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Elements of the Immune System

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1 Elements of the Immune System
Cells of the Immune System Chemical Mediators Cytokines, Chemokines, Complement, Eicosanoids Apoptosis Acute Phase Response Inflammation Fever Innate/Specific Immunity

2 Cells of the Immune System
Cells of the Immune System (white blood cells [WBCs], leukocyte) Hematopoietic stem cells to: Myeloid cell line Monocytes/macrophages, neutrophils, eosinophils, basophils, megakaryocytes, erythrocytes (red blood cells [RBCs]) Lymphoid cell line B lyphocytes , T lymphocytes, natural killer (NK) cells

3 Cells of the Immune System Hematopoietic cell differentiation; Fig 11-1

4 Cells of the Immune System
White blood cells distinguished by Morphology/stain Function Cell surface markers Clusters of differentiation (CD) Major histocompatibility complex (MHC) antigens MHC I (CD8) on all nucleated cells MHC II (CD4) on antigen presenting cells

5 Cells of the Immune System Lymphoid Organs
Primary lymphoid organs (sites of hematopoiesis) Bone marrow Thymus – T cell maturation Secondary lymphoid organs (sites of T cell activation) Lymph nodes Peyer’s patches Tonsils Spleen

6 Cells of the Immune System
Polymorphonucleocytes (PMNs) or granulocytes refers to neutrophils, eosinophils and basophils. Howerver, term “PMN” generally refers to the most abundant of these, neutrophils Neutrophils = PMNs = segmented neutrophils (“segs”) Take up hemotoxylin (basic) and eosin (acid) (H&E) stains = pink multilobed 50-70% of circulating WBCs Professional phagocytic cell (Immature) band (unsegmented) forms to mature segmented neutrophils Bacterial infection = mobilization = increased number of neuts with some bands = shift to the left In blood 7h, in tissues 3 days 1st line defense against bacteria but short lived

7 Cells of the Immune System
Neutrophils: continued Granules = lysosomes Primary (azurophilic) O2-independent = Elastase, lysozyme, defensins, O2-dependent = myeloperoxidase Secondary (specific) O2-independent = lactoferrin, lysozyme O2-dependent =NADPH oxidase cofactors

8 Cells of the Immune System
Neutrophils: continued Receptors for recognition of microbes by neutrophils Receptors for opsonins Receptors of complement (C’) proteins Receptors for Fc portion of Abs Toll-like receptors (TLRs) Seven-transmembrane alpha helical receptors; stimulate migration for bacterial peptides for chemokines

9 Cells of the Immune System
Mononuclear phagocytes Monocytes in blood (3-8% of WBC) differentiate into macrophages in tissues Macrophages (Macs) Professional phagocytic cells like neutrophils Terminology: Kupffer cells (liver), histiocytes (CT), microglial cells (brain), osteoclasts, alveolar Macs “Reticular Endothelial System” (RES) old term referring to all monocytes and macrophages

10 Cells of the Immune System
Macrophages : continued Contribute to both innate and adaptive immunity Monocytes in blood for 1 day; Macs live months/years in tissues Unlike neutrophils, macs proliferate Antigen-presenting cell (APC) other APCs = B cells and dendritic cells (DCs) Respond slower than PMNs but live longer in tissues Secrete many cytokines: shock Activated (angry) Macs better killers than neutrophils Phagocytize more vigorously, use more O2, more enzymes,

11 Cells of the Immune System
Macrophages: continued Recognition of microbes by macrophages Receptors for opsonins Receptors for C’ proteins Receptor for Fc portion of Abs Toll-like receptors Mannose receptors Bind terminal mannose & fucose on bacterial glycolipids and gl-proteins Seven-transmembrane alpha helical receptors; stimulate migration for bacterial peptides for chemokines

