling response (Fc[gamma]IIIR in NK cells and Fc[epsilon]RI in granulocytes)


How are NK cells similar to Th cells? CTLs? Innate immune cells?

1. Th = produce IFN-gamma to activate macrophages
2. CTLs = use perforin and granzyme to lyse microbes
3. innate = dependent on activating receptors that are GERMLINE encoded (MHCs) and not dependent on previous antigen exposure
[morphologically like T/B cells, but categorized with innate immune cells]


What is the concentration of NK cells in the blood relative to other lymphocytes?

less than 10% (low)


What kind of co-receptors do NK cells have? What APCs do they recognize and how does this affect the function of NK cells?

-Co-receptors = CD16+ (innate im.), CD56+ (Th/CTL cells), CD2+, CD3- (on Treg)
-have ACTIVATING (with B7) and INHIBITORY (with MHC I) receptors
-Recognizes B7 + MHC I = no killing
-Recognizes ONLY B7 and no MHC I = secrete granzymes/perforin


How are NK cells similar to Th cells? CTLs? Innate immune cells?

1. Th = produce IFN-gamma to activate macrophages
2. CTLs = use perforin and granzyme to lyse microbes
3. innate = dependent on activating receptors that are GERMLINE encoded (MHCs) and not dependent on previous antigen exposure
[morphologically like T/B cells, but categorized with innate immune cells]


NKs react to which cytokine from macrophages? What do they secrete in return?

IL-12 = cause secretion of IFN-gamma/more IL-12 to cause killing of phagocytized microbe via NOX/MPO/iNOS


What are NK conjugates with target cells?

tight adhesions due to activating receptor binding with B7; granzymes/perforin granules are secreted at junction and taken into target cell via receptor-mediated endocytosis


Describe NK cell importance in virus infected cells and in tumors.

-virus-infected = NK cells provide resistance to viral infections because they will increase the innate immune response (IFN-gamma)
-NK cells recognize and cause lysis of tumor cells via an ACTIVATING LIGAND secreted on the tumor cell (very little MHC I on tumor cells); without NK cells, tumor will grow significantly


Describe ADCC in the context of NK cells.

IgG-coated antigen recognized by Fc[gamma]RIII- expressing NK cell, causing granule secretion


NK cells require MHC to kill target cells. T/F

FALSE! only need B7 binding from target cell to ACTIVATING RECEPTOR; MHC I turns NK off


What is an immunogen?

an antigen that produces an immune response


Name the factors of antigens that produce increased immunogenicity. Decreased.

-Increased = large, complex, bacteria, slow-release adjuvant, intermediate dose, subQ (because not normal entry)
-Decreased = small, simple, soluble, high/low dose, no bacteria, rapid release, IV/intragastric


Describe the differences between passive and active immunity. Give examples of each.

-Passive = receiving preformed antibodies, rapidly, T1/2 is about 3 weeks (short), ex) IgA in breast milk
-Active = exposure to foreign antigen, slow protection, long duration (memory cells), ex) natural infection or VACCINE


What are PRRs (think specificity!)? Give some examples of PRRs in the innate vs adaptive immune system.

pattern-recognition receptors to recognize self
(ex) innate = toll-like receptors in endothelial cells; nod-like receptors; adaptive = TCRs, BCRs


_______ leads to great diversity in adaptive immunity PRRs. Name the genes that encode these TCRs/BCRs.

-somatic recombination
-genes = ***


In a primary immune response against an antigen, ______ memory cells and _____ antibodies are made. Therefore, in a secondary response to the same antigen, the number of ______ cells is increased and the ______ for that antigen is increased. (Rapid response!)

-B memory


Give the pros and cons for (a) live attenuated vaccine (b) inactivated vaccine

(a) PROS = strong, life-long immunity b/c T cell response; CONS = may revert to virulent form (ex: Polio)
(b) PROS = stable/safer than Live b/c B cell response; CONS = weaker immunity, requiring booster shot


From most to least, which cells comprise the WBC differential? Indicate if an increase in that cell leads you to believe there is an infection of a particular pathogen.

