Immuno Test 2 (Part 1) Flashcards
(158 cards)
1
Q
Properties of Cytokines
A
- Act locally in PARACRINE or AUTOCRINE fashion
- Usually NOT in bloodstream, only IN SICK PEOPLE
- Have small number of HIGH-AFFINITY CELL SURFACE RECEPTORS to produce changes in pattern of RNA and protein synthesis
- At at VERY LOW CONCENTRATIONS (10^-10- 10^-12)
- Utilize JAK/STAT of the RAS-MAP kinase pathways
2
Q
Cytokine Signaling
A
- Bind to homodimeric or heterodimeric receptors, CONSTITUTIVELY BOUND TO JAKS
- JAKS activated by CONFORMATION CHANGE in the receptors that allows TRANS and/ or AUTO-PHOSPHORYLATION of the two bound JAKS
- These in turn PHOSPHORYLATE THE CYTOKINE RECEPTORS
- Stat protein bind the phosphorylated receptor, allowing the JAKS to PHOSPHORYLATE the STATS
- Stats form DIMERS AND TRANSLOCATE and accumulate in the NUCLEUS, where they REGULATE GENE EXPRESSION
3
Q
Cytokines
A
Critical Role in:
1) INFLAMMATORY REACTIONS (pro and anti)
2) LINKING INNATE and ADAPTIVE IMMUNITY
3) Activation of T CELLS (Th1/ Th2)
4) Activation of B CELLS and AB PRODUCTION (Isotope Switching)
5) Control of HEMATOPOIESIS
4
Q
Pleitrophy (Cytokines are pleiotropic)
A
Exhibit multiple effects on growth and differentiation of a variety of cell types
- Ex: IL-4
5
Q
Properties of Individual CYTOKINES
A
1) REDUNDANCY
- There is overlapping and redundancy between cytokines
- IL-2, IL-4, IL-5 —> Proliferation
2) SYNERGY
- Cytokines can Synergies the effects of each other
- IL-4 + IL-5 —> Induces class switch to IgE
3) ANTAGONISM
- Cytokines can antagonize the effects of each other
- IL-4 + IFN-gamma —> Block class switch to IgE induced by IL-4
6
Q
Cytokine Cascade
A
- A cascade is where one cytokine includes the production of another
- Th cells (IFN-gamma)–> Macrophage (IL-12) —> Th cells (IL-2, IFN-gamma, TNF-beta, etc..)
7
Q
TNF
A
- Produced by Macrophages and T cells
Endothelial cells: activation (inflammation, coagulation) Neutrophils: Activation Hypothalamus: Fever Liver: Synthesis of Acute Phase Proteins Muscle, Fat: Catabolism (Cachexja) Manny cell types: Apoptosis
8
Q
IL-1
A
- Produced by Macrophages, Endothelial cells, T lymph, Fibroblasts, Platelets
Endothelial cells: Activation (Inflammation, coagulation)
Hypothalamus: Fever
Liver: Synthesis of Acute Phase Proteins
9
Q
Chemokines
A
- Produced by Macrophages, Endothelial cells, T Lympho, Fibroblasts, Platelets
Leukocytes: Chemotaxis, Activation
10
Q
IL-12
A
- Produced by Macrophages and Dendritic Cells
NK and T cells: IFN-gamma synthesis, increased cytolytic activity
T cells: Th1 differentiation
11
Q
IFN-gamma
A
- Produced by NK cells, and T Lympho
Activation of Macrophages
Stimulation of some Antibody Responses
12
Q
IFN- alpha and IFN-beta
A
- Produced:
IFN-alpha: Macrophages
IFN-beta: Fibroblasts
All cells: antiviral state, increased class I MHC expression Activates NK Cells
13
Q
IL-10
A
- Produced by Macrophages, and T Cells (Th2
Macrophages: Inhibition of IL-12 production, reduced expression of costimulators and Class II MHC molecules
14
Q
IL-6
A
Produced by Macrophages, Endothelial cells, and T cells
Liver: Synthesis of Acute Phase Proteins
B cells: Proliferation of Antibody-producing cells
15
Q
IL-15
A
- Produced by Macrophages, others
NK Cells: Proliferation
T Cells: Proliferation
16
Q
IL-18
A
- Produced by Macrophages
NK Cell and T Cells: IFN-gamma synthesis
17
Q
Cytokines and Actue Inflammation
A
- Some cytokines are Pro-Inflammatory
- Cytokines respond to infection, immune responses, inflammation, and trauma
Pro-Inflammatory Cytokines:
-IL-1
-TNF-alpha
-IL-6
-IL-8
-IL-11
-IL-12
-IL-15
-IL-18
PRO-INFLAMMATORY CYTOKINES have NF-KAPPA B DEPENDENT Transcription!!!!!!!
Anti-Inflammatory Cytokines:
- IL-10
- TGF-beta
- Control inflammation and promote healing
ANTI-INFLAMMATORY CYTOKINES are NF-KAPPA B INDEPENDENT!!!!!!!
18
Q
Pro-Inflammaotry Cytokines
A
- TNF, IL1, and IL-6 are the major Pro-Inflammatory Cytokines
TNF= first most important!!!
19
Q
Pro-Inflammatory Cytokines
A
- Work LOCALLY but promote SYSTEMIC INFLAMMATION
- TNF (need less) and IL-1 (need more) are PROTOTYPIC Pro-Inflammatory Cytokines
- They produce fever, systemic inflammation, shock, and death
- Reducing the activities of TNF and IL-1 is accomplished by NEUTRALIZING ANTIBODIES, SOLUBLE RECEPTORS, and RECEPTOR ANTAGONIST
- Blocking TNF and IL-1 has been high SUCCESSFUL in patients with RHEUMATOID ARTHRITIS, INFLAMMATORY BOWL DISEASE, or GRAFT-vs-HOST DISEASE
- Blocking TNF and IL-1 HAS NOT BEEN SUCCESSFUL in humans with SEPSIS!!!!
20
Q
Effects of TNF/ IL-1
A
- Have Local and Systemic Effects
Systemic: (SYSTEMIC MANIFESTATIONS OF INFLAMMATION)
- Fever
- Leukocytosis
- Incr Acute Phase proteins
- Decr Appetite
- Incr Sleep
Local:
1) Vascular Endothelium: (INFLAMMATION!!!!)
- Incr Expression of Leukocyte ADHESION MOLECULES
- Production of IL-1, cheekiness
- Incr Procoagulant and Decr Anticoagulant activity
2) Leokocytes: (INFLAMMATION!!!!)
- Activation
- Production of Cytokines
3) Fibroblasts: (REPAIR!!!!)
- Proliferation
- Incr Collagen Synthesis
21
Q
TNF
A
- Primarily produced by Macrophages and Monocytes (TNF-alpha), T Lympho (TNF-beta), Neutrophils, and NK Cells
- ENDOTOXIN (LPS) is the MOST POTENT INDUCER OF TNF!!!!!!
- Interacts with ENDOTHELIAL CELLS to INDUCE ICAM-1, VCAM-1, and E-SELECTIN, permitting the egrets of granulocytes into inflammatory loci
- TNF is PRIMARY MEDIATORY OF SEPTIC SHOCK!!!!!!!!!
- Potent ACTIVATOR OF NEUTROPHILS, Mediating Adherence, Chemotaxis, Degranulation, and the Respiratory Burst
- Binds to TNF RECEPTOR I (TNFR p75!!!!!!!) anf TNF REceptor II (TNFR p55!!!!!!!)
- TNF Induces ANTITUMOR IMMUNITY through direct CYTOTOXIC Effects (APOPTOSIS) on Cancerous Cells
22
Q
IL-1
A
- Primarily produced by Macrophages and Monocytes but is also produced in less amounts by other cells such as Neutrophils, Endothelial cells, Keratinocytes, and other cells
- Interacts with CNS to produce FEVER, LETHARGY, SLEEP, and ANOREXIA
- Stimulates ICAM-1, VCAM-1, and E-Selectin on Endothelial cells, but “SECOND IN LINE” after TNF
- Only IL-1 INDUCES production of IL-2 by, and PROLIFERATION of, CD4 T Lymphocytes
- IL-1 stimulates synthesis of ACUTE-PHASE PROTEINS (“SECOND IN LINE” after IL-6)
- Can be NEUTRALIZED by natural IL-1 Receptor Antagonist, IL-1ra!!!!!!!!!!
