beginning early and becoming the major source during the 2nd semester
Bone Marrow Phase
- includes other lymphatic tissues
- beginning in 2nd trimester and becoming the only location in adulthood
General Trends of Hematopoeisis
1. Cell diameter decreases
2. Cytoplasm becomes less basophilic (hemotoxylin staining)
3. Hemaglobin deposition imparts a pink color
4. Nuclear to cytoplasmic ration decreases (nuclear diameter decreases
5. Nuclear color changes from purplish red to dark blue
6. Nuclear chromatin becomes condensed
Hemopoietic Stem Cells (HSCs)
- gives rise to all blood cell lineages
Hemopoietic stem cells (HSCs)
Pluripotent, gives rise to all 3 germ layers and all blood cell lineages
-can give rise to all three germ layers (endoderm, mesoderm, epiderm)
- gives rise to all blood cell lineages
- can differentiate into non-blood cell lineages outside of the bone marrow
Stem Cell Factor
-produced by bone marrow stromal cells
- also fetal tissue
- c-kit receptor
-signal induces self renewal and differntation
- same as C kit ligand
Stem Cell Factor
C-Kit Ligand Produced by BM stroma
C-kit receptor: expressed by HSC. RTK. Activates MAPK, PI3K, Jak/STAT and other kinase pathways. Proto-oncogene. Signaling: self-renewal, differentiation (directed by probability & environmental niche) synergistic w/ other signals
Stem cell factor
C-kit ligand, produced by bone marrow stomal cells
-produced by bone marrow stromal cells
- also fetal tissue
- c-kit receptor
-signal induces self renewal and differntation
-same as Stem Cell Factor
- expressed by HSC
- Tyrosine Kinase Receptor (activate a number of pathways including MAPK, PI3-K and JAK/STAT)
- signal induces 1. Self renewing and 2. differentiation directed by probability and by the environmental niche/ synergistic with other signals
expressed by HSC, TKR, proto-oncogene, signaling induces self-renewal and differentiation
(Fe-protoporphyrin IX) 4 Nitrogens, one Fe2+, binds one O2
First step of heme synthesis. Glycine + succinyl-CoA --> ALA via ALA synthase (committed, rate-limiting). 2 ALA --> porphobilinogen via PBG synthase/ALA dehydratase.
Second step of heme synthesis. 4 porphobilinogen --> protoporphyrin ring. Protoporphyrin + Fe --> heme via ferrochetolase
Alpha globin chain
Beta globin chain
Chromosome 11 (also non-alpha chains)
Underproduction of globin chains (excess heme), results in microcytic hypochromic anemia, decreased mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH)
Microcytichypochromicanemia with prominent targetcells on peripheral smear. Mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCG) decreased.
HbAdecreased, HbA2 and Fcanincrease (or other abnormal Hb: S, C, H, Barts, E).
Reduced production of alpha. UpB or gamma.
HemoglobinHdisease: loss of 3/4alpha genes in adult. Formation of hemoglobinH (B tetramers).
Thalassemiamajor: loss of all4alpha genes in utero, most severe form, hemoglobinBarts (gammatetramers), hydropsfetalis.
Impaired production of Bglobin, excessalpha.
Elevated Hb F, possibly A2.
B thalassemia majormostsevere, Cooley'sAnemia.
Transports Fe in plasma from site of absorption/storage to marrow
Adult hemoglobin. 2 alpha, 2 beta chains
Fetal hemoglobin. 2 alpha, 2 gamma chains.
Adult hemoglobin 2. 2 alpha, 2 delta chains.
Reduced Hb, no oxygen bound
Hb bound to O2, can be measured by pulse oximetry
<3% total Hb, Hb carrying oxidized (ferric) iron, loses ability to carry O2
Converts methemoglobin back to hemoglobin, found in erythrocytes
Oxidized, partially denatured Hb, May result in RBC destruction and hemolysis, usually due to sulfur-containing drugs or aromatic amine drugs
Oxidized, partially denatured. Cannot carry O2.
