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Immunity > Immunology Lecture Objectives > Flashcards

Immunology Lecture Objectives Flashcards

1
Q

What are framework regions (FR) and hypervariable (HV) regions of antibodies?

A
  • Sequences in Variable Region in heavy and light chains
  • FR = similar to other antibodies
  • HV = highly variable among antibodies
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2
Q

Where does the antigen bind to the antibody?

A

ANtigen binds to a region of the antibody formed from the association of the variable light and variable heavy regions.

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3
Q

Antibodies are the secreted version of the ___ cell antigen receptor.

A

B-cell

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4
Q

How are T cell antigen receptors (TCR) different from BCRs?

A
  • TCR structures are similar (essentially the variable region attached to the T cell membrane)
  • TCR is NOT secreted like an antibody
  • Antigen binding site is highly variable
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5
Q

How is TCR and BCR diversity created?

A
  1. V(D)J Recombination: genomic DNA has multiple Vα and Jα segments (plus 1 constant Cα segment), 1 of each variable segment is transcribed into mRNA
  2. V to J Somatic Recombination: DNA between V and J gene segments is excised and ends are fused together. The join is “messy” w/ random addition/deletion of nucleotides.
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6
Q

What are the 2 types of immunological tolerance?

A
  • Central Tolerance: Removal of self-reactive clones, occurs in the 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 the self reactive clones in check
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7
Q

CD#?

A
  • CD = Cluster of Differentiation
  • Classified by the reference monoclonal antibodies to which they bind
  • Helper T Cells - CD4
  • Killer T Cells - CD8
  • Tregs - CD25
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8
Q

MHC Class I vs II Antigen Processing Pathway

A
  • Class I: Virus enters cell, degraded, enters ER and binds to MHC I, transported to Golgi and placed on cell surface to signal CD8 (Killer T Cells)
  • Class II: Bacteria enters cell in vesicle, merges w/ endosome, degrades into peptides and binds to MHC II, moves to cell surface, recognized by CD4 (Helper T Cells)
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9
Q

Natural Killer Cells

A
  • Capable of destroying other cells, particularly virus-infected cells and tumor cells
  • Can attack large paracites
  • Do not express TCR or BCR
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10
Q

“Specific” Defenses: Humoral vs Cell-Mediated Immunity

A
  • Humoral Immunity: B cells defend the body against antigens and pathogens in body fluids
  • Cell-Mediated Immunity: T cells defend against abnormal cells and pathogens inside living cells
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11
Q

What is an adjuvant?

A

An agent that stimulates the immune system and increases the response to a vaccine, but does not have a specific antigenic effect in of itself. (“clean” antigens will not activate the immune response - must be mixed w/ adjuvants)

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12
Q

What is the technique used to detect WBCs in peripheral blood?

A
  • Complete Blood Count
  • Flow cytometry
  • Measure Side Scatter (granularity) vs. Forward Scatter (cell size)
  • Granulocytes are large and granular, Monocytes are less granular, Lymphocytes are the smallest and least granular
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13
Q

What is a double positive signal in FACS? (Fluorescence Activated Cell Sorting)

A

Mix of cells w/ both proteins

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14
Q

What are some components of innate immunity?

A
  • Barriers (epithelium, defensins, lymphocytes)
  • Effector Cells (Neutrophils, Macrophages, NK cells, dendritic cells)
  • Circulating Effector Proteins (Complement, Mannose-binding lectin)
  • Cellular Proteins (Pattern Recognition Receptors)
  • Induced Signaling Proteins (Cytokines)
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15
Q

Define PRR

A

Pattern Recognition Receptor (PRR)

A protein or protein complex that recognizes a commonly found molecular signature not found in normal host

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16
Q

Define PAMP & DAMP

A

Pathogen-Associated Molecular Pattern (or Damage Associated)

Proteins, carbohydrates, lipids, nucleic acids, or combinations recognized by PRRs (Pattern Recognition Receptors)

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17
Q

Describe 5 major molecular patterns recognized by PRRs and their associated pathogen

A
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18
Q

What are Toll-like receptors?

What are their 2 cellular locations?

