1) Innate Immunity, Ab+Antigens, Antigen Recep. & Gen. of Div. Flashcards by Josh Murdock

The 4 themes of Immunology are

1) Generation of (X)
2) (Y) vs. (Z) discrimination
3) Protection by (A) or destruction of non-self
4) (B)

X = Diversity
Y = Self
Z = Non-self
A = Neutralization
B = Memory

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Physical Barriers in Innate Immunity

Skin, Mucosa

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Humoral Innate Immunity (Agglutinins/Collectins): Must be (X) to get effective agglutination

X = Multivalent

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Humoral Innate Immunity: Antibacterial (X)

X = Peptides

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Which complement pathway is antibody dependent

Classical (Alternative pathway is independent)

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What 5 processes does the Complement system engage

Bacterial lysis
Phagocytosis
Mast cell activation
PMN recruitment
Clearance of immune complexes

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What type of Interferons are produced by both infected and sentinel cells to block further viral replication?

Type I Interferons (IFN-Alpha, IFN-Beta)

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High levels of type I Interferons induce (X) and (Y)

X = PKR (dsRNA dependent protein kinase)
Y = an Oligo A Synthase

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PKR Mechanism
Must bind to (X) in a virally infected cell cytosol to be active. It is able to distinguish between host (X), which do not activate it, and viral (X), which do. When active, often blocks both (Y) and (Z) translation leading to
cell death and blockade of viral replication

X = dsRNA
Y = Viral
Z = Host

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Oligo A Synthase Mechanism
Must bind to (X) within cell cytoplasm to be
active. Once activated, the synthase makes oligo A, which can activate an
(Y) degrading enzyme (Z). The (Z) then destroys both viral and host (Y), also leading to cell death

X = viral dsRNA
Y = RNA
Z = RNAse L

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Cell Mediated Innate immune Response: Phagocyte subclasses

PMNs, Macrophages, etc.

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NK cells secrete (X) for macrophage recruitment

X = IFN-Gamma

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Virally infected cells and tumor cells can have downregulation of MHC-I and (X) can recognize cells with low levels of MHC I and lyse them.

X = NK Cells

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Recognize heat shock proteins and aren’t MHC restricted

GammaDelta T cells

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Pattern Recognition Receptors: NOD1

Binds (X) components found on (Y)

X = peptidoglycan
Y = Gram- Bacteria

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Pattern Recognition Receptors: NOD2

Binds (X) components found on (Y)

X = peptidoglycan
Y = either Gram+ or Gram- receptors (bacteria)

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NLRP family responds to cytosolic PAMPs and DAMPs by forming (X) which create active forms of (Y)

X = Inflammosomes
Y = IL-1 and IL-18

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Canonical inflammosome is activated by variety of bacterial products, crystals, ions, extracellular ATP, or other danger signals. NLRP proteins interact to form an
(X) through prionization. Bind to (Y), an adapter, to form the inflammasome, along with procaspase-1, which is inactive. Pro-caspase-1 is cleaved to form active Caspase-1. Caspase-1 cleaves (Z) to induce further inflammation. Inflammasome activation also can lead to inflammatory cell death
(A). Cell death is caused by an effector protein, (B), which pokes holes in the cell membrane

X = Oligomer
Y = ASC
Z = pro-IL-1 and pro-
IL-18
A = pyroptosis
B = Gasdermin D (Gsdmd)

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Non-canonical inflammosome: Activated by cytosolic (X) which binds directly to (Y). (Y) directly cleaves Gsdmd which then activates the NLRP3/ASC inflammasome and leads to (Z) production

X = LPS
Y = Caspase-11 (Caspase 4/5 in humans)
Z = IL-1

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What Pattern Recognition Receptor binds bacterial peptides which begin with fMet rather than Met?

fMet receptor

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What Pattern Recognition Receptor recognizes bacterial carbohydrates? (non self sugars on pathogens)

Mannose receptor

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(X) and (Y) are cytosolic proteins that reside in each cell with a CARD domain and a helicase domain. They are sensors for dsRNA present in infected cells only. They induce (Z) and (A)

X = RIG-I
Y = MDA-5
Z = type I IFN
A = NFkB

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Cytosolic DNA Receptors: (X) and (Y)