12 Cells of the Immune System
Toll-like receptors (TLRs): from Drysophila “toll” protein = family of membrane proteins on PMNs, Macs, and dendritic cells that recognize microbial molecules. Stimulate innate immune responses by these cells TLR receptors on humans cells (TLR-1 – TLR-13) Recognize pathogen-associated molecular patterns (PAMPs) LPS, peptidoglycan, teichoic acid, lipoarabinomannan, flagellin, fungal glycans, unmethylated cytosine-guanosine DNA, RNA2, other Some TLRs need second signal; TLR-4 recognized LPS-CD 14

13 Cells of the Immune System
Receptors and responses of phagocytes

14 Cells of the Immune System
Phagocytosis/killing of microbes by neutrophils and Macs Phagocytosis Phagocytosis = >0.5 um; pinocytosis for smaller particles Microbes adhere to surface receptors which deliver signals Cytoskeleton-dependent process of engulfment Cup-shaped membrane projects around microbe If projected membranes don’t meet properly, get coiling phagocytosis? Vacuole “zips-up” and pinches off = phagosome Phagocytosed microbes (hopefully) killed by neuts and Macs Phagocytosed microbial peptides presented in surface MHC II molecules of Macs (not neutrophils)

15 Cells of the Immune System
Coiling phagocytosis

16 Cells of the Immune System
Phagocytosis/killing of microbes by neutrophils and Macs Killing Phagocytes must be activated to kill Neuts activated by surface receptors TLR, Fc, C’ receptor Macs activated by those, mannose receptor, and receptor for IFN-g Phagosome fuses with lysosome = phagolysosome = killing site Oxygen-dependent killing by neutrophils and Macs Phagocyte oxidase in phagolysosome membrane reduces O2 into reactive oxygen intermediates (ROIs) such as superoxide with NADPH Superoxide dismuted to H2O2 Neuts - myeloperoxidase converts H2O2 + Cl ions to hypochlorous ions Macs – inducible nitric oxide synthase (iNOS) catalyses conversion of arginine to citrulline, releasing diffusible NO gas. NO + H2O2 or O2- = toxic radicals Oxygen-independent killing by neutrophils enzymes from granules kill Gram negative organisms by disrupting membranes and other mechanisms

17 Cells of the Immune System
Neutrophils vs Macrophages Both are professional phagocytic cells Neutrophils move to insult first Macrophages (but not neutrophils) proliferate Macrophages (but not neutrophils) contribute to adaptive immunity Macrophages (but not neutrophils) are APCs Neutrophils (but not macrophages) produce myeloperoxidase Macrophages (but not neutrophils) produce nitric oxide Macrophages are major producers of cytokines Over-production of Mac cytokines = shock

18 Cells of the Immune System
Mast Cells Derived from marrow Relatively large (10-13 um), tissue-residents cells Connective tissue: skin, lung alveoli, GI mucosa, nasal mucosa Receptors: (1) IgE antibody (2) TLRs (3) complement ~100 densely packed metachromatic granules contain Histamine, TNFa, other preformed inflammatory mediators Activate receptors = degranulation and release of mediators Inflammation Immediate hypersensitivity with cross-linking of IgE

19 Cells of the Immune System
Basophils Similar to mast cells but circulating, different lineage, and small (5-7 um) Least common circulating WBC - <0.3% Takes up hematoxylin (basic) stain – blue High affinity IgE receptors; triggered when Ag binds to IgE Late phase of IgE-associated allergic reactions in tissues

20 Cells of the Immune System
Eosinophils Take up eosin = red 1-6% of circulating WBCs Granules with phosphatase, peroxidase, basic proteins Receptors for IgE, IgG, and IgA Allergic reactions and parasitic infections Release reactive proteins some toxic to parasitic worms Phagocytic cell ???

