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Effector B Cells with Ab in membrane
Memory Cells (Plasma Cells do not have these)
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Primary Lyphatic Tissue
- Antigen Independent Differentiation
- Bone Marrow
- Thymus
- Bursa
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Secondary Lymphatic Tissue
- Antigen dependent differentiation
- Lymph Nodes
- Spleen
- MALT, SALT, etc.
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Function of Epithelial Cells in Thymus
- Support
- Produce cytokines to advance differentiation
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Thymocytes
Lymphocytes in the thymus
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Extravasation
Process of leaving vascular system and entering thymus
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Epithelial vs Macrophage Function in Thymus
- Epithelial- Self identity is established (positive selection)
- Macrophages- Ensure don't trigger immune response with self (negative selection)
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Dendritic Cells react with antigen here and present it to T cell
Lymph Nodes
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Three Areas of Lymph Nodes
- Cortex - B Cell Region
- Paracortex- T Cell Region (mostly Th)
- Medulla- Plasma Cell Region
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Follicles
- Assemblages of lymphocytes in the cortex of lymph nodes.
- Mostly naive but can interact with antigen here
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Germinal Center
- Where lymphocytes interact in lymph node. When B cell is activated by Th cell, a follicle will surround the germinal center
- Another site of selection (FDC participates in selection process)
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Centrocytes
- New name for cell that has gone through the germinal center. Will eventually become a memory cell.
- No germinal center means no memory cells
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Spleen (PALS)
Majority of spleen is RBCs, but also sheathe of WBC called Pari Arteriolar Lymphoid Sheaths
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Layer of Cells in PALS
- Macrophage (APC)
- B Cells
- T Cells
- Blood Vessel
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How naive T Helper Cells Enter Lyph Nodes
From blood stream (not lymphatic)
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Post Cappillary Venule
- Lines blood vessel
- Tall epithelial layer (HEV) with unique cell surface components where cells can leave vascular system and enter lyphoid tissue
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Selective Receptor Development
During margination (leukocytes leaving circulation), the organ tells the epithelial cells to express certain receptors to allow specific cells to pass
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Diapedesis
- Process of squeezing through
- Chemokines regulate receptors
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4 Categories of Cellular Adhesion Molecules (CAMs)
- Mucin-like CAM
- Integrins
- (didn't note other two)
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Leukocyte Adhesion Deficiency
- Occurs when CD11/CD8 integrins are defective
- These two are components of ICAMs
- Leukocytes can,t get out so no inflammation
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Phagocyte Migration
- Due to breach of non-specific barriers
- Manufacture CAMs and receptors on nearby epithelium
- Occur due to vasoactive factors
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Sources of Vasoactive Factors
Injured tissue: membrane manufactures leukotriene (signal) which stimulates Mast Cells to produce vasoactive factors
Bacterial membranes: Trigger macrophages (also mast cells) to release vasoactive factors
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Compliment acting as vasoactive factor
Complement acts as a chemotactic factor, drawing leukocytes up concentration gradient
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TLR4
Toll Like Receptor that binds LPS
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Lymphocytes with TLR
Natural Killer Cells
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Receptor Mediated Phagocytosis
Phagocyte usually has to bind multiple receptors to pathogen. Then engulf it in phagosome
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C3b and CR1
C3b binds to general component of bacteria and is then received by CR1 on phagocyte
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Mechanism of Kill
- Phagosomal Killing-
- Granuloma Formation
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Phagosomal Killing
- Protein Kinase C on phagosomic membrane
- NADPH oxidase- toxic chemical (neutrophils make so much that they kill themselves)
- Myeloperoxidase- only found in neutrophils
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Granuloma Formation
Immune system surrounds pathogen with phagocytes
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Complement + Antibody = Bacteria Death
- Antibody= heat stable
- Complement= heat labile
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Classical Pathway
- C1 is activated when encounters Ag-Ab complex
- Leads to formation of MAC
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Alternative Pathway
- Very fragile pathway
- Involves many steps
- Evolutionarily the oldest pathway
- Leads to C3b without antibody (true innate)
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Lectin Pathway
- Manos Binding Lectin (MBL) is soluble and binds to bacteria. Serves as an opsinin.
- Doesn't require antibody (true innate)
- Leads to same pathway as classical, but different starting units
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Membrane Attack Complex
- C5 - C9
- Best used for lysing Gram Negative
- C8 Drill
- C9 Case for drill
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C5b Convertase
Comes in 2 forms. One for classical pathway and one for alternative pathway
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Many Checks of Alternative Pathway
- H Factor competes with B factor (inhibitory factor)
- Factor I + Factor H = attachment site for C3b which makes iC3b (innactive)
- CR1 binds Factor 1 which competes for the binding site on C3b
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Alternative Pathway Result
Usually just opsinin. Difficult to get to C5 convertase
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Other roles of C3b
- Attach to Fc receptor to clean up Ab-Ag complexes
- Bind receptors on RBC and go to spleen
- Attach to virus attachment sites to prevent access
- *Needed to reach C5
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Mast Cells Interacting with Complement Factors
C3a reacts to cause increase in chemotactic and vasoactive factors
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C Reactive Proteins (CRP)
- Produced by liver in response to IL-1 and IL-6 from macrophage.
