PRIN 13 Inflammation Flashcards
What does the Lymphatic System include?
Lymph nodes Lymphatic Vessels Tonsils Thymus Spleen Peyer's Patches
What IS Lymph?
An ultra filtrate of blood
contains tissue fluid, WBC, fats & chyle) from GI
What makes lymph flow through vessels?
Contraction of skeletal muscle
One-way valves
Superficial & Deep Drainages … what do they follow?
Superficial drainage follows the veins
Deep drainage follows the arteries
What are the 2 major deep lymph drainage pathways?
Right Lymphatic Duct
- drains R side of head R side of thorax
- drains into R subclavian vein
Thoracic Duct
- drains all the rest of the body
- drains into L subclavian vein
When are lymph nodes palpable?
Superficial Nodes are palpable when inflamed
(eg):
Cervical nodes > 1cm
Inguinal nodes > 1.5cm
Which are the palpable lymph nodes?
EPIC-Ap
Cervical Axillary Epi-trochlear Inguinal (superfic) Popliteal
Which are the NON-palpable lymph nodes?
Parasternal
Aortic
Iliac
Inguinal (deep)
Inflammation which lymph nodes is suggestive of cancer?
Supra-clavicular Nodes & Virchow’s/Sentinal Nodes
from abdomen & thorax
Pathway of lymph drainage in breasts
Lateral & Inferior regions … axillary nodes
Medial regions … Parasternal Nodes … Subclavian Nodes … Subclavian Veins
Pathway of lymph drainage in testes
Lumbar & aortic nodes
not palpable
Pathway of lymph drainage in scrotum
Superficial inguinal nodes
palpable
What are central/primary lymphoid organs?
Sites of generation & early maturation of WBC
Bone Marrow
Thymus
What are Secondary Lymphoid Organs?
Lymph nodes
Spleen
Tonsils
Mucosal Tissue …
What arises from Hematopoietic Stem Cells?
Lymphoid Progenitors
(B&T cells)
&
Myeloid Progenitors
What arises from Myeloid Progenitors?
Granulocyte / Macrophage Progenitor
*BEN, Monocytes (Macro & DCs)
Megakaryo & Erythrocyte Progenitor
*Platelets & RBC
What is pus?
Accumulation of dying neutrophils responding to the site of infection
What is left shift?
Sign of Early neutrophil release from BM
L Shift Products look more like monocytes and have not developed the normal multi-lobed nucleus
What are the 3 APCs?
“Big-MD”
Macrophages
DCs
B-cells
What is the function of the spleen?
Capture Ags from blood
What are germinal centers?
LOCATED IN LYMPH NODES
Region where lymphocytes have been stimulated by Ag
Result: Clonal expansion of activated B-cells
What is the Paracortical area of the lymph nodes?
Site where T-cells are interacting with APC & B-cells
Within the spleen, what is Red Pulp & White Pulp
RED: where aged RBCs are destroyed
WHITE: lymphoid areas
Which cells serves as the bridge between Innate and Adaptive Immune Systems?
Dendritic Cells
What do neutrophils respond to?
Chemotactic factors
Neutrophils migrate toward higher concentration of chemotactic factors
Which cells are phagocytic?
Nasty-MD
neutrophils
monocyte/macrophage
DCs
Within the complement system, what are the 3 pathways?
Classical
Lectin
Alternative
Within the complement system, when do all 3 pathways unite?
Cleavage of C3:
C3a - anaphylatoxin
C3b - cleaves C5
What do T cells do?
Circulate through system checking out antigens presented on the MHC of APCs
What do Abs do?
Bind to Ag of microbes & serve as a flag. Microbe cell becomes coated in Abs (ADCC)
(antibody coated cell)
Signals for destruction via phagocytosis by NK & Macrophages
NOTE: Abs kill INDIRECTLY by simply acting as an opsonin
What system kills via MAC?
Complement System
kills via Membrane Attack Complex
(lyses cells)
Which complement pathway is initiated by Ab-Ag complex?
Classical Pathway
What is the clinical result of not having a functional Complement System?
Infection
Autoimmunity
What do NK cells do?
Attack cells with intracellular disturbances that do not look normal
(eg) tumor cell, virus infected cell
What do Neutrophils do?
Devour extracellular pathogen. In the process of neutrophills sacrifice themselves
What is pus?
Dying / Dead neutrophils
What are PMNs?
aka Neutrophils
Polymorphic Nuclei
Why do cancer patients receiving treatment have poor immune response?