21 Cells of the Immune System
Megakaryocyte Large ( um diam) WBC with lg nucleus Neutrophils have a diameter of um In bone marrow Produces ~3000 platelets per cell Platelets are anucleate cytoplasmic fragments Smallest circulating blood cells (2 um diam) Erythrocyes 6 um diam with 2 um thickness 10 day life span in circulation Form blood clots and release mediators from granules

22 Cells of the Immune System
Dendritic Cells (DCs) = an antigen presenting cell (APC) Myeloid origin primarily Terminology Precursor DCs in circulation Immature DCs in tissues: capture Ag but do not present; to nodes Have sticky, octopus-like arms (dendrites) Fc receptors, mannose receptors, Toll-Like Receptors (TLRs) Langerhan’s cells in skin Mature DCs in T-cell zones of lymph nodes; present Ag Fewer receptors but more MHC-I and II molecules on surface

23 Cells of the Immune System
Lymphocytes: smaller than myeloid leukocytes; lg nucleus and agranular cytoplasm B cells: APCs; antibody production (plasma cells); memory cells Surface with Igs, MHC II, C’ receptors T cells: helper T cells and cytotoxic T cells 60-80% of blood lymphocytes Surface with TCR, CD3, CD4, CD8 NK (natural killer) cells; lg granular Fc receptors for ADCC Recognize and kill virally infected cells

24 Cells of the Immune System
Natural Killer (NK) cells Large granular lymphocyte (not B or T cells; no surface Ig or TCR) 5-20% of monocytes in blood Stimulated by INFa, INFb, from virally infected cells Stimulated by TNF and ILs from TH1 cells and activated Macs and DCs Granules with perforin, granulysin (creates pores) and granzyme (induces apoptosis) Like cytotoxic T cells (but cytotoxic T cells = adaptive immunity) Kills cells with reduced MHC I expression Activates Macs by secreting INFg No specific immunity or memory Similar to neutrophils and Macs in this respect Also IgG Fc receptors for antibody dependent cell cytotoxicity (ADCC) adaptive immunity (induced apoptosis)

25 Cells of the Immune System
Activation of responses: How PMNs, Macs, NKs recognize bugs Macs and PMNs Opsonin receptors Receptors for bacterial carbohydrates (mannose) - Macs Toll-like receptors (TLRs) Natural Killer cells Altered surface of virally infected cells Reduced expression of MHC I antigen - MHC I on cells inhibits NK cell activation Receptor for IgG Fc component For ADCC

26 Cytokines / Chemokines
Cytokines = proteins secreted by immune cells in response to microbes or other antigens (Ags) or other cytokines that mediate inflammatory and immune reactions. Major communicators between immune cells Chemokines = family of structurally homologous low-molecular weight cytokines that stimulate movement of leukocytes to tissues

27 Cytokines Interferons (INFs)
Type I = mediate innate response to viral infections INF-a = family of related peptides produced by monocytes INF-b = single protein produced by fibroblasts and other cells Although structurally different, bind to same receptor, same responses paracrine action: virally infected cells secrete to non-infected cells induce enzymes that interfere with transcription of viral RNA/DNA increase expression MHC I molecules Type II / INF-g = innate/adaptive response to intracellular infections Produced by T cells, NK cells Activates macrophages

28 Cytokines Tumor necrosis factor alpha (TNF-a)
- sometimes referred to as “cachectin” (induces weight loss) - produced mainly by activated monocytes / macrophages - NK cells, mast cells, activated T cells also - Recruit and activate neutrophils and monocytes/macrophages to sites - Induce macrophages to secrete chemokines - Stimulate vascular endothelial cells to express adhesion molecules Low conc = local inflammation Large conc to circulation: induce fever and promote acute phase response TNF-b – like TNF-a but produced by T cells

