Immunology Lecture Objectives Flashcards

Question

What are Dendritic Cells? What are their effects? What are 2 major types?

Answer 1

* DCs are antigen-presenting cells (ex. Langerhans cells of skin) * Types: * **Myeloid dendritic cells (mDC) -** produce IL-12, express TLR2,4, Effective in antigen-presentation * **Plasmacytoid dendritic cells (pDC)** - express TLR7,9, express interferon-alpha * Some are immunosuppressive

Answer 2

1. **_Alternative Pathway_**: Spontaneous C3 activation and binding to pathogen surface 2. **_Mannose-Binding Lectin Pathway_**: Binding of MBL to mannose on pathogen surface 3. **_Classical Pathway_**: Antibody binds pathogen, complement binds Ab \*\*Pathways merge at activation of C3 → C3b (+C3a)

Answer 3

1. Opsonization (Tagging) of pathogen (phagocytosis → killing) 2. Assembly of MAC (Lysis → killing) 3. Release of chemotactic fragments: C3a, C4a, C5a (Recruitment of inflammatory cells)

Answer 4

Type I Interferons: IFN α and β

Answer 5

* Nucleic Acids: * Single-strand RNA * Double-strand RNA * CpG (dinucleotide)

Answer 6

1. Toll-like Receptors (TLR) - Membrane 2. RIG-like Receptors (RLR) - Cytoplasm

Answer 7

* _Pro-Inflammatory Cytokines:_ IL-1, TNF, IL-6 * Phagocytes, Dendritic Cells, Epithelial and Endothelial cells

Answer 8

* **Innate****:** always functional (in genome), immediately available, responds to _common features of classes_ of microbes, no specific memory, stimulates adaptive immunity * **Adaptive:** requires exposure to microbe/antigen, time lapse between exposure and defense, highly specific response, generates specific memory, focuses & potentiates innate response

Answer 9

* _TLR Activation_: Release pro-inflammatory cytokines that increase adaptive immunity * _IFN Activation_: activate adaptive immunity (via MHC induction, DC maturation, Th1 biasing, B-cell class switching)

Answer 10

* Major Histocompatibility complex is on antigen presenting cells - activates T-cell receptors on T-cells (both interact w/ immunogenic peptide) * Human Leukocyte Antigens (HLA) in humans

Answer 11

* **_Class I_****:**"endogenous" antigens, presents peptides from proteins synthesized within the cell * **_Class II_:**"exogenous" antigens present peptides from proteins endocytosed into the cell

Answer 12

* Binds cytosolic pathogens (endogenous) * Presented to CD8 T cells * Effect on presenting cell - cell death * Found on virally infected cells (all cells but RBCs)

Answer 13

* Binds "exogenous" antigens * Presented to **CD4** T Cells * Leads T Cells to activate to kill intravesicular bacteria and activate B cells * Found on cells that activate the immune system (B cells, Macrophages, antigen-presenting cells, epithelial cells of thymus, some T cells)

Answer 14

* **_Class I_** * Heterodimer composed of Heavy chain (α₁, α₂, α₃) + β₂-microglobulin (free-floating IG domain that binds to heavy chain) * 1 transmembrane region * Closed peptide binding groove (binds peptides 7-10AAs) * **_Class II_** * __Heterodimer composed of α chain and β chain * 2 transmembrane regions * Open peptide binding groove (binds 12-24 AA peptides)

Answer 15

* Peptides have anchor residues that bind to pockets in floor of peptide binding groove * Binding motifs (sequences) - strong for MHCI but weak for MHCII * Anchor residues vary more in class II * MHC molecules are unstable when a peptide is not bound * MHC-peptide complexes are **good indicators of infection**

Answer 16

1. Production of proteins in cytosol via a virus/pathogen 2. Proteolytic degradation of viral protein (via Ubiquitin and proteasome) 3. Transport of peptides from cytosol to ER via **TAP** (Transporter Associated with Antigen) which forms pore in the ER membrane 4. MHCI-peptide complex assembled in ER (w/ help of **Tapasin** - protein that bridges between TAP and MHCI and edits peptide so it is high affinity) 5. Surface expression of peptide-class I complexes

Answer 17

1. Uptake of extracellular proteins via endocytosis 2. Proteins processed in endosome/lysosome 3. Biosynthesis and transport of class II MHC molecules from ER to endosome (**Invariant Chain** binds to peptide binding groove of MHCII and facilitates txp from ER to endosome - preventing premature endosome binding, **CLIP** is portion in groove) 4. MHCII-peptide complex formation (**HLA-DM** is a class-II like molecule that associates w/ MHCII-CLIP, removes CLIP and edits peptide so only high affinity ones are presented, like **Tapasin**) 5. Expression of peptide-MHC complexes on cell surface

Answer 18

* Collect proteins, some from pathogens * Break down proteins into peptides * Shows MHC-peptide to T cells to **initiate adaptive immune response** * ex. Dendritic cells, Macrophages, B cells

Answer 19

* Most efficient antigen-presenting cells (initiate most immune responses) * 2 sites of origin: * _Myeloid Dendritic Cells (mDC):_ from bone marrow, produce IL-12, express TLR2,4, effective in antigen presentation * _Plasmacytoid Dendritic Cells (pDC)_: from spleen/periphery/lymphoid, express TLR 7,9, express high levels of interferon-alpha (for viral infections)

Answer 20

* Mature upon antigen encounter (via TLR ligation) * _Immature DCs_: want to capture antigens, express Fc receptors and mannose receptors, and have a short half life * _Mature DCs_: present antigens to T cells, do not express Fc or mannose receptors, activate costimulatory molecules, and half a long half life

Answer 21

* DCs ingest viral infected cells and display viral peptides bound to MHC class I molecules (MHCI normally has endogenous peptides) * Most viruses do not infect DCs directly and DCs initiate most immune responses * Cross presentation provides a mechanism by which naive CD8 T cells get activated * MHCI is also good at presenting exogenous antigens

Answer 22

* Contains genes involved in antigen processing and presentation (except invariant chain and β₂m) * MHC is **polygenic** (allows immune response to broad set of peptides) * Class I - 3 genes (HLA A, B, & C) * Class II - 3 or 4 genes (HLA-DR, DP, DQ) * Chromosome 6 * **Polymorphic** - many # of alleles (alt forms of same gene)

Answer 23

* Line the peptide-binding groove and determine peptide binding

Answer 24

* Naive T cells differentiate into memory and effector cells after first exposure to antigen * Effector T cells produce effector molecules like cytokines (IL-4, IFN-γ) * Memory T cells are long-lived - respond quickly if re-exposed to same antigen and rapidly produce more memory and effector cells

Answer 25

* **Costimulation -** T cells must receive 2 signals to be fully activated * _Signal 1_: Binding of a TCR to antigen-HLA complex on the dendritic cell, which induces activation and expansion of T cells * _Signal 2_: Costimulatory signal given by binding of **CD28** (on T-cell) to **B7** (on DC) * No T-Cell response w/o costimulation

Answer 26

* Malignant tumor cells expressing TRA (Tumor Restricted Antigen) but no costimulatory molecules * Naive CD8 T cells specific for TRA can't be activated w/o costimulation * Tumor grows progressively

Answer 27

* **CTLA-4** is upregulated on T cells after they are activated, it also binds to **B7** on APCs, preventing **CD28** from binding and shutting down the T cell response * Can cause a signaling block (signal from CTLA-4 cancels signal from CD28) or it can block the binding of CD28 to B7 * Mice w/o CTLA-4 die days after birth due to massive T cell infiltration