Sulfonamides, aromatic amine (phenacetin).
Usually <3% of total Hb, hemoglobin carrying CO produced during heme degradation to bilirubin. Also formed by CO poisoning.
Carrying CO produced during heme degradation to bilirubin (or from CO poisoning).
Hb bound to CO2
Ferric reductase (Dcytb)
Reduces dietary ferric iron (Fe3+) to ferrous iron (Fe2+) for absorption into apical surface of duodenum epithelial cells
Facilitates transcellular movement of Fe2+, cotransports Fe2+ and H+ inside cell
-inhibitor of tyrosine kinase receptor
- used to treat leukemia
non-specific inhibitor of RTKs, used to treat chronic myeloid leukemia
Lineage Restricted Progenitor Cells
- Descendents of HSCs in bone marrow
- Multipotent, non-renewing
- Previously referred to as colony forming unites (CFU)
1. Common Myeloid Progenitor Cells (CMP)
2. Common Lymphoid Progenitor Cells (CLP)
Lineage Restricted Progenitor Cells
From HSCs in bone marrow
Multipotent, non-renewing. Also known as CFUs. Two categories: Common Myeloid Progenitor (CMP) Common Lymphoid Progenitor (CLP)
(contain clotting factors and activators, adhesion and vasoconstrition signals, hydrolytic enzymes and clot resorption signals
Mitochondria, peroxisome, glycogen, granules (contain clotting factors and activators, adhesion and vasoconstriction signals, hydrolytic enzymes and clot resorption signals).
-open canalicular system (OSC)(remnants of membrane channels that subdivided the precursor megakaryocyte into platelets)
-Dense tubular system (storage for calcium ions, originates form RER of precursor)
Open canalicular system (OCS):
-Remnants of membrane channels that subdivided precursor megakaryocyte.
-Storage for calcium ions
-Originates from rER of precursor megakaryocyte.
6 step process of thrombopoiesis
Location of thrombopoeisis
CMP in thrombopoeisis
under influence of cytokines: GM-CSF and IL-3
megakaryocyte-committed progenitor cell
-monopotent stem cell
-endomitosis (chromosomes replicate but cell does not divide)
-under influence of cytokines, they differentiate Thrombopoeitin
-scattered azurophilic granules
division of the nucleus
division of the cytoplasm
chormosomes replicate but cell does not divide
-regulator of platelet production
-produced by the liver (less in kidneys and bone marrow)
-prevents apoptosis of megakaryocytes
-promotes megakarycoyte maturation
-promotes proliferation of Committed thrombocytic Precursors
-synergistic affect with platelets agonists (promotes thrombosis)
Primarily from liver (BM & kidneystoo, sk musc). Promotesproliferation of committed thrombocytic precursors, maturation of megakaryocytes. Preventsapoptosis of megakaryocytes. Synergist with platelet agonists (promotesthrombosis).
c-Mplreceptor (on platelets, megakaryocytes and precursors)
Acts on HSC too. Constitutive and facultative production. Induced by inflammcytokines (esp IL-6) and thrombocytopenia
regulates platelet production, produced by liver, prevents apoptosis of megakaryocytes, c-MPL receptor
Decrease in TPO
expressed on platelets, megakaryocytes and precurors
-activating mutations in these components
-too many platelets, abnormal clotting
Activating mutation in component(s) of thrombopoiesis. Too many platelets.
too many platelets
too many platelets due to a secondary mechanism
Secondary (not thrombopoiesis) cause of too many platelets.
too many platelets due to secondary mechanism (not mutation)
not enough platelets
secretory vesicles filled with cytotoxic enzymes and peptides
-release via degranulation
contain cytotoxic enzymes, cause allergies and inflammation
Azurophilic (nonspecific) granules
filled with enzymes that function in phagocytosis
(cells contain granules)
neutrophils, eosinophils, and basophils
-Lymphocytes (T cells, B cells, and NK cells)
-cells without specific granules
highly basophilic, uncondensed nucleus
-spherical nucleus iwth 3-5 nucleoli
-small amount of granules
-Nucleus large & round, reddish-blue, fine chromatin
-nucleus = 2-4 lobes, heterochromatin located in the periphery
-cytoplasm - lacks staining
Polymorphonuclear neutrophils, larger than RBC, 2-4lobes, heterochromatin at periphery, cytoplasmlackstaining.