Neutrophils (increased = bacteria)
Lymphocytes (B/T)
Eosinophils (parasite!)
[New Lingerie Makes Everyone Bone]


_____ is the common progenitor of innate immune cells (minus NK cells) whereas ______ is the common progenitor of lymphocytes and NK cells.

-MYELOID progenitor cell
-LYMPHOID progenitor cell


NK cells are activated by _________ cytokines.

IFN-∂, IFN-ß, IFN-gamma, IL-12


A histological stain shows a cell with a large Golgi complex and RER. Which type of lymphocyte is this?

B-cell because must secrete Ab's!


What is the major difference between naive and activated/effector/memory B-cells? T-cells?

-B = Naive has IgM/IgD on PM and high CXCR5; Active/Effector/Memory has IgG/IgA/IgE, secretes antibodies, high CD27
-T = Naive has high CCR7 and CD45RA while Active/Memory has low CCR7 and high CD45RO


_____ mature in the bone marrow while ____ mature in the thymus. Peripherally, these cells get activated in the _____ or _____ or ____.

-Lymph nodes
-Mucosal and cutaneous lymphoid tissues (MALT/SALT)


The spleen captures antigens that are innately _____ while the lymph node captures antigens from the _____ and ______.

-blood borne
-connective tissue


In the spleen, the T cells are located in the ________ (in the middle) while the B cells are located in the ______ (on the edge of the spleen). In the Lymph node, the T cells are in the _______ while the B cells are in the ______.

-PALS = periarteriolar lymphoid sheath
-Parafollicular cortex
-Lymphoid follicle


What is SALT and where are the immune cells located? MALT? What is special about the ileum?

-SALT = skin-associated lymphatic tissue (cutaneous); intraepidermal lymphocytes in epidermis and T cells/Macrophages/DCs in dermis
-MALT = mucosa-associated lymphatic tissues; intraepithelial lymphocytes then lymph drains to lymph node (in area called LAMINA PROPRIA in gut)
-ileum MALT = has T/B cells but also has PEYER's PATCH in order to not degrade good bacteria; M cells present antigens


Describe the function and different cell markers of Th1, Th2, Treg, CTL, B and NK cells:

1. Th1 = kill microbe infected cells/tumor cells; CD8+/CD3+
2. Th2 = activate B cell differentiation/macrophages; CD4+/CD3+
3. T regs = suppress T cell function; CD3+/CD4+/CD25+
4. CTL = helper/cytotoxic T cells; CD3+ and either CD4+/CD8+
5. B cells = produce Ab; FcR, CD19, CD21
6. NK = kills VIRUS-infected cells, damaged cells, tumors; CD16, FcR-gamma


MHC I loads proteins that are derived from _____ the cell whereas MHC II loads proteins derived from ____ the cell



Where are MHC I receptors present? Describe the process of MHC I presentation.

-all cells
1. proteins in cyto tagged for degredation by ubiquitin (on lysine residues)
2. proteasomes degrade peptides via unfolding into 4-20 aa sequences
3. peptides ending in hydrophobic aa fed through TAP transporter in ER membrane (6-15 aa residues)
4. peptide and ß2 microglobulin bind MHC I (∂ chain) via help from tapasin/chaperones
5. Exocytosed to membrane and presented to Th1 cells (CD8+)!!


On MHC I receptors, ___ amino acids differ, but anchor proteins are mostly ____ and ____ and amino acid #9 near carboxy terminal is _____.



Describe what the chymotrypsin-like area of a protease cleaves. What is special about IFN-gamma and proteases?

-cleaves right after hydrophobic amino acids (trypsin = basic, caspase = acidic)
-IFN-gamma induces the expression of 3 proteasome subunits (LMPs) which increase chymotrypsin-like activity (genes encoded in MHC area)


Which two genes associated with proteasomes are encoded in MHC genes? What is the new proteasome with subunits called?

-MHC gene has LMP and TAP (transporter for peptides into the ER)
-Proteasome + more chymotrypsin activity = IMMUNOPROTEASOME


_____ is thought to tether newly synthesized MHC I molecules to TAP.



When a virus infects the following cells, what MHC class is it presented on?
(a) skin (b) kidney (c) lung epithelial

(a) MHC I (because viral proteins secreted WITHIN cell)
(b) MHC II (because virus is engulfed)
(c) MHC I/II (debris is eaten by macrophages and can be cross-presented by accident)


Name where TCRs interact with MHC receptors. How does this facilitate the recognition of a cell as foreign or self?