What are the outcomes of TLR stimulation?

A
  • TLR is a membrane PRR with broad pathogen specificity
  • Located in plasma membrane or endosome membrane (binding domain either extracellular or inside endosome)
  • TLR stimulation leads to:
    • Acute Inflammation and Stimulation of Adaptive Immunity (via NF-κB)
    • Antiviral State (via IRFs, expression of type 1 interferon)
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19
Q

Name 2 types of cytoplasmic Pattern Recognition Receptors (PRR)

A
  • RIG-like Receptors (RLR) - for nucleic acids in viruses (RNA)
  • NOD-like Receptors (NLR) - for peptidoglycans in gram +/- bacteria and bacterial toxins
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20
Q

What are the roles and properties of neutrophils (PMNs)?

A
  • Predominant WBC
  • First cells entering site of acute inflammation
  • Respond to chemotax and are activated by fmet peptides and other signals (e.g. chemokines)
  • Activated by “pro-inflammatory cytokines” (TNF, IL-1) produced by macrophages or endothelial cells
  • Potent bacterial killers (phagocytic)
  • Short half life (6-8 h)
  • Does not present antigen
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21
Q

What are the roles and properties of Monocytes and Macrophages?

A
  • Monocyte: immature macrophage
  • Macrophage: differentiate and take residence as “sentinels” in many tissues (ex. Kupffer cells in liver), or differentiate in response to inflammation (activated by T cell cytokines)
  • Functions: Phagocytosis, Antigen Presentation, Cytokine Production/signaling
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22
Q

What are 2 major outcomes of macrophage activation?

A
  • ​Inflammation, Increased Adaptive Immunity
    • via cytokines
  • Killing of Microbes
    • via Reactive Oxygen Species (ROS), Nitric Oxide, and Phagocytosis
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23
Q

How do NK cells distinguish damaged or infected cells from healthy cells?

A
  • Balance of Inhibitory and activating signals
    • Activating receptors: recognize stress molecules (carbs, proteins)
    • Inhibitory receptors: recognize normal MHC complement on healthy cells (viral infections cause loss of MHC-1, cancer cells are deficient in MHC-1)
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24
Q

How do Natural Killer cells kill their targets?

A
  • Produce cytokines (INF-γ → macrophage activation)
  • Apoptosis results from:
    • Interaction of Fas (target) w/ Fas Ligand
    • Perforin/Granzyme system
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25
Q

What are Dendritic Cells?

What are their effects?

What are 2 major types?

A
  • 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
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26
Q

What are the 3 ways that complement can be activated? Where do they merge?

A
  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)

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27
Q

What are 3 outcomes of complement activation?

A
  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)
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28
Q

What are the key cytokines activated when viruses stimulate innate immunity?

A

Type I Interferons: IFN α and β

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29
Q

What are molecular components of viruses that can act as PAMPs?

A
  • Nucleic Acids:
    • Single-strand RNA
    • Double-strand RNA
    • CpG (dinucleotide)
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30
Q

List 2 classes of Pattern Recognition Receptors (PRRs) for viral components and where they are located.

A
  1. Toll-like Receptors (TLR) - Membrane
  2. RIG-like Receptors (RLR) - Cytoplasm
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31
Q

List 3 major pro-inflammatory cytokines and 2 cell types that produce these molecules.

A
  • Pro-Inflammatory Cytokines: IL-1, TNF, IL-6
  • Phagocytes, Dendritic Cells, Epithelial and Endothelial cells
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32
Q

Innate vs. Acquired Immunity

A
  • 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
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33
Q

What are some ways the innate immunity interacts with the acquired immunity?

A
  • 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)
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34
Q

Describe the significance of the MHC

A
  • 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
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35
Q

What kind of peptide cargo is found on MHC Class I and Class II molecules?