Primary granules: elastase and myeloperoxidase, can barely be resolved.
Secondary: lysozyme and other proteases. Weak staining, responsible for name. Smaller, even.
50-70% total leukocytes
larger than erythrocytes
-nucleus=bilobed, heterochromatin located in periphery
-cytoplasm =eosinophilic staining due to presence of specific granules and azurophilic granules
Larger than RBC. Bilobed nucleus. Heterochromatin at periphery. Cytoplasm eosinophilic staining (refractilespecific granules brightred, azurophilic granules).
Facilitatemacrophagocytosis of microorganisms.
Major basic protein (MBP)
- Primarycomponent of crystallinecenter of eosinophil
- Binds to and disruptsmembrane of parasites (Fc receptor)
- Causes basophils to release histamine via Ca-dependent mechanism
1-5% of leukocytes (not likely to see).
Major Basic Protein
1. predominant component of crystalline center of eosinophil granule
2. binds to and disrupts the membrane of parasites (mediated by Fc receptor)
3. Causes basophils to release histamine by a Ca2+ dependent mechanism
Eosinophil Cationic protein
1. Neutralizes heparin
2. together with MBP, causes the fragmentation of parasites
-larger than erythrocytes
-nucleus=lobed, obscured by INTENSE basophilic staining
-heterochromatin located at the periphery
-Cytoplasm=basophilic staining due to the presence of specific granules and azurophilic granules
-less than 1% circulating WBC
Larger than RBC. Bilobed, obscured by intensebasophiliccytoplasm of large darkblue-stainingspecific granules (sulfatedcarboxylicacidproteins, heparin). Heterochromatin at periphery. IgEreceptors, release histamine.
Basophilia (> 150/uL) in acutehypersensitivity, viral infections, chronicinflammation such as rheumatoid arth and ulcerative colitis.
<1% leukocytes. Likely won'tsee.
-Nucleus = indentation site at center
-cytoplasm = Golgi apparatus and centrioles located at indentation, small dense azurophilic granules, smooth and rough ER, mitochondria
Largest of WBCs. Indentation at center of eccentric, kidney-shaped nucleus. Fine chromatin. Cytdoesn'tstain (light blue, grey). Lysosomes give fine, granular appearance. Golgi and centrioles at indentation. Smalldenseazurophilic granules. sER & rER. Mitochondria.
3days in blood. Diff at local tissues. Macro=CT. Osteoclasts. Langerhans cells. Microglia. Redpulp. Kupffer cell. Alveolar macrophage.
Lysosomesincrease in number when monocyte becomes macrophage.
monocytes that have migrated to tissues
skin: Langerhans cell
spleen: red pulp
phagocytose or pinocytose Ag, not as effective as DCs at activating naive T cells, but very good at activating memory T cells.
Granulopoiesis (part of myelopoeisis)
Location: bone marrow with final differentiation of most occuring in connective tissue after extravasation due to signaling
Uptake from duodenum. Marcrophage degradation of hemeoglobin porphyrin ring to biliverdin.
"Iron buffer system," takes up excess circulating iron, releases iron when circulating levels are too low
Storage form of iron (bound to apoferritin), deposited in liver and reticuloendothelial system (RES)
Above normal RBC count, RBC production > RBC destruction (high altitude, EPO)
Too many RBCs. Higher viscosity; bad.