(X) cGAS
(Y) STING

dsRNA binds to cGAS, which makes a cyclic dinucleotide, cycic GMP-AMP (cGAMP). cGAMP causes STING to translocate to the Golgi, where it serves as a scaffold for IRF3. IRF3 goes to the nucleus and stimulates transcription of type I interferons (which induce the antiviral state in neighboring cells), as well as autophagy which helps redirect cytosolic microbes to the lysosome

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Cytosolic DNA Receptor (recognizes cytosolic dsDNA, and forms a caspase-1 canonical inflammasome)

AIM2

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PRRs: Location of TLRs and PAMP/DAMP Ligands | TLRs 1-9

Plasma membrane and endosomal membranes of dendritic cells, phagocytes, B cells, endothelial cells, and many other cell types Various microbial molecules including bacterial LPS and peptidoglycans, viral nucleic acids

PRRs: Location of NOD-like receptors (NLRs) and PAMP/DAMP Ligands (NOD1/2, NLRP Family [inflammosome])

Cytosol of phagocytes, epithelial cells, and other cells Bacterial cell wall peptidoglycans (NOD1/2) Intracellular crystals (urate, silica); changes in cytosolic ATP and ion concentrations; lysosomal damage (NLRP family)

PRRs: Location of RIG-like receptors and PAMP/DAMP Ligands | RIG-1, MDA-5

Cytosol of phagocytes and other cells Viral RNA

PRRs: Location of Cytosolic DNA sensors (CDSs) and PAMP/DAMP Ligands (AIM2, cGAS)

Cytosol of many cell types Bacterial and viral DNA

PRRs: Location of C-type lectin–like receptors (CLRs) and PAMP/DAMP Ligands (Mannose receptor, Dectin)

Plasma membranes of phagocytes Microbial surface carbohydrates with terminal mannose and fructose (Mannose Receptor) Glucans present in fungal cell walls (Dectin)

PRRs: Location of Scavenger receptors and PAMP/DAMP Ligands | CD36

Plasma membranes of phagocytes Microbial diacylglycerides

PRRs: Location of N -Formyl met-leu-phe receptors and PAMP/DAMP Ligands (FPR and FPRL1)

Plasma membranes of phagocytes Peptides containing N -formylmethionyl residues

PRRs: Location of soluble receptor (Pentraxins) and PAMP/DAMP Ligands (C-reactive protein)

Plasma Microbial phosphorylcholine and phosphatidylethanolamine

PRRs: Location of soluble receptor (Collectins) and PAMP/DAMP Ligands (Mannose-binding lectin, Surfactant proteins SPA and SP-D)

Plasma Carbohydrates with terminal mannose and fructose (Mannose-binding lectin) Various microbial structures (SP-A, SP-D)

PRRs: Location of soluble receptor (Ficolins) and PAMP/DAMP Ligands (Ficolin)

Plasma N -Acetylglucosamine and lipoteichoic acid components of the cell walls of gram-positive bacteria

PRRs: Location of soluble receptor (Complement) and PAMP/DAMP Ligands (Complement proteins)

Plasma Microbial surfaces

PRRs: Location and target of TLR1:TLR2

Cell surface, Bacterial lipopeptides

PRRs: Location and target of TLR2

Cell surface, Bacterial peptidoglycan (GP Bacteria)

PRRs: Location and target of TLR4

Cell surface, LPS (GN Bacteria)

PRRs: Location and target of TLR5

Cell surface, Bacterial flagellin

PRRs: Location and target of TLR2:TLR6

Cell surface, Bacterial lipeptides

PRRs: Location and target of TLR3

Endosome, dsRNA

PRRs: Location and target of TLR7

Endosome, ssRNA

PRRs: Location and target of TLR8

Endosome, ssRNA

PRRs: Location and target of TLR9

Endosome, CpG DNA (viral or bacterial, unmethylated DNA)