A
  • Class I:“endogenous” antigens, presents peptides from proteins synthesized within the cell
  • Class II:“exogenous” antigens present peptides from proteins endocytosed into the cell
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36
Q

MHC Class I

A
  • Binds cytosolic pathogens (endogenous)
  • Presented to CD8 T cells
  • Effect on presenting cell - cell death
  • Found on virally infected cells (all cells but RBCs)
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37
Q

MHC Class II

A
  • 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)
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38
Q

Compare the structures of MHC class I and class II

A
  • 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)
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39
Q

Describe MHC-peptide binding

A
  • 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
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40
Q

Describe the MHC Class I peptide-binding pathway

A
  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
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41
Q

Describe the MHC Class II peptide-binding pathway

A
  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
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42
Q

What are Antigen Presenting Cells and what is their role?

A
  • 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
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43
Q

What are Dendritic cells and what is their role?

2 sites of origin?

A
  • 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)
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44
Q

How are dendritic cells activated and matured?

A
  • 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
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45
Q

What is MHC class I cross presentation?

A
  • 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
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46
Q

Describe the Human Leukocyte Antigen (HLA) genetic region

A
  • 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)
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47
Q

Polymorphisms in MHC?

A
  • Line the peptide-binding groove and determine peptide binding
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48
Q

Describe the differentiation of T Cells

A
  • 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
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49
Q

Describe T cell activation (signal 1 and signal 2)

A
  • 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
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50
Q

How does lack of costimulation impact Tumors?

A
  • 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
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51
Q

How are T cell responses turned off?

A
  • 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
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52
Q

Describe therapeutic Costimulatory blockades on T-cells

A
  • 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
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53
Q

What is YERVOY and how is it used?

A
  • 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
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54
Q

What is the structure of the TCR complex? Describe how the components are involved in early signaling events in T-cell activation

A
  • 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)
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55
Q

What are the functions of major T cell subsets in immune responses?

A
  • CD8 - Killer T cells (cytotoxic), recognizes complex of viral peptide w/ MHCI and kills infected cell directly
  • CD4 -
    • ​TH1 - 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
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56
Q

What are regulatory T Cells and what do they do?

A
  • 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)
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57
Q

Consequence of TCR binding to MHC too strongly and too weakly?

A
  • Too strong - T cell is activated and causes autoimmunity
  • Too weak - immune deficiency
  • Only intermediate affinity cells will survive pos and ne selection
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58
Q

Describe T cell development and selection

A
  • 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
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59
Q

Explain Central & Peripheral Tolerance

A
  • 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)
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60
Q

How does thymic function change with age?

A
  • 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
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61
Q

Describe the structure and function of the Ig molecules

(including subunits, molecular domains in each subunit, and the function of each domain)

A
  • 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
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62
Q

What are mechanisms underlying immunoglobulin diversity?

A
  • 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
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63
Q

Describe the B cell development

A
  • 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
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64
Q

Describe how B cells produce antibodies

A
  • 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
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65
Q

How is IgG and IgM response different in primary vaccination & booster?

A
  • 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
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66
Q

What is a monoclonal antibody? How are they produced? Side Effects?

A
  • 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
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67
Q

Describe how antibodies are used as diagnostic indicators

A
  • 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
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68
Q

What is the humoral immune response? 4 ways it is done?

A
  • 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
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69
Q

How are self-reactive B cells deleted in bone marrow?

A
  • Negative Selection
  • Central tolerance - autoreactive cells eliminated in central lymphoid organ (bone marrow)
  • Peripheral tolerance - this process occurs outside of bone marrow
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70
Q

T-dependent vs. T-independent B cell antigens

A
  • T-Dependent: Thymus-dependent
    • B cell responses to proteins 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
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71
Q

What are the 2 steps of B-cell activation?

A
  1. Crosslinking of the BCR - phosphorylation of multiple receptors
  2. Complement - mediates B cell activation, mediated by MHC Class II antigen presentation
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72
Q

What are the different types of B cells and what are their functions?

A
  • 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, 1st 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
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73
Q

Describe the germinal center reaction and how this results in isotype switched, high affinity antibodies.

A
  • 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
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74
Q

Describe how Affinity Maturation occurs in the Germinal Center Response

A
  • 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
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75
Q

Describe how Isotype Switching Occurs in the Germinal Center Response

A
  • Class switch recombination leads to the production of antibodies w/ heavy chains of different classes
  • AID is also necessary, requiring CD40 ligation
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76
Q

Describe the basic principles of Acute inflammation including:

  • Stimuli
  • Reactions of blood vessels
  • Reactions of leukocytes
  • Termination and outcomes of acute inflammation
A
  • 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
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77
Q

What are the mechanisms of acute inflammation?