-Recognizes at (1) MHC ∂1 and ∂2 chains (2) peptide presented
-positive selection of TCRs that bind weakly to self-MHC + self-peptide; therefore if TCR binds strongly or not at all, then will activate [ALLOREACTIVITY!!!]


Describe the positive selection of T cells during maturation in the thymus. What sometimes happens in transplanted tissue?

1. Thymic epithelium presents MHC I/MHC II + self peptides
2. T cells that have STRONG binding to both MHC + self peptide and NO binding to both MHC + self peptide are degraded
3. Cells can bind weakly via 2 routes: (a) little MHC binding and more self-peptide binding (b) more MHC binding and little self-peptide binding
4. In PERIPHERY--> if binds strongly, will cause activation
-Transplanted tissue = you have ALLOREACTIVITY because donor MHC/selfP bind strongly to host TCRs and create immune response (GVHD)


Describe the molecular structure of (a) Class I MHC (b) Class II

(a) ONE ∂ heavy chain with one ß2 microglobulin light chain linked via disulfide bonds; ∂1/∂2 contain peptide binding cleft pocket [contributing to whole beta pleated sheet] and ∂3 is Ig domain; 8-10 residues
(b) TWO heavy chains (∂ and ß); ∂1 and ß1 contain peptide binding cleft pocket [each contributing half of beta sheet] and ∂2/ß2 have Ig domains; 10-16 residues or bigger


Where are MHC II receptors present? Describe the process of MHC II presentation.

-only APCs
1. phagocytosis of pathogen (virus/small bacteria)
2. Proteolysis via lysosomal proteases (CATHEPSINS)
3. FUSE will endosome containing MHC II (from ER, bound to invariant chain)
4. Load peptides on MHC II
5. Exocytosis of endosome; displayed to Th2 (CD4+) cells


How are MHC II receptors produced and brought to the lysosome for loading?

1. made in ER and "capped" by INVARIANT CHAIN (Ii) so that self-peptides are not presented on MHC II molecules [li caps 3 MHC II molecules at once]
2. tagged for Golgi then lysosome (LL sorting signal)
3. in lysosome, proteases cut INVARIANT CHAIN and leaves CLIP peptide in binding site
4. HLA-DM destabilizes Ii in acidic environment (by knocking it out) and allows antigenic peptide to bind


What gene encodes a molecule to take out INVARIANT CHAIN in MHC II receptors and replace it with an antigen?

[only time when MHC II won't fall apart when it has no peptide--DM stabilizing it]


Can self peptides be presented by class II MHC molecules? Explain.

1. anything targeted to the lysosome
2. must engulf dead self-cells if they are damaged
[in viral infection, BOTH CD4+/CD8+ cells are activated because of viral proteins (infected cell) produced by host cells as well as engulfing the virus extracellularly]


What is cross-presentation and which cells does it occur in? What are some theories as to why this occurs?

-when MHC I present extracellular peptides/antigens
1. ER fuses with endosome
2. antigen crosses phagosome
3. ER-derived phagosomes contain TAP/export machinery


What type of molecule presents lipids to T cells? How does this work?

CD1 molecules (NOT ENCODED IN HLA); only in APCs
-heavy ∂ chain and light ß2 microglobulin chain; NKT cells are specific CD1 T-cells that recognize CD1 molecules;
-lipids loaded in ER via INVARIANT CHAIN


When I say "Cell Mediated Immunity" what do you think of??

T cells!


T cell signaling typically require the binding of _____ receptors.

two or more


What are the 2 regions of TCRs and BCRs? Describe them.

-Variable regions = genetically diverse; VDJ regions (different between clones; from same clone = same); in BCRs, affinity can change to increase; TCRs affinity is always the same
-Constant regions = genetically conserved


What are the key distinguishing factors between BCRs and TCRs?

1. BCRs can change affinity for an antigen; TCRs are MHC-restricted!
2. TCRs only recognize peptides, BCRs recognize proteins, lipids, etc.
3. TCRs only in membrane where BCRs undergo isotype switching (Ig's)
4. TCRs have alpha/beta (gamma/delta) chains and BCRs have heavy/light chains


Describe T cell maturation into naive lymphocytes.

