Immunity Flashcards

Question

Describe the role of polygenicity and polymorphism in MHC molecules and its implication

Answer 1

HLA = MHC genetic locus in humans on Chromosome 6; contains >200 genes that encode proteins involved in antigen processing/presentation Polygenic: contains several different MHC genes that together produce range of phenotypic variation; Class 1: A, B, C; Class II: DR, DP, DQ Polymorphism: multiple alleles for each MHC gene e.g 195 alleles for Class 1 A gene --> binds peptides with different motifs Implication: A) Diversifies immune response --> allows MHC binding to any peptide generated within in cell --> can alert immune system to every possible pathogen that enters body EVEN if pathogens mutate to avoid detection B) Every individual has unique haplotype (combination of MHC alleles) --> different set of MHC molecules with different binding specificities *Do HLA typing to determine compatibility prior to transplant - given for A, B, and DR (since they have greatest # alleles)

Answer 2

1) Pathogen in cytoplasm (e.g. virus) produces protein 2) Protein eventually degraded 3) Transporters (TAP acts as membrane pore, Tapasin (makes sure only high affinity peptides presented) bring protein to the ER; ERAP trims peptides 4) MHC Class I binds peptide in the ER --> exocytosed out of cell and moves to cell surface 5) Antigen-MHC complex bound by CD8 T cell

Answer 3

1) Protein antigens phagocytosed by APC into endocytic vesicle 2) Processed in endosome/lysosome 3) Class II MHC transported from ER into endosomes, facilitated via invariant chain (prevents premature binding) 4) HLA-DM removes CLIP from peptide binding groove (makes sure only high affinity peptides presented) --> Class II MHC binds peptide in the endosome 5) Antigen-MHC complex exocytosed out of cell to the cell surface 5) Complex recognized and bound by CD4 T cell

Answer 4

Dendritic cells endocytose viral infected cells and display these viral peptides to MHC Class I (even though Class I is usually for endogenously synthesized antigens) Implication: essential for viral immunity --> way to signal to DCs there is a viral infection and initiate immune response through CD8 T cells, since most viruses do not infect DCs directly (e.g. are not intracellular pathogens)

Answer 5

Other/non-classical genes of HLA region have little polymorphism, many have unknown functions 1) H2-M3 (mouse): MHC Class 1b molecule that presents fmet peptides from bacteria 2) MIC: induced by cellular stress, important for areas where you need immune response but dont have DCs 3) HLA-G: expressed on fetus-derived placental cells that migrate into uterine wall; protect these cells from being killed by NKCs 4) HLA-E: inhibition of NKCs; if it is not there or downregulated--> cell is killed

Answer 6

1) Function of APCs: break down antigen peptides and display MHC-antigen complex to T cells --> initiate adaptive immune response through costimulation 2A) Dendritic cells: constitutive expression of Class II MHC; constitutive expression of B7 costimulators increased by maturation, induced by IFNgamma; activate naive T cells --> clonal expansion and differentiation into effector T cells 2B) Macrophages: low expression of Class II MHC; only interacts with effector T cells, NOT naive T cells --> kill phagocytosed pathogens (Cell-mediated immunity) 2C) B cells: constitutive expression of Class II MHC increased by IL-4; CD40 costimulators induced by T cells and antigen receptor cross-linking; only interacts with effector T cells, NOT naive T cells --> differentiates into plasma cells that produce antibodies (humoral immunity)

Answer 7

Naive T cells see MHC-antigen peptide complex presented by DC and recognizes it as foreign --> clonal expansion and differentiation into either memory cells or effector cells --> effector T cells + antibodies persist for weeks after exposure (protective immunity) immunological memory: on second exposure to antigen, memory T cells can rapidly differentiate into effector cells + more memory cells *T cells recognize linear peptides only, only cell-associated (not soluble)*

Answer 8

1. Activation Signal 1: TCR must recognize and bind to HLA-antigen complex on APC (ONLY Dendritic cell can activate naive T cell) Signal 2: Costimulation; most important is CD28 on T cell binding to B7 1/2 (CD80/86) on DC; costimulatory molecules upregulated by activated APCs 2. Inactivation CTLA-4 upregulated on T cells post activation --> binds with B7 on APC with higher affinity than CD28 --> inhibitory signals (dont know exact mechanism)

Answer 9

T cell anergy (unresponsiveness) when T cells bind antigen in the absence of costimulatory signals (Signal 1 w/out Signal 2) *one reason that tumors are hard to clear, since there is no upregulation of costimulatory molecules e.g. B7

Answer 10

1) Enhancing CTLA4 through injected fusion protein CTLA-4-Ig (abatacept, beletacept)--> outcompetes CD28 to bind to B7 and blocks Signal 2 --> T cell becomes anergic --> prevents autoimmunity 2) Blocking CTLA4 activity through inhibition with antibody YERVOY --> prevented from binding B7 to inhibit the cell --> T cell remains active --> used to treat tumors (e.g. melanoma) though patients can experience autoimmunity

Answer 11

1) Complex of proteins: T cell receptor (TCR) + CD3 co-receptors + zeta chain signaling capacity is through ITAM motif on the intracellular tails of the CD3 molecules + zeta chain 2) TCR complex clusters within membrane lipid rafts upon peptide-MHC recognition--> TCR co-receptor CD4/CD8 binds to MHC and activates Lck protein --> Lck phosphorylates ITAMs --> ZAP-70 binds to the phosphorylated ITAMs --> stimulates multiple cascades including calcineurin --> calcineurin activates NFAT -- goes into nucleus and promotes production of IL-2 --> IL-2 promotes further differentiation of T cells

Answer 12

1) TH1: induced by intracellular microbes; produces IFNgamma (inhibits TH2) and IL-2 (T cell differentiation); involved in macrophage activation and IgG class-switching; role in autoimmune diseases 2) TH2: induced by extracellular helminths e.g. worms; produces IL-4 (B cell differentiation), IL-5 (B cell differentiation + induces eosinophils), IL-10 (inhibits TH1), IL-13 (alternative macrophage M2 activation); involved in mast cell activation and production by B cells; role in IgE class-switching /allergic response 3) TH17: induced by extracellular bacteria + fungi; IL-17A,17F,22 cytokines: involved in inflammation and neutrophil response; role in organ autoimmunity

Answer 13

1) treg = regulatory T lymphocytes, formed from CD4+ T cells in thymus that recognize self too well Express FoxP3 transcription factor and require IL-7 (B and T cell survival signal), IL-2, TGFbeta 2) Functions: inhibit activation of naive T cells + inhibit T cell effectors --> used to prevent autoimmunity by shutting down T cell response when self antigen is recognized Mechanism of action: potentially multiple, don't know how they actually work --> could release inhibitory cytokines, granzyme B, sequester IL-2, peripheral immune suppression of self-reactive cells 3) IPEX - autoimmune disease with DM1 and death by age 2 due to Foxp3 mutation; many autoimmune diseases could be due to treg mutation/resistance