Phases of Adaptive Immunity 1. Recognition of (X) 2. (Y) Activated 3. Effector phase of antigen elimination 4. Return to homeostasis with (Z) cells that remain

``` X = Antigen Y = Lymphocytes Z = Memory ```

Two signal theory of adaptive immunity

First signal: Antigen Second signal: (Danger signal), microbial products or the innate response to microbial products

Main defense against extracellular microbes

Humoral immunity (B cell produced antibodies)

Two types of humoral immunity

1. Active - Your own antibody response (Primary, Secondary) 2. Passive (transfer of antibodies/cells generated by another host) (Maternal/fetal, Ig Immunization, Transferal of cells)

(X): every individual has numerous clones, each of which arose from a single cell with a unique receptor that recognizes a specific antigen

X = clonal selection

Antibody stucture: (X) heavy chains, (Y) light chains. Variable regions (with (Z)) and constant regions

``` X = 2 Y = 2 Z = CDRs (Complementarity determining regions) ```

What does papain cleave an Ab into?

2 Fab and 1 Fc

What does pepsin cleave an Ab into?

1 F(ab')2 and 1 constant tail (pFc')

IgA: (X) immunity. Forms (Y) with (Z)

``` X = mucosal Y = dimer Z = J-chain ```

IgD: Most important as marker of (X) as their receptor

X = naive B cells

IgE: What is its main purpose?

Immediate type hypersensitivity (allergies). Dealing with helminth infections

IgG: Seen after the (X) response. Forms (Y)

``` X = Primary (it is secondary) Y = Monomer ```

IgM: Initial Isotype (primary response) (seen before (X) to IgA, IgE, and IgG). Forms (Y) with (Z)

``` X = Isotype switching Y = Pentamer Z = J-chain ```

Antibody Function: As non-soluble, membrane bound (X): Recognition of antigen by the (X) leads to B cell activation and proliferation.

X = B cell receptor

Antibody Function: Soluble, free Ab (List 6 general functions)

1. Neutralization 2. Classical pathway complement activation 3. Opsonization 4. Antibody-dependent cellular cytotoxicity (ADCC) 5. Agglutination 6. Immediate type hypersenistivity

Antibody Function: Neutralization: Neutralizes toxins or antigens by (X) them (all secreted Ab)

X = binding

Antibody Function: Complement pathway (classical). (X) binds to constant regions of antibodies (Y). (Z) coats microbes and increases opsonization. Small fragments of (A) attract leukocytes to the site of inflammation. (B) creates holes in microbial membranes, leading to osmotic lysis

``` X = C1q Y = IgM, IgG Z = C3b A = C3 and C5 B = Membrane Attack Complex ```

Antibody Function: Opsonization: Secreted (X) coats free antigen and (Y) on phagocytes see the bound antigen and phagocytize it (IgG)

``` X = IgG Y = FcγR receptors ```

``` Antibody Function: Antibody dependent cellular cytotoxicity (ADCC): Binds directly to antigen on cell and (X) on NK cells phagocytize the cell (this is the (Y) role of NK cells) (IgG) ```

``` X = FcγR Y = adaptive ```

Antibody Function: Immediate type hypersensitivity: (X) is generated after the first exposure to an antigen. (Y) have free (Z) which bind secreted (X) very tightly. When the second exposure to the same antigen occurs, the (X) bound to the MC is crosslinked, leading to degranulation of the (Y) and (A) release (mechanism for allergies, anaphylaxis, etc). (X)

``` X = IgE Y = Mast cells and basophils Z = FcεRI A = Histamine ```

Anibody Function: Mucosal immunity: (X) is dimerized, binds to a receptor on the (Y) of intestinal cells, is transcytosed to the luminal side of the cell (with some of the receptor removed by (Z)) where it protects against mucosal pathogens. Interestingly, oral protein often leads to tolerance, not immunity. (IgA, IgM)

``` X = IgA Y = blood side Z = proteolysis ```

Antibody Function: Neonatal Immunity: Maternal (X) crosses the placenta via (Y) to fetus. Additionally, (Z) are in breast milk.