1. bone marrow expresses IL7 to cause progenitor cells to proliferate and express pre-antigen receptor (ß-chain protein expression)
2. T cells not expressing ß chain (variable/constant regions) will die (CKPT 1)
3. more IL7 causes expression of ∂chain; ∂ and ß chains connected via disulfide bonds
4. if no ∂ chain (variable/constant regions), then T cells will die (CKPT 2)
5. NAIVE T Cells! (circulate through body until activated)


Describe the transcription and expression process of the ß variable chain in T cells. The ∂ variable chain. [Process same in B cells except Heavy is like ß and Light chain is like ∂ and C-mew is like C]

1. D (diversity) and J (joining) recombination via splicing
2. V + DJ
3. VDJ + ß constant region (VDJ-C)
4. expressed with surrogate light chain until ∂ chain made
1. V+ J
2. VJ-C
*Note: several D, J but only a few C regions in T cells {many C regions for isotype switching in B cells}


What is TCR ∂/ß and BCR H/L chain hypervariability? In what regions does this occur?

-hypervariability refers to differences in amino acids in VDJ regions of ∂/ß and H/L chains; THESE ARE THE REGIONS THAT CONTACT THE ANTIGEN!!
-CDR1/CDR2/CDR3 are the most hypervariable on each the ∂ and ß chain (or Heavy and Light chains; B cells have two identical binding variable regions)


Describe the 2 layers of genetic diversity in TCRs? What happens when there is a mutation in the TdT gene?

1. combinatorial: different VDJ regions
2. Junctional: via removal of nucleotides, addition of nucleotides by TdT enzyme AND strand repair during recombination (i.e. mutations)
-mutation in TdT gene causes lack of repair, and potentially an autoimmune disease!


For T cells, the Induction phase happens in the _____ and the Effector phase happens in the _____. Describe each of these phases.

-Lymphatic tissues/spleen/MALT/SALT = antigen recognition causes T cell expansion/differentiation via IL-2 release and IL-2 autoreceptors (depending on MHC-antigen type) and increase in coreceptor expression, either CD4+/CD8+
-Peripheral tissues = migration to site of infection; encounter antigens and activate effector T cells to either release cytokines for chemokinetics/inflammation or CTL granules
**NOTE: During clonal expansion, there will be CD4+ and CD8+ cell types, each with the same genetic type of TCR


Describe antigen recognition by a T cell.

1. naive T cells transiently bind APCs to sample them, but when binds strongly, will upregulate LFA1 (integrin) to eventually bind ICAM in epithelium
2. Th cells bind MCH II via TCR-CD4+ and CTL bind MHC I via TCR-CD8+
3. Upregulation of CD28 and binding to B7 on APC causes secretion of IL-2 (autocrine to cause proliferation)


What is ANERGY?

when Naive T cell binds MHC-peptide via TCR-coreceptor complex but does not bind any B7 via CD28 (T cell), so it will not elicit a response


Describe each T cell receptor and what it binds to:
(a) CD3/zeta
(b) CD4
(c) CD8
(d) CD28
(e) CTLA4
(f) LFA1

(a) CD3/zeta = signal transduction via ITAM (immunoreceptor activation motif); present on ALL T cells!!
(b) CD4 = MHC II binding co-receptor
(c) CD8 = MHC I binding co-receptor
(d) CD28 = B7 binding of APC (ITAM) turning signal ON early in response
(e) CTLA4 = binding B7 turns signaling OFF late in response (ITIM = immunoreceptor INactivation motif)
(f) LFA1 = binds ICAM on APC endothelium and increases integrin stability via chemokine stimulation (by APC) and change in LFA1 conformation


Which type of cells present B7, MHC II and PRRs when activated? (3)

-DCs/Macrophages = upon ingestion/PAMP-PRR binding, increase B7, levels of MHC and secrete IL12; T cells are ANERGIC if do not secrete B7 (nonbacterial pathogen with no PAMP-PRR [TCR/BCR] recognition)
-B cells = Ig binds antigen, causing endocytosis and increasing B7/MHC II expression


What are PAMPs?

pathogen-associated mapping patterns; PAMPs bind PRRs (pattern recognition receptors)


CD28 and LFA1 binding in T cells cause what to happen?

