9/19 Flashcards
(44 cards)
Properties of Inflammatory Mediators
Tightly controlled: made only in response to stimulus like microbes or material from necrotic cells, inflammation only occurs when needed
Reaction is specific: trigger well defined receptors and signaling pathways, but most unknown
Short lived: quickly decay, enzymatic cleavage, scavenged, or inhibited
Cascading Effect: release of one mediator can stimulate the activation of other mediators that can amplify or counteract the initial response
Plasma
Colorless fluid part of blood in which RBCs and WBCs are suspended
Water, electrolytes, enzymes, clotting factors, and some proteins
Contains fibrinogen, serum doesn’t have fibrinogen (doesn’t have the clotting factors)
Basics of Plasma Derived inflammatory Mediators
End products of a group of serine proteases produced in the liver
Zymogens activated in a stepwise manner by a previously activated enzyme, usually need proteolytic cleavage
Zymogens in circulating plasma and sequestered in ECM of tissues
Simplified Complement Cascade
Three ways for proteolytic cleavage of C3- by C3 Convertase-
1. Classical: fixation of C1 to antibody bound to antigen
- Alternative: microbial surface molecules like LPS or endotoxins in absence of antibody
- Lectin: plasma mannose-binding lectin binds to carbs on microbes and directly activates C1
C3b does positive feedback on Alternative pathway, opsonization of neutrophil/macrophage after binding to microbe surface, activates C5 convertase
C5b helps form membrane attack complex (MAC) with C6-C9
C3a and C5a involved in inflammation and histamine release, recruits and activates leukocytes to kill microbes, microbe permeable to water and ions then lysis
C5a is chemotactic agent for leukocytes and activates the lipooxygenase pathway of cell derived m ediators
Kinin System
Factor XIIa from the coagulation cascade converts prekallikerin to kallikerin, which cleaves high molecular weight kininogen (HMWK) into bradykinin
Bradykinin binds to B1 receptors and activates endothelial cells to get NO and prostaglandin synthesis that leads to vascular permeability, vasodilation, pain, and contraction of nonvascular smooth muscle like bronchi/uterus
HMWK can activate Factor XII to get positive feedback
Kinin System Regulation
- Kininase: rapidly inactivates bradykinin
- ACE: inactivates bradykinin in the lungs, ACE inhibitors lead to higher bradykinin to cause angioedema of the face and chronic cough due to contraction of smooth muscle in the bronchi
Coagulation System
Factor XII (Hageman factor) circulates in the blood and becomes activated when touch negative thing like collagen, basement membrane, or activated platelet that arise during inflammation
Clotting factors activate thrombin to convert fibrinogen to fibrin for a durable blood clot
Enhances inflammation: thrombin induces expression of cell adhesion molecules and production of cytokines, chemokines, prostaglandins, NO, and platelet activating factor
Fibrinolytic System
Curbs clot formation to prevent it from getting out of hand and keeps its area focused
Kallikerin and plasminogen activator (from Endothelium, leukocytes, and other tissues) cleave plasminogen into plasmin
Plasmin lyses blood clots, cleaves C3 to get fibrin split products which increase vascular permeability, also can activate Factor XII
Defense Mechanism of innate Immunity based on Site of Infection
Extracellular-
Interstitial, blood, lymph: complement, macrophages, neutrophils
Epithelial cell surfaces: antimicrobial peptides
Intracellular-
Cytoplasmic: NK cells
Vesicular: activated macrophages
Physical Barriers of Innate Immunity
Goblet cells secrete mucus that trap microorganisms and prevent them from penetrating epithelial barriers
Tears, urine, saliva, gastric acid, mucus, coughing, sneezing
Types of Innate Immunity
Physical barriers
Coagulation and platelets
Defensins
Innate immune cells
Coagulation and Platelets for Innate Immunity
Coagulation System: plasma enzymes that form blood clots to immobilize microorganisms and prevent them from entering blood/lymph, leads to bacterial destruction
Platelets: release prostaglandin, enzymes, GFs, and cytokines that help with anti-microbe defense, wound healing, and inflammation
Activate neutrophils and dendritic cells
Defensins
