Immune System
Kathryn Clarkson, Chapters 6 & 7
Moby Thomas, Chapters 8 & 9
Chapter 6
Human Defense Mechanisms ( table p.176)
Innate resistance or Immunity (natural or native immunity)
· 1st line of defense at birth
Inflammatory response
· 2nd line of defense
Adaptive immunity
· 3rd line of defense
· acquired or specific immunity
· slow & specific
· memory
First line of defense: Physical, Mechanical, & Biochemical Barriers
· physical barrier (cellular roadblocks)
o sloughing of dead skin cells
o coughing or sneezing
o vomiting or urination
· mechanical barrier
o hairlike cilia
o low surface temp inhibits microorganisms
· Biochemical Barriers (synthesize & secrete to trap & destroy)
o Mucus, perspiration, saliva, tears & earwax
o Use of proteins to destroy pathogens
§ Epithlial-Derived Chemical
· Antimicrobial peptides
o Cathelicdins (one….LL-37)
o Defensins (eight)
§ ά require activation by proteolytic enzymes
§ rich in granules of neutrophils for killing bacteria
§ β are synthesized in active form
· Collectins (in lungs….surfactant proteins A & D)
o Promote phagocytosis
o Interact with acquired immune system
§ Bacteria-Derived Chemicals
· Normal bacteria flora
o Prolonged antibiotic treatment alter normal flora leading to overgrowth Candida albicans or Clostridium difficile
o Lactobacillus produce hydrogen peroxide, lactic acid, bacteriocins, ect. to prevent infection of vagina & urinary tract
Second Line of Defense: The Inflammatory Response (p.179)
· 2nd line of defense
· prevent infection
· depends on activity of cellular & chemical components
· nonspecific to stimulus
· Vascular response (redness, heat, swelling, & pain)
o Blood vessel dilation
o ↑ vascular permeability & leakage of fluid out of vessel
o WBC adherence to inner vessel wall & migration to injury
o Arterioles constrict briefly near injury
o Vasodilation slows blood velocity & ↑ local blood flow to injured site
o ↑ flow & capillary permeability result in leakage of plasma, causing edema
o ↑ blood flow & concentration of RBCs at site of inflammation causes warmth & redness
o Leukocytes adhere to vessel wall
o Biochemical mediators (histamine, bradykinin, leukotrienes, substance P, & prostaglandins) stimulate endothelial cells that line capillaries & venules to retract allowing leukocytes and plasma to enter surrounding tissue
o Once in tissue, cells, & chemicals associated with inflammatory response :
§ Drainage by lymphatics facilitates Limit & control process
§ Prevent infection & further damage
§ Interact with components
§ Prepare area for healing
o acquired immunity through antigens activating B & T lympocytes
o Inflammation & repair phases
§ Destroy & remove injurious agents from site
§ Wall off & confine agents
§ Stimulate adaptive immune response
§ promote healing
· Acute inflammatory response
o Begins immediately
o Takes 8-10 days
o Involves vascular response, activation of plasma protein systems, & activation of variety of cells.
· Plasma Protein Systems
o Complement system
§ Complement componets (10% circulating serum protein)
§ Important because collaborate with every other component
§ Proteins most potent defenders against bacterial infection.
§ Activated when 1st protein is proteolyically cleaved into active fragments
§ Complement activation before converge at third component (C3) is accomplished by
· Classical pathway— activated by antibodies bound to antigens. Begins with C1 & forms antibody complex (immune complex). C1 complex consist of C1q & 2 CLr and Cls. After binding, C1q changes resulting in Clr coming into proximity with C1s activating to become enzyme (C1esterase) whose substrates are C4 & C2. The result uses C3 as substrate resulting in production of C3a & C3b.
o C3 convertase—complex with C3
o C13 has C5 as substrate, resulting in conversion of C5 to C5a & C6b.
o C5 convertase—complex with C5
o Can activate heparin, DNA or RNA, C-reactive protein (↑ in blood during inflammation)
o C3b inactivated by protein factor H & I
· Lectin pathway—activated by bacterial carbohydrates
o Antibody-independent
o Activated by plasma protein Mannose-binding lectin (MBL)
§ Activate C4 & C2 to create C3 convertase
· Alternative pathway—activated by gram-negative bacterial & fungal cell wall polysaccharides
o Initiated by lipopolysaccarides (endotoxin) on bacterial surface, yeast cell wall carbohydrates (zymosan) that bind C3b & protect it from factor H and destruction. C3b can then react factor B. Then recognized by enzyme, factor D, which activates factor B, producing factor Bb. Now have unstable C3b/Bb until bind with properdin (P). C3b/Bb/P produces C3b, resulting in C3b/Bb/P/C3b that is C5 convertase converging alternative pathway with classic pathway
§ Cascade continue to form membrane attack complex (MAC), creating pores in bacteria membrane, influx of water & ions, resulting in cell lysis and destruction of pathogen.