-IL2 expression, upregulation of IL2∂ (a high-affinity receptor to IL2), upregulation of CD40L and clonal expansion to produce TCR-coreceptor equivalent CD4+ and CD8+ cells
-there are many more CD8+ (CTL) cells in infection, especially viral
-The TCR-Coreceptor T cells recognizing antigen will outcompete IL2∂Rs of other T cell clones in area--->differentiation into EFFECTOR and MEMORY cells that migrate out of lymphoid tissue


Describe differentiation of Effector T cells and which type of T cells/chemokines are present per particular infection.

-Differentiation = CD40L on T cells recognize CD40 on APCs in periphery and different cytokines in periphery...
(a) IFN-gamma/IL12 released by phagocytes who have ingested microbes (virus, intracellular bacteria) cause TH1 cell differentiation and production of more IFN-gamma to activate macrophage killing of intracellular bacteria/IgG production
(b) IL4 produced by Eosinophils via FceR-IgE-antigen complex cause TH2 cell differentiation and production of IL4, IL5 (cause increase in eosinophils!) and IL10/IL13 for isotype switching/activation of B cells (cause increase in mast cells via IgE) [helminths, allergies]
(c) TGFß, IL6 and IL23 cause TH17 differentiation and production of IL17 for neutrophil (PMN) inflammation, phagocyte killing of extracellular bacteria/fungi **this is the cause of some autoimmune responses


What are Memory T cells?

Part of effector cells; either CD4+ or CD8+; survive after infection; DO NOT PRODUCE CYTOKINES OR KILL CELLS unless recognize an antigen for another time


Describe the difference between CD8+ T cell direct and indirect activation.

1. Direct = antigen-MHC + APC
2. Indirect = antigen-MHC + Th1 help


Which chemokines do endothelial cells secrete? what does this do?

TNF-alpha and IL1; due to adhesion of T cell via LFA1-ICAM and TCR-co-receptor binding MHC I-peptide (switch to LFA1∂ and VLA4 receptors for increased LFA1-ICAM and VLA4-VCAM1 binding)


_____ and ____ -expressing T cells are located in the lymph nodes. They lose these receptors and express ____ , ____ and ____ when they are activated and are going to migrate to the infected area to help them adhere.

-L-selectin (binds L-selectin ligand in lymph tissues)
-CCR7 (chemokine receptor that binds CCL21/19)
-E-selectin ligand
-P-selectin ligand
-CXCR3 (binds CXCL10)


What are the 2 major roles of CD4+ T helper cells?

1. increase efficacy/efficiency of cell-mediated immune response (IFN-gamma/CD40L-CD40 binding)
2. strengthen/modify humoral immune response (CD40L-CD40 binding for isotype switching for complement/opsonizing IgG antibodies)


CTLs express Fas Ligand, which binds _____ on target cells, causing _____. CTLs in general, can act on _____ target(s).

Fas Receptor
multiple cell


How do Th cells enhance CTL cell capabilities?

CD8+ T cells need many co-stimulatory signals to be activated (many CD28-B7 binding), so if too little B7, then will not activate; CD4+ cells can bind low [B7], secrete IFN-gamma and activate upregulation of APC B7 and CD40 as well as upregulate Th/CTL CD40 ligand expression for increased binding


Describe the serology of a girl with Toxic Shock Syndrome, a Staphylococcus aureus infection (extracellular). Also, define superantigen.

-LOTS OF NEUTROPHILS!!! because extracellular bacterial infection; treat with antibiotics; increase in IL1/TNF∂, IL2 (T cell proliferation) and IFN-gamma (Th secretion)
-superantigen = cross-links different clones of T cells with MHC II-expressing APCs regardless of affinity-->causing a cytokine storm; almost NO specificity


Describe the steps of B cell maturation in the bone marrow.

1. IL7 causes proliferation
2. expression of HEAVY chain part of Ig (FIRST CHECKPOINT)
3. expression of LIGHT chain part of IG (SECOND checkpoint)
4. NAIVE B cell with IgM expression


Describe the molecular structure of a BCR.