Rate of synthesis > destruction
Below normal RBC count, RBC destruction > RBC production
Free hemoglobin in plasma, caused by hemolytic anemia, autoimmune processes, transfusion reactions, and drug-induced hemolysis
Free hemoglobin in urine, caused by hemolytic anemia, autoimmune processes, transfusion reactions, and drug-induced hemolysis
Underproduction of Hb alpha chains, results in excess beta or gamma chains. HbH: loss of 3/4 alpha chain genes results in HbH (beta tetramers) Thalassemia major: loss of all four alpha genes, results in HbBarts (gamma tetramers, hydrous fetalis
Underproduction of Hb beta chains, results in excess alpha or gamma chains Beta-thalassemia major: most severe form, "Cooley's anemia"
Bilirubin, bile acids/salts, cholesterol
In RBC: Hb-->heme-->biliverdin (heme oxygenase)-->bilirubin (biliverdin reductase)--> transported to liver (albumin) In liver: bilirubin (unconjugated)-->bilirubin diglucuronide (conjugated) (UDP-GT)-->transport to intestine (bile duct) In intestine: bilirubin-->urobilinogen (bacteria)-->stercobilin (excreted in feces) In kidneys: urobilin excreted in urine
Accumulation of bilirubin in extracellular fluid, results in yellow discoloration of skin, sclera, and mucus membranes. Bilirubin >2 mg/dL
Hepatitis: decreasedconjugation or excretion. High conj and unconj bilirubin, total levels 5-10 mg/dL.
high serum and urine conj. bilirubin, low urobilin/stercobilin in stool (dark urine, light stool).
Cause: mechanical obstruction of bile into into intestine (e.g. gallstones or tumors)
Endothelial cell properties
antiplatelet: block platelet adhesion and aggregation
anticoagulant: inhibit coagulation
fibrinolytic: dissolve clots
Endothelial cells produce:
NO and prostaglandin (PGI2): impede platelet adhesion and aggregation, vasodilation, synthesis stimulated by thrombin and cytokines. Adenosine diphoshpatase (Adp): ADP favors attachment of platelets to ECM, Adp degrades ADP
-Natural killer cells
90% small, unactivated, 10% large, activated
-90% of lymphocytes in blood stream
-nucleus = slightly indented, intensely staining
-cytoplasm = thin pale, blue rim, some granules, golgi, mitochondria, and free ribosomes
90% of lymphocytes in blood. Dormant. Nucleus slightlyindented, intenselyblue staining. Cytoplasmthin pale blue (basophilic) rim. Somegranules, golgi, mitochondria and free ribosomes.
activated lymphocytes and natural killer cells
Activatedlymphocytes and NKcells. Nucleus only slighlyindented. Occasional primary granule (lysozome) present.
Granulocyte-Macrophage Colony Stimulating Factor
Maturation of BM cells into dendriticcells and monocytes.
Produced at sites of infection to mobilizeneutrophilsfromBM. Both used to recover from chemotherapy as well as BMtransplantation.
Fetal: yolk, liver, spleen.
Postnatal: BM, thymus.
Secondary: lymph nodes, spleen, GI and respiratory tracts.
X-linked sever combined immunodeficiency
Markedly decreasedT cells; normal or increasedB cells, reduced serum Ig.
Cytokinereceptor common gammachain gene mutations, defectiveT cell maturation due to lack of IL-7 signals (lack of IL-7receptor).
Granulocyte colony stimulating factor
Neutrophils. Produced by endothelium, fibroblasts, macrophages in all organs
Ferric or ferrous. Ferrous more readilyabsorbed. Ferricreduced at ExC membrane by ferricreductase (Dcytb) before absorption.
DMT1contransportferrous and H+ into cells.
Ferrous enters lumen and binds mobilferrin (ferroportin: expression regulated by hepcidin) at basolateral. Exit cell, converted to ferric, bindstransferrin for transport
Heme iron intake
From myoglobin in meats and hemoglobin.
HCP1 transport. Hemeoxygenase splits heme iron, releases freeferric, converted to ferrous, continue as in nonheme (exit, conversion to ferric, tranferrin).
Too much iron in body
Inhibits ferroportin at basolateral aspect of enterocytes and in macrophages. Fe homeostasis.