``` X = IgG Y = FcRn Z = IgA and IgG ```

Ab-Antigen Binding: Binding happens at the end of the (X) regions, with the binding site determined by (Y) (CDRs), especially (Z).

``` X = VH and VL Y = complementarity determining regions Z = CDR3 ```

CDRs look like fingers reaching toward the antigen and present on both the (X) and (Y) chains

``` X = Heavy Y = Light ```

Ab-Antigen Binding: Antigens are delivered to (X) in the (Y)

``` X = follicular B cells Y = Lymph node ```

What 2 cell types take up and present antigen in the LYMPHATICS?

1) Follicular dendritic cells | 2) Subcapsular sinus macrophages

What migratory cells take up and present antigen from the periphery in the lymph nodes?

Activated dendritic cells

Multivalent structures can cluster (X) and give a T-independent signal to activate B cells

X = BCRs

Small molecules that need to be conjugated to a carrier to get an immune response are called (X)

X = Haptens

Haptens are (X) (they can be bound by an antibody once the antibody is made). They are not (Y) (They cannot provoke an antibody response on their own)

``` X = antigens Y = immunogens ```

All cells have multiple V, D and J segments to be used in (X)

X = V(D)J recombination

V(D)J recombination: D segments are only on (X) and (Y) genes

``` X = heavy chain (BCR) genes Y = beta chain (TCR) genes (TCR-Beta, TCR-Delta) ```

What is the goal of gene rearrangement?

Create diverse (10^9) receptors with very few genes

Gene rearrangement begins in the developmental stage in (X) and (Y) cells

``` X = pre-B Y = pre-T ```

What do V, D, and J stand for?

``` V = Variable region D = Diversity region J = Junctional region ```

What are the two rearrangement events in VDJ recombination?

First joining a D to a J and then a V segment to the | fused DJ segment

Gene rearrangement control: Each segment must be flanked by a (X)

RSS, Recombination Signal Sequence

What is an RSS

Adjacent to the coding region is a conserved heptamer (CACTGTG or its reverse complement CACAGTG) followed by a spacer (see next section) and then a relatively conserved nonamer

The spacer in an RSS is either approximately (X) in length or approximately (Y) in length. RSSs with (X) spacers recombine only with RSSs with (Y) spacers. The (X)/(Y) spacer rule This prevents V-V, D-D, J-J recombination

``` X = 12 bp Y = 23 bp ```

What are the VDJ gene rearrangement sequence (4 steps)

1 - Synapsis 2 - Cleavage 3 - Hairpin opening and end-processing 4 - Joining

VDJ recombination: STEP 1: Cleavage of the DNA to create a double stranded break. (X - 2 molecules) form a tetrameric complex that recognizes (Y) and creates a single strand (ss) break (or “nick”) between the (Z) and coding sequence

``` X = Recombination activating gene-1 (RAG-1) and recombination activating gene -2 (RAG-2) Y = RSSs Z = heptamer ```

VDJ recombination: STEP 2: The coding sequence free end displaces the other strand, forming a (X) at the (Y) end of the coding sequence

``` X = hairpin Y = 3’ ```

VDJ recombination: STEP 3: | What plays a significant in opening the DNA hairpin?

Artemis

VDJ recombination: STEP 4: Junctional diversity is generated by adding or removing nucleotides. 1. Addition of (X) –a random addition of up to (Y) extra nucleotides directed by (Z) in a non-template dependent manner 2. Addition of (A) (these compensate for uneven cleavage of hairpins)

``` X = N nucleotides Y = 20 Z = terminal deoxynucleotidyl transferase (TdT) A = P nucleotides ```

VDJ recombination: STEP 5: What 3 double strand break repair proteins (enzymes) helps join the newly processed ends? Without these enzymes, recombination does not take place and there are no B or T cells

DNA PKcs, XRCC4, DNA ligase IV

Combinatorial Diversity generated by VDJ recombination and juxtaposition of 2 randomly generated chains (Heavy-light or alpha-beta). How many V, D, and J segments can be combined randomly to make IgG heavy chain?

45 V, 23 D, 6 J

(X) is the largest contribution to the diversity of antigen receptors. Removal of nucleotides (endonucleases) or addition of N or P nucleotides at the V-D, D-J, or V-J junctions

X = Junctional diversity

What are the VDJ steps in BCR Heavy and Light Chain rearrangement?

Heavy Chain D-J rearrangement Heavy Chain V-DJ rearrangement Light Chain V-J rearrangement

What are the VDJ steps in TCR alpha and beta chain rearragement

TCRβ D-J rearrangement TCRβ V-DJ rearrangement TCRα V-J rearrangement

There are 2 mechanisms for VDJ Recombination: 1) Segments in SAME orientation recombine by (X) 2) Segments in OPPOSITE orientation recombine by (Y)