-2 heavy chains (VDJ and C regions), 2 light chains (VJ regions); linked by disulfide bonds; receptor has anchor in PM
-Fab region = Heavy VDJ and Light VJ; two identical binding sites


How are Naive B cells activated/undergo isotype switching?

1. microbes/toxins/particles into LYMPHOID tissues presented via DC in follicle + Th cell activation causes long-lived plasma cells secreting IgG, IgA and IgE (must have already been exposed)
2. in marginal B cell zone in lymphoid tissues and in MALTS/SALTS [Peyer's patches, tonsils, etc.], B cells recognize lipids/polysaccharides/etc and produce short-lived IgM (primary exposure)


When naive B cells recognize an antigen, they need to (1) have ______ via more than one IgM AND (2) either a complement receptor, like ______ or _____, activated by C3d or a toll-like receptor, activated by a _____ molecule. This causes activation of the B cell clonal expansion/differentiation. Naive B cells will now become ___ B cells.

-CR2 (with ITAM)
-CD21 (with ITAM)
-PAMP (pathogen-associated protein)


Effector B cells have _______ (4 things).

1. clonal expansion
2. increased cytokine receptors/B7 on mother B cell to respond to T cells
3. migration out of lymphoid follicles into parafollicular area to interact with T cells via B7-CD28 binding and MHC-TCR binding; B cells increase expression of CD40 (to bind CD40L on T cell)
4. secretion of low-level IgM (primary response), then when binds T cell, high IgG (secondary response)


_______ is caused by somatic HYPERMUTATION in the variable regions of memory B cell Ig's during clonal expansion with secondary exposure. These different mature B cells will undergo apoptosis unless they receive a survival signal from _______. This is called _____.

-Affinity maturation
-APC follicular DC's (follicular Th cells also promote survival)
-high affinity selection


What are the 3 antibody-mediated mechanisms in host defense?

1. complement activation causing opsonization
2. phagocytosis enhanced by antibody/complement components bound to pathogen
3. neutralization via Fc regions


What is another name for antigen specificity?



Which two antibodies contain J-chains, binding Fc regions of Ig's? Which is used for opsonization/complement activation? Which IgG's are specific for inflammatory response? Which Ig's aid with ADCC?

-IgA (dimer) and IgM (pentamer; also bound via disulfide bonds)
-*IgG, IgM
-IgG1, IgG3
-IgG, IgE (helminths!)


When there is no Th signal, splicing on ____ region causes secretion of ____ antibodies.



_____ and ___ from Th cells cause isotype switching in B cells. T cell secretions of IFN-gamma causes switching to ______, IL-4 causes switching to ______ and TGFß causes switching to ______.

-IgA (mucosal immunity)


During isotype switching, T-independent activation by peptides/lipids/polysaccharides/etc. can only produce _____ antibodies while T-dependent activation by peptides can produce _____.

-IgM (little/no affinity maturation)
-IgA/IgE/IgG (strong affinity, strong response)


Where do plasma cells live?

in bone marrow of gut mucosa


What is an opsonin? How do IgG/IgA neutralize antigens (4 ways)?

-Opsonin = coats particles to enhance phagocytosis; bind FcR's on phagocytes, causing NOX, MPO and iNOS activation
1. prevent entry of microbe/antigen
2. prevent binding to host cells
3. block spread of infectious microbes
4. block binding of microbial toxins to host receptors
***IgA neutralizes commensal bacteria in the gut!


What is the major host defense mechanism to gram (-) encapsulated bacteria?



Which two Fc receptors have the highest affinity for Ig's?

Fc-gammaRI and FceRI [on eosinophils]
[NK cells have Fc-gammaRIII to secrete perforin/granzyme]


The complement cascade ___ be activated in the presence of innate immunity and/or ___ be activated in the presence of adaptive immunity. This leads to the ______ of the immune response and is considered to be a part of the _____ immune system.



Describe the ALTERNATIVE complement pathway.