Answer 28

* Strategy to block the function of autoreactive T cells & **prevent autoimmunity** * Inject soluble **CTLA-4-Ig**, which binds to **B7** and prevents T cell from receiving costimulation

Answer 29

* **YERVOY (Iplimumab)** is a monoclonal antibody that **binds CTLA-4**, and prevents it from binding to **B7** (prevents costimulatory blockade) * This enhances tumor immunity * Anti-tumor T cells can stay active and clear the tumor * Side effect: pt experiences autoimmunity

Answer 30

* TCR is a heterodimer w/ α and β chain (each have transmembrane domains) with 2 intracellular ζ proteins w/ **ITAMs** (Immunoreceptor Tyrosine Based Activation Motif) * 2 associated CD3 molecules on either side (both heterodimers) * TCR complex and coreceptors cluster in a **lipid raft** upon antigen recognition * **LCK (Lymphocyte specific protein tyrosine motif)** phosphorylates the tyrosines in **ITAMs** on zeta chains * **ZAP-70** binds to phosphorylated ITAM, becomes phosphorylated, and phosphorylates adaptor protein **LAT** (Linker for activation of T cells)

Answer 31

* **_CD8_ -** Killer T cells (cytotoxic), recognizes complex of viral peptide w/ **MHCI** and kills infected cell directly * **_CD4_ -** * **T_H1 -** recognizes complex of bacterial peptide w/ **MHCII** and activates macrophage * **Helper T** - recognizes complex of antigenic peptide w/ **MHCII** and activates B cell * **_Other (Natural Killer T Cells, NKT)_** **-** recognize H2-M3, response is quick (a few days) but don't respond any faster after 2nd infection

Answer 32

* **Tregs** suppress immune function of other T cells * They express transcription factor **FOXP3**, which inhibits T-cell activation and inhibits T-cell effector functions * Multiple Mechanisms: * Produce Inhibitory cytokines * Direct Cytolysis of effector T cells * Targeting Dendritic Cells * Metabolic disruption (suck up IL2, necessary for growth of other T cells)

Answer 33

* Too strong - T cell is activated and causes **autoimmunity** * Too weak - **immune deficiency** * Only intermediate affinity cells will survive pos and ne selection

Answer 34

* _Positive Selection_: picks out the T cells w/ useful TCRs (5% of thymocytes survive) * expression of MHC in thymus is required for pos selection * _Negative Selection_: eliminates the T cells w/ dangerous TCRs (30% positively selected T cells survive) * T cell recognition of self peptide-MHC is necessary for pos and neg selection * self-peptides = host's proteins

Answer 35

* **_Tolerance_** **-** making sure your immune system doesn't attack your own body * **_Central Tolerance_ -** removal of self reactive clones (in thymus and bone marrow) * **_Peripheral Tolerance_ -** ignorance (hide your self antigens), Anergy (shut down the self-reactive clones), Suppression (use other molecules, proteins, or cells to keep self-reactive clones in check)

Answer 36

* Thymic function decreases with age (produce fewer T cells) * Older people depend on the T-cells they already have (fewer naive T cells) * Some lymphocytes expand dramatically

Answer 37

* 2 identical heavy chains bound by 2 disulfide bonds * 2 identical light chains bound to heavy chain by 1 disulfide bond * Each chain made up of a **variable** and **constant** region * **Variable Region** = 7 domains (framework and specificity) * **Constant Region** = 4 domains on heavy chain, 1 region on light chain

Answer 38

* _Combinations between heavy chain and 2 light chains_: IGL-λ on Chr 22 and IGL-κ on Chr 2, IGH on Chr 14q32.2 * _Combinatorial V(D)J joining - V(D)J somatic recombination_: \> 58k heavy chains, 200 κ chains, and 128 λ chains * _Junctional Diversity_: Recombination Signal Sequences **(RSSs)** are junctions between gene segments * _Alternative RNA Splicing_ * _Class Switch Recombination_: Excised DNA fragment changes gene to create different Ig class * _Somatic Hypermutation_ * _Genetic Variation_: paternal gene have fewer C and V gene segments

Answer 39

* **_Bone Marrow_:** Stem cell → pro-B cell → Large pre-B cell (secretes pre-B cell receptor) → Small pre-B cell (µ chain) → immature pre-B cell (displays Ig) * **_Blood_:** Antigen activated B cell migrates to blood

Answer 40

* **_Blood_:** Antigen activated B cell migrates to germinal center in spleen & lymph nodes * **_Dark Zone_****:** Clonal expansion and Somatic Hypermutation * **_Light Zone_:** Those w/ improved affinity are selected, others die via apoptosis. Selected B-cells class-switch * **_Blood_:** Form plasma cells (secrete IgG, IgA, IgM) and Memory B Cells

Answer 41

* **_Primary_:** more IgM than IgG, short duration, low antibody affinity, low Ig generated * **_Secondary_****:** IgG \> IgM, high antibody affinity, long duration, less of a time lag

Answer 42

* Generated from a clone derived from a single B-cell * Specific, only reacts w/ 1 epitope * _Production_: * antigen injected into mouse, spleen cells isolated & fused w/ myeloma cells * Fused cells expand → inject in mouse * _Side Effects_: allergic reactions, fever, chills, headache, NVD, low BP, rash, weakness

Answer 43

* ELISA * Coat plate w/ a specific Ab, add Ag to each well * Add secondary "detecting antibody" (w/ biotin) that is specific for same antigen @ a different epitope * Add **Horseradish peroxidase** and **Streptavadin** * Add **TMB** - generates fluorescence if sample contains the antigen

Answer 44

* Destruction of extracellular pathogens and prevention of spread of intracellular infections by the production of antibodies by **B Cells** * 4 ways: * Neutralization * Opsonization * ADCC (antibody dependent cellular cytotoxicity) * Complement Activation

Answer 45

* **Negative Selection** * _Central tolerance_ - autoreactive cells eliminated in central lymphoid organ (bone marrow) * _Peripheral tolerance_ - this process occurs outside of bone marrow

Answer 46

* _T-Dependent_: Thymus-dependent * B cell responses to **protein****s** that need T cell help * _T-Independent_: Thymus-independent * B cell responses to **microbial constitutes (ex. macterial polysaccharides)** that do not need T cell help

Answer 47

1. _Crosslinking of the BCR_ - phosphorylation of multiple receptors 2. _Complement_ - mediates B cell activation, mediated by MHC Class II antigen presentation

Answer 48

* **_B1 B cells_**: make IgM that normally circulates in the blood called **natural antibodies** (they are highly cross-reactive, bind w/ low-affinity to antigens), made from fetal liver stem cells, *1^st line of defense* * **_Follicular:_** produce most antibodies that mediate adaptive immune response (\>70%) * **_Marginal Zone_:** reside in marginal sinus of white pulp in the spleen, function unclear, BCR diversity, contribute to adaptive immune response * Marginal and B1 are *T-independent,* Follicular is *T-dependent*

Answer 49

* 2nd phase of immune response occurs when activated B cells traffic into lymphoid follicles and form germinal centers * _Outcomes_: * *Affinity Maturation* (somatic hypermutation of variable region to form high affinity antibodies) * *Isotype Switching* (different kinds or isotypes of antibodies) * *Generation of memory B cells* (bigger, faster, better B cell response second time around) * *Long-lived plasma cell differentiation*

Answer 50

* Selection of the high affinity antibodies * **AID** - Activation Induced Deaminase (dangerous) * Mutator turned on in B cells by CD40 ligation * Mutate V regions * Antigen is limiting so it favors high-affinity B cells

