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Foundations 2 > 9/19 > Flashcards

9/19 Flashcards

1
Q

Properties of Inflammatory Mediators

A

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

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2
Q

Plasma

A

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)

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3
Q

Basics of Plasma Derived inflammatory Mediators

A

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

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4
Q

Simplified Complement Cascade

A

Three ways for proteolytic cleavage of C3- by C3 Convertase-
1. Classical: fixation of C1 to antibody bound to antigen

  1. Alternative: microbial surface molecules like LPS or endotoxins in absence of antibody
  2. 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

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5
Q

Kinin System

A

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

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6
Q

Kinin System Regulation

A
  1. Kininase: rapidly inactivates bradykinin
  2. 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
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7
Q

Coagulation System

A

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

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8
Q

Fibrinolytic System

A

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

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9
Q

Defense Mechanism of innate Immunity based on Site of Infection

A

Extracellular-
Interstitial, blood, lymph: complement, macrophages, neutrophils

Epithelial cell surfaces: antimicrobial peptides

Intracellular-
Cytoplasmic: NK cells

Vesicular: activated macrophages

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10
Q

Physical Barriers of Innate Immunity

A

Goblet cells secrete mucus that trap microorganisms and prevent them from penetrating epithelial barriers

Tears, urine, saliva, gastric acid, mucus, coughing, sneezing

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11
Q

Types of Innate Immunity

A

Physical barriers

Coagulation and platelets

Defensins

Innate immune cells

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12
Q

Coagulation and Platelets for Innate Immunity

A

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

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13
Q

Defensins

A

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

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14
Q

Macrophages

A

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

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15
Q

Dendritic a Cells

A

Phagocytic cells, antigen presenting cells

Most potent activator of T cells

Can traffic and transport antigens

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16
Q

Toll-like Receptors

A

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

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17
Q

Major Histocompatibility Complex

A

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

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18
Q

Respiratory Burst

A

Metabolic change accompanied by transient increase in oxygen consumption that occurs in neutrophils and macrophages when they phagocytose pathogens

19
Q

Septic Shock

A

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

20
Q

Cytokines Induced by TLR Signaling in Macrophages

A

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

21
Q

Neutrophils

A

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

22
Q

Type I Interferons (IFNalpha/beta)

A

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

23
Q

Natural Killer Cells

A
  1. 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

  1. 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

24
Q

Mast Cells

A

Express Fcepsilon receptors that bind IgE, allergen crosslinks IgE, mediators like histamine are released

IgE often for allergens and parasites

25
Q

Basophils

A

Have Fcepsilon receptors that have IgE bound

Bind parasites and allergens, release inflammatory mediators like IL-4 that is for T cells

26
Q

Eosinophil

A

IgE receptors to limit parasite infections, but can contribute to allergies

27
Q

Arachidonic Acid Metabolites STP

A

Ligand like C5a bind to a cell receptor and activate phospholipase C and the IP3/DAG pathway with Ca2+, PKC activates MAPK which then activates phospholipase A2 (PLA2)

PLA2 releases arachidonic acid from the membrane, AA converted into eicosanoids

Cyclooxygenase: converts AA to prostaglandins
Lipoxygenases: convert AA to leukotrienes or lipotoxins

Convert these basic eicoanoids into cell specific eicosanoids which can bind to G protein coupled receptors on other cells

Steroids inhibit Phospholipase A2

28
Q

Cyclooxygenase Pathway

A

Involved in vascular and systemic reactions of inflammation

Occurs in mast cells, macrophages, endothelial cells, and other cells

COX-1 (constitutively active) and COX-2 (Induced by IL-1 / TNFalpha, inhibited by IL-4) do cyclooxygenase to convert AA into Prostaglandin G2 then H2, inhibited by aspirin

PGI2 (Prostacyclin): made by endothelial cells, vasodilation, inhibits platelet aggregation

TxA2 (Thromboxane): made by platelets, vasoconstriction, bronchoconstriction, promotes platelet aggregation

PGD2: mast cells, vasodilation, increase vascular permeability, bronchoconstriction, eosinophil recruitment

PGE2: in tissues and does classic signs of inflammation, pain, fever cuz interact with IL-1, vasodilation, increase vascular permeability

PGF2alpha: uterine smooth muscle contraction and initiates parturition, bronchoconstriction

29
Q

Lipoxygenase Pathway: Leukotrines

A

Makes leukotrienes for inflammation

Arachidonic acid converted to 5-lipoxygenase then 5-HPETE to become the different leukotrienes

LTB4: chemotactic agent for neutrophil aggregation to Endothelium and activates them by helping to make their ROS

LTC/D/E4: bronchconstriction, vasoconstriction, increase vascular Permeability more than histamine

30
Q

Lipoxygenase Pathway: Lipoxins

A

Inhibit inflammation and neutrophil chemotaxis/adhesion to endothelial cells

Transcellular synthesis: leukocyte converts AA to LTA4 and then it diffuses into platelet where it becomes 12-LOX, finally becomes LXA4 and LXB4

31
Q

Inhibition of Eicosanoid Synthesis

A

Aspirin and other NSAIDS are cyclooxygenase inhibitors that prevent prostaglandin synthesis, don’t work on Lipoxygenase

32
Q

Platelet Activating Factor

A

Derived from membrane lipids of neutrophils, monocytes, activated endothelial cells, platelets, and basophils

Phospholipase A2 cleaves membrane lipid into AA and lyso-PAF that can be put back into the membrane or turned into activated PAF