Cancer treatment targets quickly dividing cells. Neutrophil development is inhibited
What is ROS?
Reactive Oxygen Species
molecules produced in “oxidative bursts” that function in lysosomes
(eg) H2O2, radicals, HOCl
Which cells kill pathogens by production of ROS?
MEN
Neutrophils
Macrophages
Eosinophils
What is CGD?
Chronic Granulomatous Disease
Impaired innate immune system due to lack of oxidative bursts (ROS)
Results in recurrent bacterial infections
What is the primary, most IMPORTANT role of DCs?
Antigen Presentation
PAMP vs PRR
Which cell has what?
MICROBE-PAMP
(pathogen associated molecular pattern)
PHAGOCYTE-PRR
(pattern recognition receptor)
Note: each PRR only recognizes one PAMP
How is Homeostasis maintained in the Innate System?
EARLY:
Neutrophils & Macrohages act as the alarm signal & trigger inflammation
LATER:
DCs down-regulate inflammation & promote healing
What happens within a few minutes following tissue injury?
Vasodilation Increased Blood Flow Increased Permeability Resident Macrophages defend Extravasation
What happens within a few hours following tissue damage?
Neutrophil infiltration into tissues
The first immune cells to attack pathogen is what?
How does it do it?
Resident Macrophages have PRR that recognize PAMP on pathogen.
- **Phagocytosis …
- **Call the alarm: Release Cytokines: IL1, IL6, TNFa
What are the LOCAL effects of the released cytokines?
IL1, TNFa:
up-regulate adhesion molecule
NO, IL1, IL6, TNFa:
Vasodilate
Increase Vasc. Perm.
TNFa:
Promote chemotaxis & activation of neutrophils
What releases NO?
Local endothelial cells
What explains pain during acute inflammation?
Kinin Cascade
activated by contact with collagen & BM
FUNCTION: cleaves HMWK into Bradykinin
What is Bradykinin ?
What does it do?
9aa peptide
Promotes vasodilation
Increase Vasc. Perm.
Stimulates pain nerve fibres
What activates Mast Cells?
C3a
C5a
TLR
What do Mast Cells Release?
Histamine
IL6
TNFa
(cytokines are released contributing to redundancy)
What is Histamine?
What does it do?
Small amine molecule that binds to receptors on endothelial cells & smooth muscle cells
Causes:
Promotes vasodilation
Increase Vasc. Perm.
By 6 hours following injury, what immune cells predominate?
Neutrophils (PMNs)
Steps in Neutrophil Extravasation
(1) Rolling adhesion
(2) Tight Binding
(3) Diapedesis
What mediates neutrophil tight binding?
LFA-1 on Neutrophil
ICAM-1 on endothelial cell
Besides neurophils, what other immune cells respond to the cry for help?
Monocytes
Recruitment is more gradual than PMN recruitment
What are the SYSTEMIC effects of cytokines?
IL-1, IL-6, TNFa:
To Brain … released prostaglandins … fever
To Liver … Secrete APRP (CRP) etc..
IL-6, TNFa:
To Bone Marrow … Leukocytosis … neutrophilia
Exogenous
Bacterial Infection
MHC2
CD4+ T_helper
Endogenous
Viral
MHC1
CD8+ CTL
What are the 3 signals that activate T Cells?
(1) MHC-Ag to TCR
(2) Costimulation
(3) Cytokines help differentiation of T Cells
What do CTLs do?
Cytoxic T Lymphocytes (when activated) kill by inducing the infected cell to undergo apoptosis
Which cells can present via MHC1?
All cells in the body … any cell can become virally infected
Which cells can present via MHC2?
APCs: “Big MD”
Macrophages
B-cells
DCs
Which are the BEST APCs?
Why?
2 reasons
(1) have the most PRRs
(2) provide the best costimulation of Naive T cells
What is an example of a co-stimulatory signal as presented by a DC?
B7 on DC interacts with
CD28 on T-Helper
What is an example of cytokine release finishing the activation of a T-helper cell?
IL-2 via autocrine by T-helper
“self kick in the pants”
What type of cytokines does the DC release?
IL-12, TNFa
How do Abs kill a microbe?
INDIRECTLY:
*bind Ag of pathogen and act as flag calling NK cells to come and kill
What do NK cells do?
Wander the system and hunt down cells that don’t look quite right ….
(eg) tumor cells, cells covered in Abs, infected cells
Besides its role in complement activation, what does C3b do?