29 Cytokines Interleukins – “made by leukocytes and act on leukocytes”
Interleukin-1 (IL-1) = similar to TNF Made by activated Macs, neutrophils, endothelial cells, epithelial cells IL-2 - produced by activated T cells; act in autocrine manner on T cells IL-3 - multilineage colony stimulating factor; Produced by T cells and promotes expansion of marrow progenitor cells of blood cells. IL-4 – produced by T cells; Stimulate IgE production by B cells IL-5 - Produced by T cells; stimulate growth and activation of eosinophils IL-7 - Produced by bone-marrow stromal cells; stimulate B and T cells IL-10 - Produced by activated Macs; inhibits Macs; homeostatic control IL-12 – produced by activated monocytes; stimulates interferon gamma production by T and NK cells; mediator of innate response

30 Chemokines Chemokines (chemotactic cytokines) = lg family of structurally homologous cytokines produced by various cells in response to inflam mediators that stimulate leukocyte movement and regulate leukocyte migration from blood to tissues. Alpha chemokines = C-X-C chemokine Two cysteines separated by one amino acid Beta chemokines = C-C chemokine Receptor = seven-transmembrane alpha helical receptor

31 Complement Complement (C’) = 35 proteins, primaily in plasma
Nomenclature = numbers and letters “a” usually designates small soluble peptide “b” usually designates peptide that binds to cell surface 3 pathways to produce C3 convertase (C3 into C3a and C3b) Classical: discovered first; activated by Ag/Ab complexes IgM, IgG1, and IgG3 are isotypes that “fix” C’ Alternative: activated by bacterial surface compents (LPS) Lectin: activated by mannose binding lectin (MBL) C3b + C3 convertase = C5 convertase which cleaves C5 C5b modifies C6, C7, C8, C9 to membrane attack complex (MAC)

32 Complement Classical pathway Lectin pathway
IgM>IgG “fix” C1q which activates C1r to cleave C1s Activated C1s cleaves C2 (C2a, C2b) and C4 (C4a, C4b) C4bC2b = C3 convertase C4bC2b binds to C3b = C5 convertase Lectin pathway Mannose-binding protein (MBP) binds to mannose on cell surface polysaccharides MBP then binds to MBP associated protein -1 & MASP -2 MASP-1 and MASP-2 cleave C2 and C4 = C4bC2b = C3 convertase Alternative (properdin) pathway C3 in plasma spontaneously splits into C3a and C3b; become inactive If C3b binds to bacterial surface component (LPS), becomes stable C3b binds factor B = C3bB Factor D cleaves B from C3bB to C3bBb = C3 convertase Factor P (properdin) stabilizes C3bBb C3bBb binds to another C3b = C3b3bBb = C5 convertase

33 Complement Complement pathways

34 Complement C’ products perform multiple functions:
Chemotactic factors: C5a recuit leukocytes Anaphylatoxins: C3a, C5a promote acute inflammation by causing release of vasoactive mediators from mast cells. Opsonins: C3b adheres to bacterial cells Complement receptor CR1 on PMNs, Macs, and B cells Facilitates phagocygtosis Membrane Attack Complex: C5b,6,7,8,9 [(C5b,6,7,8)1 (C9)n] C7 is hydrophobic and inserts into lipid bilayers Gram negative bacteria have lipid outer membrane C9 polymerizes at C5-C8 to form pores Water enters cell = swelling and rupture Calcium also enters cells which induces apoptosis

35 Eicosanoids Eicosanoids = arachidonic acid (AA) metabolites
AA derived from 20 carbon FA in membrane phospholipids AA produced from membrane with phospholipase A2 Action of enzyme inhibited by glucocorticoids Prostaglandins, leukotrienes, thromboxanes Local “hormones” produced by mast cells and other cells Mediator in inflammation after infection or injury Cyclooxygenase pathway - prostoglandins and thromboxanes Inhibited by aspirin and other NSAIDS Lipoxygenase pathway – leukotrienes, lipoxins