Answer 51

* Class switch recombination leads to the production of antibodies w/ heavy chains of different classes * AID is also necessary, requiring CD40 ligation

Answer 52

* Stimulated by bacterial interaction w/ mast cells, relsease histamine and cytokines * **Vasodilation** * Neutrophil emigration and phagocytosis, if it continues \> 48 h: mononuclear cell emigration & phagocytosis * Resolves w/o any lasting tissue damage, short duration

Answer 53

* innate vs. adaptive immunity * _innate_ - germline encoded, present before infection (Toll-like Rs, C-type lectin Rs, Nod-like Rs) → inflammatory cytokines * _adaptive_ - after exposure to microbes * cytokines, vasoactive amines, and eicosanoids * Mast Cells: activation of IgE receptors → **Cytokines, degranulation, eicosanoids (leukotrienes, prostaglandins)** * changes in microvascular permeability * neutrophil adhesion, migration, and diapedesis * phagocytosis

Answer 54

* Phospholipids form Arachidonic acid via *phospholipases* * inhibited by **steroids** * Arachidonic acid forms: * **Leukotrienes** via *5-lipoxygenase* (chemotaxis) * **inhibited by **Lipox. Inhib** * **Prostaglandins** via *cyclo-oxygenase* (vasodilation) * **inhibited by **aspirin, indomethacin (NSAIDs)**

Answer 55

* **Neutrophils/Jeuvenile:** *Acute* bacterial infections and sepsis * **Eosinophils:** Parasitic infections * **Lymphocytes (B & T)****:** Viral infections, *chronic* bacterial infections

Answer 56

* Endothelial cells retract (due to injury), become leaky * Histamine leakage from post-capillary venules * do not contain VSM, but still constrict due to histamine treatment

Answer 57

* **Exudation** = higher protein concentration, and higher specific gravity due to increased hydrostatic pressure (removal of permeable barrier) * **Transudate** (Edema) - caused by increased hydrostatic pressure, or decreased osmotic P (lower specific gravity, lower protein concentration)

Answer 58

* Lack of NADH/NADPH activity * inhedited, usually in males * infections of skin, lymph nodes, lung, bone, etc. * Granulomatous reactions w/ lipid filled histiocytes and abscesses * Lack of *NADH oxidase*

Answer 59

* **_Vasodilation_****:** prostaglandins, NO, histamine * **_Increased vascular permeability_:** histamine, seratonin, C3a, C5a, bradykinin, leukotrienes (C4, D4, E4), PAF, Substance P * **_Chemotaxis & Leukocyte Activation_:** TNF, IL-1, C3a, C5a, leukotriene B4, bacterial products, cytokines, histamine * **_Fever_:** IL-1, TNF, prostaglandins * **_Pain_:** prostaglandins, bradykinin * **_Tissue Damage_:** neutrophil/macrophage lysosomal enzymes, oxygen metabolites, NO

Answer 60

* Irreversible tissue changes initiated by: * Parenchymal cell death & tissue destruction * Growth of new blood vessels (angiogenesis) * Production of connective tissue (fibroblast invasion) * ex. Chronic cholecystitis - interstitium expanded

Answer 61

* Acute & chronic process * Encapsulated accumulation of pus (usually neutrophils) with tissue destruction and formation of a new cavity

Answer 62

* Accumulation of pus (usually neutrophils) in an existing body cavity (e.g. pleural space, pericardial sac)

Answer 63

* Inflammation and hypoxia * Chemokines bind to endothelial receptors to affect endothelial cell migration and angiogenesis * also act indirectly by secreting VEGF (pro-angiogenic) * tyrosine kinase activity

Answer 64

* some macrophages become **multi-nucleated giant cells** * contains **epithelioid macrophage**, lymphocytes, foreign body or necrotic center * Surrounded by mononuclear cells that look like epithelium * Ex. **Tuberculosis**

Answer 65

* _Pleitropy_ - 1 cytokine → different effects on many cell types or on 1 cell type * ex. **IL-1** (synthesis of acute phase proteins in hepatocytes, osteoclast bone resorption, increased adhesion of neutrophils) * _Redundant_ - different cytokines have same or overlapping effects

Answer 66

**_Cytokines_:** * Soluble proteins, ≥ 18 kD * Signal through protein kinases * Stimulate growth, differentiation, defenseive immune system, local & systemic manifestions of infection/disease **_Chemokines_:** * Smaller (8-10 kD) * Signal through G-protein coupled receptor * Chemotactic, attract inflammatory and effector cells

Answer 67

* Antiviral protection (innate defense) * 13 INF-αs, INF-β, INF-ε, INF-ω, INF-κ (variable functions) * Chr. 9 * Uses **Jak-STAT** signal pathway * _Mechanisms_: direct antiviral effect, interact w/ innate & adaptive immune system, apoptosis * Downside - may promote autoimmune response in Lupus pt

Answer 68

* **Jak** (Janus Kinases) - specific for leukocytes * mediates phosphorylation of cytokine receptors * Mediates phosphorylation and dimerization of STATs * **STATS** (Signal Transducer and Activator of Transcription) - latent transcription factors * Translocated to nucleus, binds sequences in promoter and facilitates transcription * Used by **Type I Interferons**

Answer 69

* IL-1 & TNF-α (Also IL-6) * Produced by many cell types (monocytes and macrophages) * Effects depend on level & persistence of production: * _Low_: promotes local inflammation and stimulates body's response to damage/infection * _High_: shock, coagulation, death * _Chronic_: weight loss (cachexia), loss of CT and bone

Answer 70

* **Th1 produces INF-γ** * ****Macrophage activation, IgG production, autoimmune diseases * **Th2 produces IL-4, IL-5, IL-13** * Mast cell, eosinophil activation, IgE production * Allergic diseases

Answer 71

**IL-10** inhibits immune responses (except when it activates)

Answer 72

* **IL-2** is a key cytokine for the proliferation of T cells * Cytokines stimulate production of different kinds of T cells (they are produced by these different Th cells and then feedback) * Cytokines are also used in **Ig Heavy Chain Isotype Switching** * Released from helper T cell to stimulate Activated B cell

Answer 73

* Small proteins (8-10 kDa) * Signals for **chemotaxis** and "homing" via gradients of chemokine concentration * Attract circulating lymphocytes into secondary lymphoid organs * Modulate **cell adhesion** * Signal through receptors on target cells * Receptors are GPCRs

Answer 74

* **_Chemokines_** * _Old_: (*functional*) IL-8, eotaxin, Monocyte Inhibitory Factor (MIF) * _New:_ (*Structural*) CCLx, CXCLx etc. * **_Chemokine Receptors_** * systematic - add R (CCLx receptor = CCRx)

Answer 75

* **CCR5 facilitates HIV infection** * CD4 is main HIV receptor on T cells and other cells * Either of 2 chemokine receptors, **CXCR4** (on T cells) and **CCR5** (on macrophages & T cells) permit productive infection * People w/ mutated CCR5 are resistant to HIV

Answer 76

* **Pharmacodynamics** - the *drug's effect on the body* (integration of molecular actions into an effect on the whole organism) * **Pharmacokinetics** - the *body's effect on the drug* (determines therapeutic efficacy, duration of action, half-life)

