Chapter 2: Inflammation, Disorder and Wound Healing Flashcards
What is the overall effect of inflammation ?
To allow inflam. cells, plasma protein and fluids to exit blood vessels and go into the interstitial space.
What are the two kinds of inflammation
Acute and Chronic
What two things are always present in acute inflammation ?
Edema and Neutrophils (neutrophils are really the hallmark of acute inflammation)
What two occurrences lead to the presence of acute inflammation ?
Acute infection (figh pathogen) and tissue necrosis (Clear dead tissue)
Toll Like Receptors are found on cells of the innate immune system and are implicit in Acute Inflammation. What is the co-receptor for these and what do they respond to ?
CD14
Respond to PAMPS (Pathogen Associated Molecular Patterns)
CD14 specifically responds to LPS (Gram -)
The activation of CD14 and TLR will lead to the activation of which intracellular immune mediator ?
NF-kB (translocates to the nucleus and cause activation of multiple immune mediator genes etc.
Which cells are part of the innate immune system ?
Mast, Macrophages, Neutrophils, Eosinophils
What releases Arachadonic Acid (AA) from the membrane ?
Phospholipase A2
What are the two enzyme systems that act on AA ?
Cyclooxygenase –> PG’s
Lipoxygenase 5 –> LT’s
Which PG’s are responsible for VASODILATION and VASCULAR PERMEABILITY ?
PG D2 ,E2 and I2
PG will make you DIE (mnemonic) due to hypotension and edema.
Where in the vasculature does vasodilation occur ?
Arteriole
Where in the vasculature does vascular permeability occur ?
Post capillary venule
Which prostaglandin is related to production of Pain and Fever (also vasodilation and permeability) ?
PGE2
Feever = E2
Which LT is responsible for neutrophils attraction and activation ?
LTB4
What other molecules besides LTB4 is responsible for neutrophil attraction ?
C5a, IL8 and Bacterial Products.
What do LTC4, D4 and E4 mediate ?
Vasoconstriction, Bronchospasm and Increased Permeability ( post capillary venule).
How do LTC4, D4 and E4 increase vascular permeability despite causing vasoconstriction ?
They cause the vascular pericyte cells to contract. This pulls the epithelial cells apart creating a gap in which vascular fluids can leak out of.
What three things activate Mast Cells ?
Direct Damage to Tissue
C3a and C5a
Crosslinking of antigen with IgE on cell surface
What is the immediate effect occurs due to Mast Cell activation by the three processes listed ?
Release of prestored histamine vesicles
What does Histamine release lead to in the vasculature ?
Vasodilation
Vascular permeability
(Much like PGD,E,I2)
What is the common effector created by the Classical, Alternative and MBL pathways in complement activation ?
C3 Convertase
Explain the components of the Classical Pathway of Complement activation ?
IgG or IgM bind to pathogen.
C1 binds to IgG or IgM on pathogen
Leads to Activation of C3 Convertase
(GM makes Classical Cars, lets go see one (C1))
Explain the components of the Alternative Pathway of Complement activation ?
Microbial products directly activate complement
Leads to C3 Convertase production
Explain the components of the MBL Pathway of Complement activation ?
MBL binds to Mannose moieties on pathogen leading to activation of complement and formation of C3 convertase
Products of C3 Convertase activity
C3 –> C3a and C3b
C3b leads to the production of ..
C5 convertase
Products of C5 Convertase
C5a and C5b
What does C5b complex with to lead to the formation of the MAC ?
C6-9
What is the overall effect of MAC ?
Lyse cells
C5a and C3a are also known as …. and lead to …..
Anyphylaxotoxins
Mast Cell degranulation and release of Histamine (anaphylaxis is due to huge amount histamine release )
Besides leading to the activation of the C5 Convertase, C3b also allows for …
Opsonization
It is an opsonin that Ab’s bind to. Helps phagocytes internalize pathogens and necrotic cells>
Besides being and anayphylaxotoxin, C5a is also a chemoattractant for …..