A
  • 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
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78
Q

What are eicosanoids? 2 main enzymes that form products?

A
  • 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)
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79
Q

What types of leukocytes are formed from different pathogens?

A
  • Neutrophils/Jeuvenile: Acute bacterial infections and sepsis
  • Eosinophils: Parasitic infections
  • Lymphocytes (B & T): Viral infections, chronic bacterial infections
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80
Q

What are the morphologic patterns of acute inflammation?

A
  • 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
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81
Q

What is inflammatory exudation?

A
  • 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)
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82
Q

What is chronic granulomatous disease?

A
  • 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
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83
Q

What are the mediators of inflammation and their modes of action?

A
  • 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
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84
Q

Describe the basic principles of chronic inflammation

A
  • 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
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85
Q

What is an abcess?

A
  • Acute & chronic process
  • Encapsulated accumulation of pus (usually neutrophils) with tissue destruction and formation of a new cavity
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86
Q

What is an empyema?

A
  • Accumulation of pus (usually neutrophils) in an existing body cavity (e.g. pleural space, pericardial sac)
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87
Q

What stimulates angiogenesis?

A
  • 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
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88
Q

What is fibrosis?

A
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89
Q
  • scar formation
  • terminal stage of inflammation
  • Inflammatory cells leave, number of live cells increases
  • Predominant interstitial collagen (collagen type I)
  • leads to hypoxia and death
  • Growth factors, cytokines, and decreased metalloproteinase activity leads to fibrosis
A
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90
Q

What is a granulomatous inflammation?

A
  • 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
91
Q

Define pleiotropy and redundancy & give an example of each

A
  • 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
92
Q

How do chemokines differ from cytokines?

A

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
93
Q

Describe the major effects of type I interferons

A
  • 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
94
Q

What are the roles of Jak and Stat proteins? Which cytokines utilize them?

A
  • 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
95
Q

What are the major pro-inflammatory cytokines? What are their effects in inflammation?

A
  • 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
96
Q

What is a major transcription factor in the pathway of pro-inflammatory cytokines?

A

NFκB

97
Q

What are the major cytokines produced by Th1 and Th2 cells?

A
  • 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
98
Q

How does IL-10 differ from cytokines such as IL-1, TNF, and Type I INFs?

A

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

99
Q

Explain how cytokines released during innate immune response affects the differentiation of T or B cells.

A
  • 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
100
Q

What are 2 major functions of chemokines?

A
  • 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
101
Q

Chemokine and Chemokine receptor nomenclature?

A
  • Chemokines
    • Old: (functional) IL-8, eotaxin, Monocyte Inhibitory Factor (MIF)
    • New: (Structural) CCLx, CXCLx etc.
  • Chemokine Receptors
    • systematic - add R (CCLx receptor = CCRx)
102
Q

What is the role of CCR5 on HIV infection?

A
  • 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
103
Q

Pharmacodynamics vs. Pharmacokinetics

A
  • 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)
104
Q

List some typical drug targets

A
  • 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
105
Q

Define conceptually the possible outcomes of drug-receptor interactions

A
106
Q

List major targets of anti-cytokine therapy and their clinical uses.

A
  • 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

107
Q

What are DMARDs?

A
  • “Disease Modifying Anti-Rheumatoid Drugs”
  • Leflunomide or Methotrexate
  • Prevent proliferation of lymphocytes, reduce inflammatory process
  • Treats Rheumatoid Arthritis
108
Q

What is Etanercept? How does it work?

A
  • 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
  • t1/2 = 115 h
  • As effective as other drugs like MTX, but combination is more effective
109
Q

What is Infliximab? How does it work?

A
  • 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
110
Q

How are IL-1 cytokines targeted? What is this used for clinically?

A
  • 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
111
Q

What is Abatacept? How does it work?