§ Most important Opsonin tag pathogenic organism for destruction
§ C4a are anaphylatoxins that induce rapid degranulation & histamine release from mast cells causing vasodilation & ↑capillary permeability
§ C5a is major chemotactic factor for neutrophils
§ Chemotactic factor attracts leukocytes to site of inflammation
§ Anaphylatoxic activity necessary in early inflammation close to site to induce mast cell degranulation & ↑ # of soluble mediators to enhance permeability & vasodilation.
§ Chemotactic activity require longer period & distal to inflammatory site to attract leukocytes from circulation
§ Caroxypeptidase—plasma enzyme removes terminal arginine on both peptides producing C3a desArg & C5a desArg which preserve healthy tissue
§ C3b can break down diminishing biologic activity.
§ Complement cascades can be activated by 3 different means and its products have 4 functions.
· Opsonization
· Anasphylatoxic activity resulting in mast cell degranlation
· Leukocyte chemotaxis
· Cell lysis
o Clotting system—form fibrinous meshwork at injured site
§ Prevents spread of infection
§ Keeps microorganism & foreign bodies at site of greatest inflammatory activity
§ Forms clot
§ Provides framework for future repair & healing
§ Main substance is Fibrin, end product of coagulation cascade
§ Classic & alternative converge after activating C5. Extrinsic pathway & intrinsic pathway converge at factor x proceeding until fibrin is formed.
§ Activated also by collagen, proteinases, kallikrein, plasmin, & endotoxins (bacterial products)
§ Fibrinopeptides A & B cproduce fibrin & ↑ permeability by enhancing effects of bradykinin (formed in Kinin system)
o Kinin system
§ Primary role to activate & assist inflammatory cells.
· Primary kinin is Bradykinin, causes vasodilation, acts with prostaglandins to induce pain, smooth muscle contraction, ↑ vascular permeability & may ↑ leukocyte chemotaxis
o May prolong phases ofinflammation
o Probable cause endothelial cell retraction & ↑ permeability in later phase of inflammation
§ Activated by stimulation of plasma kinin cascade
· Prekallikrein activator
· Factor XIIa
o Hageman factor
· Kallikrein converts kiniogen to bradykinin
· Lys-bradykinin—convert bradykinin
· Kinins are controlled by kininases
o Systems consist of inactive enzymes or proenzymes required for activation (complement cascade event)
o Interactions Among the Plasma Protein Systems (p.184)
§ Plasmin degrades fibrin and fibrinogen & activates complement cascade through C1, C3, & C5, & Hageman factor (factor XII) and produce prekallikrein activator. This impacts all 3 plasma protein systems
· Activates clotting cascade through factor XI
· Control clotting
· Activation of kinin system
· Activation of C1
§ Plasma regulated by plasminogen
§ Tight control of inflammatory response are for:
§ Protection against infection
§ Potent biochemical mediators for strict control to injured site
§ C1 esterase inhibitor (C1inh) binds to C1r & C1s to inhibit further activation of classic complement cascade.
· Cellular Mediators of Inflammation
o Granulocytic or monocytic lines of leukocytes in blood & tissue
o WBCs primary granulocytes (neutrophil, eosinophils, & basophils)
o Platelets, agranular monocytes, & various lymphocytes
o Mast cells
o Lymphoid derived natural killer cells (NK cells)—recognize & destroy cells altered by viral infection or malignancy.