Neutrophils
Other Neutrophils attractants : LTB4, IL8 and Bacterial Products.
Where is Hageman Factor (Factor XII) produced and what activates its circulating form ?
Liver
Exposed sub endothelial COLLAGEN.
Hageman Factor leads to the activation of which three systems ?
Coagulation and Fibrinolytic (Major Roll Player in DIC***)
Complement
Kinnin System
Hageman Factor Activation of Kinnin leads to the cleavage of HMWK to ….
Bradykinin
What processes does Bradykinin mediate ?
Vasodilation
Vascular Permeability
PAIN (other mediator of pain ? PGE2 !)
What are the 4 Major Signs of Acute Inflammation ?
Redness and Warmth
Swelling
Pain
Fever
Which processes lead to Redness and Warmth ? Which molecules mediate this ?
Vasodilation
PGD,E,I2
Histamine
Bradykinin
What leads to swelling ? What molecules mediate this ?
Increased vascular permeability (post capillary venule)
HISTAMINE**, PGD,E,I2. LTC,D,E4 , Bradykinin and Tissue Damage.
Which molecules mediate pain ?
PGE2 and Bradykinin (sensitize sensory nerve endings)
What mediators do Macrophages release that activates COX in the perivascular cells of the hypothalamus ?
IL-1 and TNF
Macrophages are activated by pyrogens
What is produced by COX in the perivascular cells of the hypothalamus that leads to increased temperature set point and thus fever ?
PGE2
What are the 4 processes that lead to movement of Neutrophils out of the blood vessels ?
Margination
Rolling
Adhesion
Transmigration/Chemotaxis
What leads to margination of WBC’s ?
Vasodilation (arteriole) and slowing of the blood so that WBC’s can move out of the central blood flow towards the periphery.
Rolling requires the interaction between Sialyl Lewis X and selections. Which cells are these found on respectively ?
Sialyl Lewis X (WBC)
E and P Selectins (Endothelium)
What molecules lead to the up regulation of P selectins on the vascular endothelium ?
Histamine
What molecules lead to the up regulation of E selections on the endothelium ?
TNF and IL-1
Adhesion of WBC’s to the endothelium is due to the interaction between Integrins and ICAM/VCAM. What cells are these found on respectively ?
Integrins: WBC’s
ICAM/VCAM: Vascular endothelium
What molecules lead to the up regulation of Integrins on WBC’s ?
C5a and LTB4 (These are also chemoattractant for neutrophils)
What other molecules are chemo-attractants for neutrophils ? IL8 and Bacterial Products.
What molecules up-regulate CAM/VCAM on endothelium ?
TNF and IL-1 (the same molecules that regulate Selectins on vascular endothelium)
(TNF and IL-1 are also released by macrophages and lead to COX activity in the Hypothalamus –> PGE2 activation and fever.)
Leukocyte Adhesion Deficiency is caused by an autosomal recessive defect in …..
Integrins (CD18 subunit)
What is the earliest manifestation of Leukocyte Adhesion Deficiency ?
Delayed Separation of Umbilical Cord. (Necrotic tissue that is usually phagocytically removed by the presence of neutrophils –> separation)
Two other signs of LAD: Increased circulating neutrophils and frequent infections that do not produce pus (non-pyogenic).
Where do WBC’s migrate across the endothelium ?
POST CAPILLARY VENULE (this is the site of increased permeability KNOW IT !!!)
Again, what are the molecules that lead to chemotaxis and migration by WBC’s (neutrophils in this case) ?
C5a, LTB4, IL-8 and Bacterial products
What two opsonins enhance the phagocytosis of pathogens and necrotic tissue ?
IgG and C3b (C3b is an opsonin and also leads to activation of the C5 Convertase)
Formation of which intracellular organelles are needed for proper functioning of phagocytes ?
Phagolysosome (Phagosome + Lysosome)
This syndrome is characterized by neutropenia, increased risk for pyogenic infection, giant granules in leukocytes, albinism, defective hemostasis and peripheral neuropathy ?