23
Q
IL-6
A
- Primarily produced by Mononuclear Phagocytic Cells but also by other cells like T and B Lympho, Fibroblasts, Endothelial cells, Keratinocytes, Hepatocytes, and Bone Marrow Cells
- IL-6 MOST IMPORTANT Inducer of ACUTE-PHASE PROTEINS
- IL-6 shares Several ACTIVITIES with IL-1, including INDUCTION OF PYREXIA (fever) but IL-1 is more important for induction of fever
- IL-6 STIMULATES differentiation of B Lympho into MATURE PLASMA CELLS producing Abs
- IL-6 has a PRIMARY ROLE in Th17 IMMUNE REGULATION!!!!!!!!!!1
24
Q
IL-8
A
- Produced by Macrophages in response to an Inflammatory Stimulus
- Onset of Inflammation, MAST CELLS release IL-8 from their granules
- A CHEMOTACTIC FACTOR NEUTROPHILS, but not Monocytes
- Involved in NEUTROPHIL ACTIVATION
25
IL-12
- PRIMARILY derived from DENDRITIC CELLS and MACROPHAGES which produce much more IL-12 than B Cells, PMNs, and Mast cells
- HETERODIMER that consists of IL-12p40 and IL-12p35 subunits!!!!!!!!!!!!!!!
- CELL-MEDIATED IMMUNITY via Activation of Th1 cells
- Stimulates IFN-gamma production and activates and induces Proliferation, Cytotoxicity, and Cytokine production of NK CELLS
- SYNERGIZES with IL-8 also know as IFN-gamma INDUCING FACTOR, to stimulate IFN-gamma release
26
IL-15
- Produced by Mononuclear Phagocytic Cells although Epithelial cells, Fibroblasts are additional sources
- MOST IMPORTANT activity of IL-15 is ACTIVATION of NK CELLS!!!!!!!
- Similar to IL-2, IL-15 is a T CELL GROWTH FACTOR!!!!!!!!
- Chemotactic for T LYMPHOCYTES!!!
- IMPORTANT for the survival of CD8 MEMORY CELLS!!!
27
IFN-gamma
- Primarily made by Th1 CELLS and NK CELLS
- Critical in many INNATE and ADAPTIVE IMMUNITY Aspects
- Most Important CYTOKINE for CELL-MEDIATED IMMUNITY by orchestrating an Immune Response to INTRACELLULAR PATHOGENS!!!!!!!!!!!!
- MAJOR ACTIVATOR of Intracellular killing of pathogens by Macrophages, by STIMULATING PHAGOCYTOSIS, SECRETION, RESPIRATORY BURST, and NITRIC OXIDE production
28
Il-12 and IFN-gamam SYNGERY
- Th1 cells produce IFN-gamma that activate Macrophages
| - Macrophages produce IL-12 which activates Th1 Cells
29
IFN-gamma
STIMULATES:
1) Killing by NK Cells and NEUTROPHILS
2) Expression of MHC I and II
3) Ag PRESENTATION BY APCs
4) CYTOKINE PRODUCTION by APCs
5) EXPRESSION of ICAM-1
INHIBITS:
1) ALLERGIC RESPONSES by Suppressing many IL-4 mediated effects!!!!!!!!! (NO IgE!!!)
- Has modest ANTIVIRAL ACTIVITY unlike Type I Interferons IFN-alpha and IFN-beta
30
Anti-Inflammatory Cytokines
- IL-10, IL-1 Receptor Antagonist (IL-1ra), and TGF-beta
- Inhibit Pro-Inflammatory response
- Act in concert with Other Inhibitors to REGULATE THE HUMAN IMMUNE SYSTEM
- Physiological ROLE IN INFLAMMATION and Pathologic role in SYSTEMIC INFLAMMATORY stare are INCREASINGLY RECOGNIZED
31
IL-10
- Important Immuno-regulatory cytokine
- PRIMARILY INDUCED by Macrophages, B cells, and T Regulatory Cells
- INHIBITS production of:
- IL-1 beta
- IL-6
- IL-8
- IL-12
- TNF-alpha by Mononuclear Phagocytes
INHIBITS:
1) Expression of CLASS II MHC by APCs!!!!!!!!!!
2) Expression of co-stimulatory molecules the CD80 and CD86 by APCs
3) Production of IFN-gamma and TNF-beta by Th1 Lympho (CELL-MEDIATED IMMUNITY)
4) Production of IL-4 and IL-5 by Th2 (ANTIBODY MEDIATED IMMUNITY)
- Controls TOLERANCE to Environmental Allergens!!!
32
TGF-beta
- Most PLEIOTROPIC of the CYTOKINES!!! (Stimulatory and Inhibitory effects on numerous cells)
- PRIMARILY PRODUCED by Macrophages and T Regulatory Cells
- STIMULATES Fibrosis promoting WOUND HEALING and SCAR formation
- INHIBITS PROLIFERATION B Cells and CD8+ T Lympho
- INHIBITS Macrophage and NK Cells
- INDUCES APOPTOSIS in B cells and CD8+ T Lympho
- REGULATES the differentiation of Th17 Lympho
33
M1/ M2 Macrophages
M1: (Classical)
- Induced by TLR-ligands and IFN-gamma
- Produce: IL-1, IL-12, IL-23 ---> INFLAMAMTION
- Produce: ROS, NO, and Lysosomal enzymes ---> PHAGOCYTOSIS AND KILLING OF BACTERIA AND FUNGI
M2: (Alternative)
- Induced by IL-13 and IL-4
- Produce IL-10 and TGF-beta ----> ANTIINGLAMMATORY EFFECTS
- Produce Proline Polyamines, TGF-bets ----> WOUND REPAIR, FIBROSIS
34
IL-2
Action:
- Survival, Proliferation, and Differentiation of Effector and Regulatory T Cells
Resources:
- CD4+ and CD8+ T cells
35
IL-4
Action:
- B Cell Switching to IgE
Source:
- CD4+ T cells, Mast Cells
36
IL-5
Action:
- Activation of Eosinophils
Source:
- CD4+ T Cells, Mast Cells
37
IFN-gamma
Action:
- Activation of Macrophages
Source:
- CD4+ and CD*+ T cells, NK Cells
38
IL-17
Action:
- Stimulation of Actute Inflammation
Source:
- CD4+ T Cells
39
TGF- Beta
Action:
- Inhibition of T cells activation; Differentiation of Regulatory T cells
Source: CD4+ T cells, many other cells
40
Cytokine Network in Adaptive Immunity with Th0 cells and APC
1) APC produces IL-12 then becomes Th1 (Makes IL-1 and IFN-gamma) ---> CTL
2) Low levels of IL-4 then becomes Th2 (Makes IL-4) ---> Plasma Cell
3) APC produces IL-1, IL-6 becomes Th17 (Makes IL-17A, IL-17F, IL-22, and IL21)
- Has IL-23R
4) APC produces TGF-beta, IL-2 becomes Treg (Makes IL-10)
- Has IL-2Ralpha
41
Differentiation of Different T-helper subsets is controlled at the Transcriptional Level
1) T-BET = TH1 cells!!!!
2) GATA-3 = TH2 CELLS!!!!
3) RORgammaT = TH17
4) FOXP3 = T REGULATORY CELL
42
TH1
Cytokine:
- IFN-gamma
Immune Reaction:
- Macrophage Activation; IgG production
Host Defense:
- INTRACLLULAR MICROBES
Role in Diseases:
- Autoimmune diseases; tissue damage associated with CHRONIC INFECTIONS
43
TH2
Cytokine:
- IL-4
- IL-5
- IL-13
Immune Reaction:
- Mast Cell, Eosinophil activation
- IgE production
- Alternative Macrophage Activation
Host Defense:
- HELMINTHIC PARASITES
Role in Diseases:
- Allergic Diseases
44
TH17
Cytokine:
- IL-17A
- IL-17F
- IL-22
Immune Reactions:
- Neutrophilic Monocytic Inflamamtion
Host Defense:
- EXTRACELLULAR BACTERIA, FUNGI
Role in Disease:
- Autoimmune and Inflammatory Diseases
45
IL-2 Controls Proliferation of T Cells
- Naive T cells express low-affinity IL-2 receptors (IL-2R) complex, made up of the Beta and Gamma C chains
- On ACTIVATION by antigen recognition and costimulation, the cells produce IL-2 and express the alpha chain of the IL-2R forming the HIGH-AFFINITY IL-2 receptor
- Binding of IL-2 to its receptor INITIATES PROLIFERATION of the T cells that recognized the antigen
46
Proliferation of T Cells
- IL-2 STIMULATES PROLIFERATION of T Cells
- IL-2 STIMULATES EXPRESSION OF IL-2R which is not present on Naive T cells, but is SYNTHESIZED within a few hours after activation
- IL-2 acts only on cells which express HIGH_AFFINITY IL-2R
- IL-2R INCREASES the number of IL-2R on the cells!!!!!