Answer 14

T cell development (from hematopoietic stem cells in thymus): Of all TCRs --> positive selection (pick out T cells with useful TCRs that interact with your MHC molecules) --> negative selection i.e. central tolerance (eliminate the T cells that have too high MHC-peptide affinity and would cause disease) complicated process of genetic rearrangements, differentiation, maturation, etc. T cell recognition of self peptide-MHC complex necessary for selection

Answer 15

Function: cure for leukemia and other cancers, doesnt require immunosuppressive rugs Mechanism: Irradiate and kill all cells of the immune system --> replace with bone marrow from a donor to reconstitute the immune system --> mismatched genotype bw epithelial (host) and immune cells (donor) age has major impact on survival -- decreases post 40 years

Answer 16

A) Subunits: 2 identical heavy chains and light chains (allelic exclusion) bound by disulfide bonds B) Domains: Light chain has 2 (constant CL and variable VL) and heavy chain has 4 (constant CH1, CH2, CH3 and variable VH) + hinge domain H C) Constant domains - identical in all molecules of the same class Variable domains - N-terminal domains; each domain has 2 regions: 3 hypervariable complementarity determining regions CDR (antigen-binding site) and framework regions FR (hold CDRs in place) Paratope = 6 CDRs (3 from VL and 3 from VH)

Answer 17

Large, complex antigen has several epitopes Each epitope is bound by specific antibody that is produced by clone of plasma cells --> multiple clones required to produce population of antibodies that can bind to different epitopes *these antibodies can be from different classes*

Answer 18

One type of heavy chain IGH found on chromosome 14 Two types of light chains: IGL-lamda on chromosome 22 and IGL-kappa on chromosome 2 --> two types of antibodies: IGH + IGL-lambda and IGH + IGL-kappa

Answer 19

V(D)J somatic recombination - happens in every B and T cell during devlpt (bone marrow and thymus); Antibody genes complex are in gene segments E.g. Heavy chain IGH gene complex consists of regions VH, D, JH, and CH which each contain multiple gene segments; Light chain gene complexes contain VL, JL, and CL Of these gene segments, one is chosen randomly from each region and spliced to form exon --> RAG1 and RAG2 proteins create double stranded breaks through the segments + random insertion/deletion of nucleotides --> huge diversity of possible antibodies *since T cells also use V(D)J --> As many TCRs as there are antibodies

Answer 20

RSSs (recombination signal sequences) flank the V, D, J gene segments --> recognized by VDJ recombinase enzymes --> recombination occurs at junctional segments; not precise so leads to duplication, deletion, mutation, etc.

Answer 21

Class switching is irreversible, takes place in B cells during germinal center response, only affects constant regions of the heavy chain gene First antibody made is always IgM VDJ segment (and thus variable region) stays the same, but DNA fragment excised from constant region of heavy chain--> creates new antibody e.g. IgG --> new isotope/class, which is determined by identity of the heavy chain (each class has different Fc region)

Answer 22

Post-transcriptional splicing of the constant gene region of the heavy chain --> yields different products (secreted antibody or membrane BCR, IgM or IgD) *product retains same idiotype (VDJ rearrangement of variable chain) and isotype (e.g. IgM, based on type of heavy chain)

Answer 23

Takes place along with class switching during germinal center response (the two together are called "affinity maturation") programmed process of mutations to the variable regions of Ig genes --> allows immune system to respond to new threats over course of lifetime also the reason why secondary immune response produces antibodies with higher affinity problems lead to B cell lymphomas or other cancers

Answer 24

Maternal and paternal chromosomes can have different numbers of constant and variable gene segments due to deletions/mutations

Answer 25

Primary: IgM>>IgG, low antibody affinity and takes 10-14 days before Ig appears and only small amount Ig made, requires high dose of antigen, short duration germinal center response happens so memory B cells, affinity maturation, isotope switching, etc. Secondary: IgG>>IgM, high antibody affinity and takes 2-3 days before Ig appears and large amount made; requires low dose of antigen and long duration --> Secondary immune response is "bigger, better, faster"

Answer 26

Humoral immune response = antibody-mediated --> Destruction of extracellular pathogens and prevention of spread of intracellular infections Function of antibodies: 1) neutralization - blocks binding of pathogen 2) opsonization - microbe tagged and bound to Fc receptor on phagocyte--> phagocytosed 3) ADCC - antibodies recruit cytotoxic NKCs via Fc receptors--> infected cell is killed 4) complement activation - activate through classical pathway --> more opsonization by C3b, inflammation via C3a and C5a, forms membrane attack complex that kills pathogen via osmotic lysis (poking holes)

Answer 27

Bone marrow (Stromal cells in marrow provide development signals): hematopoietic stem cell --> immature B cell Checkpoint 1: after heavy chain is arranged, put preBCR on cell surface with surrogate light chain to see if there is tonic signal; otherwise, cell is killed via apoptosis Checkpoint 2: real light chain binds to heavy chain --> see if there is tonic signaling from assembled BCR; otherwise, cell killed via apoptosis; If checkpoints passed --> immature B cells goes into the blood Selection: via central tolerance in the bone marrow to remove self-reactive (v high affinity) B cells via apoptosis (Extrinsic Fas/FasL binding pathway); some cells get a second chance via receptor editing Some self-reactive B cells that escape negative selection in the bone marrow are inhibited by Bregs (mechanism unknown)

Answer 28

B cell activation takes place in secondary lymphoid organs e.g. spleen, lymph nodes (where they come into contact with antigens) Signal 1 for both types is crosslinking of BCR, assisted by complement system 1) T-dependent antigens: protein antigens that cannot produce antibody responses in humans without T cells; BCR binds TD antigen --> antigen take up and degraded --> presented on follicular B cells with MHC II --> recognized by CD4 T Cells --> Signal 2 = CD40 (B cell) + CD40L (T cell) linkage; results in high-affinity Ab and long-lived plasma cells 2) T-independent antigens: bacterial antigens that induce antibody response no matter what; usually contain repetitive patterns that crosslink BCRs on B1B or marginal zone B cells; Signal 2 = TLR activation; results in mainly IgM and short-lived plasma cells

Answer 29

1) survival signals for increased survival and proliferation 2) Increased expression of B7 costimulatory molecule --> in order to activate more T cells 3) Secretion of cytokines e.g. IL-4 --> differentiation of B cells 4) Increased migration of B cells towards T cells --> in order to activate more T cells

Answer 30

Immature B cell activated by antigen on CD4 T cell matures, travels through circulation to spleen/lymph node, and forms germinal centers --> clonal expansion Germinal center response (in T dependent antigens): - affinity maturation (somatic hypermutation of variable region via AID enzyme and then selection of B cells with higher affinity receptors, others die off) *unique to B cells* --> higher affinity antibodies - isotype/class switching (isotype is based on constant region of heavy chains, also mediated by AID enzyme) - differentiation into either memory B cells or long-lived plasma cell (churns out Ab)