PAF short lived and binds to PAF receptor (GPCR) that’s constitutively expressed on platelets, endothelial cells, and leukocytes

Functions-
1. Enhance platelet aggregation and degranulation

  1. Activates leukocytes: leukocyte endothelial cell adherence, mobility, chemotaxis, oxidative burst, and synthesis of lipid mediators/cytokines
  2. Activates endothelial cells: increase vascular Permeability, vasodilation via NOS
33
Q

Nitric Oxide

A

Inducible NOS in macrophages, neutrophils, and endothelial cells by IL-1, TNF, and IFN-gamma

Helps kill microbes via free radical mechanism involving peroxynitrite

Oxygen dependent Pathway with L-Arg

Antagonist for platelet aggregation and adhesion, and also against leukocyte adhesion

Smooth muscle cells: makes cGMP from guanylate cyclase, decreased sensitivity of myosin to calcium induced contraction, muscle relaxation and vasodilation

34
Q

Histamine

A

Vasoactive: dilation of arterioles, increases venule permeability

Mast cells line blood vessels, store large granules of histamine, rapid since already made

Release Factors for Histamine-
1. Physical injury: trauma, hot/cold

  1. Antibody binding, IgE in allergic reactions
  2. C3a and C5a
  3. Histamine releasing proteins from leukocytes, substance P, IL-1, IL-8

Histamine Receptors-
H1 Receptor on Endothelial Cells: contraction of myosin to create vascular permeability

H1 on lung Smooth Muscle Cells: brinchoconstriction

H1 on eosinophils: stimulates chemotaxis

H2 on vascular smooth muscle: relaxation and vasodilation, inhibits eosinophil chemotaxis

35
Q

Anaphylatoxins

A

C3a and C5a induce inflammation

Helps mast cells degranulate

Increased permeability of blood vessels increases fluid leakage and extra version of complement/plasma proteins

Monocytes and neutrophils migrate into tissues, microbicidal activity of macrophages and neutrophils increased

36
Q

Complement Fixation

A

Attachment of C3b to pathogen surface which labels the pathogen for phagocytosis

37
Q

Alternative Complement Pathway: C3

A
  1. C3 made by liver and constitutively present in blood, hydrolyzed in blood naturally, binds factors B and D in local environment of microbes to form C3 comvertse (Bb)

C3 converts cleaves C3 into C3a and C3b

C3b binds to surface of pathogens (complement fixation), positive feedback loop cuz forms C3bBb that can recruit other C3s and cleave them to bring more C3b to pathogen surface

CR1 receptor on macrophages bind C3b coated pathogens and phagocytose into lysosome

38
Q

Alternative Complement Pathway: C5

A

Directly kills pathogen

Alternative C5 convertase (C3b2Bb on pathogen surface) cleaves C5 into C5a and C5b

Membrane Attack Complex: C5b brings C6-8 to pathogen surface then C9 comes to form pore

MAC not have much clinical significance if deficient like with Japs

39
Q

Lectin Complement Pathway

A

Second pathway, after alternative pathway

Mannose binding lectin is attached to Mannose Associated Serine Protease (MASP-1 and 2)

Mannose binding lectin binds to pathogen surface, MASP-2 cleaves C4 and C2, C4b and then C2a binds to pathogen surface to form Classical C3 Convertase

Classical C3 Convertase cleaves C3 to do normal alternative pathway stuff

40
Q

Classical Complement Pathway

A

Last pathway to be activated

C1 has three parts: C1q,r,s

41
Q

Cytokine Classification

A
  1. Type I Cytokine Family-
    A: Short-chain Cytokine: Growth hormone, EPO, prolactin, leptin
    B: Long-chain Cytokine: IL-2,3,4,6,12
  2. Type II Helical Cytokine-
    A: interleukins: IL-10,22,26, produced by leukocytes
    B: interferon: IFN type I is IFNalpha/beta and type II is IFNgamma, help cells resist viruses
  3. IL-1 Family: IL-1beta,18,Ra, made by leukocytes
  4. TFN-Family: TFNalpha and LTbeta
  5. Chemokines- guide WBCs where they’re needed
    A: CC19,20,25 and CXCa-b,12,14 plus IL-8
42
Q

IL-2 Receptor Signaling

A

Induces T cell proliferation

Naive T cells express low affinity IL-2 receptor (beta/gamma chains), activated T cells have high affinity IL-2 receptor (alpha/beta/gamma)

Activated T cells also secrete IL-2 via autocrine manner, cause STP with a JAK Stat pathway, activate proto-oncogene and cyclins to cause T cell proliferation

43
Q

Interferon-Gamma Receptor Signaling

A

Use JAK-STAT pathway

Regulates expression for antiviral, inflammatory, and anti-tumor responses

Enhance expression of MHC, TFs and cytokine receptor for T cell differentiation, induce isotype switching in B cells to produce specific antibodies

44
Q

IL-8 Receptor Signaling

A

CXCR1/2 receptors on neutrophils bind IL-8, neutrophils travel through blood, binding to IL-8 brings to site of infection

IL-8 (CXCR8) is made by macrophages from a STP involving a TLR, neutrophil binding to IL-8 promotes extravasation of neutrophils into site of infection

IL-8 binds to a GPCR (normal for chemokines), activate genes that enhance ability of neutrophils to enter infection site and also phagocytose/kill pathogens

Foundations 2 (18 decks)

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