Answer 77

* G Protein Coupled Receptors * Ion Channels (ex. Ca²⁺ channels tasrgeted by antagonists for vasodilation, angina, arrhythmias, HTN) * Transporter pumps (ex. Omeprazole, Proton Pump inhibitors) * Enzymes that produce bioactive molecules (ex. aspirin inhibits cyclooxygenase) * Receptor Tyrosine Kinsase (ex. receptors for endogenous ligands: EGF, PDGF, insulin, VEGF and others targeted by antibodies that block ligand binding) * Non-human drug targets

Answer 78

* **IL-1** (RA) * **TNF-α** * *Etanercept* - for RA * *Infliximab* - Crohn's, RA * **T-Cell Activation** - *Abatacept -* RA * **BAFF** - *Belimumab* - Lupus Other clinical uses: Psoriasis, IBD, Ulcerative Colitis

Answer 79

* "Disease Modifying Anti-Rheumatoid Drugs" * Leflunomide or Methotrexate * Prevent proliferation of lymphocytes, reduce inflammatory process * Treats Rheumatoid Arthritis

Answer 80

* Targets TNF-α * For RA * It is derived from a receptor, soluble portion of TNF-α receptor is fused to synthetic IgG heavy chain * Binds TNF-α with high affinity and neutralizes its biologic activity * Administered subcutaneously, weekly * t_1/2 = 115 h * As effective as other drugs like MTX, but combination is more effective

Answer 81

* Targets TNF-α to treat **Crohn's and RA** * Reduces blood levels of TNF-α and may dislodge TNF-α bound to cells * Given by IV over 2 hr period every 2 weeks initially (3x), then every 8 weeks (some patients require 6-7 weeks) * Chimeric antibody (from mouse) - variable regions from mouse

Answer 82

* *Anakinra* treats RA * Endogenous protein, made in lab * IL-1 receptor antagonist * Blocks cellular effects of IL-1 * Administered by daily subcutaneous injection (injection site rxns common) - not widely used * Can be given w/ MTX but not TNF agents

Answer 83

* Targets **T-cell activation** to treat **RA** * Impacts costimulation of T cell by APC * CTLA-4 is upregulated on T cells after T cell is activated, it also binds to B7 (like CD28 on T cell does) * Prevents binding of CD28 * shuts down T cell response * *Abatacept* = CTLA-4-Ig * Given IV at 2 wks and 4 wks then monthly, should not be given w/ other biologic agents

Answer 84

* Targets **BAFF** (BLyS) to treat **Lupus** * Neutalizes BAFF to limit B-cell proliferation and survival

Answer 85

* Injection site reactions * Infusion reactions (fever, rash, dyspnea, low BP) * Cytopenias * Infections (sepsis & TB) * Malignancies, lymphomas * Hepatotoxicity (infliximab) * **EXPENSIVE**

Answer 86

* Active infection * If TB+, treat latent TB first * Pre-existing demyelinating disorders * Pregnancy category B

Answer 87

* Enzyme that adds terminal sugars to core glycan on RBC * Gene is on Chromosome 9 * 3 alleles: * A - adds terminal N-acetylgalactosamine * B - adds terminal galactose * O - no activity * A and B genes are co-dominant

Answer 88

* IgMs * Preformed antibodies that are opposite to a person's blood type * ex. person w/ Type A blood has Anti-B antibodies even w/o exposure to B antigen

Answer 89

* No h → H antigen conversion * Appears as Type O on routine typing (no A & B antigens, produces anti-A and anti-B) * Also **produces anti-H** * Reacts w/ Type O RBCs, agglutination

Answer 90

* **Donor and Recipient blood types should be identical** * In emergencies, O, Rh- erythrocytes can be used as a "universal donor" * Donor antigens should not bind recipient antibodies * Donor antibodies should not bind recipient antigens

Answer 91

Donor red cells must lack antigens which bind recipient's antibodies

Answer 92

Donor plasma must lack antibodies which bind recipient's red cells

Answer 93

* Intravascular lysis (antibody coated RBCs, complement lysis) * Macrophage in liver and spleen phagocytosis of Ab and complement coated RBC * Hb is liberated - toxic for kidneys * Cytokines released * Disseminated Intravascular Coagulation (DIC) possible - localized clotting cuts off blood supply to organs, clotting factors used up, so bleed out even w/ DIC

Answer 94

* Non-glycosylated cell surface protein on RBC membrane * **Rh₀D** gene (if you have this gene, you are Rh+) * Rh- (deletion in gene) - **will make antibodies (IgG) if exposed** * IgG can cross the placenta * Doesn't activate complement well * Opsonizes RBCs and facilitates phagocytosis into the spleen

Answer 95

* Important in fetus - Erythroblastosis fetalis, Hemolytic disease of newborns, Hydrops fetalis * Rh- mothers sensitized by Rh+ fetus * Rh + Fetal RBCs enter circulation during birth of 1st child * Subsequent Rh+ babies - hemolysis by maternal antibodies (IgG) that cross placenta * Treated w/ **Rhogam** (anti-Rh₀D antibody) during 3rd trimester and within 72 h of birth

Answer 96

* Anti-Rh₀D Antibody * Given within 3rd trimester and within 72 hours of birth to a Rh- mother * Destroy fetal RBCs before it can initiate immune response * Ab-mediated immune response * Cytokines interrupt antigen specific B cells turning into plasma cells * ABO incompatibility can have partial protective effect

Answer 97

* _Anti ABO_- abundant Ag, **IgM**, activate complement well, destroy RBCs in blood stream, *intravascular* hemolysis * _Anti Rh_- sparse Ag, **IgG**, doesn't activate complement well, Ab coated RBC destroyed by macrophage in liver and spleen, *extravascular* hemolysis

Answer 98

Detects cell-bound antibodies (used to test patient's RBC for bound IgG, diagnose autoimmune hemolytic anemia)

Answer 99

Detects anti-red-cell IgG in plasma (ex. Detects sensitization of an Rh- mother to Rh+ antigen, check maternal serum)

Answer 100

* Malignancy of antibody-producing plasma cells * Usually IgG (60%), or IgA (25%), rarely IgE * Detected by narrow "M-spike" of antibodies in γ band of serum electrophoresis (doesn't show which isotype is elevated) * Polyclonal = multiple proteins produced, broader spike * Immunofixation determines which isotype is elevated

Answer 101

1. Platelet adhesion (via vWF and platelet receptor GPIb/IX/V) 2. Shape change 3. Granule release (ADP, TXA₂) 4. Recruitment 5. Aggregation (hemostatic plug) - *via binding of fibrinogen to 2 fibrinogen receptors* **(GPIIb/IIIa, αIIbβ3)** *on different platelets* ** * stimulated by Serotonin, Epi, PAF, Thrombin, ADP, TXA₂, Vasopressin, and Collagen)

Answer 102

* Produced in megakaryocytes in bone marrow * **Normal = 150k-300k** (*Thrombocytopenia* - too few, *Thrombocytosis* - too many) * 7-10 d lifespan * Larger platelets are **prothrombotic** and **younger** (size corresponds w/ reactivity) * Activated by **ADP**

Answer 103

* W/ injury, adheres to exposed collagen and facilitates platelet tethering to subendothelial BM * binds to receptor on platelet **(GPIb/IX/V)** * Largest **circulating** multimer, bound to **FVIII** * Involved in 1° and 2° hemostasis

Answer 104

* Low (\< 10 - 20 k) result in **petechiae** (1-3 mm, red/purple, do not blanche) * Purpura = 3mm-1cm * Ecchymoses = \>1 cm

Answer 105

* Formation of platelet "sealant" of **cross-linked fibrin** * Formation of **fibrin** from **fibrinogen**