Answer 31

B1 in fetal liver --> matures into B1B cells --> mediate T-independent response, short-lived plasma cells that make IgM (natural antibodies) that act as first line of defense B2 in bone marrow --> mature into B2B cells --> either follicular B2B (produce most antibodies, mediate T dependent response) or marginal zone B2B cells (facilitate T-independent response) Other type of B cells: regulatory B cells, similar to tregs in that they shut down responses

Answer 32

1) Trigger: trauma, immune reactions, anaphylatoxins (C3a, C5a), tissue necrosis, foreign bodies 2) Recognition: TLRs --> binding leads to transcription, production, activation, and release of inflammatory cytokines; Inflammasome --> activates caspase 1 --> activates IL-1B 3) Recruitment of neutrophils to extravascular space/site of tissue damage: Margination (accumulation on vascular surface) --> rolling (neutrophils roll on endothelial surface by binding/detaching to selectins- expression of which are upregulated by cytokines) --> adhesion mediated by integrins (ICAM/VCAM) - expression of which are upregulated by cytokines --> extravasation via diapedesis --> neutrophils move towards infection site via chemotaxis (chemical gradient) 4) Removal of agent: Activated neutrophils phagocytose particles (opsonization via Fc receptors on IgG, engulfment, and ROS killing) + secrete more cytokines 5) Regulation of response: Neutrophils dominate for first 24 hours then apoptose, replaced by monocytes/ macrophages, which phagocytose neutrophils that have broken apart 6) Repair: Ultimately, cells exit and tissue bed restored to original state

Answer 33

1) Rubor - redness 2) Calor - heat 3) Tumor - swelling 4) Dolor - pain 5) Functio laesa - loss of function

Answer 34

Recognition of injury: Mast cells IgE receptor activated and release granules that contain various inflammatory agents (e.g. histamine), also release cytokines + eicosanoids 1) Histamine --> Arteriolar vasodilation --> increased blood flow --> leads to redness (erythema) and warmth 2) Histamine --> Increased vascular permeability (due to retraction of endothelial cells) --> protein + fluid moves into interstitial space (EXUDATE) --> Edema 3) Increased blood viscosity --> stasis (small vessels packed with RBCs) --> margination (neutrophils accumulate along vascular endothelial surface)

Answer 35

1) ROS: synthesized via NADPH oxidase in lysosomes to kill ingested pathogens, but can also cause injury 2) NO: cytotoxic agent in activated macrophages; also leads to vasodilation

Answer 36

1) Leukocytes lack NADPH oxidase --> no H202 generated --> decreased oxidative burst --> pathogens are not killed --> recurrent, life-threatening infections see granulomas as a sign of chronic inflammation (contain giant cells due to macrophage fusion) 2) Immune granulomas: caused by insoluble particles inducing cell-mediated immune response Foreign-body granulomas: e.g. splinter

Answer 37

Irreversible tissue changes initiated by parenchymal cell death due to prolonged inflammatory response 1) infiltration of mononuclear cells (mostly macrophages but also lymphocytes, plasma cells) 2) tissue destruction 3) attempts at healing: Angiogenesis (growth of new blood vessels) and fibrosis (production of new connective tissue) --> scarring

Answer 38

Mediators are TNF, IL-1, and IL-6 released by leukocytes in response to pathogen (e.g. bacterial LPS) 1) Fever due to prostaglandins e.g. PGE2 (give NSAIDs to reduce fever) 2) Increased levels of C-reactive protein CRP (track levels of CRP as biomarker of inflammation), fibrinogen 3) leukocytosis = increase in WBC (due to accelerated release from bone marrow --> immature cells enter blood --> "left shift")

Answer 39

Whether regeneration or scarring depends on whether cell tissues are labile, stable, or permanent and whether framework is intact or destroyed 1) Regeneration (labile/stable cells with framework intact): proliferation of uninjured cells and replacement of stem cells, induced by growth factors e.g. VEGF 2) Scar formation: EGF leads to specialized granulation tissue + VEGF leads to increased number of new bv --> fibroblasts migrating and laying down ECM (collagen) --> fibrosis

Answer 40

Cytokines: signal proteins that bind to membrane receptors to coordinate communication between cells; v potent molecules produced in v small amounts for v short periods of time Immune functions: 1) formation of immune system --> proliferation, differentiation 2) Homeostasis --> targets cells to immune tissues 3) Response to infections/inflammation

Answer 41

1) Pleiotropy: 1 cytokine can have multiple and different effects on a single cell type, depending on time of exposure and concentration of cytokine; different cell types respond differently to 1 cytokine 2) Redundancy: Different cytokines can have same/overlapping effects --> backup system so we do not rely on a single gene product

Answer 42

1) Chemokines are a subset of cytokines and: - are smaller - signal through G protein coupled receptors (not kinase-coupled receptors as with other cytokines) - are chemotactic --> attract cells to site of inflammation and attract circulating lymphocytes to secondary lymphoid organs (e.g. T cells to APCs, B cells to follicles) - modulate cell adhesion 2) Nomenclature: based on pattern of cysteines in the structure; 1 or 2 cysteine bridges --> CCLx, and receptor is CCRx 3) Need CCR5 chemokine receptor binding WITH CD4 binding for HIV infection --> research into inhibiting CCR5 binding for HIV therapy

Answer 43

Type 1 Interferons: IFN alpha and beta (NOT gamma) -- generally co-expressed; Activation: IFN binds to IFNAR receptor --> stimulates Jak-STAT pathway Effects: 1) Paracrine: bind to neighboring cells and induce protein synthesis --> cells become more resistant to viral infection (direct antiviral effect) 2) Autocrine: feedback onto viral infected cell to induce apoptosis 3) Stimulate cells of innate and adaptive immune system --> increased Class I MHC presentation; maturation of dendritic cells + Class II MHC/HLA upregulation; stimulate B cells to produce more antibodies

Answer 44

Cytokine binds to receptor --> receptor dimerizes and activates Jak--> Jak phosphorylates tyrosine residues of receptor + STATs --> STATs dimerize and translocate to nucleus --> binds to promoter region --> induces transcription of proteins Used by Type 1 interferons IFN alpha/beta, IL-10 (inhibits Th1), IL-2, and IL-4/5 *IL-2 (T cell differentiation) and IL-4 (B cell differentiation) both have gamma common chain subunits

Answer 45

1) TNF, IL-1, and IL-6; produced by leukocytes (macrophages) 2) Functions: promote acute inflammations to fight infection (activate neutrophils, destroy harmful agents) and repair damage locally; initiate and coordinate defenses 3) High levels can cause fever, shock, death; chronic levels can cause weight loss, loss of connective tissue/bone 4) NFkB