1. C3 spontaneously hydrolyzed --> C3a + C3b
2. C3b covalently attached to microbe and cleaves Factor B---> Ba + Bb
3. formation of C3bBb = C3-convertase!!
4. C3-convertase cleaves C3 --> C3a +C3b
5. formation of C3bBbC3b = C5 convertase
6. C5-convertase cleaves C5 -->C5a +C5b
7. C5a causes INFLAMMATION and C5b binds C6, C7 and C8 (respectively)
8. these all bind multiple C9's to form a pore (MAC) for LYSIS!


Describe the CLASSICAL complement pathway.

1. IgM and IgG (IgG1/IgG3) bind microbial surface antigens
2. C1 cross-links Fc regions of IgMs (IgGs)
3. C1 is activated and cleaves C4 ---> C4a + C4b and cleaves C2 ---> C2a + C2b
4. C4b2a form = Classical C3-convertase
5. Classical C3-convertase cleaves C3 --> C3a +C3b to form C4b2aC3b = C5 convertase
6. C5-convertase cleaves C5 -->C5a +C5b
7. C5a causes INFLAMMATION and C5b binds C6, C7 and C8 (respectively)
8. these all bind multiple C9's to form a pore (MAC) for LYSIS!


Describe the LECTIN complement pathway.

1. MANNOSE-BINDING-LECTIN (MBL) bind microbial surface antigens (BACTERIA)
2. C1 cross-links Fc regions of IgMs (IgGs)
3. C1 is activated and cleaves C4 ---> C4a + C4b and cleaves C2 ---> C2a + C2b
4. C4b2a form = Classical C3-convertase
5. Classical C3-convertase cleaves C3 --> C3a +C3b to form C4b2aC3b = C5 convertase
6. C5-convertase cleaves C5 -->C5a +C5b
7. C5a causes INFLAMMATION and C5b binds C6, C7 and C8 (respectively)
8. these all bind multiple C9's to form a pore (MAC) for LYSIS!


What are the 3 complement functions?

1. opsonization via C3b binding of phagocytes
2. Cytolysis (MAC attack!)
3. Inflammation via C3a, C4a and C5a fragments stimulating chemotaxis and oxidative burst in PMN's/macrophages


What are the 3 complement inhibitors? What is Factor I? What is C1 inhibitor?

1. MCP = cofactor for Factor I prevents C3b/C4b activation (classical/leptin pathway)
2. DAF = inhibits Bb binding to C3b (alternative pathway)
3. CR1 = cofactor for Factor I to prevent C3b/C4b activation (classical/leptin pathway)
-Factor I = cleaves C3b/C4b into inactive forms to prevent C3 convertase
-C1 inhibitor = prevents C1 from working, so no C4/C2 convertase (classical pathway)


What would a deficiency in C3 cause? How about C9/MAC? C1 Inhibitor deficiency?

1. C3: increased susceptibility to infections; can be fatal early in life
2. C9/MAC: increased suceptibility to neisseria infections and meningococcal disease
3. C1 Inhibitor: hereditary angioneurotic edema = excessive complement activation leading to edema within larynx/other tissues


What is expressed to allow for maternal antibodies to cross the placenta?

neonatal FcRN = imports antibodies for passive protection of the fetus (IgG's mostly)


What is an adjuvant? Why is it used? What does the US typically use as an adjuvant?

ADJUVANT= a substance that when mixed with the antigen enhances immunogenicity of that antigen (like a non-virulent bacteria); increasing immune response
-increased antigen uptake by APCs or activation of PRRs to activate/increase T cells/co-stimulator molecule (B7, CD40, etc)/cytokine expression
-Aluminum hydroxide gel (Alum)


What is IMMUNOLOGIC TOLERANCE? When is this implored in medicine? How long is tolerance in T cells? B cells?

-specific unresponsiveness to normal, adaptive immune system
-when have allergies, you are overly sensitive and must increase your tolerance to foreign antigens
-long lived
-short lived (with T cells; without T cells it is absent)



antigens that elicit functional activation of lymphocytes; requires co-stimulation of T cells by activated APCs (PAMPS, microbes); acute antigen exposure



antigens that elicit functional INACTIVATION/KILLING of lymphocytes bearing receptors for that antigen -->recognizing self as foreign



antigens ignored by lymphocytes; i.e. ANERGIC state lymphocytes (no B7 receptor, no CD40 receptor, etc.)