Bilirubin that has been converted by bacteria in intestine to urobilinogen (stercobilinogen). Goes onto form either stercobinogen (colorless) then oxidized to stercobilin; urobilinogen (after reabsorption; colorless) then to kidney, oxidized to urobilin.
2 UDP-glucuronicacid + bilirubin (unconjugated) to bilirubindiglucuronide (conjugated)
Biliverdin to bilirubin
Increase indirect bilirubin
- Low levels conj enzymes newborn
- Hepatic damage
Increase direct bilirubin
- hepatic damage
- bile duct obstruction (clay-colored stool)
- Dubin-Johnson (black liver)
- Rotor syndrome
Clot buster precursor, converted to plasmin by tPA (tissue plasminogen activator) or urokinase
clot buster, converts plasminogen to plasmin, activity increased 500-fold by fibrin
Increases entry of IgG, complement, and other immune cells to tissues
Increased fluid drainage to lymph nodes
Fever, shock, mobilization of metabolites
+macrophages to kill phagocytosed (intracellular) microbes via CD8 (CD40 & IFN-γ) & NK cells (IFN-γ only). Induces ROS & NOS w/in lysosome. +TH1 diff, inh TH2 (w/IL-12). B cell switch to IgG (complement, opsonization), inh IgE. +antigen processing on APCs (MHCI & II, costimulators, proteasome, transporters). +extravasation like TNF.
Source: CD4 (TH1), CD8 (T cells activated by antigen, enhanced by IL-12) & NK cells (activated by surface markers on infected cells, IL-12)
Inhibition of T cell activation and of leukocytes; differentiation (induction) of reg T cells. Counteracts effects of inflamm cytokines on neutrophils and endothelial cells. +B cells to produce IgA (mucosal immunity). Healing (fibroblasts and macrophages; collagen synth & matrix remodeling). Angiogenesis.
Source: CD4 reg T cells; antigen-stimulated T cells; LPS-activated phagocytes; many other cell types
Similar to IL-4. Allergic inflammation: fibrosis; B cell class switch IgE. Bronchial mucus production (unique to 13). Chronic asthma; interstitial lung diseases and parasitic infection. Inflammation via recruitment: VCAM-1 on endoth cells; extravasation granulocytes & monocytes.
Source: TH2 during early phase allergy; TH1 & NK too (?). Basophils, eosinophils.
Receptor: B cells, monocytes/mac, DC, eos, bas, fib, endoth, bronch epith. NOT T CELLS.
TCR must be specific for both peptide and HLA
the ability of T cells to recognize Ag's when associated with the organism's own HLA haplotype, providing a dual recognition system critical to T cell function.
No CD8+ T cells
IgG, efficient C' activation
IgG, carbohydrate Ags
No CD4+ T cells
IgG, high affinity to Fc receptors on phagocytic cells (opsonization)
IgG1 & 3
Eliminated with CD4+ T cell help
Protozoa: Leishmania Trypanasoma cruzi
Protozoa: Plasmodium falciparum
Fc receptor for IgG
NK cells, monocytes/macrophages & granulocytes
Fc receptor for IgG
B cells, monocytes/macrophages & granulocytes
Fc receptors for IgG
Peptide fragments presented by HLA-I, cell death by CD8+ T cell
signal transduction, part of TCR complex, present on all T cells
TH cells, signal transduction.
Ligand: MHC-II (expressed on APCs)
produce IFNgamma, promote cellular activity and macrophage activation, target killing of pathogens in phagolysosomes (intracellular microbes), associated with autoimmune disease, tissue damage, and chronic infection
Produce IL-4, IL-5, and IL-13, promote humoral immunity, isotype switching, alternative macrophage activation, associated with allergic disease
Binds B2 of MHC II.
TC cells, signal transduction.
Ligand: MHC-I, expressed by APCs and CTL target cells
Binds a3 of MHC I.