Chediak-Higashi Syndrome
What is the main cause of Chediak Higashi syndrome ?
Autosomal recessive defect in protein trafficking that leads to inhibited phagolysosome formation.
What is the most effective form in intracellular killing by phagocytes ?
O2 dependent
What is the ultimate final molecule that is responsible for oxygen dependent killing ?
Bleach (HOCL)
What is the first step in production of HOCL ?
O2 –> superoxide (via NADPH Oxidase)
What is the second rxn in creating HOCL ?
Superoxide –> H2O2 (via Superoxide Dismutase)
What is the last rxn in creating HOCL ?
H2O2 –> HOCL (via Myeloperoxidase, MPO)
Chronic Granulomatous Disease (CGD) is due to a defect in which enzyme ?
NADPH Oxidase
CGD is marked by recurrent infection and granuloma formation involving which kind of organisms ?
Catalase Positive (Catalase is capable of breaking down H202)
Which organisms (5) are often seen in granulomas of CGD ?
S.aureus P. cepacia S.marcescens Nocardia Aspergillus
How does catalase allow organisms to survive in CGD ?
Normally, organisms produce a small amount of H202. People with CGD can use this (since their endogenous H202 production is inhibited) to make HOCL.
Organisms with Catalase break down H2O2 making this form of killing impossible.
What is the test that screens for CGD ? What is a positive result for CGD ?
Nitroblue Tetrazolium
Normal patients have NADPH Oxidase and can metabolize NBT to a blue color. Those w/o NADPH oxidase will not metabolize this and will not produce a blue color : Positive Screen = Colorless.
MPO deficiency leads to ineffective production of HOCL. What organisms will patients with this defect be at high risk for ?
Candida
(Patients with MPO still have effective NADPH so they will have an oxidative burst that can kill Catalase + organisms (will have Negative NBT test = blue color produced)
In what granules will you see oxygen independent killing ?
Secondary Granules of leukocytes etc.
Review: what are the three phases of Acute Inflammation ?
Fluid
Neutrophil
Macrophage
How do macrophages enter the peripheral tissue ?
Same as neutrophils: Margination, Rolling, Adhesion and extravasion.
What type of granules help Macrophages destroy ingested material ?
Secondary (02 independent mechanisms).
Note: Opsonins help macrophages phagocytize material ( c3b and IgG)
What are the anti-inflammatory molecules secreted by Macrophages that mediate resolution and healing ?
IL-10
TGF-B
What are the pro-inflammatory molecules secreted by Macrophages that mediate the continued recruitment of neutrophils and therefore Acute Inflammation ?
IL-8
Structure formed by Macrophages due to acute inflammation and fibrosis
Abscess (cytokines and growth factors mediate this)
What cells do macrophages present antigen to in order to mediate CHRONIC INFLAMMATION ?
CD4+ Helper cells.
What cells are characteristic of Chronic Inflammation ?
Lymphocytes and Plasma Cells in Tissue
What are some stimuli for chronic inflammation ?
Viral Infection Mycobacteria Fungus Parasites AI Disease Foreign Material Certain Cancers
What constitutes the T-cell Receptor Complex ?
TCR
CD3
Antigen presented to the TCR comes attached to which molecules ?
MHC-I
MHC-II
MHC-I complexes with which class of T-Cells ?
CD8 T-Cells
MHC-II complexes with which class of T-Cells ?
CD4 T-Cells
CD4+ recognize what kind of antigen that is presented on MHC-II molecules ?
Extracellular !
CD4+ activation involving TCR + MHC-II also requires a secondary signal between B7 and CD28 to cause activation. Which cells have B7 on them ? Which Cells have CD28 on them ?
APC has B7 and MHCII
CD4+ Cells has TCR and CD28
28/7 = 4 ~
TH1 cells are required for the proper function of which 3 cells ?
Macrophages
B-cells
CD8 Killer Cells
What do TH1 cells secrete to activate Macrophages ?
IFN-g (causes them to turn into histiocytes, more about this later)
What do TH1 cells secrete to affect B-cells ?