A
  • 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
112
Q

What is Belimumab? How does it work?

A
  • Targets BAFF (BLyS) to treat Lupus
  • Neutalizes BAFF to limit B-cell proliferation and survival
113
Q

What are limitations of pharmacological uses of cytokines and cytokine inhibitors?

A
  • Injection site reactions
  • Infusion reactions (fever, rash, dyspnea, low BP)
  • Cytopenias
  • Infections (sepsis & TB)
  • Malignancies, lymphomas
  • Hepatotoxicity (infliximab)
  • EXPENSIVE
114
Q

What are contraindications to anti-cytokine therapy?

A
  • Active infection
  • If TB+, treat latent TB first
  • Pre-existing demyelinating disorders
  • Pregnancy category B
115
Q

What is glycosyltransferase?

A
  • 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
116
Q

What antigen is on type O RBC?

A

H

117
Q

What are natural antibodies?

A
  • 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
118
Q

What is Bombay O blood type?

A
  • 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
119
Q

Whole Blood Transfusion Rules

A
  • 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
120
Q

Erythrocyte Transfusion Rules

A

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

121
Q

Plasma Transfusion Rules

A

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

122
Q

What are some transfusion reactions?

A
  • 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
123
Q

Rh gene?

A
  • 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
124
Q

What is Rh incompatibility disease? How is it treated?

A
  • 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
125
Q

What is Rhogam?

A
  • 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
126
Q

Anti ABO vs Anti Rh?

A
  • 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
127
Q

What is the Direct Coomb’s Test?

(Direct Antiglobulin Test, DAT)

A

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

128
Q

What is the Indirect Coomb’s Test?

(Indirect antiglobulin test, IDAT)

A

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

129
Q

What are negative vs. positive agglutination results?

A
130
Q

What is multiple myeloma? How is it diagnosed?

A
  • 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
131
Q

What are the events of primary hemostasis?

A
  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, αIIbβ​3) on different platelets ​
  • stimulated by Serotonin, Epi, PAF, Thrombin, ADP, TXA2, Vasopressin, and Collagen)
132
Q

Where are platelets produced? How many is normal? What does platelet size say?

A
  • 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
133
Q

What is the function of von Willebrand factor in the coagulation process?

A
  • 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
134
Q

What do low platelet counts result in?

A
  • Low (< 10 - 20 k) result in petechiae (1-3 mm, red/purple, do not blanche)
    • Purpura = 3mm-1cm
    • Ecchymoses = >1 cm
135
Q

What is secondary homeostasis?

A
  • Formation of platelet “sealant” of cross-linked fibrin
  • Formation of fibrin from fibrinogen
136
Q

What are other names for Factors I, II, and XIII?

A
  • I = Fibrinogen/Fibrin (stabilizes platelet plug)
  • II = Prothrombin/thrombin (activates fibrinogen to fibrin)
  • XIII = Tissue transglutaminase (cross-links fibrin to stabilize clot)
137
Q

What are the 3 pathways for coagulation?

A
  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
138
Q

What is Tissue Factor?

A
  • 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
139
Q

Outline the steps in normal coagulation and list the coagulation complexes involved in each step.

A
  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
140
Q

What is Factor VIII?

A
  • 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
141
Q

What is Factor V?

A
  • 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
142
Q

What are the three pro-coagulant complexes that are essential to coagulation?

A
  1. Tissue Factor :: Factor VIIa :: IXa ≈ Factor X
  2. Factor IXa :: VIIa ≈ Factor X
  3. Factor Xa :: Va ≈ Factor II (Prothrombin)
143
Q

What are the Vitamin K dependent coagulation factors?

(Vitamin K dependent Zymogens)

A

Procoagulant: II, VII, IX, X

Anticoagulant: Proteins C, S, Z

(II, VII, IX, X, and Protein C are Serine Proteases)

144
Q

What is the role of Vitamin K in factor synthesis and how does the drug, Warfarin, interfere with this?

A
  • 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
145
Q

What are important steps of the intrinsic pathway?

A
  1. Contact activation - Factor XII activated on contact w/ neg charged surface (PO42-)
  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
146
Q

What is Factor XIII important for?