Signal transduction costimulation (2nd signal)
Ligand: B7, expressed on APCs
Signal transduction, negative regulation (CD28 antagonist)
Ligand: B7, expressed on APCs
CD28 (T cell) binding B7 (APC)
results in IL-2 production, turns T cell on, clonal expansion
CTLA-4 (T cell) binds B7 (APC)
Shuts down IL-2 production, turns T cell off.
expressed on CD4+ T cells, interacts with CD40 on APCs to strengthen adhesion, prolongs T cell-APC contact
Effect of blocking CTLA-4
less downregulation of T cells. May be used for T cell deficiencies or cancer (prostate)
Produce IL-17, neutrophilic, monocytic inflammation, target extracellular bacteria/fungi, involved in host defense and pathogenesis of autoimmune and inflammatory disease
suppress T cell function
expressed on activated T cells. Ligand: ICAM-1/VCAM-1, stable arrest on cytokine-activated epithelium at site of infection
β2 Integrin: ICAM-1; endothelium, APCs
β1 Integrin: VCAM-1: endothelium
expressed on activated T cells.
Ligand: CXCL10, activation of integrins and chemotaxis
Expressed on activated T cells. Binds CXCL10 (chemotaxis). Integrin upregulation (LFA and VLA).
Antigen that generates an immune response (not all antigens generate response).
Small molecule with epitope, need attachment to larger molecule to elicit immune response.
Cleaves C3b and C4b by using factor H, MCP, C4BP or CR1 as cofactors.
Binds C3b and displaces Bb; cofactor for factor I-mediated cleavage of C3b.
Analagous to C4BP, but for C3b. Prevents formation of C5 convertase. Factor H:C3b complex target for factor I
H binding only occurs if C3b deposited (on self cell).
C3b on microorganism protected from H. Alternative pathway.
Binds C4b and displaces or prevents association of C2A; cofactor for factor I-mediated cleavage of C4b. C4b dissociation from existing C3 convertase.
C4BP:C4b complex then a target fro factor I
Cofactor for factor I-mediated cleavage of C3b or C4b.
Found on self membranes.
Displaces C2a from C4b classic and Bb from C3b alternative (dissociation of C3 convertase)
Blocks C9 binding to C5b678 on cell surface.
C3b and C4b hydrolyzed
Classical and lectin PWs
Binds C1r and C1s, dissociation from q.
Removes MASP enzymes from MBL complex
Binds C3b molecules on surface of cells, cleavage by factor I. Self vs. non-self.
Binds to fluid phase C5b67, prevents binding to membranes. Does not prevent binding with 8 and 9, but inconsequential.
peptide binding groove btw. alpha1 and alpha2 domains
closed ends: limits size to 8-10 AAs
alpha chain translated in ER as glycoprotein, interacts with beta2 microglobulin. HLA-I then interacts with cytosolic proteins. Then transported to cell surface. Can express 6 different types of HLA-I on a single cell (two alleles for A, B, and C).
Primarily on APCs: macrophages, dendritic cells, and B cells. Present Ag to CD4+ T cells.
Composed of 2 proteins: alpha and beta chains, both encoded by HLA-D region. Peptide binding groove formed by alpha1 and beta1 domains. Open ends, allows binding of larger peptides. Alpha and beta chains are strongly associated, not covalently linked.
Alpha and beta chains synthesized in ER, interact with invariant chain (stabilize alpha and beta chains, blocks peptide binding groove, directs transport of HLA-II to endocytic compartment).
In endocytic compartment: Ii is degraded. HLA-II binds Ag that enters cell via endocytosis. HLA-II/peptide complex then transported to cell surface. Protein Ag's come from outside the cell.
Peptide binding features
Low affinity, slow "on" rate, very slow "off" rate, allows time for HLA-peptide complex to interact with T cell. Same molecule of HLA has capacity to bind multiple peptides.
Convert proteins to peptides for display.
thymic epithelial cells
some endothelial cells
DC: pinocytosis; activation.
MΦ: pinocytosis & phagocytosis; better at activating memory T cells, primarily CD4+.