Acts as Opsonin
C3b binds to pathogen and enhances the ability of a macrophage to engulf it
What does TH1 do?
secretes INFy which activates macrophage to up-regulate lysosome mechanisms
Acute vs Chronic Inflammation
What are the predominant cells involved?
ACUTE:
Neutrophils
CHRONIC:
T Cells, Macrophages
Acute vs Chronic Inflammation
What is a bacterial example of cause?
ACUTE:
S aureus
CHRONIC:
M. Tuberculosis
HOW does M Tuberculosis cause chronic inflammation
Bacteria survive in lysosomes of macrophages
Macrophages accumulate and started going “crazy” whereby they spew out their proteolytic enzymes
What is a Tuberculous granuloma?
Attempt to section off damaged area in lungs caused by exploded macrophages …. leads to loss of lung tissue function
Which cell is involved in the clean up after infection and inflammation is resolved?
Macrophages
What is Meningitis?
Inflammation of the meninges.
caused by N. meningitidis
Why did the Meningitis patient get a rash that eventually led to necrosis?
MOA?
Bacteria had entered the blood stream (bacteremia) and circulated the system getting stuck in the smallest capillaries.
The rash was caused by the body mounting an inflammatory response. Bacteria damaged endothelial cells. Inflammatory response resulted in the vessels becoming extremely leaky.
Why was Rifampin given to Anna’s roommates?
Rifampin = RNA polymerase inhibitor
Given as a chemo-prophylactic measure
What is DIC?
Dessiminated Intravascular Coagulation
blood clots form throughout the body’s small blood vessels.
These blood clots can reduce or block blood flow through the blood vessels, which can damage the body’s organs.
Platelets get used up and internal bleeding occurs
Anna’s acute phase response resulted in …
Fever
neutrophilia
high CRP
What is vasculitis?
Inflammation of SMALL blood vessels in response to encounter with pathogen stuck in capillaries
Which cell type infiltrates in large numbers into the rash sites:
Neutrophils
Why is Neissaria Meningitis so dangerous?
gram - bacteria releases LPS toxin as it dies
Signs of Sepsis
Bacteria present in blood stream accompanied by inflammatory response result in:
- *Fever
- *Elevated HR & RR
What marks the entrance into Septic Shock?
BP drops even though we are administering fluids
Disseminated Intravascular coagulation
What tests are done?
d-dimer
platelet count
prothrombin time
We must monitor our Meningitis patient for this!
What are the three amigos?
IL-1
IL-6
TNFa
Which cells present MHC-1?
Which cells present MHC-2?
MHC-1:
All nucleated cells
MHC-2:
APC’s only (B cells, DCs, Macrophages)
What is the role of MHC I?
recognizing altered self and presents Ag to CTLs
i.e.: samples the intracellular milieu and presents intracellular antigens on the surface of cells
What is SIRS?
systemic inflammatory response syndrome
How do we diagnose Disseminated intravascular coagulation?
fall in blood platelet levels
What induces immediate endothelial cell retraction?
NO
histamine
What is the predominant immune cell type in granulomas
Macrophages
Which one of the following phases of drug development is most likely to include healthy human subjects?
Phase 1
Where does peptide loading of MHC Class I molecules with endogenous antigens occur?
ER
What are the phagocytes?
neutrophils,
macrophages/monocytes
DCs
Which cells are involved with resolving inflammation?
Macrophages
Which complement protein also acts as an opsonin?
C3b
Which complement proteins trigger mast cell degranaulation?
C3a, C5a
Which cell types can produce reactive oxygen species via a respiratory burst?
MEN
Neutrophils
Eosinophils
Macrophages
Which cell type takes up microbes via antigen-specific receptors, then processes and presents microbial antigens?
B-cells
note … Ag specific!!!
Which cell type releases nitric oxide, a potent vasodilator?
Macrophages
Are neutrophils phagocytic and Ag presenting?
Phagocytic only
They simply follow the trail of chemo tactic factors, gobble up cells and then die
How do CTL kill?
Once in direct contact with affected cell, CTL releases Perforin & Granyme B into it … triggers Caspases … apoptosis
In the case of persistent and localized antigenic stimulation (i.e.: mycobacterium, sutures, parasitic eggs etc) the immune system responds by walling off the antigen. What type of process is this?
Chronic Inflammation
Which cells are involved in resolving inflammation.
Macrophages
Which cell type presents antigen and activates naïve TH?
DCs
Which cell type takes up microbes via antigen-specific receptors, then processes and presents microbial antigens?
B cell
Which cell type releases nitric oxide, a potent vasodilator?
Macrophage, Endothelial Cells