Answer 46

1) Hypertrophy: non-dividing permanent cells get bigger (e.g. CNS, muscle) 2) Hyperplasia: new cells from proliferating mature cells as well as stem cells 3) Atrophy: decrease in size (both in cell number and size) due to stress, disuse, decreased nutrients or hormones 4) Metaplasia: adverse environment leads to reversible change in cell type through reprogramming of stem cells e.g. Barrett's esophagus (SES --> simple columnar with goblet cells) 5) Autophagy: lysosomal digestion of cellular components due to nutrient depletion

Answer 47

Reversible injury: cellular swelling (failure of ion pumps - due to hypoxia) and fatty change (lipid vacuoles in cytoplasm); mt swelling, plasma membrane blebbing, chromatin clumping Irreversible injury (Necrosis): inability to reverse mt dysfunction, disturbance in membrane functions, karyolysis (nuclear fading), pyknosis (nuclear shrinkage), karyorhexis (nuclear fragmentation) dead cells replaced by myelin figures --> degraded into fatty acids --> become calcified

Answer 48

1) ATP depletion - due to hypoxia, mt damage, toxins 2) Mt damage --> necrosis (hypoxia, toxins) or apoptosis (leakage of pro-apoptotic proteins) 3) Release of Ca2+ from mt, SER, or extracellular--> mt damage, nuclear damage, ATP depletion 4) Increased ROS due to oxidative stress --> DNA mutations, membrane damage, protein misfolding 5) membrane damage - plasma, mt, or lysosome --> necrosis 6) protein misfolding/DNA damage --> ER stress --> apoptosis (e.g. Alzheimer's, Huntington's, Parkinson's)

Answer 49

Apoptosis: requires ATP, often physiologic, plasma membrane intact, cell shrinks, no leakage --> no inflammation; leads to apoptotic body that is phagocytosed Necrosis: passive (no ATP), always pathologic, plasma membrane disrupted, cell swells, no phagocytosis, leakage --> inflammation Necroptosis: genetically programmed (like apoptosis) but no caspase activation --> TNFR1 recruits RIP1 and RIP3

Answer 50

1) Intrinsic: Cell injury (DNA damage, no growth signals, misfolded proteins)--> inhibits Bcl2 in mt membrane and activates BH3 sensors --> Activate Bak/Bax --> create pores in mt --> caspase cascade --> executioner caspases --> apoptosis 2) Extrinsic: Fas/TNFR ligand binding --> receptors cross linked --> bind adaptor proteins via death domain FADD --> recruit caspase 8 --> executioner caspases --> apoptosis

Answer 51

1) Abnormal metabolism --> fatty liver due to alcoholism, protein malnutrition 2) Antitrypsin mutation --> defect in protein folding --> abnormal protein accumulation 3) Enzyme mutation --> storage disease e.g. LSDs --> accumulation of endogenous material 4) Ingestion of indigestible materials --> accumulation of exogenous materials e.g. carbon, silica

Answer 52

1) Coagulative: underlying tissue architecture preserved; characteristic of infarcts 2) Liquefactive: CNS infarcts, bacterial/fungal infections destroy tissue and turn into liquid mass 3) Gangrenous: ischemic limb that undergoes coagulative necrosis through several tissue layers; "Wet" =liquefactive due to bacterial infection 4) Caseous: due to tuberculosis; tissue architecture obliterated, surrounded by granuloma inflammation 5) Fat: due to release of activated lipases, can see outlines of necrotic fat cells --> can see calcifications

Answer 53

1) Antigens are located on the RBC membrane; h antigen --> H --> A (if you add galNac) OR B (if you add galactose) 2) Antibodies are in the plasma; they are IgM, T-independent, natural Ab--> make antibodies to antigens we do not express, produced against similar structures in intestinal bacterial microbes (by 9 mos)--> destroy RBC in blood stream (intravascular hemolysis) 3) A (AA or AO) --> A antigen + Anti-B antibodies B (BB or BO) --> B antigen + Anti-A antibodies AB (AB) --> A and B antigens + No antibodies O (OO) --> H antigen + Anti-A and Anti-B antibodies

Answer 54

Bombay-O: do not have the enzyme to convert h --> H antigen --> RBCs have anti-H antibodies --> will have transfusion reaction if they receive Type O blood Appears as Type O, recognize bc anti-H Ab in blood sample will agglutinate Type O RBCs

Answer 55

Whole blood contains antigens and antibodies --> donor and recipient blood types should be identical Under emergency conditions - can use O, Rh- RBCs (contain no antigens)

Answer 56

1) Rh0/D antigen --> Rh+ (DD or Dd) have it, Rh- do not (dd) 2) Antibody produced by Rh- on exposure to Rh+ blood; Ab are IgG and can cross placenta, opsonize RBCs and stimulate phagocytosis (Extravascular hemolysis via Fc gamma receptors) 3) Rh- mother exposed to Rh+ positive cells during first birth --> makes Anti-Rh+ antibodies subsequent Rh+ fetus --> secondary immune response --> anti-Rh+ IgG crosses placenta and kills fetal RBCs --> fatal hemolytic disease 4) Mother given Rhogam antibody (anti-Rh+ immune globulin) before/after birth --> destroys fetal RBCs before they can trigger maternal immune response; high Ab levels lead to feedback immunosuppression of B cells

Answer 57

If RBC has antigen on surface --> IgM antibody can bind several RBCs at once --> forms latticework = agglutination IgM (ABO) can agglutinate bc they are pentamers --> big enough to bridge zone of repulsion between large, (-) RBCs IgG (Rh, other minor blood groups) are not big enough

Answer 58

1) DAT: detects antibodies that are bound to RBCs but cannot agglutinate them; used to test for bound IgG, diagnose autoimmune hemolytic anemia Add Coombs reagent (anti-IgG antibody) --> these antibodies bind to the Fc portion of the RBC antibody --> link RBC antibodies together --> RBCs agglutinate 2) IDAT: detects antibodies in patients plasma that have not yet been bound; use to detect anti-Rh+ ab in mother's serum (maternal-fetal Rh incompatibility) Add RBCs with antigen of interest (e.g. Rh+) to patient's plasma serum --> if there are anti-D antibodies, they will bind to the RBCs but not agglutinate --> then add Coombs reagent (anti-IgG antibody) --> RBCs will agglutinate *Coombs reagent produced by immunizing animals with human antibodies and isolating the anti-human antibodies*

Answer 59

1) Multiple myeloma - malignancy of antibody-producing plasma B cells; most common lymphoid malignancy and usually happens in older patients multiple=multiple tumor cells by the time condition is detected; myeloma=tumors formed in bone marrow where plasma B cells live 2) spike in gamma band which represents the excess of one type of antibody --> monoclonal gammopathy; does NOT show which particular class is elevated can be heavy chain secretion or light chain secretion (bence-jones proteins in urine) 3) Immunofixation : separate proteins on strips and flood strip with antibodies specific for particular class e.g. IgA --> if antibody binds, precipitate forms and electrophoresis band widens