Which demographics are immunologically immature? What are 3 examples of the loss of immunological tolerance?

neonates and the elderly (memory cells poop out)
1. autoimmunity = recognizing self peptides as foreign
2. GVHD/transplant rejection = recognizing donor peptides as foreign
3. allergy = recognizing normal environmental antigens as foreign


Central tolerance is obtained by _____ cells in the generative lymphoid organs (bone marrow/thymus). What happens if central tolerance is not complete? Peripheral tolerance, on the other hand, is obtained by ____ cells in the peripheral lymphoid tissues.

-immature (must go through maturation checkpoints)
-If CT not complete, self-reactive lymphocytes can escape and are typically quiescent or non-self lymphocytes are expressed and can escape


What is avidity?

the sum of all the affinity interactions on a cell --> required for activation of certain cells via costimulatory receptors, etc.


Describe the Positive and Negative selection of Central T cell Tolerance. What happens when there is a defect in Negative selection? How does this relate to B cell +/- selection?

1. In thymus, no CD4+/CD8+ expressed = DOUBLE-NEGATIVE = thymocytes
2. expression first of TCRß the TCR∂ chains cause expression of both CD4+/CD8+ = DOUBLE POSITIVE
3. POSITIVE SELECTION = thymic cortex, epithelial cells; recognition that the cells have either CD4+ or CD8+ (those that don't will undergo apoptosis; death by neglect)
4. NEGATIVE SELECTION = move to thymic medulla where epithelial cells express AIRE gene; recognize high avidity self-antigens (those that have strong avidity undergo apoptosis)
**NOTE: exception to negative selection = T reg
-Defect in Negative Selection causes AUTOIMMUNITY because recognition of self-peptide
-same except positive selection looking at rearrangement of IgL chains to not recognize self and negative selection looking at low avidity for self to survive


What is the AIRE gene and where/when do you see its expression? What is APECED and why does this pose a clinical problem?

-The AIRE gene causes expression of TF in thymic medullary epithelial cells to increase the rate of self-peptide expression (from all different kinds of cells in body) to present to maturing T cells; the self-peptides will help T cells undergo NEGATIVE selection
-APECED is an immune disorder that causes a mutation in the TF encoded by the AIRE gene; therefore, NEGATIVE SELECTION IS DECREASED LEADING TO AUTOIMMUNITY; make autoantibodies to immune proteins, like IL17 (see Candidias); usually in young patients


Why are Treg cells excluded from negative selection? What is IPEX syndrome?

-they express Foxp3+ (plus CD4+/CD25+); remember, Treg cells aid in suppressing the immune response and so SHOULD recognize self-peptides (Peripheral tolerance; activated in periphery by self-antigen and IL-2)
-IPEX syndrome is when mutation in Foxp3 causes too much immune response due to loss of Treg cells; leads to death if not treated (with CTLA4 antibodies)


In contact-dependent Peripheral T cell Tolerance, Tregs bind directly to mature T cells via ______ with _____ , causing T cell suppression. In contact-independent Peripheral T cell Tolerance, Treg cells secrete high levels of ____ and ____ to inhibit T cell activation (ANERGY). What is CTLA4-Ig?

CTLA4 (binds low expression of B7 on Treg)
ITIM (inactivating)
-CTLA4-Ig is a CTLA4 fused with a modified Fc molecule in order to bind B7 on APCs to inhibit CD28 binding of T cells; used for autoimmune-compromised patients (Orencia)


Peripheral B cell Tolerance features B cells that _____ as opposed the _____, like normal naive B cells.

-inactive (anergic; no expression of inhibitory receptors)
-self-reactive (regulated by inhibitory receptors)


Which gender tends to develop autoimmunity more?

females 4:1


Mutations in MHC (HLA gene) is the cause of autoimmunity. (T/F)

FALSE! Not only cause--caused by environmental trigger usually


Inefficient display of self-peptides usually causes a defect in ____ tolerance where mutant MHC may not stimulate Tregs in ____ tolerance. (AUTOIMMUNITY)



Autoimmunity: Microbes inducing ________, can cause self-reactive T cells to activate or can produce peptides similar to self-peptide, called ______.

-costimulatory molecule expression
-molecular mimicry