o All remove debris for healing
o Inflammation hard to control with drugs
o Cellular Receptors (table p. 185 &186)
§ T-cell receptor or TCR, B-cell receptor or BCR
· Develop during somatic rearrangement of DNA
· Pattern recognition receptors (PRRs)
o (Skin, respiratory tract, gastrointestinal tract, genitourinary tract)
o monitor flaws in external barriers that result in cellular damage & infection
o On surface, but some are secreted
· Toll-like receptors (TLRs)
o 10 different receptors
o expressed as homdimers or heterodimers
o have early contact with pathogenic microorganisms
o recognize PAMPs
o recognize host factors produced by stressed or damage cells
o interactions with PAMPs result in activation of cell & release of soluble products (cytokines) that ↑ resistance to pathogenic micro organism
o bridges between innate resistance & acquired immune response through induction of cytokines that ↑ response of lymphocytes to foreign antigens on pathogens
§ Recognize molecular pattern on infectious agents or their products (pathogen-associatede molecular patterns (PAMPs)
§ Release soluble products (cytokines)
· Complement receptors
o Recognize fragments produced through activation of complement system
o Include C3a, C4a, C5a and C1q
· Scavenger receptors
o Facilitate recognition and phagocytosis of bacterial pathogens, damaged cells, & altered soluble lipoproteins associated with vascular damage (HDl, acetylated LDL, oxidized LDL)
o On macrophages to identify &remove old RBCs & cells undergoing apoptosis
o CD14 recogniezs complex of LPS & LPS-binding protein (regulated during inflammation by cytokines IL-6 & IL-1 & helps remove endotoxin
o Mast Cells
§ Initiate inflammatory response
§ Responsible for effects oninflammation by
§ Mast Cell Degranulation
· Histamine cuases temporary, rapid constriction of large vessel walls & dilation of postcapillary venules resulting in ↑ blood flow to microcirculation
o Cause ↑ vascular permeability
o H1 (promotes inflammation) & H2 receptors ( bound with H1 result in anti-inflammation, suppression of leukocyte function)
o H1 (bronchoconstriction) (augmentation of neitrophil chemotaxis)
o H2 (inhibition)
§ Chemotactic factors, neutrophil chemotactic factor, & ECF-A are released
§ Chemotaxis—directional movement of cells along chemical gradient formed by chemotactic factor
· Neutrophil chemotactic factor attract neutrophils
· ECF-A attract eosinophils
§ Mast Cell Synthesis of Mediators
· Leukotriens
o Acidic, sulfur-containing lipids effect smooth muscle contraction, ↑ vascular permeability
o Important in later stages of inflammatory response---stimulate slower & more prolonged responses
· Prostaglandins
o ↑ vascular permeability & neutrophil chemotaxis
o induce pain
o produced by action of the enzyme cyclooxygenase & classified in groups (E, D, A, F, & B)
o smooth muscle contraction
o suppress release of histamine & lysosomal enzymes (responsible for killing & digesting organisms)
o Enhancement or suppression of inflammatory response may be related to concentration of prostaglandins.
o Aspirin & NSAIDs block synthesis of prostaglandins of E series & inhibit inflammation
· Platelet-activating factor (PAF)
o Endothelial cell retraction to ↑ vascular permeability
o Leukocyte adhesion to endothelial cells & platelet activation
o Initiate allergic responses
o Phagocytosis
§ Ingest & disposes foreign material & organisms
§ Biochemical products (histamine, TNF-ά, bradykinin, prostaglandins) produced early at inflammatory sites diffuse to the vessels & affect leukocytes & endothelial cells. Both respond by producing new adhesion molecules on their surfaces.
§ Initial change ↑ adhesion causing leukocytes to adhere to walls of capillaries & venules, process called margination or pavementing.
§ Adhesion moles expressed later lead to diapedsis
§ Endothelial cells release nitric oxide (NO)
· Causing vasodilation
· Suppress mast cell function
· ↓ platelet adhesion & aggregation
o Leukocytes attracted to inflammation site by chemotaxis
o Phagocytosis involves 4steps:
§ Opsonization (recognition of target & adherence) (glue)
§ Engulfment (ingestion or endocytosis
§ Formation of phgosome
§ Fusion with lysosomal granules within phagocyte
§ Destruction of target
§ Engulfment (endocytosis) by pseudopods form intracellular phagocytic vacuole or phagosome
§ Phagosome fuse with lysosomes & discharge contents creating phagolysosome where destruction of bacteria takes place by oxygen dependent & oxygen-independent mechanisms
§ Phagocytosis is accompanied by burst of oxygen by phagocyte termed respiratory burst resulting from shift of cell’s glucose metabolism to hexose-monophosphate shunt
§ Destructive effects of enzymes released by dying phagocytes are minimized by natural inhibitors found in blood such as ά¹-antitrypsin, plasma protein produced by liver.
§ Inherited deficiency of ά¹-antititrypin results in chronic lung damage & emphysema
o Neutrophils
§ Polymorphonuclear neutrophil (PMN)
§ Predominant phagocytes in early inflammation, 6 to 12 hours after injury
§ Macrophages & lymphocytes replace neutrophils 24 hours later
§ Mature cell incapable of dividion & sensitive to acidic environment
§ Becomes component of purulent exudates or pus & removed via lymphatic system
§ Primary role removal of debris in sterile lesions & phagocytosis of bacteria in nonsterile lesions
o Monocytes & Macrophages
§ Largest normal blood cells, produced in bone marrow, develop into macrophages at inflammation site.
§ Kupffer cells in liver, alveolar macrophages in lungs, & microglia in brain.
§ May appear 24 hours at inflammatory site, but usually arrive 3 To 7 days
§ Chemotactic factors released by neutrophils attract them
§ Long term defense, survive & divide in acidic inflammation
§ Involved in activation of adaptive immune system
§ Macrophage Activation
· Several bacteria are resistant to killing by granulocytes & can survive inside macrophages
· Cyokines ↑ macrophage activity
o Eosinophils
§ Primary defense against parasities
§ Regulate vascular mediators released from mast cells
o Natural Killer Cells
§ Recognition & elimination of cells infected with viruses
o Platelets
§ stop bleeding
§ degranulation
· Cellular Products