- If Ag is cleared, the IL-2R NUMBER DECLINES!!!!
- TGF-beta BLOCKS IL-2 INDUCED Proliferation is a KEY mechanism of control of T cells proliferation
47
Cytokines Control the Th1/ Th2 Differentaition
- IL-12 INDUCES differentiation of Th0 cells into TH1 cells!!!
- TH1 cells characteristically SECRETE IL-2, IFN-gamma, and TNF-beta (lymphotoxin) and promote CELL-MEDIATED IMMUNITY!!!!!!!!!!!!!
- IL-4 induces differentiation of TH2 cells, which SECRETE IL-4, IL-5, IL-6, IL-10, and IL-23
- TH2 cells ACTIVATE B LYMPHOCYTES resulting in up regulation of ANTIBODIES (HUMORAL IMMUNITY!!!!!)
- TH1 and TH2 cells have MUTUALLY INHIBITORY EFFECTS on the reciprocal phenotype
- IFN-gamma Inhibits TH2 cell proliferation!!!!!!!!
- IL-10/ IL-14 INHIBIT TH1 cell proliferation!!!!!
48
TH1/ TH2 Response
- DC ARE CRITICAL in diviing differentiatoin towards Th1 or TH2 phenotype
- Subpopulations of specialized DCs for the STIMULATION of EITHER Th1 of Th2 population
- IL-12 INDUCES TH1 cells!!!!!!!
- IL-4 INDUCES TH2 cells!!!!!
- IL-12 and IFN-gamma SYNERGIZE in Selective differentiation of TH1 cells
- IFN-gamma/ IL-12, and IL-4 MEDIATE the mutual antagonism of Th1 and Th2
49
Role of TH1 in Host Defense
- IL-12 CONTROLS Th1 differentiation
- TH1 PRODUCES IFN-gamma which activates phagocytes to KILL PHAGOCYTIZE MICROBES (CLASSICAL PATHWAY M1)
- TH1 cells STIMULATE the production of ANTIBODIES with promote Phagocytosis of microbes
- AB = IgG!!!!!!!!!!!!!!!!!
50
Th1 in Infections with Intracellular Microbes
1) Wild type (IFN-gamma+, IL-12+) can control infection of tuberculosis
2) IL-12 KNOCKOUT (IFN-gamma+, IL-12-) can NOT control tuberculosis infection and die because no TH1 ADAPTIVE IMMUNITY
3) IFN-gamma KO MICE (IFN-gamma-, IL-12+) die EARLY because Macrophages are not activated properly in the absence of IFN-gamma!!!
51
TH2 Cells in Host Defense
- Th2 cells produce IL-4 which STIMULATES PRODUCTION of IgE ANTIBODY!!!!!!!
- IgE participates in the ACTIVATION OF MAST CELLS by protein Antigens
- IgE binds to HELMINTHS!!!
- Produce IL-5, which ACTIVATES EOSINOPHILS!!!!!!!
- Eosinophils DESTROY THE HELMINTHS!
- IL-4 induces ALTERNATIVE activation of Macrophages (M2)
52
Cytokines Control Ab Isotype Switch
IgM:
- Complement Activation
IgG (and subclasses): ---> IFN-gamma!!!!!
- Fc receptor dependent phagocyte repsonses
- Complement activation
- Neonatal Immunity (placental transfer)
IgE: ---> IL-4!!!!!!!!
- Immunity against Helminths
- Mast Cell degranulation (Immediate Hypersensitivity)
IgA: ---> TGF-beta, BAFF
- Mucosal Immunity
- Transport of IgA through Epithelia
- HELPER T cells: CD40L, and Cytolines help produce these ANTIBODIES!!!!!!!!
53
Maturation of MHC-Restricted T cells
1) WEAK RECOGNITION of Class II MHC + peptide = POSITIVE SELECTION (CD4+ Mature T Cell) -> CD4+/ CD8-
2) WEAK RECOGNITION of Class I MHC + peptide = POSITIVE SELECTION (CD8+ Mature T Cell) -> CD8+/ CD4-
3) NO RECOGNITION of MHC + peptide = FAILURE OF POSITIVE SELECTION (Death by Neglect)!!!!!!
4) STRONG RECOGNITION OF either Class I or II MHC + peptide = NEGATIVE SELECTION!!!!!!
- Ag- independent maturation of T cells occurs in the THYMUS. Only stem cells are from Bone Marrow
- T cell starts out at CD4+/ CD8+ Immature T cells!!!!!!!
54
T Lyphocytes
- Only 1 in 10^6 have specific TCR can recognize a given pathogen
- TCR recognize peptides within Class I and II MHC
- CD4 or CD8 co-receptors binds to CLASS II and CLASS I
- Naice T cells are ACTIVATED by APCs (Dendritic Cells) and Proliferate
- PATHOGEN-SPECIFIC T Cells are MADE by CLONAL EXPANSION "On Demand"!!!!!!!!!
55
Activation of T Cells Occurs in LN
1) Antigen uptake by Langerhan (Immature dendritic cells) cells
2) Langerhan cell leaves the skin and enter the Lymphatic System
3) Langerhan cells enter the LN to become dendritic cells expressing B7!!!!!!!
4) B7-Positive Dendritic cells Stimulate Naive T cells!!!!!
- Langerhan's cells are immature DCs do not express B7!!!!!
56
Lymph Node: Morphology
- Ag is delivered for T cells by activated Dendritic Cells via Lymphatic Vessels
- DC loaded with Ag move into T cell Zone located in PARAFOLLICULAR CORTEX!!!!!! aka INNER CORTEX
- Naive T cells enter the LN via blood stream
57
Functional Role of CD4 and CD8
- CD4 T Cells = Class II MHC
- CD8 T Cells = Class I MHC
- CD4 and CD8 co-receptors function to concentrate the ATTENTION of T helper cells and CTLs on the PROPER MHC
- CD4 and CD8 help to clip onto CLASS II or CLASS I MHC
*** CD4 and CD8 are SIGNALING CO-Receptors!!!!****
58
T Cells are MHC Restricted
- T cells initiated by singling CASCADE
- The Alpha and Beta chains have very SHORT INTERCELLULAR DOMAINS
- Signaling is mediated OTHER PROTEINs comprising TCR Complex!!!
- CD3 PROTEINS (gamma, delta, epsilon and zeta) have CYTOPLASMIC TAIL that is long enough to SIGNAL
**** TO ACTIVATE T CELLs we need ALL: TCR, CD3, and CD4 or CD8
59
Co-Stimulation: CD80- CD28
- T Cells must receive a co-stimulatory Signal
- With co-stimualtion about 100 fold fewer of clustered TCRs are NEEDED FOR ACTIVATION
- B7 PROETINS (CD80 and CD86) which expressed on APC, are co-stimualtor molecules
- B7 molecules plugging into CD28 RECEPTOR expressed on T Cells
- Thus, Co-stimulation POTENTIATES the activating single from TCR-Ag-MHC!!!!
*** Proliferation and differentiation of T cells specific for bacterial protein!!!!
60
Co-Stimulatory Signal
1) Resting APC (No Costimulators) = ANERGY (No response or functional inactivation)
2) Activated APC (Costimulators expressed) = T Cell Proliferation!!!
- Newly activated T cells produce IL-2 and thus stimulate their own proliferation
- Activated T cells doubled every 6 hours!!