- Serves as an opsinin, but binds C1qrs to activate it
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Four Classical Inflammation Signs
Redness
Vasoactive Factors contract smooth muscle to redirect blood flow to area
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Four Classical Inflammation Signs
Heat
- Extra blood
- Metabolic activity
- Bacteria have narrow tolerance to heat
- If doesn't work locally, will develop fever
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Four Classical Inflammation Signs
Swelling
Vasoactive factors cause epithelium to loosen so that liquid plasma can enter
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Four Classical Inflammation Signs
Pain
Vasoactive factors, but more importantly kinin cascade
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Defensins
- Antimicrobial peptide
- One of the most ancient immune defenses
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Origin of Alternate Pathway
- Arose in invertebrates
- Echinoderms
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Coelomacites
- Wandering phagocytic cells in echinoderms
- Give rise to C3 analogous protein & Factor B analogous protein
- Produce IL1 analog in presence of pathogen (self proliferation)
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IL1
Macrophages release this to trigger proliferation of T cells
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Sponge
Amoeboid immunocytes
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Tunicates
Have MHC like proteins
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Vertebrates
- Only ones to have true lymphocytes
- Lampreys were first
- Sharks were first to show T and B cell differentiation (first to have thymus and spleen)
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Evolution of Bone Marrow
Hematopoietic Stem Cells are sensitive to UV, so better to encase in bone
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Classic Ig Bivalent Structure
- 2 Identical Heavy Chains
- 2 Identical Light Chains
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N terminus vs C terminus
- N terminus is on Fab
- C terminus is on Fc
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Genetics of H chain and L chain
- L chain duplicated twice next to each other
- H chain duplicated four times
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4 Basic Effector Activities
- Neutralization of pathogen
- Complement Activation
- Opsinization
- Ab-Dependent Cellular Cytotoxicity (ADCC Reaction)
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Constant Regions of H Chain
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Amino Acids of Hinge Region
Glycine and Lysine
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Papain
Cuts hinge region into 3 sections
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Mecaptoethanol
Breaks disulfide bonds (4 regions)
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Pepsin
Cuts away Fc at disulfide bridge. Retains bivalent structure to bind 2 antigens
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Light Chain Constant Regions
- Kappa (dominant form)
- Lambda
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Hypervariable Regions
Vs
Framework Regions
- Hypervariable is antigen detecting
- Also complementarity determining region (CDR)
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N--CDR1, CDR2, CDR3--C
CDR3 is most variable
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Affinity vs Avidity
Affinity- Strength of association between antibody and antigen
Avidity- Attachment to several epitopes of antigen
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Cross Reactivity
- Some antigens occur on classes of microorganisms
- An antibody can attack any of these that it recognizes
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B Cell mIg
- Doesn't have signal transduction machinery
- borrow from Iga and IgB
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IgM and IgA
- IgM can have 1 or 5 antibodies
- IgA can have 1, 2, 3, or 4 antibodies (usually 2)
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J Chain
Binds Fc Regions to polymerize antibodies
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Isotype vs Allotype vs Idiotype
- Isotype- constant region
- Allotype- constant region
- Idiotype- variable region
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IgA and Secretion
- Dimeric IgA binds secretory receptor
- Enclosed in phagosome
- Moves across
- Leaves as Secretory IgA (SIgA)
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Poly Ig Receptor (pIgR)
- Presence of J chain brings them together
- Linkage is broken within phagosome
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Complement activating Ig
IgG and IgM
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Difference between membrane bound Ig and secreted Ig
Secreted has hydrophilic end, membrane bound has hydrophobic end that anchors it to membrane
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IL-1-like cytokine in starfish mobilizes this cell in response to bacteria
Coelomocyte
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Congenitally athymic
DiGeorge Syndrome
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Periarteriolar Lymphoid Sheath
White Pulp
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Found in the cortex of the thymus
CD4+CD8+cell
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Portal for naive lymphocytes to peripheral compartment organs
HEV
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Defensive agent secreted by macrophage
Lysozyme
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NADPH Phagosome Oxidase Deficiency
Chronic Granulomatosus Disease
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Integrin Deficiency
Leukocyte Adhesion Deficiency
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Systemic Inflammatory Cyokine-Induced
Fever
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Composed of proteolytic digestion products of C1qrs activity
C3 Convertase
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Urease secretion is an evasive tool against this defense
Stomach Acid
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Found in the medulla of the bursa of fabricus
B cells
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Endproduct of all three complement pathways
MAC
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Peripheral compartment organ focused on IgA secretory responses
Peyer's Patch
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Legionnarie's Disease bacterium inhibits its formation
Phagolysosome
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