Answer 60

Pharmacodynamics: effect of a drug on the body-- interactions between receptors and inhibitors/activators Pharmacokinetics: effect of the body on a drug --> in terms of absorption, metabolism, elimination; determines therapeutic efficacy and duration of action

Answer 61

Biologics = engineered antibodies - injection site reactions - cant be given orally; need to be given subcutaneously, via IV - cytopenias with anti-TNF therapy --> monitor CBCs - infections - cost --> biologics (large proteins) are v expensive bc they are tailored On the other hand, methotrexate and leflunomide are DMARDs (Disease modifying anti-rheumatic drug): inhibit DHFR --> less targeted immunosuppression by preventing lymphocyte proliferation --> oral pill, less expensive

Answer 62

Chimeric - part of the variable region of the antiobdy is from another species e.g. mouse; "xi" in generic name Humanized - as many portions of the mouse variable region have been converted to human sequence to minimize immune response; "mu" in generic name

Answer 63

Anti-cytokine therapy used to treat autoimmune diseases of chronic inflammation (RA, IBD, lupus) 1) Anti-TNF alpha agents used to treat RA etanercept (ENBREL) - binds TNF via TNF receptors attached to Fc portion of IgG1 --> neutralizes biological activity infliximab (Remicade) - chimeric monoclonal antibody --> reduces blood levels of TNF alpha; also treats Crohn's adalimumab (Humira) - humanized monoclonal antibody --> complexes with soluble TNF alpha and inhibits

Answer 64

2) IL-1 inhibitor used to treat RA anakinra (Kineret) - IL-1 receptor antagonist, endogenous protein --> blocks cellular effects of IL-1 Not widely used bc has to be injected daily; can be given with methotrexate but not the anti-TNF agents

Answer 65

3) B cell inhibitor used to treat lupus belimumab (Benylsta) - monoclonal antibody to BAFF (B cell activating factor/survival signal) --> reduces excess levels of BAFF that lead to inflammation

Answer 66

1) Primary (where lymphocytes are produced): bone marrow, thymus 2) Secondary (where B and T cells are found together and interact with APCs): Peyer's patches - defends mucosa, spleen-- defends blood, lymph nodes- defends tissue fluids 3) Tertiary: transient aggregations, can occur anywhere

Answer 67

Bone marrow: B and T cells born in the stromal cords, get into circulation via vascular sinuses; both arise fro hematopoietic stem cell --> B cells mature in marrow and are sent straight to secondary lymphoid tissues; T cells mature in the thymus

Answer 68

1) Thymus: bilobed, distinct cortex and medulla, NO B nodules or reticular fibers Contains endodermally derived epithelial reticular cells (ERCs, found ONLY in thymus, aggregate into Hassell's corpuscles in the medulla) --> promote maturation of T cells along with macrophages (which remove failed recruits) and DCs --> maturation occurs as the T cells migrate through the thymus 2) T cells enter through HEV, start in subcapsular zone (CD4-/CD8-) and migrate through cortex (CD4+/CD8+) --> learn self from non/self and mature --> become either CD8+ or CD4+ by the time they reach the medulla and exit --> secondary lymphoid tissues * need 5 layer blood:thymus barrier to keep antigens out of cortex and getting into contact with maturing cells (medulla doesnt need specialized barrier bc T cells are already mature)

Answer 69

Lymph node: macrophages and DCs attach to Type II collagen reticular fibers and monitor lymph B and T cells are both in the cortex: T cells are in paracortex; B cells segregate into primary follicles in the cortex near the subcapsule--> become secondary and develop germinal center when exposed to antigen Lymphocytes carried in through afferents; majority squeeze through epithelium of high endothelial venules (HEVs) --> then hop onto reticular fibers to travel throughout node

Answer 70

Flow: afferent lymphatics pierce lymph node capsule to deliver lymph --> subcapsular sinus (unique to lymph node) --> lymph passes through cortex and then medulla (opportunities for interactions bw antigens in lymph and immune cells in the node!) --> lymph exits from hilus via efferent lymphatic --> returns to circulation via thoracic duct or right lymphatic duct

Answer 71

B and T cells segregated 1) Palatine tonsil: antigen exposure through SSE epithelial crypts that extend through the tonsil; starry night appearance due to macrophages 2) Peyer's patches: in ileum, covered by specialized follicular epithelial incl M cells which take up antigen via transcytosis and deliver to immune cells 3) Spleen: has capsule but no cortex, medulla, afferent lyphatics; white pulp --> immune surveillance (T cells assemble into PALs that cover the artery, B cells are in follicles nearby); red pulp --> remove old RBCs that are slow moving from cord to splenic sinus

Answer 72

1) Papain --> 2 Fab segments and 1 Fc segment 2) Pepsin --> 1 (Fab')2 segment + fragments of heavy chain Fab = fragment antigen-binding region, composed of complete light chain and amino terminal of heavy chain, linked by disulfide bond Fc = terminal parts of heavy chain constant region; responsible for antibody effector functions e.g. complement fixation, binding to cell membrane Fc receptors (Fab')2 = 2 Fab fragments + additional hinge region

Answer 73

Women are most attracted to men whose MHC genes are very different from her own

Answer 74

Doherty and Zinkernagal won the Nobel Prize for discovering how T cells recognise their target antigens through MHC proteins Doherty was nonconformist and outsider Zinkernagal failed at surgery before discovering interest

Answer 75

Paul Erhlich coined chemotherapy and magic bullet; co-win Nobel Prize for theory on body producing antibodies to combat pathogens

Answer 76

Daniel Bovet won Nobel Prize for discovery of histamines

Answer 77

Interferon was the subject of Flash Gordon comic in the 60s

Answer 78

In some Asian cultures, blood type is considered to be predictive of personality A: creative and earnest B: wild and selfish AB: rational and indecisive O: sociable and vain

Answer 79

AIRE = autoimmune regulator gene that encodes TF (transcription factor) expressed in the thymus Function: mediates transcription of ectopic genes --> turns on expression of peripheral antigens not normally expressed in thymus --> expands T cell repertoire --> key for mediating self/non-self and preventing autoimmunity Mutations lead to autoimmune disease APS (failure of parathyroid, adrenal glands)

Answer 80

1) We don't actually know -- usually arise spontaneously; tend to be chronic since trigger cannot be eliminated Potential mechanisms: loss/resistance to tregs; normal self-antigens modified by drugs, environment, mutations; molecular mimicry 2) How infection triggers autoimmunity: A) molecular mimicry = exposure to pathogen v similar to self-antigen --> immune response against pathogen --> activated T cells and B cell antibodies cross-react with self-antigen B) infection provides environment that promotes lymphocyte activation --> release of previously sequestered antigens which react with self-reactive T cells 3) How drugs trigger autoimmunity: A) Drug hypersensitivity= drug metabolite complexed with host protein, is reversible; B) drug interferes with peptide binding to MHC --> T cells see cell as non-self