Answer 106

* **I = Fibrinogen/Fibrin** (stabilizes platelet plug) * **II = Prothrombin/thrombin** (activates fibrinogen to fibrin) * **XIII = Tissue transglutaminase** (cross-links fibrin to stabilize clot)

Answer 107

1. **Extrinsic Pathway:** Factor VII, Tissue Factor * Vessel wall injury increases TF expression by EC * Circulating VII binds TF & is activated (Ca²⁺-dependent) * IX recruited to complex & activated 2. **Intrinsic Pathway:** Factor XII, XI, IX * IXa activates X 3. **Common Pathway:** Factor X, II (Prothrombin) * Xa activates Prothrombin (II), Thrombin (IIa) activates fibrinogen to form fibrin * **Amplification** - Thrombin activates more IX and VIII

Answer 108

* Transmembrane protein * **Not normally accessible** (synthesized and expressed by endothelial cells and monocytes) * Expression triggers first step in coagulation (Extrinsic Pathway) * **_Ebola_** - causes monocytes to make excess TF, consumes clotting factors and patients bleed, *bleeding diapidisis*

Answer 109

1. Activated endothelial cells express additional **TF** (triggers extrinsic pathway) 2. Circulating **Factor VII** binds **TF** and is activated **(VIIa) -** Ca²⁺ dependent * Recruits & activates Factor **IX** 3. Initiation of coagulation (Common Pathway) * **IXa** activates **X**, **Xa** activates **Prothrombin (II)** to **Thrombin (IIa)** * **Thrombin** cleaves **Fibrinogen** to **Fibrin** 4. Amplification #1 - **Thrombin** activates more **IX** and **VIII** to accelerate **Factor** **X** activation 5. Amplification #2 - **Thrombin** activates **Factor V** to accelerate **Prothrombin** activation

Answer 110

* Anti-hemophilic factor (soluble cofactor) * Activated by thrombin * Circulates in plasma in complex w/ vWF, which stabilizes it and extends half-life of VIII from 8 min to 8 hrs * **No enzymatic activity**, it is an **accelerant**/catalyst for **Factor IXa**

Answer 111

* soluble co-factor, **no enzymatic activity**, **accelerant/catalyst** for Factor Xa * Xa-Va complex converts prothrombin to thrombin 300,000x faster than free factor Xa

Answer 112

1. Tissue Factor :: Factor **VIIa** :: **IXa** ≈ Factor **X** 2. Factor **IXa** :: VIIa ≈ Factor **X** 3. Factor **Xa** :: Va ≈ Factor **II** (Prothrombin)

Answer 113

Procoagulant: **II, VII, IX, X** Anticoagulant: **Proteins C, S, Z** (II, VII, IX, X, and Protein C are *Serine Proteases*)

Answer 114

* Factors have glutamate-rich N-terminus * Carboxylation of GLU residues required for activation * Carboxylation is **Vitamin-K dependent** * **Warfarin** inhibits recycling of Vitamin K from epoxide to hydroquinone form * blocks vitamin K dependent *reductases*

Answer 115

1. Contact activation - **Factor XII** activated on contact w/ neg charged surface (PO₄^2-) 2. **HMKG** is required for **F XI** to bind to neg surface 3. **XIa** binds and activates **IX** 4. **Thrombin** pos feedback - activation of **XI** contributes to propagation of clot

Answer 116

* XIIIa cross-links fibrin chains * Activated by thrombin * Deficiency is rare but can cause significant bleeding

Answer 117

* Anti-coagulant * high affinity receptor for **thrombin** **(II)** - sink for excess thrombin * TM neutralizes thrombin's procoagulant activity * Co-factor for thrombin-dependent activation of **Protein C**

Answer 118

* **Vitamin K dependent** **Anticoagulants** (endogenous) * Inhibitors of pro-coagulant system * Activated by thrombin-thrombomodulin * C = enzymatic, S = nonenzymatic cofactor * APC (activated Protein C) regulates **Factor V** activity

Answer 119

* Avoids excess lymphocyte activation and tissue damage during normal immune responses to pathogens and infections * Prevents inappropriate immune responses and reactions specific for self-antigens (self-tolerance) * Failure of tolerance control mechanisms leads to *autoimmunity*

Answer 120

* **Breakdown in self tolerance** * Normal T-cell activation (normal response against pathogens) * CD4, CD8 T cells, B cells, DCs, macrophages * No Regulatory cells (reg T cells, reg B cells, reg DCs)

Answer 121

* **Central Tolerance** - selection of B and T cells * Apoptosis, Change in receptors (B cells only) * Develop into regulatory T lymphocytes (CD4+ T cells only) * **FoxP3** - inhibit T cell activation and inhibit T cell effector functions * **Peripheral Tolerance** - Anergy, Apoptosis, Suppression

Answer 122

* _Phenotype_: CD4+, IL-2 (CD25) high, IL-7 (CD127) low, Foxp3+, GITR+ * _Significance_: FoxP3 mutations - autoimmune disease (**IPEX**) - manifests with T1 diabetes, watery diarrhea, failure to thrive, dermatitis, death in first 2 y * _Mechanisms_: Inhibitory cytokines, Cytolysis, metabolic disruption, Targeting Dendritic cells * _Therapeutic Potential_: induction or activation of Treg in immune disease

Answer 123

* Autoimmune disease w/ mutation in **AIRE (autoimmune regulator)** in the **APS gene** * Parathyroid gland failure, impacts Ca metabolism (teeth & nails), susceptibility to candida yeast infection, Addison's disease (adrenal failure) * **w/o AIRE, self-reactive T cells won't be deleted**

Answer 124

* Environment influences autoimmune diseases * ex. RA & smoking - PAD turned on and citrillunated proteins formed (arginine → citrulline) * Cells die from toxicants and relsease self-antigens * **Genetics matter** * most human autoimmune disesase are polygenic (multiple systems affected) * **MHC genes** - genetic association

Answer 125

* **_Molecular Mimicry_:** infection → immune response against pathogen that looks like self → activated T cells and antibodies from B cells cross-react w/ self-antigens * **_By-Stander Activation_:** Infection provides environment that promotes lymphocyte activation * Infection → disruption of cell or tissue barrier → release of sequestered self-antigen → activation of non-tolerized cells → autoimmunity

Answer 126

* Some autoimmune diseases are prevented by infection * Excess prevention of early childhood exposure to dirt and pathogens can stunt the development of the immune system leading to increased autoimmunity in developed world

Answer 127

* _Autologous_ = from self * _Syngeneic_ = from identical twin * _Allogenic_ = from another human (not twin) * _Xanogeneic_ = one species to another (usually from pig)

Answer 128

* **MHC** (Major Histocompatibility Complex) encodes the antigens that dominate transplant rejection * comprised of many genes, polymorphic * MHC encodes MHCI and MHCII (**HLA** is human MHC) * MHCI = HLA-A, HLA-B, HLA-C (1 from each parent) * MHCII = HLA-DQ, HLA-DP (1 from each parent), HLA-DR (1 or 2 from each parent) * MHC molecules look similar despite being polymorphic * **positive selection** - allows T cells w/ high affinity for self MHC to live, these may recognize donor as MHC-foreign

Answer 129

* **_Direct Recognition_:** * Transplanted tissue contains DCs, which migrate out of graft to lymph node, and present alloantigens to host T cells (CTLs) - recognize and attack cells of graft, *DCs provide costimulation* * **_Indirect Recognition_:** * Donor MHC are ingested by recipient DCs and processed and presented by *self MHC* to T cell * CTLs would be specific for alloantigens bound to self-MHCI and cannot recognize or kill donor graft * Subsequent rejection mediated by **CD4 T cells** (*Abs contribute to rejection)*