61
Il-2 is T Cell Growth Factor
- Activation is completed, the T helper cell and APC are separated
- APC foes on to activate OTHER T CELLS
- T CELL Proliferates in order to INCREASE THE NUMBER OF Ag- specific cells
- Proliferation driven by IL-2 "T cell growth factor"
- Naive T cells DO NOT HAVE IL-2 receptor (IL-2R) expressed on surface
- ACTIVATED T CELLS produce large amount of IL-2 and EXPRESSED IL-2R
62
IL-2 and IL-2R in T Cell Proliferation
**** Secretion of IL-2 causes the IL-2R to change from low affinity to high affinity!!!!!!!
- Expression of IL-2Raplha chain
- Formation of high-affinity IL-2Ralpha,beta,gamma COMPLEX!!!
63
Re-Stimulation of Activated T Cell
- FIRST TIME ACTIVATED T CELLs and proliferate and PRODUCE ONLY IL-2 (not committed to Th1 or Th2 yet)
- These cells are re-stimultaed by APC (Second Contact with APC) and begin to SECRETE OTHER CYTOKINES( Committed Th1 to Th2)
- (IFN-gamma +TNF) or (IL-4, IL-5, IL-10)
- Activated T cells "go home" after T CELL HOMING!!!
- Homing is COMING TO THE TISSUE form which the Ag-loaded Dendritic cell has arrived to the LN
- TISSUE MACROPHAGES are involved in re-stimulation of the arrived T cells!!!
64
Commitment of Activated CD4 T Cell
- T Helper cells to PRODUCE a set of PARTICULAR CYTOKINES
- T Helper Subunits:
- Th1: Produce IFN-gamma, IL-2, and TNF-beta
- Th2: Produce IL-4, IL-5, and IL-10
- This process is called DIFFERENTIATION or COMMITMENT of T Helper Cells
Th1: Activates MACROPHAGES, Induces B cells to Produce Opsonizing Antibody
Th2: Activates B cells to make Neutralizing Antibody; Has various effects on Macrophages
65
T Cell Microenvironment
- Tissue Macrophages and their Secretory PRODUCTS help to CONTROL the FUNCTIONAL COMMITMENT OF T HELPER CELLS!!!!!
- Microenvironment or Cytokine Field
- The presence of Activated MACROPHAGES and IL-12 drives the commitment towards TH1 Cells!!!
- The presence of IL-4 PROMOTE Commitment towards TH2 cells
*** THE ABSENCE OF IL-12 GENERATES TH2 CELLS*****
66
TH1 and TH2 in Immune Responses
1) TH1: CELL MEDIATED IMMUNITY (CD8)
- MACROPHAGE ACTIVATION and killing of Phagocytosed microbes
- Has CD40 to CD40L connection
- TH1 can produce Ab (IgG) but it is SECONDARY to the ACTIVATION of MACROPHAGES
2) TH2: HUMORAL IMMUNITY (CD4)
- ANTIBODY SECRETION
- Neutralization and Elimination of Ag
- Has CD40 to CD40L connection
67
Co-Stimulation #2: CD40- CD40L
- Activated T cells express CD40L protein
- CD40L proteins are plug into CD40 expressed by APC
- Increased expression of MHC and B7 by APC
- T cell and APC perform constant STIMULATION OF EACH OTHER!!!
- UPREGULATED expression of CD40 makes APC MORE POTENT!!!
- UPREGULATES expression of CD40L required for helping to ACTIVATE B CELLS
68
Th1 and Th2 Cells in Immune Responses
1) Th1:
- Macrophage activation (enhances microbial killing) by IFN-gamma
- Opsonization and phagocytosis by Complement Binding and Opsonizing Antibodies (IgG!!!!), by IFN-gamma
2) Th2:
- Produces IgE (Creates a receptor on Mast Cell surface) which causes MAST CELL DEGRANULATION
- IL-5, Causes EOSINOPHIL ACTIVATION
69
Cross- Presentation: CD8+ Activation
- CD8+ T cells are activated in the LN by Dendritic cells, loaded with Ags exactly as CD4+ T cells are
- CTLs recognize Class I MHC-associated peptides
- Activated CD8+ cells PROLIFERATE and LEAVE the LN!!!
*** CD8+ T cells are activated by Mechanisms that involved the Cross-presentation of Antigens to CD8+ T Cells!!!
1) Cells infected with intercellular microbes (viruses) are ingested by DC
2) These Ags are presented on Class I (not Class II)
3) Mechanism called Cross-Presentation- some viral Ags are released fro PHAGOSOME in cytoplasm of CD and then presented within CLASS I MHC (Proteasome)
4) Cross-presentating APC display microbial peptides within Class II MHC for CD4+ Helper T cells
70
Th1 CD4+ T cells and Activation of CD8+ T Cells
1) CD8+ T Cells recognize Ag + constimulators on professional APCs ---> CTL Differentiation WITHOUT HELPER T CELLS!!!
2) CD4+ Helper T cells Produce cytokines that STIMULATE CTL Differentiation
- CD4+ releases IL-2 to cause CTL Differentiation
3) CD4+ Helper T Cells ENHANCE the ability of APCs to STIMULATE CTL DIFFERENTIATION
- CD40 to CD40L
71
CD8 Cytotoxic T Lymphocytes
- Activated in LN by Dendritic Cells loaded with Ag for which the TCRs on CD4+ T cells are specific
- CTLS recognize Class I MHC peptides
- CD8+ cells PROLIFERATE and LEAVE the LN
- CTLs activates to release (excites) their GRANULE CONTENTS when they find the target cell
- The granule contents include PERFORIN and GRANZYMES!!!
- APOPTOSIS is induced in the target cell by granzyme
- CD8+ Lymphocytes also Secrete IFN-gamma which ACTIVATED MACROPHAGES
72
Two Mechanisms of Killin
1) Granzyme and Perforin
- Apoptosis caused by Granzyme B or Perforin
2) Fas-L-Fas (CD95)
- Fas-L binds to the CD95 receptor on the Target Cell and causes APOPTOSIS!!!
73
Nontraditional T Cells part 1
- Have gamme/delta TCRs and CD3
- DO NOT express CD4 or CD8 co-receptors
- Abundant in INTESTINE, UTERUS
74
Nontraditional T Cells part 2
- Considered component of Adaptive Immunity:
- Rearrangment of TCR genes to produce junctional diversity
- Development of a memory PHENOTYPE
- Various subsets of gamma delta T cells may also be considered PART OF THE INNATE IMMUNITY:
- A restricted TCR may be used as a PATTERN RECOGNITION RECEPTOR
- Gamma delta TCRs are MUCH LESS DIVERSE than tradition TCRs
- Gamma delta TCRs DO NOT NEED APCs and RECOGNIZE UNPRESENTED AGS!!!!!!!!!!!!!!!!!
- They are not MHC-RESTRICTED as traditional TCRS!!!!!
- Gamma delta T Cells kills CELLS THAT BECOME STRESSED as a result of microbial infection
75
NonTraditional T cells Function
1) Lysis of infected or stressed cells, through production of GRANZYMES
2) Cytokine and Chemokine production, to regulate other immune and non-immune cells
3) B cell help and IgE production
4) Priming of alpha/eta T Cells via Antigen Presentation, an express MHC CLASS II ANTIGEN and FUNCTION as APCs
5) Dendritic Cell Maturation, and IL-12 production
6) Regulation of STROMAL CELL function via Growth Factor Production
76
Natural Killer T Cells Part 1
- NKT cells should NOT BE CONFUSED WITH NK (Natural Killer) Cells!!!!!!!
- HETEROGENOUS GROUP OF T CELLS!!!!
- Share properties and CD MARKERS of BOTHER T CELLS and NK CELLS
- NKT cells RECOGNIZE Self and foreign LIPIDS and GLYCOLIPIDS!!!!
* *************Lipids and Glycolipids should be presented within NON-POLYMOPRHIC CD1d molecule- Ag presenting complex LIKE MHC****************!!!!!!!!!
- NK cells Constitute only 0.2% OF ALL peripheral blood T CELLS!!!!!!
77
Natural Killer T Cells Part 2
- Activated NKT cells PRODUCE large quantities of IFN-gamma and IL-4!!!!!
- NKT RAPIDLY RELEASE of Cytokines
- They can PRMOTE or SUPPRESS different immune responses
- Dysfunction of DEFICIENCY OF NKT lead to:
1) AUTOIMMUNITY (diabetes or Atherosclerosis)
2) CANCERS
3) Progression of ASTHMA
NKT receptors:
- SEMI-INVARIANT V alpha 14- J alpha 18 TCR!!!!