A
  • XIIIa cross-links fibrin chains
  • Activated by thrombin
  • Deficiency is rare but can cause significant bleeding
147
Q

What is thrombomodulin?

A
  • 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
148
Q

What are proteins C and S?

A
  • 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
149
Q

Explain the basis of immune regulation (self-tolerance)

A
  • 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
150
Q

Define autoimmunity

A
  • 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)
151
Q

Explain the mechanisms that mediate self-tolerance

A
  • 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
152
Q

Discuss regulatory T cell function

A
  • 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
153
Q

What is APC/APECED?

A
  • 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
154
Q

How do genetics and environment influence autoimmune disease development?

A
  • 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
155
Q

Describe the interactions between infection and autoimmunity

A
  • 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
156
Q

What is the hygeine hypothesis?

A
  • 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
157
Q

What are different types of transplants?

A
  • Autologous = from self
  • Syngeneic = from identical twin
  • Allogenic = from another human (not twin)
  • Xanogeneic = one species to another (usually from pig)
158
Q

What are the antigens in transplants that are recognized as foreign by the immune system?

A
  • 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
159
Q

Describe the pathways by which the immune response against transplants are initiated.

A
  • 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)
160
Q

Discuss immune mechanisms of graft rejection

A
  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
161
Q

Discuss the prevention and treatment of graft rejection.

A
  • 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)
162
Q

Discuss hematopoietic stem cell transplantation and Graft vs. Host disease

A
  • 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
163
Q

Describe Type I hypersensitivity reactions

A
  • 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
164
Q

What are the functions of mast cells?

A
  • Defend against parasitic worms & protozoa
  • Products attract eosinophils
  • Degranulation occurs w/ cross-linking of IgE by antigen (must be multivalent)
165
Q

What are examples of allergy mediators?

A
  • 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, inflammation, IL-4)
166
Q

Describe skin testing for allergies

A
  • 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)
167
Q

What is RAST?

A
  • Radioallergosorbent test - detects level of IgE
  • Allergens coupled to beads, serum added (IgE binds beads)
  • Labeled anti-IgE added & measured to quantify IgE
168
Q

What is allergy desensitization?

A
  • 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
169
Q

How is the hygeine hypothesis related to allergies?

A
  • Insufficient Th1 Stimulation due to Minimal contact w/ viruses and bacteria
  • Overactive Th2 Response due to unbalanced immune system
170
Q

Describe Type II Hypersensitivity reactions

A
  • 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
171
Q

Describe Type III hypersensitivity reactions

A
  • 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)
172
Q

Describe Type IV hypersensitivity

A
  • 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
173
Q

How is histamine synthesized and stored in specialized cells in the body?

A
  • 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
174
Q

Define the different mechanisms that trigger histamine release throughout the body.

A
  • 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)
175
Q

What are the basics of the signaling cascade in activated mast cells?

A
  • 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
176
Q

What are the 4 types of histamine receptors? Their specific distribution in the body? Specific physiological responses they facilitate?

A
  • 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
177
Q

What are the major physiological effects of histamine?

A
  • 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)
178
Q

State the mechanism of action of non-histamine receptor-targeting drugs

A
  • 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
179
Q

1st gen vs. 2nd gen H1 antihistamine?

A
  • 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
180
Q

H1 antihistamines?

A
  • 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
181
Q

H2 antihistamines?

A
  • 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
182
Q

Name some 1st gen antihistamines

A
  • Diphenhydramine
  • Tripelennamine
  • Chlorpheniramine
  • Promethazine
  • Hydroxyzine
  • Cyclizine
  • Meclizine
  • Cyproheptadine
183
Q

Name some 2nd gen H1 antihistamines

A
  • Cetirizine
  • Loratidine
  • Fexofenadine
184
Q

Name some 3rd gen H1 antihistamines

A
  • Levocetirizine
  • Desloratadine
185
Q

Name some Degranulation Inhibitors

A
  • Chromolyn
  • Nedocromil
186
Q

Name some H2 antihistamines

A
  • Cimetidine
  • Ranitidine
  • Famotidine
  • Nizatidine
187
Q

What is the kinin cascade?