Answer 130

1. **Hyperacute** (Within minutes, mediated by Abs specific for Ag on graft, Natural IgM Abs specific for blood group antigens ), Leads to complement activation, endothelial damage, inflammation and thrombosis 2. **Acute** (days-weeks, mediated by T cells and Tb specific for alloantigens, T cells may be CTLs that destroy graph or CD4 T cells tahht secrete cytokines), leads to parenchymal cell damage, interstitial inflammation, endothelialitis * Current target of immunosuppressive therapy 3. **Chronic** (months-years, fibrosis of graft & narrowing of graft blood vessels, T cells secrete cytokines that stimulate proliferation of fibroblasts and VSM in graft, Abs also contribute), principal cause of graft failure

Answer 131

* **Immunosuppression** (drugs inhibit T cell activation and effector functions), but drugs are non-specific and patients are susceptible to infections & have increased incidence of cancer * Matching donor & recipient HLA alleles by tissue typing decreases rejection (but many patients can't wait for a match, and immunosuppression is fairly successful)

Answer 132

* HSCs are injected into a recipient - restore bone marrow damaged by irradiation and chemo to treat leukemia * _Issues_: have to ablate bone marrow to make room, causes deficiency of blood cells, immune system reacts strongly against allogenic HSCs, **requires** **HLA typing** * **_GvHD_** - allogenic T cells attack recipient's tissues * usually not life-threatening in most transplants if host reacts back * For marrow transplants, can be life-threatening if host lacks functional immune system * If whole blood is tranfused to immuno-incompetent patients, it is irradiated to kill T cells

Answer 133

* Immediate (min) * Allergy (Atopy) * _Mechanism_: **Th₂** activation **(secretes IL-4)** → **IgE** formation (class-switch) * **IgE** binds **Fc (FcεRI)** receptor on mast cells & basophils * secondary exposure - cross link pre-formed surface IgEs & release of inflammatory mediators by mast cells, eosinophils, basophils * Ex. Hay fever, food allergies, asthma, allergic rxn to penicillin, expulsion of worms & insect infections

Answer 134

* Defend against parasitic worms & protozoa * Products attract eosinophils * Degranulation occurs w/ cross-linking of IgE by antigen (must be multivalent)

Answer 135

* _Primary_ (stored) * Histamine & serotonin (vascular permeability, smooth muscle contraction) * Eosinophil & Neutrophil chemotaxis mediators * Protease (mucus secretion, CT degradation) *tissue damage* * _Secondary_ (synthesized) * Leukotrienes (vascular permeability, **sm contraction**) * Prostaglandins (**vasodilation**, sm contraction, platelet activation) * Bradykinin (vascular permeability, sm contraction, pn) * Cytokines (recruit immune cells, i**nflammation**, IL-4)

Answer 136

* Small amounts of allergen are introduced by intradermal injection or superficial scratching * Local mast cells will degranulate & cause wheal (edema) & flare (redness due to vasodilation)

Answer 137

* **Radioallergosorbent test** - detects level of IgE * Allergens coupled to beads, serum added (IgE binds beads) * Labeled anti-IgE added & measured to quantify IgE

Answer 138

* Allergy shots or immunotherapy * Small amounts of Ag over time induces **Tregs** * ↑ IL10 causing Th2 ↓, and IgE decreases * Blocking antibody * IgG increases, binds to allergen before attaches bound IgE * 90% efficacy for bee stings, more variable for respiratory

Answer 139

* **Insufficient Th1 Stimulation** due to Minimal contact w/ viruses and bacteria * **Overactive Th2 Response** due to unbalanced immune system

Answer 140

* Antibody-mediated cytotoxicity * Hours * IgM or IgG dependent (Ab binds to antigens on cell surfaces) * _3 main mechanisms_: * Opsonization then phagocytosis by macrophage, neutrophils * Activates classical complement pathway (MAC attack) * ADCC - Antibody dependent cell-mediated cytoxicity (NK cells) * Ex. transfusion rxn, hemolytic disease of newborns, autoimmune disease, drug-induced hemolytic anemia

Answer 141

* 4-12 hours * Immune complex disease (caused by circulating Ag-Ab complexes which lodge in small vessels and filtering organs) * **IgG** is Ab in compled (lesser IgM) * Larger complexes cleared by phagocytes * Smaller complexes accumulate and deposited in blood vessels * **C3a and C5a** (anaphylatoxins) induce mast cell degranulatino, inflammatory mediators, neutrophil recruitment, release lytic enzymes, activate platelets) * **Arthus Reaction** - 4-12 h, local deposition of Ab/Ag complex * Localized (*farmer's lung, insect bites)* or systemic (*serum sickness, Lupus)*

Answer 142

* **48-72 hours** - delayed type hypersensitivity (DTH) * Mediated by antigen-specific TH1 cells (recruit macrophages, granuloma formation, activate CTL, cell killing) * Ab-independent * Skin test - Ag introduced intradermally (ex. Tb test - rxn indicates prior exposure) * ex. Allergy to metal salts or other small reactive chemicals (haptens) - contact dermatitis to coins, jewelry, nickel * ex. Transplanted organ rejection * ex. Skin contact rxn to poison ivy

Answer 143

* Synthesized from **decarboxylation of Histidine** (in mast cells, basophils, enterochromaffin-like cells, histaminergic neurons) * Sequestered and bound in cytoplasmic granules of _mast cells_ and _basophils_ * Histamine is produced and stored in the vesicles of _ECL cells_ of the gastric mucosa and _histaminergic neurons_ of the CNS

Answer 144

* _Immunological Release_: antigens/allergens bind to IgE antibodies on the surface of pre-sensitized mast cells and basophils causing aggregation of high-affinity IgE receptors (FcεRI) thus triggering degranulation * _Mast cell injury/damage_: can effect *rapid* degranulation and *local* release of histamine * _Endocrine or Neuronal Stimulation_: endocrine stimulation of ECL cells or neuronal stimulatino of histaminiergic neurons can trigger rapid histamine exocytosis * _Chemical displacement_: many compounds (including therapeutic agents) can stimulate the release of histamine from mast cells *without prior sensitization* (organic bases or basic peptides - ex. morphine, tubocuranine, antibiotics, wasp venom)

Answer 145

* re-exposure to antigen/allergen causes FcεRI-bound IgE to cross-link - activating receptors * MAPKKK signaling cascades - lead to prostaglandin release and uregulation of other cytokines * Lead to production of **DAG** (diacylglycerol) to form Ca²⁺ and **InsP₃**to form PKC ⇒ degranulation and release of histamines

Answer 146

* **H1 -** *(sm musc, endothelium, periph neurons, postsyn hist neuron in brain)*, itch, pn, secretion from mucosa, vasodilate, edema, bronchoconstrict, contract gut * **H2 -** *(stomach gastric mucosa - parietal cells, cardiac musc, smooth musc, mast cells, basophils, postsyn histaminergic neuron in brain)* gastric acid secretion, vasodilation, ↑ HR, neg feedback of histamine release * **H3 -** *(presynaptic histaminergic neurons in brain, myenteric plexus)* ↓ NT release * **H4 -** *(eosinophils, DCs, basophils, monocytes, T cells)* differentiatino of myeloblasts and promyelocytes, chemotaxis, secretion of cytokines and upregulation of adhesion factors