37 Eicosanoids Eicosanoid metabolism

38 Eicosanoids Eicosanoids = arachidonic acid (AA) metabolites
Prostaglandins: Prostaglandin D2 (PGD2) binds to receptors on smooth muscle cells and acts as a vasodilator and bronchoconstrictor Chemotaxis of neutrophils in inflammation Leukotrienes Leukotriene C4 (LTC4), LTD4, LTE4 bind to receptors on smooth muscle, causing prolonged bronchoconstriction – asthma Lipoxins A4 (LXA4) and LXB4 are anti-inflammatory mediators

39 Apoptosis Apoptosis = DNA cleavage, membrane blebbing, changes in membrane lipid distribution, detachment of cells Apoptosed cells express molecules recognized by neutrophils Damaged cells removed cleanly as apposed to necrosis where damaged cells release contents in environment. Important for eliminating unwanted lymphocytes Induction by activation/cleavage of series of 14 caspases which cleave cellular elements. Caspases activated by Intrinsic: mitochondrial membrane of inactive lymphocytes leak; products activate caspase = programmed cell death or death by neglect Extrinsic: repeatedly activated T cells up-regulate FasL; reacts with Fas on same or adjacent cell NK cell and cytotoxic T cell release perforin, granulysin and granzyme

40 Acute Phase Response Acute Phase Response = production of proteins by liver in response to infection, trauma, inflammation, malignancies Within hrs of event but remain elevated during chronic insults From IL-1, TNF, INFg, etc by monocytes, Macs, endothelial cells Unique proteins: C-reactive protein (CRP) = reacts with C polysaccharide of pneumococci serum amyloid A (SAA) Elevated “normal” proteins: C’ components, fibrinogen etc. Other liver protein synthesis reduced: albumin; anemia of chronic disease? Objective evidence for disease in occult infections or diseases Tests CRP measurement (ELISA) Erythrocyte sedimentation rate (ESR) increased

41 Erythrocyte sedimentation rate
The erythrocyte sedimentation rate (ESR), also called a sedimentation rate, is the rate at which RBCs precipitate in a period of 1 hour. It is a non-specific measure of inflammation. To perform the test, anticoagulated blood is placed in an upright tube, and the rate at which the RBCs fall is measured and reported in mm/h. The ESR is governed by the balance between pro-sedimentation factors, mainly fibrinogen, and those factors resisting sedimentation, namely the negative charge of the erythrocytes (zeta potential). When an inflammatory process is present, the high proportion of fibrinogen in the blood causes red blood cells to stick to each other. The red cells form stacks called 'rouleaux' which settle faster

42 Inflammation Inflammation = complex reaction to microbes & necrosis
Vascular responses, migration/activation of leukocytes, systemic Destroy, dilute, wall off injury Injured tissue replaced by fibrous tissue = scarring and repair Mediated by chemical factors Terminated when insult eliminated and by anti-inflam mechanisms Types of inflammation Acute = rapid onset (seconds or minutes), short duration (hrs, days) with exudate and neutrophils Chronic = slow onset with long duration and characterized by macrophages and lymphocytes, new blood vessels, fibrosis, (granulation tissue), tissue necrosis

43 Inflammation Acute Inflammation
Vessel dilation, leaky microvasculature, emigration of cells & fluid Fluid migration from circulation to tissues: Transudate = normal, low protein content, sp gravity < 1.012 Exudate = with inflammation; high protein, cells Edema = fluid but few cells Purulent (pus) = lost of cells, mostly neutrophils Stimuli Infections Trauma, tissue necrosis, foreign bodies Chemical agents Hypersensitivity reactions

44 Inflammation Acute inflammation: continued
Vasodilation induced by histamine, NO on vascular sm muscle Leaks due to endothelial gaps in venules Histamine, leukotrienes Primarily from mast cells rapid contraction of cytoskeletal proteins IL-l, TNF, INFg = delayed, endothelial cell retraction Extravasation of leukocytes Margination of leukocytes with slowing of blood flow Rolling = leukocyte transient adherence to endothelial cells Adherence due to up-regulation of selectins, integrins, other Mediated by histamine, platelet activating factor (PAF), TNF, IL-1, Pavementing = leukocytes firmly adhere to endothelial cells Diapedesis = movement of leukocytes thru vascular wall to tissues