``` X = Deletion Y = Inversion ```

Adaptive Immune Response 1) Generation of (X) (need to recognize an amazing (X) of antigens) - VDJ recombination and somatic hypermutation 2) Determining (Y) (to identify dangerous pathogens/tumors/etc) - (Z) in development, (A) in the periphery 3) Protection via (B) or destruction of non-self - Destroy pathogens/tumors/etc 4) (C) - Faster response in the future

``` X = diversity Y = self v. non-self Z = Central Tolerance (negative selection) A = peripheral tolerance and anergy B = neutralization C = Memory ```

Innate vs. Adaptive Dichotomies

Innate (germline encoded receptors, broad reactivity; agglutinins, complement, phagocytes, NK cells, etc) Adaptive (receptors generated by DNA recombination, have specificity and memory; TCR/BCR, etc)

What 2 categories are under adaptive immunity?

Humoral (B cell produced Ab, etc.) & Cell Mediated (CTLs, etc)

What 2 categories are under T cells?

MHC I/CD8+ T cells (CTL, intracellular pathogens) MHC II/CD4+ T cells (helper T cells, TH)

What 3 categories are under Helper T Cells

Th1 v. Th2 v. Th17

2 classifications for lymphoid organs, their purpose, and examples of each

Central lymphoid organs (sites of generation): bone marrow and thymus Secondary lymphoid organs (sites of activation): lymph nodes, spleen, Peyer’s patches (gut)

Morphology of the Thymus

Cortex, medulla (T cell development)

Lymph node morphology: cortex of primary follicles (X) cells and secondary follicles ((Y), where response to antigen happens); and medulla. T cells lie in between follicles in (Z).

``` X = naïve B Y = germinal centers Z = T cell zone/paracortex ```

Spleen morphology: (immunologically relevant) (X) pulp. The area around the arterioles (Y) is the T cell zone and there are lymphoid follicles with (Z) which are the B cell zones.

``` X = white pulp Y = periarteriolar lymphoid sheaths Z = germinal centers ```

Innate Immunity: NK Cells: i. Origin: (X). ii. No rearrangement of (Y) genes iii. Function: 1. Cell mediated cytotoxicity - e.g. lyse cells found to have low or no self (Z) a. Kill target cells by the same mechanisms as CD8+ T cells (A) b. Express a complex array of activating and inhibitory receptors (e.g. (B), which recognize MHC Class I molecules). 2. Antibody Dependent Cellular Cytotoxicity (intertwined with the adaptive immune response) 3. Early (C) production- e.g. before an effector T cell response has been mounted or has been recruited 4. Secretion of a slew of (D)

``` X = bone marrow Y = TCR or Ig Z = MHC I A = perforin, granzyme, TNFa, FasL, TRAIL B = KIRs C = IFN-g D = cytokines ```

Innate Immunity: B1 B Cells: Secrete “(X)” in body cavities (pleura, peritoneum). Somewhat restricted set of V regions and very little use of (Y), BCR recognizes (Z)

``` X = natural antibody Y = N nt Z = common foreign epitopes ```

Innate Immunity: γδ T cells | X) specificity than normal (αβ) T cells. Recognize (Y

``` X = Less Y = bacterial proteins/lipids ```

Innate Immunity: Intracellular Infections (viral, mycobacterial, rickettsial, listerial...) Antigens can be on cell surface (like viral proteins in the cell membrane) which can be dealt with by (X) or other tools, but most are dealt with via adaptive immunity (i.e. virally infected cells release cytokines, dead cells release viral particles, (Y) get activated, upregulate MHC II and (Z), travel via lymphatics to draining LN, the APCs activate (A), the CTLs kill the infected cells)

``` X = natural antibodies Y = APCs Z = B7.1/B7.2 A = naïve CD8+ T cells (CTLs) ```

Adaptive Immunity: In the (X), rearrangement of the BCR or TCR occurs (as well as elimination of (Y)), in the periphery, these naïve cells continuously recirculate among the (Z) until they see antigen (which may never happen) and proliferate/activate into (A)

``` X = central lymphoid organs Y = self reactive cells Z = SLO A = mature lymphocytes ```