Answer 81

RA = systemic autoimmune disease Citrullination: Altered self due to enzymatic chemical conversion of arginine --> citrulline (has =0 instead of =NH) T cell sees as non-self --> IgM and IgA autoantibodies directed against citrullinated peptides --> T cells and antibodies enter joints and cause tissue injury via cytokine production /inflammation --> destruction of tissue and bone Treatment options: TNF inhibitors (etanercept), IL-1 antagonist (anakinra), anti-IL-17 antibodies, anti-B cell monoclonal antibody (rituximab)

Answer 82

1) Autologous: transplant between locations in same individual 2) Syngeneic: transplant between genetically identical individuals e.g. identical twins 3) Allogeneic: transplant between different individuals of same species 4) Xenogeneic: transplant between different species

Answer 83

Adaptive immune system --> graft rejection mediated by T cells; shows memory + specificity (cardinal features of adaptive system) Major histocompatibility complex locus (HLA in humans)--> encodes the antigens that dominate transplant rejection Each individual has a unique set of MHC I (ABC) and II (DR DP DQ) alleles inherited from parents --> donor MHC can appear to be self-MHC + foreign peptide complex--> direct allorecognition by host TCR via cross-reaction

Answer 84

1) Direct recognition: transplanted tissue contains DCs --> migrate out of graft into lymph nodes --> present alloantigens to CD8 T cells --> generation of alloreactive T cells that attack donor cells 2) Indirect recognition: donor MHC ingested by host DCs --> donor MHC processed and presented by self-MHC molecule --> recognized by CD4 T cells --> secretion of cytokines --> inflammation In both pathways, DCs provide costimulation via B7

Answer 85

1) Hyperacute: rejection occurs in minutes, mediated by circulating antibodies specific for donor antigens that are already present before transplantation (IgM Abs for ABO, MHC due to pregnancy, previous transfusion, etc.); not common bc of cross-matching 2) Acute: rejection occurs in days to weeks; mediated by T cells and Ab specific for alloantigens; use immunosuppressive therapy to block activation of alloreactive T cells 3) Chronic: rejection occurs over months to years; mediated by T cells that react against alloantigens --> secrete cytokines --> fibroblast and vascular SM proliferation --> fibrosis + arteriosclerosis; principal cause of graft failure

Answer 86

Hematopoietic stem cell (HSC) transplantation: Ablate recipient bone marrow --> injected HSCs If mature allogenic T cells are transplanted along with the HSCs --> T cells can attack the recipient tissue --> Graft versus host disease (GvHD) --> scaling rash, jaundice, keratinocyte apoptosis in most cases, host can recognize the donor T cells and kill them; BUT if host is immunosuppressed --> cannot destroy donor T cells --> death SOLUTION: irradiate donor tissue to kill donor T cells

Answer 87

Type I Hypersensitivity: 1) Time course: immediate (minutes); Atopy = allergic reaction- heightened immune response to allergen 2) Sensitization: TH2 activation --> IgE antibody --> binds to Fc receptor on mast cells and basophils 3) Mechanism: On secondary exposure: multivalent allergen binds to IgE and crosslinks (cannot be hapten/univalent antigen)--> degranulation of mast cells + production of eicosanoids --> release of inflammatory mediators (e.g. histamine) + chemoattractant for eosinophils 4) Symptoms: sneezing, coughing, itching, anaphylaxis (need epi pen); skin lesions have wheal (Swelling) and flare (Redness)

Answer 88

Type II Hypersensitivity: 1) Time course: hours; transfusion rxns (ABO mismatch), fetal hemolytic disease 2) IgM or IgG binds to antigens on cell surface 3) Mechanisms: Opsonization (via IgG) and phagocytosis (via neutrophils or macrophages); activation of classical complement pathway; antibody-dependent cell-mediated cytotoxicity (ADCC) where NKCs recognize Ab bound to antigen and kill the cell (but do NOT phagocytize) 4) N/A

Answer 89

Type III Hypersensitivity: 1) Time course: hours (like Type II); farmer's lung (localized), RA + lupus + serum sickness (Systemic) 2) IgG reacts with antigen to form immune complexes (Defective clearance of apoptotic nuclei) 3) Mechanism: Large insoluble complexes are phagocytosed, but small soluble complexes lodge in vessels and organs --> complement activation + mast cell degranulation --> C3a and C5a release inflammatory mediators and lytic enzymes and attract neutrophils --> inflammation and tissue necrosis 4) Arthus reaction (experimental rxn): localized vasculitis (wheal + flare) that takes hours to form due to deposition of immune complexes

Answer 90

Type IV Hypersensitivity (Delayed-type hypersensitivity): 1) Time course: 48-72 hours; contact hypersensitivity dermatitis (e.g. poison ivy), allergy to metals or other haptens, acute/chronic transplant rejection 2) N/A - mediated by antigen-specific TH1 cells 3) Mechanism: Secondary exposure: CD4 TH1 cells activated --> Secrete cytokines --> recruit macrophages 4) Symptoms: firm, red bump (induration + erythema) e.g. positive Mantoux test

Answer 91

First European to describe poison ivy was Captain John Smith

Answer 92

Clemens von Pirquet coined the term allergy, devised tuberculin skin test

Answer 93

Bee stings have been used in traditional Chinese medicine to cure disease; investigating now use in therapy for MS

Answer 94

Histidine + (Decarboxylase) --> Histamine Produced/stored in: A) cytoplasmic granules in mast cells, B) cytoplasmic granules in basophils (circulate in blood), C) vesicles in enterochromaffin-like (ECL) cells (gastric mucosa), D) vesicles in CNS neurons (use histamine as a neurotransmitter) Degraded within 1 minute; primary pathway uses imidazole-N-methyltransferase and monoamine oxidase enzmes

Answer 95

1) Immunological release (i.e. Type I Hypersensitivity): allergens bind to IgE Ab on surface of pre-sensitized mast cells --> crosslinking of Fc receptors --> degranulation 2) Mast cell injury: local release of histamine e.g. scratching your arm leads to redness/swelling 3) Endocrine/neuronal stimulation: rapid histamine exocytosis from the cytoplasmic vesicles in ECL cells or histaminergic neurons 4) Chemical displacement: Drugs that stimulate release of histamine without prior sensitization --> peptides displace histamine from granules

Answer 96

1) H1: smooth muscle, endothelium, peripheral neurons; increases IP3 and DAG --> increased itching, pain, edema, bronchoconstriction, vasodilation via NO 2) H2: gastric mucosa, cardiac and vascular smooth muscle; increases cAMP --> increased gastric acid secretion, HR, vasodilation via cAMP 3) H3: presynaptic histaminergic neurons; decreases cAMP --> negative feedback on histamine release 4) H4: hematopoietic cells e.g. neutrophils, DCs, basophils, monocytes, T cells ; decreases cAMP --> differentiation of cells, chemotaxis, cytokine secretion