Answer 147

* _Nervous System_ - itch, pn, urticaria (PNS), circadian & feeding rhythms, appetite suppression & satiety, increased wakefulness, modulation of NT release (CNS) * _Cardiovascular_ - Vasodilation (H1 - NO production, H2 - vsm cAMP production & relaxation), ↑ cap permeability (H1 - edema, low BP), reflex tachycardia due to low bp * _Respiratory_ - bronchoconstriction (H1) * _Digestive_ - acid secretion in stomach & mucus secretion in intestines (H2), contraction of gut and diarrhea (H1)

Answer 148

* _Inhibitors of Mast Cell Degranulation_ **Cromolyn & Nedocromil** * **__**Block Cl- channels, inhibit Ca²⁺mobilization and thus degranulation * Must be inhaled, used to prevent asthma attacks * _Counteract histamine Action_ **Epinepherine** * **__**Physiologic agonist of α and β adrenergic receptors * powerful, rapid bronchodilator and vasoconstrictor

Answer 149

* **_H1 Antihistamines_** * ****_1st gen_- hydrophobic (lipid soluble), readily enter CNS (sedative), anti-emetic, non-specific effects, short acting * used for insomnia, motion sickness, nausea, itching * _2nd gen_- hydrophilic (no CNS distribution, not sedative), no anti-emetic, highly selective for H1 receptor, longer-acting

Answer 150

* **_H1_**- Allergic reactions, motion sickness/vertigo/insomnia (1st gen), antiemetics (1st gen), ineffective for asthma and common cold, Prophylactic allergy treatment, Treats itching, hives, rhinitis * *_Side Effects_* - *sedation (normal dose), hyperstimulate CNS (overdose), anticholinergic effects (dilated pupils, dry eye, diplopia), nausea, loss of appetite, cardiac arrythmias, interactions w/ drugs that inhibit CYP metabolism*

Answer 151

* regulation of gastric acid secretion (block H2 receptors on parietal cells) * hydrophilic (do not enter CNS) * Specific * Treat GERD, promote healing of ulcers, treat Zollinger-Ellison, prophalactic treatment of stress-induced gastritis) * **Proton Pump Inhibitors (H+/K+ ATPase inhibitor) - ex. *Omeprazole* are more widely used** * _Adverse Effects_ - interfere w/ cytochrome P450 metabolism, neurologic effects in patients w/ impaired renal or hepatic function, diarrhea, headache, fatigue, dizziness, muscle pain, constipation

Answer 152

* Diphenhydramine * Tripelennamine * Chlorpheniramine * Promethazine * Hydroxyzine * Cyclizine * Meclizine * Cyproheptadine

Answer 153

* Cetirizine * Loratidine * Fexofenadine

Answer 154

* Levocetirizine * Desloratadine

Answer 155

* Chromolyn * Nedocromil

Answer 156

* Cimetidine * Ranitidine * Famotidine * Nizatidine

Answer 157

* Kinins cause vasodilation, increase the permeability of blood vessels, lower BP, and stimulate pain receptors * ex. Bradykinin * Prostaglandins potentiate the action of bradykinin

Answer 158

* Large family of chemical mediators derived from arachidonic acid and are found in all tissues * Part of eicosanoid family (along w/ prostaglandins, thromboxanes, and leukotrienes) * Prostaglandins and Thromboxanes are collectively known as **prostanoids** * **PGE₂** - promote gastric mucus secretion, inhibit acid secretion * **PGI₂** **(Prostacyclin)**- inhibit platelet aggregation, vasodilation * **TXA₂** does the opposite

Answer 159

**PGE₂** * Vasodilation * Increased vascular permeability * Increased sensitivity of pn receptors to bradykinin * Pain neuromodulation * Fever (pyresis)

Answer 160

* COX-2 expression induced by inflammation * Upregulated COX-2 increases PGE₂ * COX-1 produced constitutively, involved in normal homeostasis * COX enzymes convert arachidonic acid to cyclic endoperoxides

Answer 161

* Analgesic, antipyretic, anti-inflammatory (non-steroidal anti-inflammatory drugs) * **Aspirin, Ibuprofin, Naproxen, Indomethacin, Dicyclofenac** * Reduce the production of inflammatory PGE₂ to reduce edema, pain, tenderness, fever * **Inhibit COX-2** * _Side Effect_ - also reduces prostaglandins produced by COX-1 (similar structure to COX-2), gastric bleeding

Answer 162

* Product of arachidonic acid, w/ 5-Lipoxygenase * Pathway associated with inflammatory/immune responses * allergic reactions & anaphylaxis * **LTC4, LTD4, LTE4**

Answer 163

* Selective for **COX-1**, binds **covalently/irreversibly** to COX binding site in platelets * **Inhibits TXA₂** - reduces ability to coagulate * Contraindicated for people w/ GI issues or Reye's syndrome * Anti-platelet drug

Answer 164

* Highly selective for COX-2 over COX-1 * Selectively inhibit production of pro-inflammatory prostaglandins * Previously used to treat RA (ex. Rofecoxib - but withdrawn due to CV events) * **Celecoxib** is the only COX-2 inhibitor available on the market * **Increase risk of MI and stroke** (inhibit COX-2 derived PGI₂, but not COX-1 derived TXA₂ → vasoconstriction and coagulation)

Answer 165

* Anti-pyretic & analgesic, not anti-inflammatory * Reduces prostaglandin synthesis * _Side Effects_: hepatotoxicity (toxic metabolite NAPQI - necrosis of liver) * _Antidote_: **N-Acetylcysteine (NAC)** - increases stores of antioxidant glutathione in liver - promotes metabolism/excretion

Answer 166

* **Hydrocortisone, Prednisolone, Dexamethasone, Betamethasone** * Anti-inflammatory effect by down-regulating COX-2 and therefore inflammatory prostaglandins * Immunosuppressive (reduces histamine production) * *_Adverse Effects_: hyperglycemia, weight gain, diabetes, need for insulin, increased fat redistribution (buffalo hump), muscle wasting & osteoporosis, moon face, peptic ulcers, poor wound healing, increased intraocular pressure, glaucoma, cataracts, increased BP and edema* * Used for: allergic reaction, asthma, arthritis, bursitis, IBS, cerebral edema, SLE- Lupus, atopic dermatitis

Answer 167

* **Wnt** - determines positioning/polarity * **Notch** - determines what to differentiate into

Answer 168

* Epithelial cells, intraepithelial cells, lamina propria lymphocytes, mucosal B cells, dendritic cells, intestinal macrophages, mucosal basophils, eosinophils, and mast cells, M cells * _Secretory Cells_ - Goblet cells (mucus producing) * **Mucus**- viscous, polymeric mucin glycoproteins * permeable to macromolecules, barrier for undesirable elements

Answer 169

* **Cathelicidins** - chemotactic for neutrophils, monocytes, mast cells and T cells * induces mast cell degranulation * Alters transcriptional responses in macrophages * **Defensins** * microbicidal against bacteria, fungi, spirochetes, protozoa, and viruses * Present in neutrophils

Answer 170

* Small mononuclear cells interspersed between epithelial cells (mostly CD4-/CD8- or CD4-/CD8+) * Express NK cell receptors * Express integrin to interact w/ E-cadherin on epithelial cells * When activated, they send signals from the periphery to the thymus - they turn our T cells of various kinds * **As we grow, we are exposed to more antigens - generate more inducible IELs** (after 3 wk weaning period, natural IELs \< inducible IELs)

Answer 171

* **CD4** * receive signals from epithelial cells, IELs, stromal cells, and integrin receptors * Interacts w/ microbiota, different types of gut microbiota appear to induce different cytokine responses in mucosal T cells