Small antimicrobial peptides, penetrate microbial membranes and disrupt integrity
Alpha defensins: made by neutrophils, paneth cells in the intestinal crypts maintain gut microbiome
Beta defensins: broadly expressed by all leukocytes and epithelial cells in many tissues
Macrophages
Express several receptors specific for bacterial constituents: mannose, LPS, Toll like Receptors, CR3, Glu can, scavenger
Bacteria bind to macrophage receptors and get digested, present antigens from the degraded cells
Reside in tissues and produce cytokines at infection site to signal other immune cells to come
Have TLR4 for LPS, induce inflammatory cytokine transcription
Microglia in NS, osteoclasts in bone, Kupffer cells in liver, and Langerhans cells in skin
Dendritic a Cells
Phagocytic cells, antigen presenting cells
Most potent activator of T cells
Can traffic and transport antigens
Toll-like Receptors
TLR3 recognizes dsRNA in viruses and are often in endosomes
TLR4 recognizes LPS
TLR9 recognizes unmethylated CpG DNA
On dendritic cells and macrophages induce inflammatory cytokines like IL-1/6, TNFalpha, IFNgamma
On virally infected cells induce gene transcription of Type 1 interferons like IFNalpha/beta
Induces expression of MHC II and costimulatory molecules (CD80/86) in dendritic cells and macrophages
Major Histocompatibility Complex
Proteins expressed on cells that bind peptide antigens and present them to T cells
MHC I: expressed by most cell types
MHC II: expressed by dendritic cells, macrophages, and B cells
Respiratory Burst
Metabolic change accompanied by transient increase in oxygen consumption that occurs in neutrophils and macrophages when they phagocytose pathogens
Septic Shock
Severe shock caused by systemic release of TNFalpha after bacterial infection in blood
Macrophages activated in the liver/spleen secrete TNFalpha into bloodstream
Systemic edema causes decreased blood volume and hypoprotenemia
Disseminated intravascular coagulation leads to wasting and multiple organ failure
More likely if heterozygous for TLR mutation
Cytokines Induced by TLR Signaling in Macrophages
IL-6: fever, induces acute Phase protein production by hepatocytes
TNFalpha: increases vascular permeability that increases entry of complement/cells to tissues and increases fluid draining to lymph nodes
Fever, mobilization of metabolites, shock
IL-1beta: activates vascular endothelium/lymphocytes, local tissue destruction, increase access of effector cells
Fever, production of IL-6
CXCL8 (IL-8): chemotactic Factor, recruits neutrophils/basophils to site of infection
IL-12: activates NK cells
Neutrophils
Most abundant WBC, migrate rapidly to site of infection, high energy cells with short life
Phagocytose and then degrade microorganisms with toxic granules, use respiratory burst
Phagosome fuses with azurophilic/specific granules, pH of phagosome incresse and bacterium is killed, pH of phagosome decreases and then fuses with lysosome, neutrophil dies by apoptosis and eaten by macrophage
Attracted by IL-8 to site of infection
Type I Interferons (IFNalpha/beta)
Induced by most infectious agents but do worse than other interferons at limiting viral infections
TLR signaling by an infected cell initially induces INFbeta expression, secretes IFNbeta and binds to the surface of neighboring cells and itself
IFN receptor signaling induces production of INFalpha by infected cells and INFaplha/beta by neighboring cells
Type I interferons inhibit viruses from entering cells and limits viral replication in cells
Natural Killer Cells
- Healthy cells express MHC class I receptors that bind to an inhibitory receptor on the NK cell and the healthy cell lives, all cells have MHC I receptors
Some viruses remove MHC I receptors from cells, an activated receptor binds to a ligand on the virally infected cell
Release lyric granule with perforin to put hole in PM and granules that damage intracellular structures to induce apoptosis
- Normal cells don’t express MIC receptors, virally infected cells express MIC receptors that bind to NKG2D receptor on NK cell, release lyric granules
MIc also comes from trauma or malignancy
Mast Cells
Express Fcepsilon receptors that bind IgE, allergen crosslinks IgE, mediators like histamine are released
IgE often for allergens and parasites