Answer 97

1) Nervous: (peripheral) H1 induces depolarization of nerve endings in the skin --> itching/pain; (CNS) H1 and H3 involved in increased wakefulness, satiety, homeostasis 2) Cardiovascular: Vasodilation via H1 on endothelial cells (NO) and H2 on vascular smooth muscle (cAMP) --> "flare" (redness); H1 induces increased capillary permeability --> "wheal" (edema) and decreased BP --> reflex tachycardia 3) Respiratory: H1 induces contraction of bronchial smooth muscle 4) Digestive: H2 facilitates gastric acid secretion, H1 stimulates contraction of intestinal smooth muscle --> diarrhea

Answer 98

1) Allergen inhaled through nose--> Allergic rhinitis (nasal congestion, runny nose, itchy eyes, sneezing); affects upper respiratory tract 2) Allergen inhaled into lungs --> allergic bronchospasm 3) Allergen on skin (topical or ingestion) --> urticaria (hives) 4) Allergen distributed systematically --> Anaphylaxis (severe bronchoconstriction, systemic vasodilation --> decreased BP and pulse) *antihistamines not effective in treating anaphylaxis bc many mediators, not just histamine, are released* USE EPI PEN

Answer 99

1) cromolyn sodium and nedocromil block Ca2+ entry --> stabilize mast cell membranes and prevent mast cell degranulation --> reduce release of histamine; used to prevent asthma attacks (not helpful once attack is happening) 2) epinephrine --> agonist of beta and alpha adrenergic receptors --> bronchodilation and vasoconstriction --> counteracts bronchoconstriction and vasodilation 3) Sensitization shots: add blocking antibody (IgG) --> binds allergen and prevents IgE from binding to it and causing allergic reaction

Answer 100

Mechanism: inverse agonists --> bind to the inactive conformation of histamine receptor --> used to treat hives, pink eye, itching (NOT asthma, anaphylaxis) 1) First Generation eg Benadryl, PBZ, promethazine, hyroxyzine + cyclizine (all OTC): neutral so readily enter CNS --> highly sedative and anti-vomiting, also used for treating insomnia, motion sickness; short acting - metabolized in liver via cyt p450; side effects: anticholinergic (dry mouth, blurred vision), drowsiness 2) Second generation e.g. cetirizine (Zyrtec), loratidine (Claritin), fexofenadine (Allegra): ionized so do not enter CNS --> no sedative effect; selective and longer acting (12-24 hrs); formulated with pseudoephidrine --> side effects include insomnia, increased HR 3) Third generation e.g. Xyzal, Clarinex: active versions purified for greater potency

Answer 101

H2 antihistamines e.g. famotidine (Pepcid *most potent*), cimetidine (Tagamet), ranitidine (Zantac)= treatment of gastric hyperacidity e.g. gastric ulcers, GERD Blocks histamine release from ECL cell --> parietal cell not stimulated to release H+ Characteristics: hydrophilic so do not enter CNS, highly specific, work best at night; less effective than PPIs

Answer 102

Cortisone discovered by Edward Calvin Kendall while at Mayo Clinic, received Nobel prize in 1950

Answer 103

Aspirin was the first drug to be sold with child safety caps

Answer 104

Eicosanoids: Arachidonic acid metabolites, located in every tissue Membrane phospholipid --> phosphate group clipped off, released as omega 6FA arachidonic acid if cyclo-oxygenase (COX) acts on arachidonic acid --> prostaglandins PGs (vasodilation) + thromboxanes TXs (vasoconstriction) *PGs + TXs are called prostanoids* If lipoxygenase acts on arachidonic acid --> leukotrienes LTs (chemotaxis) + lipoxins LXs (inhibit chemotaxis)

Answer 105

COX1 and COX2 are isozymes COX1 -- produces prostaglandins involved in homeostasis (housekeeping), expressed constitutively COX2 -- expression induced by inflammation, produces PGE2 (main prostaglandin involved in inflammation)

Answer 106

1) PGE2: main prostaglandin involved in inflammation (via COX2) --> vasodilation, increased vascular permeability, promotes pain signal conduction through bradykinin; also protects stomach lining by promoting mucous secretion and inhibiting acid secretion (via COX1) 2) PGI2: produced by vascular endothelium; anti-platelet clotting, bv vasodilation 3) TXA2: produced by activated platelets; pro-platelet aggregation, bv vasoconstriction 4) PGF2alpha: protects stomach lining by promoting mucous secretion and inhibiting acid secretion

Answer 107

Leukotrienes: associated with allergic reactions, anaphylactic shock, dermatitis, asthma --> promote bronchospasm, vasoconstriction, edema, inflammation Antileukotrienes are non-steroidal drugs that inhibit 5-lipoxygenase or act as receptor antagonists (e.g. Montelukast - Singulair) --> less effective than corticosteroids in treating asthma, more effective in treating mast cell disorders

Answer 108

1) NSAID: e.g. aspirin, ibuprofen, naproxen (OTC); Action - inhibit COX2 --> reduce levels of PGE2 --> reduce inflammation, fever; Side effects - also inhibits COX1 --> reduced PGE2 --> GI discomfort + increased risk ulcers 2) Selective NSAIDs: e.g. Vioxx, Celebrex; Action - selective for COX2 >> COX1; Side effects - no GI upset but TXAs >>PGI2 --> increased risk cardiovascular events --> drugs withdrawn 3) Baby aspirin: type of NSAID; Action - inhibits TXA2 production in platelets >> inhibits COX2 irreversibly via acetylation--> PGI2 >> TXA2 --> reduces ability to coagulate with fibrin --> used as anti-clotting to prevent strokes, MI; Side effects - asthma (shifts arachidonic acid towards leukotriene pathway) 4) Acetaminophen: e.g. Tylenol; Action - reduces prostaglandin synthesis but we do not know mechanism --> reduces inflammation, fever; Side effects - hepatotoxicity due to toxic metabolite NAPQI (antidote = NAC --> increases glutathione)

Answer 109

Glucocorticoids are a class of corticosteroids that inhibit phospholipase (production of arachidonic acid) Endogenous corticosteroids e.g. cortisol (produced in adrenal cortex); Synthetic corticosteroids e.g. prednisone, dexamethasone, hydrocortisone Functions: (1) downregulate production of COX2 --> reduce PGE2 --> reduce inflammation; (2) reduce activity of immune cells e.g. mast cells, macrophages --> reduces production of histamine --> anti-inflammation but pro-infection; (3) inhibits transcription of IL-2 in T cells Indications: treatment of allergies (e.g. asthma, which affects lower respiratory tract); treatment of autoimmune disorders (e.g. lupus, IBD, arthritis); prevention of transplant rejection Side effects: shuts down immune response --> infections and poor wound healing, muscle wasting + osteoporosis, Cushing symptoms (fat redistribution, moon face), weight gain and hyperglycemia, depression, peptic ulcers