INF-g (causes class switching from IgM–>IgG)
What do TH1 cells secrete to activate CD8 Killer Cells ?
IL-2 !!
TH2 cells are important in the activation/differentiation of which cells ?
B-Cells
What do TH2 cells secrete to cause class switching of B-cells to IgE ?
IL-4
What do TH2 cells secrete to cause class switching of B-cells to IgA ?
IL-5
What are the two ways in which B-cells are activated ?
- Antigen Binds IgM or IgD leading to either IgM or IgD secreting plasma cells
- TH2 interactions
Initially which CD40 on the B-cell must bind CD40L on the TH2 cell. After this occurs, what does the TH2 cell secrete to activate the B-cell ?
IL-4 (IgM –> IgE)
IL-5 (IgM –> IgA, maturation to plasma cell)
CD8 Cytotoxic T-Cells complex with MHC-I which presents which kind of antigen ?
INTRACELLULAR ! (intracellular pathogens)
In order to be activated, CD8 T-Cells must bind antigen on MHC-I and receive which stimulatory signal from TH1 cells ?
IL-2 (already a card, just wanted to test my recall).
What are the two ways in which CD8 Cells kill infected cells ?
Perforin/Granzyme –> perforin creates a hole in the membrane for granzyme to enter. Granzyme activates apoptosis
CD8 FasL binds Fas on target cell activating apoptosis.
Granulomatous Inflammation is divided into two sub-types. What are they ?
Caseating
Non-caseating.
What is the CHARACTERISTIC cell of granulomatous inflammation ?
EPITHELIOD HISTIOCYTE. (Tranformed macrophage)
What is the characteristic of Non-caseating granulomas ?
Lack Central Necrosis
What are some conditions that lead to Non-caseating granulomas ?
Foreign Body Sarcoid Beryllium Crohn disease (Crypt Abscess, no necrosis) Cat Scratch (stellate shaped granuloma)
What is the characteristic of caseating granulomas ?
central necrosis
What are some conditions that lead to caseating granulomas ?
Tuberculosis
Fungal infection
the initial step in granuloma production involves Macrophages presenting antigen on MHCII to TH cells. What doe the secretion of IL-12 from the macrophage lead to ?
Differentiation of TH to TH1 cell !
After differentiation to TH1, what will this cell secrete to transform macrophage into an epitheliod histiocyte (and giant cells) ?
INF-g.
DiGeorge Syndrome is caused by a developmental failure of which embryonic structure to form ?
3/4th pharyngeal pouch
What deletion is responsible for DiGeorge ?
22q11
What anatomical structures are effected by developmental failure of the 3/4th pharyngeal pouch to form ?
Thymus
Parathyroid
Upper portion of Heart/Great Vessels
Closure of palate
Characteristics of DiGeorge syndrome include T-Cell deficiency and hypocalcemia. Why ?
Lack of Thymus and Parathyroid (respectively)
SCID is caused by defective cell mediated and humoral immunity and is usually due to which three etiologies ?
Cytokine Receptor Defect
Adenosine Deaminase Deficiency ***
MHC-II deficiency
Why will Cytokine Receptor Defect lead to SCID ?
Cytokines (like IL-4,5,12 and INF-g) are all needed for proper formation of T and B Cells
Why will Adenosine Deaminase Deficiency lead to SCID ?
ADA is responsible for the deamination of adenosine and deoxyadenosine. Build up of these two is cytotoxic to lymphocytes (T/B cells)
MOST HIGH YIELD
Why will MHC-II deficiency lead to SCID ?
MHC-II is needed to activate both B and T-cells. Without this there will be no maturation!
What is the TOC for SCID ?
Stem Cell Transplant
X-Linked Agammaglobulinemia is related to a complete lack of …
immunoglobulin (due to disordered T-cell maturation)
What receptor is defective in X-Linked Agammaglobulinemia ?
Bruton Tyrosine Kinase (x-linked)
BTK is signal for immature B-cell to become a plasma cell.
What kind of infections are seen in X-Linked Agammaglobulinemia ?