B cells: soluble Ag via sIgs; pinocytosis; effective at low Ag levels (high affinity for Ag); not as effective at presentation to naive Ts; very effective at presenting to memory Ts.
Upon Ag binding, upregulate CCR7, MHC II, B7.
pinocytose Ag and process it for presentation with HLA. Homing to T cell-rich areas in nodes and spleen. Activate naive CD4+, CD8+ T cells.
Capture of Ag
microbes enter body
phagocytosed/pinocytosed by APCs
lose adhesive markers, upregulate CCR7 (home to lymph nodes)
increase HLA and B7 expression
Lymph node: captures Ag from epithelium and CT
Spleen: captures blood-borne Ag
common HLA-associated disease (affects B*27 allele)
HLA-I: processing defects in renal cell carcinoma (TAP downregulated)
Mechanism enabling DCs to activate naive CD8 cells against viruses that do not infect DCs themselves.
Type I hypersensitivity (immediate)
different hinge structure, extra constant region
binding sites for low and high affinity IgE receptors
1/2 life: binding IgE to receptors
Control of IgG and IgE
Cross-linking of IgE on surface of mast cells and basophils
Type I Hypersensitivity
TH2, IgE, Mast Cell
FcERI (CD23a) - MCs, basophils
FcERII (CD23b) - B cells, antigen presentation
IgE 1/2 life
2 days in serum
10 days when sequester on FCERI on mast cells and basophils
high affinity FC receptors on mast cells and basophils (only cells with histamine). B cells have low affinity receptors for IgE
IgE class switching
TH2 cell dependent (IL-4, IL-14, IL-5, IL-10)
TH1 (IFNgamma and IL-12) are suppressive to atopic response
class switch: IL-4
Ag that gives rise to Type I hypersensitivity. Most are proteins.
Type I preformed mediators (5 minutes)
Type I newly generated mediators (5-30 minutes)
Low affinity IL-2R
Naive T cell
High affinity IL-2R
Activated T cell. Induced after costimulation.
Type I latent mediators (hours)
Type I late phase rxn
Persists 1-2 days, infiltration of PMN, eos, macrophages, lymphocytes, and basophils. Mast cells produce TNF-alpha and IL-1--> increased cell adhesion molecules on venular endothelial cells. Mast cells also produce neutrophil chemotactic factor. On site release of IL-5 (recruits eos). May be worse than immediate response
CD8+ T cell
Kills intracellularly infected cells. Releases perforin and granzymes.
Type II hyper sensitivity
Ab mediated: IgG/IgM/FCR/C'/surfaces
Abs bound to cell surfaces/tissue interact with FCRs on effector cells
Binding of C1 to IgG or IgM activates C' cascade
Damages target cells, localized to cells bearing the Ags
bind Fc via FCR or membrane-bound C' components. Frustrated phagocytosis (PMNs can't phagocytize tissues, release granules on site).
Cannot be transferred to another organism.
TH1, TH17, CD8
Can be transferred to another organism.
Examples of Type II
autoimmune hemolytic anemias
spontaneous, drugs, M. pneumonia
Myasthenia gravis (Abs to AChR)--> C' activation, destruction of tissues
Type III hypersensitivities
Immune complexes buildup. Similar to type II, but Ag is soluble. ICs deposit in tissue.
Three groups: persistent infection, autoimmune, inhalation of Ag.
Type III Hypersensitivity
Soluble immune complexes, neutrophils and endothelium
Type III mechanism
ICs act on basophils and platelets->vasoactive amine release (histamine, tryptophan)->endothelial cell retraction, ↑ vascular permeability-->complex deposition->platelet aggregation and C' activation->microthrombus formation->more IC deposition
Examples of Type III
Arthus rxn (allergic alvelitis "farmer's lung")
Serum sickness (large injections of foreign Ag): circulating ICs deposit in blood vessel walls and tissues->arthritis and glomerulonephritis
Stimulated by CD40, IFNγ, Microbe:TLR on DC or MΦ
Works upstream of IFN
Delayed type hypersensitivity (DTH)
Ag-dependent. MΦ activation by TH1. Rxn 24-48 hours after exposure.