45 Inflammation Leukocyte migration from blood vessels; Robbins Fig 2-6 p 53

46 Inflammation Acute inflammation: continued
Chemotaxis = migration of leukocytes to site of injury MOA “chemotactant” binds to specific receptor on leukocyte Action of second messengers result in polymerization of actin Pseudopodia extension and fusion “chemoattractants” = chemokines, C5a, leukotriene B4, bact. proteins Termination of response Stimulus ends, mediators short-lived Anti-inflammatory cytokines Lipoxins LXA4 and LXB4 Transforming growth factor B (TGF-B) from Macs

47 Inflammation Chronic inflammation = simultaneous inflammation, tissue destruction and attempts to repair Causes: Persistent infection - tuberculosis Prolonged exposure to toxic agent Exogenous = silicosis Endogenous = arthrosclerosis Autoimmunity Morphological features Infiltration with mononuclear cells (Macs, lymphocytes, plasma cells) Tissue destruction from agent and inflammatory cells Attempts to heal by connective tissue replacement

48 Inflammation Chronic inflammation: continued
Mononuclear cell infiltration Macrophages are the major player blood monocytes live 1 day, tissue Macs live months to years Overtake neutrophils as predominant cell type by 48h Macrophages proliferate (unlike neutrophils) Lymphocytes - recruited by IL-1, TNF, and chemokines from Macs Secrete INFg which activates Macs (bidirectional interaction) Eosinophils: for IgE mediated reactions – parasitic infections

49 Inflammation Chronic inflammation: continued
Granulomatous inflammation – granuloma formation Persistent infection or stimulus Aggregation of macrophages that are transformed into epithelium-like cells (epitheloid cells) Giant cells = epitheloid cells that fuse together Focus surrounded by collar of lymphocytes (and some plasma cells) Older granulomas develop rim of fibroblasts and CT Note – different from granulation tissue which is the tissue of early repair (24 h after injury) characterized by angiogenesis and fibroblast proliferation

50 Fever Fever = pyrexia = > 1oC
Neural pathways for thermoregulation in hypothalmus Cytokines of innate immune system (TNF, IL-1 = endogenous pyrogens) bind to receptors on vascular endothelial cells in hypothalmus. Endothelial cells then produce prostagland PGE2, and other eicosanoids that reset hypothalmic thermoregulatory center. LPS, other products = exogenous pyrogens (stimulate leukocytes to release cytokines) NSAIDS inhibit cyclooxygenase; block prostaglandin synthesis Fever of unkown origin (FUO) = >101F for 3 weeks Caused by infections, rheumatic fever, sarcoidosis, neoplastic diseases, drugs Note: pyogen = pus pyrogen = fever

51 Innate Immunity Protection against infection that relies on mechanisms that exist before infection First line of defense Barriers Skin (epidermis and dermis) Mucous membranes: respiratory, GI, genitourinary tracts Lacrimal apparatus: tears Saliva Epiglottis Chemical Sebum: acids Perspiration: lysozyme Gastric juice Urine transferrin

52 Innate Immunity Protection against infection that relies on mechanisms that exist before infection Second line of defense Phagocytosis Inflammation Fever Complement Intererron

53 Adaptive Immunity Protection that develops after exposure to an agent and is specific for that agent Humoral immunity – for intracellular and extracellular pathogens antibodies (Abs) Prevent reinfection and spread Eliminate agent opsonization; ab interacts with both agent and host cell) Fix complement (C’) (opsonization, bactericidal Ab) Large number (polyclonal) ; non-self Surface receptors on B cells Cell-mediated immunity (CMI) Up-regulated Macs Cytotoxic T cells

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