- CD1d
- Binds to GLYCOLIPIDS!!!!
78
Leukotriene Biosynthesis: Key Points
1) Cells Rich in COX:
- Fibroblast
- Smooth Muscle
- Epithelial
- Endothelial & Hematopoietic cells
2) Cells Rich in 5-LO:
- MYELOID CELLS
- Monocytes
- Macrophages
- Mast Cells
- Basophils
- Neutrophils (Have less COX-1 & COX-2, ONLY ONE)
79
5- Lipoxygenase Arm of the Arachidonic Acid Cascade
1) Membrane Phospholipid to Arachidonic Acid (PHOSPHOLIPASE A2)
2) Arachidonic Acid to Leukotriene (LT) A4 (5-LO, Ca2+ & FLAP)
- Adds O2 to molecule
3) Leukotriene A4 to LTB4 (LTA4 HYDROLASE)
- Adds H20 to molecule
4) Leukotriene A4 to LTC4 (LTC4 SYNTHASE)
- Adds GSH to molecule
5) LTC4 to LTD4 & LTE4 (PEPTIDASES)
80
Phospholipase A2
Substrate: Cell Membrane
Role: Liberate AA
81
5-Lipoxygenase
Substrate: Arachidonic Acid
Role: Convert AA + o2 into LTA4
82
5- Lipoxygenase Activating Protein (FLAP)
Substrate: 5-LO accessory protein
Role: Convert AA + 02 into LTA4
83
LTA4 Hydrolase
Substrate: LTA4
Role: Make LTA & LTB4
84
LTC4 Synthase
Substrate: LTA4
Role: Make LTA4 & LTC4
85
Peptidase
Substrate: LTC4 & LTD4
Role: Make LTC4, LTD4, and LTE4
86
Why are they called Leukotrienes?
- Made from Leukocytes and have a Triene in them
87
Autocoids
- LEUKOTRIENE is an AUTOCOID!!!!!!!!!! (like Prostaglandins and Thromboxane)
- Made on demand
- Biosynthesis is LATENT
- Short-lived
- Local, NOT SYSTEMIC actions
- NOT A HORMONE!!!!!!!!!
88
Leokotriene Receptors
1) CysLT (LTC4/ LTD4)
- CysLT1: LTD4 > LTC4
- CysLT2: LTC4 = LTD4
2) BLT (LTB4)
- BLT1
- BLT2
89
LTA4
Receptor: None
Action: Biosynthetic intermediate
90
LTB4
Receptor: BLT1/2
Action: Neutrophil chemotaxis and degranulation
91
LTC4 = LTD4
Receptor: CysLT2
Action: BRONCHOCONSTRICTION & Mucus Secretion, EONSINOPHIL Chemotaxis
92
LTD4 > LTC4
Receptor: CysLT1
Action: BRONCHOCONSTRUCTION & Mucus Secretion
93
LTE4
Receptor: CysLT
Action: Less Active Metabolite
94
Neutrophil Encountering a "Threat"
- Once Neutrophils encounter a threat they become self-reliant for chemotaxis, the inflammation need the threat favors EICOSANOID BIOSYNTHESIS by Neutrophils
* ** 5-Lipoxygenase (5-LO) generates lipid mediators called LEUKOTRIENES. LTB4 is the MAIN LEUKOTRIENE made by Neutrophils!!!!!!!
- LTB4 is a potent CHEMOTACTIC agent for Neutrophils
95
Pyogenic Infections
- Have Neutrophil-rich pus
96
What directs Neutrophils to the infected site?
- Neutrophils near the threat generate LTB4 which AUGMENTS their ADHESION to ENDOTHELIUM and their CHEMOTAXIS TOWARD THE THREAT!!!
IL-8: the PROTEIN that causes CHEMOTAXIS!!!!
LTB4: the LIPID that causes CHEMOTAXIS!!!!!!
97
Attacking the Threat
- In Inflammation phagocytes & granulocytes attack the threat by engulfing it, by releasing destructive OXYGEN SPECIES, proteases, and by generating mediators of Inflammation - like PGE2, PGI2, and LTB4 - which send AUTOCRINE and PARACRINE signals telling Leukocytes to menage and NEUTRALIZE the Threat
****** ALSO, tell Epithelial cells & Mesenchymal cells in the INFLAMED area to ADAPT. Migrate to Perish. The host uses LIPID MEDIATORS TO LIMIT DAMAGE that is inseparable from inflammation
98
Ciliated Columnar Epithelium in Respiratory Airways
- Membranous covering tissue (epithelium) that FUNCTION IN THE MOVEMENT OF SUBSTANCES OVER ITS SURFACE
- Located in the lining of the Respiratory Airways (Trachea, Bronchi, & Bronchioles)
99
2 Major Elements in Athama
1) Airway Inflammation
2) Airway HYPER-Responsiveness
- Th2 is involved with the inflammation in airways, and is characterized by CD4+ cells that secrete IL-4, IL-5, and IL-13, EOTAXIN (Chemokine), TNF-alpha, and LTB4 (Leukotriene)
* ***** TH@ response in important in the Initiation and Prolongation of the Inflammatory Cascade
100
Asthmatic Airway
1) Smooth Muscle Constriction of Bronchioles
2) Airway Inflammation, Mucus Discharge, Pulmonary Edema
- Airway inflammation is mostly due to LEUKOTRIENES
101
Etiology of Hypersensitivity
1) Initial exposure to Allergens generates IgE Antibodies (SENSITIZATION)
2) IgE Antibodies bind to receptos on MAST CELLS
3) Subsequent exposure to allergen binds to IgE and CROSS LINKS IgE receptors
4) CROSS-LINKING IgE receptors triggers DEGRANULATION, Release of HISTAMINE, followed by ACTIVATION of EICOSANOID BIOSYNTHESIS ( LTC4, LTD4, PGD2)
5) HISTAMINE released during Mast Cell Degranulation provokes the signs & symptoms associated with ALLERGIC IMMEDIATE HYPERSENSITIVITY
- Redness, Local Edema (swelling), Pain, and Itching
102
Histamine
- INFLAMMATORY MEDIATOR
- Histamine is discharged by GRANULOCYTES (BASOPHILS and MAST CELLS) in Connective Tissue
- Histamine INCREASES PERMEABILITY of the Capillaries to other Leukocytes and Plasma proteins which help ANNIHILATE PATHOGENS in tissue
103
Immunologic Mechanism of Histamine
- MAST CELLS sensitized by IgE Antibodies attached to their membranes, DEGRANULATE when exposed to the Appropriate Antigen (ALLERGEN)
1) Initial exposure to ALLERGEN generates IgE Antibodies (Sensitization)
2) IgE Antibodies bind to the receptors on MAST CELLS
3) Expose to Allergen binds to IgE and CROSS LINKS IgE receptors
4) CROSS LINKING IgE receptors triggers DEGRANULATION, release of HISTAMINE
104
Histamine Exit from Mast Cells
- Histamine exists inside MAST CELLS stored in GRANULES. It is released UPON DEMAND!!!!!!!!
- It is synthesized and stored (PRE-FORMED) in high concentration in granules of MAST CELLS and BASOPHILS
- Other substances in these granules include Heparin
- These substances form complexes with Histamine STORED as an INACTIVE COMPLEX
105
Histamine Activation
1) Dietary Histidine to Histamine (DECARBOXYLASE)
- Requires CO2
2) Histamine to Imidazole Aldehyde which is INACTIVE (DIAMINE OXIDASE)
3) Histamine to N-Methyl Histamine which is INACTIVE (HISTAMINE N-METHYL TRANSFERASE)
106
Histamine vs Prostaglandinds, Thromboxane, and Leukotrines
Histamine:
1) RELEASED on Demand
2) Biosynthesis is CONTINUOUS (release in INSTANTANEOUS)
3) SHORT Lived (Enzymatic Inactivation)
4) Physiology: LOCAL!!!!!!!
5) Pathology: UNWARRANTED SYSTEMIC EXPOSURE
Prost, Throm, Leuko:
1) MADE on Demand
2) Biosynthesis is INSTANTANEOUS
3) SHORT Lived (Enzymatic or Spontaneous Inactivation)
4) Physiology: LOCAL!!!!!!!!