Answer 110

Joseph Murray performed first successful organ transplant and received Nobel Prize in 1990

Answer 111

Biologics (antibodies) e.g. antithymocytes, daclizumab, muromonab 1) Mechanism: Specific Ab against lymphocyte cell surface receptors --> prevent lymphocyte activation --> immunosuppression 2) Uses: Induction therapy --> administered before other drugs e.g. calcineurin inhibitors; (daclizumab) used against acute rejection by competitively inhibiting IL-2 receptor; (muromonab + antithymocyte globulin) depleting agents that destroy CD3-bearing T cells 3) Side effects: inflammation, increased infections, acute hypersensitivity

Answer 112

Calcineurin inhibitors e.g. cyclosporine (older), tacrolimus (newer) 1) Mechanism: inhibits calcineurin phosphatase activity --> inhibits dephosphorylation/activation of NFAT --> blocks T cell production of IL-2 --> blocks T cell activation 2) Clinical uses: Prevention of transplant rejection, autoimmune disorders 3) Side effects: renal toxicity/kidney failure, toxicity enhanced by sirolimus; avoid drugs that affect p450 action

Answer 113

mTOR inhibitors e.g. sirolimus (Rapamycin), everolimus 1) Mechanism: Inhibits mTOR pathway --> inhibits IL-2 production --> blocks T cell activation 2) Clinical uses: prevention of transplant rejection, advanced renal cancer 3) Side effects: increase in cholesterol and TAGs, enhances renal toxicity from calcineurin inhibitors; avoid drugs that affect CYP3A4 or P-glycoprotein actions

Answer 114

Cytotoxic drugs e.g Azathioprine, Mycophenolate 1) Mechanism: Azathioprine contains purine analog and Mycophenolate inhibits IMP enzyme --> inhibits de novo purine biosynthesis --> inhibits DNA synthesis/transcription --> inhibits cell proliferation esp in B and T cells (which DO NOT have purine salvage pathway) 2) Clinical uses: preventing kidney rejection; autoimmune diseases 3) Side effects: (Azathioprine) bone marrow suppression; avoid allopurinol (inhibits xanthine oxidase, which metabolizes the drug); (Mycophenolate) GI upset, myelosuppression

Answer 115

Development: all mucosal surface cells come from stem cells in the crypt --> Wnt signaling tells the stem cells to migrate up, Notch signaling tells them how to differentiate Structure: Antigens pass by luminal side and mucosal microbiota --> outer mucus layer --> inner mucus layer --> epithelial layer with goblet and paneth cells and mucosal leukocytes

Answer 116

1) Mucus: viscous secretion with glycoproteins, permeable to some molecules that are conjugated to Igs 2) Paracellular pathway/ intracellular junctions: tight junctions (claudins + occludins), adherens junctions (cadherins), + desmosomes 3) Antimicrobial peptides: released upon stimulation by pathogens (cathelicidins, defensins)

Answer 117

1) Intraepithelial lymphocytes (IEL): small mononuclear T cells, both natural and induced; express NK receptors and integrin (to attach to cadherins on epithelial cells), signal to thymus to learn self/non-self 2) T cells: in lamina propria; predominately CD4; receive signals from IELs + epithelial cells and interact with microbiota to induce cytokine responses in mucosal T cells 3) B cells: antibodies in mucus (tears, saliva, etc); most common IgA and IgM --> produced by mucosal plasma cells --> Secreted out of cell, and brought back in when they bind to antigen 4) DCs: Phagocytose self-antigens e.g. food, commensal bacteria and migrate to lymph nodes to induce peripheral tolerance (this is how tregs are tolerant to gut bacteria); also imprint lymphocytes with homing receptors so they circulate back to intestine 5) Macrophages: continuously populate uninflamed intestinal mucosa, scavenge + phagocytose + repair tissue but do NOT present antigens

Answer 118

1) By M cells in FAE (follicle associated epithelium) 2) By DCs - antigens presented via costimulation (tells DCs these are pathogens) or w/out (tells DCs those are safe) 3) Igs in lumen bind to antigen --> taken up by immunoglobulin receptor

Answer 119

1) M cells deliver antigens to DCs 2) Lymphocytes activated by specialized DCs and acquire gut homing receptors e.g. CCR9 3) Lymphocytes go to mesenteric lymph nodes --> downregulate systemic homing receptor and induce proliferation of different cells 4) Lymphocytes go through blood stream to mucosa and home to effector site where local action takes place

Answer 120

1) Chronic disorder where immune system does not function properly 2) Most common is B cell defect (antibodies), then combined, then phagocytic system, then cellular, then complement system 3) Warning signs: multiple occurrences of pneumonia, ear/sinus infections; recurrent abscesses (central necrotic area surrounded by neutrophils), persistent thrush in mouth or fungal infection in skin

Answer 121

T-cell deficiency: 1) Examples: SCID (no T cells), ADA, PNP, DiGeorge (thymus atrophies --> low T cells, cleft palate, hypocalcemia), Ataxia telangectasia (IgA/IgE deficiency), Wiskott-Aldrich (low platelet count --> eczema, lymphoid malignancy - combined immunodeficiency) 2) Infections: fungal pneumonia or meningitis; herpes infections 3) Tests: CBC, B and T cell counts, HIV test, hypersensitivity skin tests

Answer 122

B-cell deficiency: 1) Examples: Burton's X-linked agammaglobulinemia (all Igs are low), IgA deficiency (most common, usually asymptomatic), Common Variable Immunodeficiency CVA (Ig low, most common symptomatic) 2) Infections: otitis media, streptococcus pneumonia, GI infections (pneumococcus or campylobacter), parasitic infections (Giardia), enterovirus infections 3) Tests: CBC, IG levels, B and T cell counts, vaccination titers (to see if there is a response)

Answer 123

Phagocytic system deficiency: 1) Examples: Chronic granulomatous disease (CGD - mutation in NADPH oxidase), Neutropenia, Chediak-Higashi (mutation in lysosomal trafficking protein --> decreased phagocytosis --> large abnormal granules, albinism + retardation) 2) Infections: bacterial infections (staphylococcus), burkholderia pneumonia, fungal infections (aspergillus) 3) Tests: CBC, peripheral smear, neutrophil oxidative bursts

Answer 124

Complement system deficiency: 1) Examples: Neisseria infections of late component of classical Complement pathway 2) Infections: bacterial (Neisseria --> meningitis or gonorrhea) 3) Tests: Total complement level (CH50) + individual component levels

Answer 125

First intention: healing occurs through direct union of skin edges by fibrous adhesion and epithelial regeneration, without granulation tissue --> small scar e.g. small wounds (surgical incisions) Second intention: healing occurs through granulation tissue formation and wound contraction by fibroblasts --> larger scar e.g. large wounds (abscesses, ulcers)