A
  • Kinins cause vasodilation, increase the permeability of blood vessels, lower BP, and stimulate pain receptors
  • ex. Bradykinin
  • Prostaglandins potentiate the action of bradykinin
188
Q

What are prostaglandins?

A
  • 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
189
Q

What is the main prostanoid in inflamation?

A

PGE2

  • Vasodilation
  • Increased vascular permeability
  • Increased sensitivity of pn receptors to bradykinin
  • Pain neuromodulation
  • Fever (pyresis)
190
Q

What are the roles of cyclooxygenase 1 and 2? (COX-1, COX-2)

A
  • 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
191
Q

What are NSAIDs?

A
  • 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
192
Q

What are leukotrienes?

A
  • Product of arachidonic acid, w/ 5-Lipoxygenase
  • Pathway associated with inflammatory/immune responses
    • allergic reactions & anaphylaxis
  • LTC4, LTD4, LTE4
193
Q

What is the mechanism of action for Aspirin? How does it induce asthma?

A
  • 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
194
Q

What are selective COX-2 inhibitors?

A
  • 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)
195
Q

How does Acetaminophen work? Side effects?

A
  • 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
196
Q

Describe the mechanism of Synthetic Corticosteroid drugs.

Adverse effects?

A
  • 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
197
Q

What signaling regulates epithelial cell positioning and differentiation?

What signaling determines cell lineage specification?

A
  • Wnt - determines positioning/polarity
  • Notch - determines what to differentiate into
198
Q

Describe the cellular constituents of the mucosal system

A
  • 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
199
Q

What are 2 examples of antimicrobial peptides?

A
  • 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
200
Q

What are intraepithelial lymphocytes?

Natural vs. Inducible?

A
  • 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)
201
Q

What are the predominant T cells in the lamina propria?

A
  • 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
202
Q

What antibodies are dominant mucosal immunoglobulins?

How are they transcytosed?

A

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
203
Q

What is the function of Follicle Associated Epithelium? (FAE)

A

Mediate cross-talk between luminal flora and mucosal immune system

204
Q

Describe the function of commensal microbiota and its relationship to homeostasis and disease

A
  • 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)
205
Q

What is the principle of induction therapy and what drugs are used?

A
  • 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)
206
Q

What is the basic principles of Maintenance Therapy?

A
  • Use multiple drugs to achieve synergistic effects and minimize toxicities
  • Calcineurin Inhibitor, glucocorticoid, mycophenolate mofetil
207
Q

Calcineurin inhibitors

  • Purpose?
  • Example?
A
  • 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
208
Q

mTOR inhibitors

  • Purpose?
  • Examples?
  • Mechanism?
  • Side effects?
A
  • 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
209
Q

Cytotoxic drugs

  • Example
  • Mechanism/purpose
  • Side effects
A
  • 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
210
Q

Immunosuppressive antibodies

A
  • 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
211
Q

Glucocorticoids

  • examples
  • Mechanism of action
A
  • 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
212
Q

What are the various parts of the immune system that can be dysfunctional in primary immunodeficiencies?

A
  • B cells
  • T cells
  • Complement system
  • Phagocytic system
  • Antibody (50%)
213
Q

Describe the warning signs of primary immunodeficiency

A
  • 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
214
Q

When should a primary immunodeficiency be considered?

A
  • 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
215
Q

What are the types of infections associated w/ each category of immunodeficiency?

A
  • 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
216
Q

Characteristics of Severe Combined Immunodeficiency? (SCID)

  • category?
A
  • 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
217
Q

Characteristics of DiGeorge Syndrome?

  • Category?
A
  • 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
218
Q

Characteristics of Ataxia Telangiectasia?

A
  • 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
219
Q

Characteristics of Wiskott-Aldrich syndrome?

A
  • 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
220
Q

What are some B-cell (Antibody) deficiencies?

A
  • 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
221
Q

What are some phagocytic disorders?

A
  • 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
222
Q

What are the basic testing procedures used in each category of primary immunodeficiency?

A
  • 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
223
Q
A

Immunity (1 decks)

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