5) Pathology: UNWARRANTED SYSTEMIC EXPOSURE
****** NOT HORMONES*********
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Types and Functions of Histamine Receptors
**** G Protein Coupled Membrane Spanning Proteins with 7 DOMAINS*********
- Histamine binds to H1-HISTAMINE RECEPTOR on VESSEL WALLS during Hypersensitivity (especially VENOUS SIDE!!!!!!!!!!!!!!!!!)
- Histamine causes VASODILATION and INCREASED PERMEABILITY of capillaries (MAIN EFFECT OF HIST)
- Histamine directly causes a PAIN by binding to H1- RECEPTORS on PERIPHERAL NERVES and by the Mechanical Pressure on the NERVES due to tissue SWELLING
108
Histamine Receptors
1) H1 Receptors:
- Nasal & Bronchial = Mucus Secretion INCREASE
- Bronchial & Intestinal = Smooth Muscle Constriction INCREASE
- Sensory Nerves = Pain INCREASE
2) H2 Receptors:
- Stomach = Gastric Acid Secretion INCREASE
**** TISSUE SPECIFIC EXPRESSION******
Tissue COEXPRESSION (H1 & H2 Receptors):
- Hear = Heart Rate INCREASE
- Blood Vessels = Peripheral Resistance DECREASE
- Skin Capillary Blood Vessels = DILATION, PERMEABILITY, PAIN SENSITIZATION
109
Mast Cell and Histamine Locations
- Mast Cells and Histamine are CONCENTRATED in certain areas of the body where the area is ANATOMICALLY VULNERABLE to Antigen or Pathogen EXPOSURE
110
Mast Cells are Concentrated at Organs Commonly Exposed to Threats
- The problem with ANAPHYLAXIS is that you are not getting enough OXYGEN to your ORGANS no matter how hard your HEAT IS PUMPING because the RELAXATION of the PERIPHERAL VESSELS does NOT allow for AMPLE amounts of OXYGEN to get to the TISSUES
- This is a RATE ISSUE
- How to fix ANAPHYLAXIS = GIVE EPINEPHRINE (Vasoconstrictor)
- Pushes the blood vessels together, to allow blood to be delivered at a faster rate by constricting the blood vessels
- EPINEPHRINE will relax BRONCHIAL SMOOTH MUSCLE (Beta-Anergic Receptors)
***** ANAPHYLACTIC SHOCK = HYPOTENSIVE SHOCK*****
111
Resident Inflammatory Cells in Tissues
1) Macrophages
2) Mast Cells
3) Eosinophils
*** TRANSIENT: migrate from blood, perform role, and depart or decay
112
Inflammatory Cells Circulating in Blood
1) Monocyte (2 to 8%)
2) Neutrophil (40 - 60%)
3) Basophil (0.5 - 1%)
4) Eosinophil (1 -4%)
5) Lymphocytes (20-40%)
113
Normal Vascular Biology
- Erythrocyte Circulation
- Neutrophil (PMN) Circulation
- PMN: MARGINATING POL
- Stick and Roll on ENDOTHELIAL CELLS
- HALF of NEUTROPHILS are in MARGINAL POOL AND HALF IN CIRCULATING POOL
- Monocyte Circulation
- Leaves circulation to become Macrophages in tissue
114
Gout Etiology & Mediators
- URATE CRYSTALS in joint provoke a "STERILE" Inflammation
- MACROPHAGES/MONOCYTES ENGULF the crystals RELEASE Inflammatory CYTOKINES (IL1b) and CHEMOTACTIC CYTOKINES (IL8) !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
- IL1b INDUCES expression of ADHESION MOLECULES on Endothelium, & COX-2 in Macrophages, Monocytes, Connective Tissue & Endothelium
- Together IL1b and IL8 INITIATE the RECRUITMENT of Neutrophils from the blood toward the LOCALE of ACTIVATED Macrophages/ Monocytes
- The activated cells (Macrophages, Monocytes, Neutrophils, and Connective Tissue Cells) create a LOCAL, progressive enrichment in LIPID MEDIATORS of INFLAMMATION as well as Complement, Coagulation, Peptides
- This Inflammatory environment manifests as Redness, Swelling, Pain, and Heat
115
Macrophages/ Monocytes trying to remove Urate Crystals
- Macrophages will not succeed in DESTROYING the Urate Acid crystals, and therefore they will make things worse in the joint
- Macrophages/ Monocytes make CYTOKINES to SIGNAL THEIR ENCOUNTer with a THREAT
- IL1b expression causes the Endothelial cells to express MORE ADHESION MOLECULES
- COX-2 INDUCTION in the Fibroblasts, Macrophages, and Monocytes then takes place INCREASING THE INFLAMMATION RESPONSE!!!!!
Together IL1b and IL8 INITIATE the recruitment of Neutrophils from the blood TOWARDS the LOCALE of activated Macrophages/ Monocytes
- IL1b INDUCES COX-2 in cells at the site of Inflammation and in adjacent ENDOTHELIUM
- COX-2 and COX-1 generate PROSTAGLANDIN mediators that CAUSE DILATION AND INCREASE PERMEABILITY of VESSELS
- POST CAPILLARY VENULES!!!!!!!!!!!!!!
116
COX Enzymes and Prostaglandins
1) Cell Membrane to Arachidonic Acid (Phospholiapse A2)
2) Arachidonic Acid A2 to Prostaglandin H2 (COX-1 "Constitutive" or COX-2 "Induction")
- IL1b cause an INDUCTION of COX-2!!!!!!!!!!!!!!!!!!!!
3) PGH2 to PGD2, PGE2, PGF2, PGI2 TxA2 (Tissue Isomerases)
4) 15-OH PG Dehydrogenase Inactivates PGD2, PGE2, and PGF2
5) Hydrolysis Inactivates PGI2 and TxA2
117
Vasculature Endothelium
- PGI2
- Causes VASODILATION
- Causes PLATELETE AGGREGATION
118
Blood Platelets
- TxA2
- Causes VASOCONSTRICTION
- Causes PLATELETE AGGREGATION
119
Vasculature
- PGE2
| - Causes PERMEABILITY
120
GI (Gut)
- PGE2
| - Causes MUCOSAL PROTECTION
121
Renal
- PGI2, PGE2
| - Causes Na+, H2) EXCRETION
122
Uterus
- PGF2a, PGE2
| - Causes PARTURITION
123
CNS
- PGE2
| - Causes TEMPERATURE (FEVER)
124
PNS
- PGE2
| - Causes PAIN SENSITIZATION
125
Skeletal
- PGE2
| - Causes Bone Remodeling
126
COX-1, PGs, and Inflammation
- IL1b STIMULATES AA release
- COX-1 CONVERTS AA into PGE2
- PGE2 causes SYMPTOMS
- Erythema
- Edema
- Pain
127
COX-2 Induction in Inflammation
- IL1b INDUCES COX-2 EXPRESSION
- COX-2 converts AA into PGE2, PGI2,....
- PGE2, PGI2, AMPLIFIES symptoms
- WORSE Erythema
- WORSE Edema
- WORSE Pain
- PGE2 and PGI2 contribute to VASODILATION, VASCULAR PERMEABILITY, local EDEMA, and PAIN
- Redness, Heat, Swelling, Pain
128
Leaky Vessels from COX-2 Induction
- Production of PGE2 and PGI2
- This causes Vasodilation and stretching of the Endothelium which leads to the FLUID LEAKING OUT!!!
- These small capillaries (Capillary Venues) is where the fluid actually leaks out!!
- LEAKY VESSELS allow Plasma EXTRAVASATION into Interstitial space (LOCALIZED EDEMA)
- IL1b INDUCES adhesion molecules on Adjacent Endothelium which INCREASES NEUTROPHIL STICKING
- Expands the Marginating Pool of Neutrophils
- IL8 is a Chemotactic factor that INITIATES DIRECTED MOVEMENT of Neutrophils from the blood, through leaky vessels and TOWARD THE LOCALE of Activated Macrophages/ Monocytes
- Neutrophils can also release NTB4 to cause more Neutrophils to go to the site of the URIC ACID. THIS IS BAD because they CANT destroy the Uric Acid and they'll just make things WORSE!!!!!!!!