**Bacterial, Enteroviral and Giardia ***
Enteroviral and Giardia due to lack of IgA
What must be avoided in X-Linked Agammaglobulinemia ?
Live Vaccines
Like in X-Linked Agammaglobulinemia, Common Variable Immunodeficiency will result in infection from…
bacteria, Enteroviruses and Giardia ! Due to defect in B and T Cells.
What else are patients with Common Variable Immunodeficiency at high risk for ?
Autoimmune disease and lymphoma !
What is the most common immunoglobulin deficiency ?
IgA deficiency ! –> Low mucosal IgA
What kind of infections are people with IgA deficiency at most risk for ?
Mucosal, especially viral
What is the cause of Hyper IgM Syndrome ?
Either a defect in CD40L (on TH2) or CD40R(On B-cell)
Why will you see IgM secretion but low or absent levels of IgA,E and G ?
The first mechanism of B-Cell activation is intact (i.e antigen binds IgM or IgD on B-cell surface –> IgM or D secreting Plasma Cells). Lots of IgM will be made but no class switching occurs since TH2 cells cannot be activated to release IL-4/5).
But the second mechanism the involves TH2 cell mediated activation of B-cell and class switching is impaired due to CD40 defect that inhibits activation.
What is defective in Wiskott-Aldrich Syndrome ?
WASP gene (X-linked)
What are the three common manifestations seen in Wiskott-Aldrich Syndrome ?
Thrombocytopenia (Petechiae), Eczema, recurrent infection
what is the leading cause of death in Wiskott-Aldrich Syndrome ?
Bleeding
What kind of infection are patients with deficiency in complement molecules C5-9 at higher risk for ?
Neisseria!
MAC is main way we deal with Neisseria
C1 inhibitor deficiency is mostly characterized by what manifestation ?
Angiodema especially at the mucosal surfaces especially PERIORBITAL EDEMA
Autoimmune disorders are characterized by immune mediated damage of tissues and involve..
A loss of self tolerance
AI is more common in men or women ?
Women of child bearing age.
What kind of hypersensitivity is Systemic Lupus Erythematosus ?
Type II (Cytotoxic) and Type III ( Immune Complex)
Typical signs associated with SLE include
Fever/Weight loss Malar Rash (Butterfly) Arthritis Renal Disease Cardiac damage Anemia
What is the most common cause of Renal Damage ?
Diffuse Proliferative Glomerulonephritis
What kind of syndrome is Diffuse Proliferative Glomerulonephritis: Nephritic or Nephrotic ?
Nephritic
Cardiac inflammation is seen in all tissues of the heart (Endocarditis, Myocarditis, Pericarditis). One of the characteristics is Libman-Sachs Endocarditis Describe this..
small sterile deposits on either side of the mitral valve
What causes anemia, thrombocytopenia and leukopenia ?
Ab’s to RBC’s, platelets and leukocytes respectively.
Is ANA specific for for SLE ?
NO , sensitive but not specific.
What Ab is highly specific for SLE ?
dsDNA antibodies
What are the main causes of death in SLE ?
RENAL (Diffuse Glomerular GN)
Infection
Endocarditis
What is the Ab present in Drug Induced SLE ?
Anti-Histone Ab
What drugs lead to Drug Induced SLE ?
Hydralazine, Isoniazid and Procainamide
What is the treatment for Drug Induced SLE ?
REMOVAL OF THE DRUG !
Antiphospholipid Antibody syndrome is seen in 30% of patients with SLE. What are the two most common anti-bodies ?
Anti-Cardiolipin
Lupus Anticoagulant
Abberent positive Syphilis tests are seen in the presence of what Ab’s in SLE ?
Anti-Cardiolipin
Lupus Anticoagulant leads to an aberration of which test ?
PTT (Increases it)
Although Lupus Anticoagulant causes an increased PTT, what is it associated with ?
THROMBOSIS
Hepatic –> Budd-Chiari
DVT
Placental –> loss of baby
What is the TOC for Lupus Anticoagulant Ab ?