Previously encountered Ag
Sensitization hapten driven in contact. Langerhan cells.
Contact (point of contact)
Granulomatous (worst), talc, persistent chronic Ag stim
T cell-mediated (CD4/CD8). Activate Mφ→local inflammation/edema (normal). If Ts are sensitized during infection (e.g. through epidermis)→continuous stimulation. 24-72 hrs post-exposure: local inflammatory response. If Ag persists→granuloma formation. Organ specific Ag: autoreactive T cells (e.g. Type I DM).
Type IV rxns
Contact: eczematous, occurs at point of contact with Ag.
Tuberculin: induced by soluble Ag, used diagnostically.
Granulomatous: clinically most important
Stages of contact sensitivity
sensitization: 10-14 days, epidermis, hapten driven, protein/hapten uptake by Langerhans cells, presented in nodes/HLA-II→sensitized effector/memory T cells
elicitation: recruit mainly TH cells to site of contact, some CTLs, proinflammatory cytokine driven, monocytes, Mφ
Tuberculin type DTH
Induced by soluble Ag, used to test for T cell-mediated response to organisms
Usually results from persistence within Mφ of intracellular microbes, other particles cell is unable to destroy. Occurs with chronic infections associated with TH1-like responses. Occurs in absence of infection (foreign body, non-immune). Substantial fibrosis.
All nucleated cells
B2 microglobulin non-HLA encoded; associates noncovalently with a3 in ER.
8-10 aas; closed ends. Each class of MHC I has a range of peptides that can bind in groove. Alpha1and2 greatest polymorphism.
B, C & A can be expressed--maternal and paternal--all at once (6 classes).
APCs; a and b chains both synthesized from HLA-D gene region. Alpha and beta strongly associated (but not covalent). 13 to 18 aas for bound peptides; open ends.
Once again, range of peptides that can bind for each allele. Alpha1 and Beta1 greatest polymorphism.
Chaperones; invariant chain; golgi; late endosome; CLIP; DM; peptide.
Greater range of peptides can bind II than I.
Inducible by TLR and IFN in phagocytes, CD40 in all, cross linking in B cells.
APCs for blood-borne antigens. Vaccinate against blood-borne pathogens in asplenic Pts.
MHC Processing Defects
Neuroblastoma: multiple defects
Renal cell carcinoma: class I Ag processing; TAP
Bare Lymphocyte Syndrome: immunodeficiency
Dental procedures. Heart valves. Endocarditis.
Pathogens, two basic mechanisms
Invasion of tissue
Production of toxins
Extracellular enzymes released by bacteria
Hyalouronidase and collagenase
Combination of invasiveness and toxigenicity.
LD50 (dose at which 50% deceased)
Variance in virulence may be genotypic or phenotypic.
Direct or indirect
Considerations: dormant or latent (carriers). Number of infectious agents released from host. Survivability of transit. Percentage of population susceptible to agent
ID50 (dose at which 50% infected)
IC vs EC pathogen
Chronic and acute, respectively
1. Translocation: stochastic crossing of PM
3. Fusion: viral envelope
Cell lysis; release of virions
Productive, latent (HSV) or tranforming (oncogenic)
Enveloped viruses (?)
Polymer of alternating N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG)
Only in gram+
Extend through entire peptidoglycan layer, appear on cell surface
Only in gram-
Composed of Lipid A, which binds LPS in the other membrane
Bacilli or rods
Slightly elongated cocci
Arranged in pairs; clusters vs chains
Staph and strep, respectively
Single polar flagellum
Several polar flagella
Several flagella at each end
Many flagella covering entire surface
Attachment to host, colonization
Toxin A: enterotoxin, fluid accumulation
Toxin B: cytopathic,
Large # spores secreted, can continue after symptom resolution
Mat, many hyphae
Mold at ambient temperature, yeast at BT
No strict anaerobes
Chitin. Cell membrane with ergosterol and zymosterol (both immunogenic)