- Neutrophils accumulate near the source of any THREAT and act as Granulocytes that discharge MEDIATORS or PROTEASES to degrade threat, or to engulf and digest the threat (PHAGOCYTES)
129
Inflammation in Gout
- In gout, Inflammation FAILS to ELIMINATE URIC ACID crystals, proteases & lysosomal enzymes DO NOT DIGEST URIC ACID
- The OXIDATIVE BURST from Granulocytes DOES NOT DEGRADE URIC ACID
- In gout, Inflammation may even AGGRAVATE the problem because Uric Acid precipitates more easily at ACIDIC pH in an abscess
- The inflammatory response was shaped for bacterial threats not Gout
130
Cytokines and Stimuli from Bacterial Infections DIFFER from Gout
Bacterial:
1) Stimulus:
- LIPOPOLYSACCHARIDE (LPS)
- BACTERIAL COMPONENTS
- Fungal Components
2) Cytokine Response:
- ROBUST: TNF- alpha plus other cytokines & interleukins IFN-gamma, IL-1, IL-8
3) Involvement:
- Often SYSTEMIC (SEPSIS POSSIBLE!!!!!)
Gout:
1) Stimulus:
- Uric Acid Crystals
2) Cytokine Response:
- IL1b and IL-8
3) Involvement:
- None
131
Inflammation in Bacterial Infection
1) Bacteria and Components (LPS) provoke an Inflammatory response
2) Tissue Macrophages/ Monocytes ENGULFING the BACTERIA release the Inflammatory Cytokines (TNF-alpha, IL-1, IFN-gamma), chemotactic Cytokines
3) LPS itself, TNF-alpha IL-1 INDUCES EXPRESSION of Adhesion Molecules on Endothelium, and COX-2 in Macrophages, Monocytes, Connective tissue and Endothelium
4) Cytokines, mediators of inflammation RECRUIT NEUTROPHILS from the blood TOWARD the LOCALE of INFECTION
- Innate host defense response is usually EFFECTIVE in an IMMUNOCOMPONENT HOST
- MYELOID cells release proteases and Lysosomal enzymes that DIGEST BACTERIA or DEGRADE their COMPONENTS
- The OXIDATIVE BURST from Granulocytes KILLS bacteria and DEGRADES their SURVIVAL MECHANISMS
- WE USE CHLOROX to INCATIVATE BACTERIA.... stole idea from Neutrophils!!!!
132
Big difference between Bacteria and Gout responses
*** LPS from Gram Neg Bacteria INDUCES expression of ADHESION MOLECULES on Endothelium, and COX-2 in Macrophages, Monocytes, Connective tissue and Endothelium
- Gram Negative bacterial infection enters the blood stream and thrives, a CONDITION develops called SEPSIS!!!!!
- This means SYSTEMIC INFLAMMATION develops throughout the ENTIRE body as the host mounts an Inflammatory response to NEUTRALIZE the infection in the BLOOD STREAM
- If the response is overwhelming, this can cause SEPTIC SHOCK, Multi ORGAN FAILURE, DEATH!!!!
133
Sepsis Physiology and Pathology
Physiology: AUTOCOID mediators act LOCALLY and BRIEFLY
Pathology: AUTOCOID MEDIATORS act SYSTEMICALLY and PERSISTENTLY!!!!!!!!!!!
- Causes and INCREASE in PGE2, PGI2, and LTB4!!!!
- Children with Leukocyte Adhesion deficiency are very prone to SEPSIS
- Diabetics are prone to SEPSIS as well because they lose feeling in their extremities and might not notice Ulcers develop which later can become infected!
134
Sepsis General Statement
- In Sepsis bacteris (LPS) and Cytokines )TNF-alpha) cause STYSTEMIC INFLAMMATION throughout the VASCULATURE!!!
- INDUCTION of COX-2 and ADHESION MOLECULES and activation of MYELOID CELLS thereby causes WIDESPREAD DAMAGE of the HOST!!!!!!!!!!!
- Systemic VASODILATION and EXTRAVASATION of PLASMA from the BLOOD to INTERSTITIAL SPACE leads to a DROP IN BLOOD PRESSURE, which is a feature of SEPTIC SHOCK!!!!!
135
Allergic Reactions
- Common in skin, nasal passages, and gut
- Can become severe if there is widespread or extensive EXPOSURE to ALLERGEN!!!
- ANAPHYLAXIS: a life-threatening condition... involving additional mediators!!!
136
Anaphylaxis
1) Respiratory tract exposed to Allergen -------> MAST CELL ACTIVATION
- Mast Cells DEGRANULATION releases HISTAMINE
2) Mast Cell activation ---> Respiratory Tract EXPOSED to EXCESS HISTAMINE
- Airway compromised!!!!!!
- Breathing impaired!!!!
- The trachea and Lungs are FLOODED with HISTAMINE
H1 Receptors:
1) Nasal and Bronchial = Mucus Secretion
2) Bronchial muscle = Constriction
3) Peripheral Vasculature EXPOSED to HISTAMINE
- Airway COMPROMISE
- Breathing Impaired
- HYPOTENSIVE SHOCK
H1 and H2 Receptors:
1) Heart = Heart Rate INCREASES
2) Blood Vessels Dilate = Peripheral Resistance DECREASES
- Blood Pressure DECREASES
3) Blood Vessels = Permeability INCREASES
- Peripheral Edema INCREASES
137
Anaphylaxis and Histamine
- With Anaphylaxis, HISTAMINE levels in the Blood RISE SUBSTANTIALLY within 10 minutes of the start of symptoms and return to normal after 30 to 60 minutes
- This INCREASE is reflected a short time later in the urine as Histamine and its PRIMARY metabolite, N-METHYLHISTAMINE is excreted!!!!
138
Leukotriens and Prostaglandins Mediators of Allergy and Anaphylaxis
- In addition to HISTAMINE release, Mast Cell ACTIVATION leads to Syntehsis of AUTOCOID LIPID MEDIATORS (LTC4, LTD4, and PGD2)
- In allergy and anaphylaxis these mediators COMPOUND the effects of HISTAMINE!!!!!!!!!
- Leads to:
1) INCREASED Capillary Permeability
2) DECREASED Peripheral Vascular Resistance
3) HYPOTENSION
4) MUCUS Secretion and Bronchoconstriction
139
LTC4, LTD4, and PGD2 Production
1) Phospholipase A2 cuts out Arachidonic Acid from the Cell Membrane
2) COX-1, -2 converts the AA into PGH2
- Needs O2
3) Mast Cells take the PGH2 and convert it into PGD2 (BRONCHOCONSTRICTION)
4) 5-LO takes the AA and converts it into LTA4
- Needs O2
5) Mast Cells take the LTA4 and convert it into LTC4 and LTD4 (BRONCHOCONSTRICTION and MUCUS SECRETION)
140
Anaphylactic shock
- Anaphylactic shock is a medical emergency that requires HEMODYNAMIC and AIRWAY SUPPORT with EPINEPHRINE (Vasoconstriction and Bronchodilator)!!!!!!!!!!!!!!!
- Also, agents must be administered to negate the action of Histamine, Leukotrienes and Eicosanoids
- PGD2 and DP Receptors are present curing BRONCHOCONSTRICTION!!!!!
141
Negative Selection of B Cells
*** BEFORE a B Cell leaves the Bone Marrow it is TESTED ON RECOGNITION of SELF AGS!!!!!******
1) B Cells with HIGH AFFINITY to ELF AGS (Soluble or membrane) are eliminated by NEGATIVE SELECTION. It prevents the development of AUTOIMMUNITY!!!!
2) The second mechanism is RECEPTOR EDITING: when a B Cell recognizes SELF AGS, it REACTIVATED Ig gene RECOMBINATION and begin to express a NEW LIGHT CHAIN
142
Phases of B Cell Activation
1) Antigen Recognition: Helper T Cell helps stimulate the Naive B Cell (IgM+, IgD+) to activate
2) Activation of B Lymphocytes: CLONAL EXPANSION of the activated B Cell
3) Effector Cells: ANTIBODY-secreting PLASMA CELLS (DIFFERENTIATION!!!!!!)