Answer 172

IgA and IgM * Produced by mucosal plasma cells or plasmablasts in lamina propria * Found in tears, nasal secretion, saliva, intestinal juice, and breast milk. * _Epithelial transcytosis_- mediated by **pIgR** (polymeric Ig receptor) * sIgA and sIgM anchors to mucin and provides immunological barrier against infection

Answer 173

Mediate cross-talk between luminal flora and mucosal immune system

Answer 174

* _Microbiome_ - members of microbial community found in particular anatomic habitat * _Metagenome_ - aggregate of genes found in microbiome that can be organized into functional metabolic repertoires * Might be linked to metabolic syndrome (fecal transplant of obese mouse into germ free mouse - makes it gain weight)

Answer 175

* 2 antibodies used: * depleting agents - **antithymocyte globulin** and **MuromonabCD3 mAb** * Immune modulators - **Daclizumab** and **Muromonab** * Delay use of nephrotoxic calcineurin inhibitors * Intensifies initial immunosuppressive therapy in high risk patients (repeat transplants, broadly presensitized patients, African Americans, pediatric patients)

Answer 176

* Use multiple drugs to achieve synergistic effects and minimize toxicities * **Calcineurin Inhibitor, glucocorticoid, mycophenolate mofetil**

Answer 177

* **Cyclosporine, Tacrolimus** * Prevention of organ rejection, used at maintenance doses, useful for psoriasis and RA * _Mechanism_- bind to and inhibit calcineurin to prevent NF-AT from promoting trancription of IL-2 gene * _Side Effects_ - **nephrotoxicity**, HTN, diabetes, tremor, hirsutism, malignancy and infections, interacts w/ drugs that affect P450 enz * _PK_- IV or oral, peak levels occur 1.5-2 h after oral admin

Answer 178

* **Sirolimus (Rapamycin), Everolimus** * _Uses_- immunosuppression, used in drug-eluting stents, anticancer drug for advanced renal cancer * _Mechanism_ - inhibit mTOR - inhibit protein kinase * _Side Effects_- increase cholesterol and TAGs, increase nephrotoxicity of calcineurin inhibitors, anemia, leukopenia, infections * _PK_- peak level within 1 hour after oral admin, absorption affected by high fat diet

Answer 179

* **Azathioprine** - interferes w/ biosynthetic pathway, inhibits purine and thus nucleotide synthesis * _Uses_- prevent kidney rejection, RA * _Side Effects_- bone marrow suppression, neoplasia, infections, metabolized by xanthine oxidase, interacts w/ allopurinol * **Mycophenolate Mofetil** - inhibits *inosine monophosphate dehydrogenase* (for purine synthesis) - suppresses lymphocyte proliferation * renal, liver, or heart transplants (can be used w/ calcineurin inhib and corticosteroids) * GI disturbances, myelosuppression, headache, and HTN

Answer 180

* Antibodies against lymphocyte cell-surface receptors can prevent lymphocyte activation * Both polyclonal and monoclonal Ab widely used, more specific than other immunosuppressants * **Anti-Lymphocyte/Thymocyte Antibodies** * **Daclizumab Monoclonal Antibody** * **Muromonab-CD3 antibody**

Answer 181

* Cortisone, Hydrocortisone (Natural), Prednisone, Prednisolone, Methylprednisolone, Triamcinolone, Dexamethasone, Betamethasone * Inhibit expression of cytokine genes **(IL-1, 2, 6, interferon, and TNF-α**. Inhibit T-cell proliferation and T-dependent immunity

Answer 182

* B cells * T cells * Complement system * Phagocytic system * Antibody (50%)

Answer 183

* Most severe ones diagnosed in infants (but \>50% diagnosed over 50 y/o) * ≥4 ear infections/year, ≥2 serious sinus infections/yr, ≥2 pneumonias/yr, ≥2 months on antibiotics w/ little effect (need via IV), ≥2 deep-seated infections (septicemia) * Failure of infant to gain weight/grow * Recurrent, deep skin or organ abscesses * Thrush in mouth, fungal infections on skin * Family Hx of primary immunodeficiency

Answer 184

* _Index of suspicion_ - frequency/severity/duration of infections, unusual infectious agents, poor response to antibiotics * _Initial evaluation_ - medical Hx, physical exam, lab testing, refer to immunologist__ * _Specific defects_

Answer 185

* _B cells_: recurrent **bacterial** sino-pulmonary infections, may have GI parasite * _T cells_: **fungal & viral** infections causing mucocutaneous candidiasis, persistent respiratory infections, chronic diarrhea, failure to thrive * _Phagocytes_: recurrent **skin** infections, poor wound healing, periodontal disease * _Late Complement Components (MAC)_: **Bacterial** infections such as Neisseria (meningitis or gonorrhea), sepsis * _NK cells_: severe or recurrent **herpesvirus** infections

Answer 186

* **T-cell Disorder** * Complete lack of T and B cell function, lack of Ig's * Lack of T cell development associated with abnormal B and NK cell development * Life-threatening infections in first months of life * Failure to thrive

Answer 187

* **T cell Disorder** * Chromosomal defect - impacts organs from 3rd and 4th pharyngeal arch (thymus and parathyroid gland) * Tetralogy of Fallot, low-set ears, cleft palate, hypocalcemia, low/absent T cells * Can have thymus transplant

Answer 188

* **T Cell disorder** - low CD3+/CD4+ and B cell defects * Mutations in ATM gene (involved in DNA repair) * Neuro defect - loss of motor skills * Spider veins * Increased susceptibility to infections

Answer 189

* **T cell disorder**, also affects B cells * X-linked recessive defect in WASP gene * Small platelets, thrombocytopenia, petechiae, bruising, bleeding, eczema * Infections (respiratory) * Autoimmune and lymphoid malignancy - poor prognosis

Answer 190

* _Agammaglobulinemia_ - X-linked or AR * arrest of pre-B cells, all Igs reduced or absent * _Selective IgA deficiency_ - **most common**, recurrent infections, allergies, usually asymptomatic, sometimes progress to CVA * due to intrinsic B cell defect, T helper cell dysfunction * _Common Variable Immunodeficiency (CVA)_ - low serum Ig, normal # B cells that don't mature normally, some lack T helper function, recurrent infections, treat w/ Ig replacement

Answer 191

* _Chronic Granulomatous Disease (CGD)_- X-linked or AR, defect in production of superoxide, variable onset, recurrent bacterial infections (*S. Aureus)* and fungi and tissue granuloma formation, pulm/cutaneous/lymph/hepatic infections common * _Chediak-Higashi Syndrome_- rare AR, mutation in **LYST** gene that txp material to lysosomes, **large abnormal granules** in neutrophils, melanocytes, hair, schwann cells, CNS, recurrent infections, albinism, mental retardation, coagulation problems, neuropathy, poor prognosis * _Leukocyte Adhesion Deficiency (LAD)_, _Hyper-IgE syndrome (Job's)_, _Neutropenia_

Answer 192

* **T-cell:** Hx, CBC, PPD and anergy, T cell subsets, HIV serology * **B-cell:** Hx, CBC, Quantitative IgG/IgA/IgM, IgE level, IgG subclasses, pre & post vaccination titers, T cell subsets * **Phagocyte:** Hx, CBC, examine peripheral smear, neutrophil oxidative burst * **Complement:** Hx, total complement level - CH50, individual complement component levels

Immunology Lecture Objectives Flashcards

(223 cards)