- MEMORY B CELL is made
4) Final Result:
- Antibody Secretion: IgM
- Isotype Switching: IgG
- Affinity Maturation: HIGH AFFINITY IgG
- One activated B cell may generate up to 4000 plasma cells, which can produce up to 10^12 molecules per day!
- Ab DO NOT go into tissue, they are usually on the surface. BUT gig can go into the tissue!!!!!
143
Ag Recognition of Naive B Cells occurs in LN
- The activation of B cells by Ag in the Lymph Node initiates the following process:
1) Ag-Activated B Cell PROLIFERATION (Mitosis)
2) Ag- Activated B Cell INCREASES EXPRESSION of:
A) Ag (MHC CLASS II)
B) B7 (CD80/ CD86)
C) Receptors for Cytokines produced by Th Cells
- Increased expression of costimulators and cytokine receptors
3) Secrete LOW LEVEL of IgM!!!!
- Inner Cortex = T Cell Zone
- Outer Cortex = B Cell Zone
144
Help From Complement
- CR2 is very IMPORTANT at the beginning of INFECTION when the amount of microbial AG is LIMITED
- CR2 binds C3d, which is a fragment of the C3b component of complement deposited on bacteria
- CR2 makes B CELLS VERY SENSITIVE TO AGS
- This illustrates the COOPERATION between INNATE and ADAPTIVE IMMUNITY
- BRC recognizes AG LABELED BY INNATE IMMUNITY as being DANGEROUS
***** NEED just a SMALL AMOUNT OF C3d to cause B cell activation because it includes the CR2 receptors which is VERY STRONG
145
Activated B Cells Migrate into the Central Zone
**** Ag-ACTIVATED B Cell migrates from the Lymphoid follicle toward the T Cell-rich zones of the LYMPH NODE****
1) After B cell activation they MIGRATE to the T cell Zone for T:B CELL INTERACTIONS!!!!
2) T cells proliferate and differentiate and the EFFECTOR CD4+ T Cells migrate to the edge of the T Cell zone for the T:B CELL INTERACTION!!!
* ** PARAFOLLICULAR CORTEX = T Cell Zone*****
* **LYMPHOIG FOLLICLE = B Cell Zone*****
- The Th cell helps provide the B cell with CD40L to bind to its CD40 and activate it!!!
- Needs CD40L and Cytokines
146
B Cells Is a Professional APC
- BRC-Mediated ACTIVATION of B Cell, AG can be ENGULFED
- Ag is processed and peptides produced as PRESENTED on the B cell within CLASS II MHC
- The presentation of peptide Ag within CLASS II MHC is an absolute REQUIREMENT for T HELPER CELL TO BE INVOLVED in ACTIVATION of B Cell
*** A single B cell can be ACTIVATED by many different CD4+ T HELPER CELLS***
147
How T Cells Activate B Cells
- Involved a DIRECT CONTACT between B Cell and T Helper Cell and CYTOKINES
- T helper cells provide STIMULATORY SIGNALS for ACTIVATION of B Cells
- Activated T HELPER CELLS express proteins called CD40L (ligand)
- A protein called CD40 is EXPRESSED ON B CELLS
*** When CD40L binds CD40, the co-stimulatory SIGNAL IS SENT*****
- If BRCs have been cross-linked, then B CELL IS ACTIVATED!!!!!
** After B cell activated causes B Cell proliferation, Initial Antibody Production, Germinal Center REACTION**
148
Ig Class Switching
- When FIRST activate, B Cell PRODUCES mainly IgM (also can produce IgD)
- During B cell maturation, it CAN SWITCH to either IgG, IgA, or IgE!!!!!!!!
- The Ab CLASS is DETERMINED by Fc REGION!!!!!
- What B Cell has to do is cut off the IgM CONSTANT REGION DNA and past on another***
149
Different Ab Functions
1) IgM:
- Complement Activation
- Original Type of Ab produced
2) IgG (Subclasses IgG1, IgG3)
- Fc receptor-dependent PHAGOCYTE RESPONSES
- Complement Activation
- NEONATAL IMMUNITY (Placental Transfer)
3) IgE
- Immunity against HELMINTHS (Eosinophil Mediated)
- MAST CELL DEGRANULATION (Immediate Hypersensitivity)
4) IgA
- MUCOSAL IMMUNITY (transport of IgA through Epithelial)
- Passed to baby by BREAST FEEDING (Passive Immunity)
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A Carrier Choice: Plasma Cell
- The CHOICE OF PROFESSION is the final step in maturation of B cell
- B cell has only 2 choices:
1) A PLASMA CELL (Ab Factory)
2) A MEMORY CELL
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Plasma Cells
- Travels to the SPLEEN or back to the BONE MARROW
- Begins to PRODUCE AB (up to 2x10^3 Abs per second)
- It is not an easy "job" - plasma cells live about 5 DAYS!!!
- A SINGLE PLASMA CELL can produce the AMOUNT OF ABS that is enough to KEEP UP WITH PROLIFERATING INVADERS such as viruses and bacteria
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Memory Cell
- Formation of IMMUNE MEMORY is paramount for ADAPTIVE IMMUNITY
- It helps to DEFEND against the SUBSEUENT INFECTIONS with the same pathogen
- Little is know how it happens
- It appears that CD40-CD40L INTERACTION IS CRITICAL in this career choice
****** MEMORY IS NOT PRODUCED when B Cell is activated WITHOUT T CELL HELP****!!!!!!
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B Cell Presonse to TI and TD Ags
1) Thymus Dependent Antigen:
- Chemical Nature: proteins
- HAS ISOTYPE SWITCHING!!!!! (IgM, IgG, IgA)
- HAS AFFINITY MATURATION!!!!! (IgG)
- Produces MEMORY B CELLS (Secondary Response)
2) Thymus Independent Antigen:
- Chemical Nature: Polymeric Antigens (LPS)
- LITTLE to NO Isotype Switching (Some IgG)
- LITTLE to NO Affinity Maturation
- Production of Memory Cells (Secondary Response) only seen with some Antigens
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Thymus- Independent Ags (TI)
Properties:
1) POLYMERIC Structure
2) RESISTANCE to DEGRADATION (persist for long periods of time and continue to stimulate the immune system)
3) POLYCLONAL ACTIVATION of B Cells
- Usually Polysaccharides, lipids, and other NONPROTEIN AGS are TI Ags
- CANT BIND TO MCH CLASS II ---> Th CANT see them
- Little is know about how TI Ags induce immune responses
- TI Ags are able to CROSS-LINK MANY BRCS to a particular B Cell
- Cross-linking MAY ACTIVATE THE B CELLS strongly enough to stimulate their proliferation and differentiation
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Two Types of TI Ags
TI-1 Ags: POLYCLONAL ACTIVATORS OF B CELLS
TI-2 Ags (Not Polyclonal) are AGS with REPEATING EPITOPES for CROSS-LINKING BRCs
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Type 1 Thymus Independent Ags
* ** B Cell activation by POLYSACCHARIDE ANTIGEN****
1) 1st Signal: B cell receptor BINDS ANTIGEN
- This is done is a non specific way
- Ex: LPS can bind many different BRCs
2) 2nd Signal: Provided by TOLL-LIKE RECEPTOR
*** NO CD4+ CELL HELP***
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Type 2 Thymus Independent Ags
*** B Cell activation by a POLYSACCHARIDE ANTIGEN***
1) 1st Signal: B Cell receptor BINDS ANTIGEN
2) 2nd Signal: Provided by CLUSTERING of BCRs!!!!!!!!!!!
**NO CD4+ Help**
- Generated against REPETITIVE AGS
- B cells activated by DIRECT BRC CROSS-LINKING
- Ab produced are MOSTLY IGM!!!!!!!!
- Ab AFFINITY to TI Ags- relatively LOW!!!!!!
- PRODUCES NO MEMORY!!!!
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Clinical Significance of TI Ags
- Many BACTERIA cell wall POLYSACCHARIDES belong to TI AGS!!!!!
- AB-MEDIATED IMMUNITY is the major mechanism of host defense against infections by ENCAPSULATED BACTERIA!!!!!
- The advantage of such response is that B Cells can be Activated RIGHT AWAY without have to wait for T cells to be Activated!!!!!
*** Patients with CONGENITAL or ACQUIRED DEFICIENCIES of AB-mediated response are very SUSCEPTIBLE TO INFECTIONS with ENCAPSULATED BACTERIA