Lifelong anticoagulation.
What is destroyed in Sjogrens Syndrome ?
Lacrimal and salivary Glands
What kind of hypersensitivity is seen in Sjogrens Syndrome ?
Type IV
What are the three chacrteristic signs of Sjogrens ?
Dry Eyes
Dry mouth (can’t chew cracker)
Recurrent Dental Carries ( Dry mouth
Along with ANA, what is the Ab associated with Sjogren Syndrome ?
Anti-ribonucleoprotein antibodies
Sjogrens Syndrome is associated with rheumatoid arthritis and what other disease ?
B-cell (Marginal) Lymphoma
Presents as unilateral parotid gland enlargement, which is unusual since most are bilateral
What cells are activated in Scleroderma ?
Fibroblasts –> deposition of collagen (Fibrosis)
Scleroderma can be split into two large categories: Localized and Systemic. What organ is involved in Localized Scleroderma ?
Skin Only
What Anti-body is present in Localized Scleroderma ?
DNA Topoisomerase II
Systemic Scleroderma is can be split into two sub-categories. What are they ?
Limited and Diffuse
Does Limited Systemic Scleroderma is associated with which syndrome ?
CREST !
Early Skin involvement with late stage visceral
What does CREST stand for ?
Calcinosis Reynaud Esophageal dysmotility Sclerodactly Telangiectasias
What auto-Ab is CREST associated with ?
Anti-Centromere Ab
Diffuse Systemic Scleroderma involves both skin and visceral organs. What are the organist that are most affected ?
GI Tract
Lungs
Kidneys
What Anti-body is associated with Diffuse Systemic Scleroderma ?
Anti-Topoisomerase I (Scl 70)
Characteristics of which three diseases are seen in Mixed Connective Tissue Disease ?
SLE
Systemic Sclerosis
Polymyositis.
What AB is associated with Mixed Connective Tissue Disease ?
Anti -U1 Ribonucleoprotein.
What are the two processes that work in combination during wound healing ?
Regeneration and Repair
When does wound healing begin ?
At the onset of inflammation
What is regeneration ?
Replacement of damaged tissue with native tissue !
Does not occur in all cell types
What are the three kinds of tissues based on regenerative capacity ?
Labile
Stabile
Permanent
Labile
possess stem cells that continually regenerate the tissue
What are the major tissues that are labile ?
Small/Large Bowel
Skin
Bone Marrow
Where are the stem cells of the bowel found ?
Crypts
Where are the stem cells of the skin found ?
Basal layer
Where are the stem cells of the blood found ?
Bone marrow Hematopoeitic Cells
What are the stem cells of the lung ?
Type II Pneumocytes
Stable
Typically quiescent in Go phase but are stimulated on injury to re-enter the cell cycle
What are some examples of Stable Cells ?
Liver
Kidney Tubule
Permanent Tissue
Lacks significant regenerative potential
What tissues are Permanent ?
Myocardium, Skeletal Muscle, Neurons
What is Repair ?
Regeneration of damage tissue with fibrous scar
When doe repair occur ?
When stem cells are lost or if cell lacks regen capability
What is first step or repair ?
FORMAITON OF GRANULATION TISSUE
What three structures/cells are found in granulation tissue ?
Fibroblasts: Deposit Tyoe III Collagen
Capillaries: Bring blood to tissue (lots of neovascularization in granulation tissue)
Myofibroblasts: Lead t contraction of wound
What is the eventual result of Repair ?
Scar Formation
What occurs to type III collagen in the course of repair ? What enzyme does this ?
It is replaced by Type I
Collagenase Enzyme
Where do you find Type I Collagen ?
Bone
SKin
Tendon
Where do you find Type II Collagen ?
Cartilage
Where do you find Type III Collagen ?
Granulation Tissue
Blood vessels
Embryonic
Where do you find Type IV Collagen ?
Basement membrane
What kind of signaling regulates regeneration and repair ?
paracrine (via growth Factors)
TGF-a
Epithelial and Fibroblast GF
TGF-b
fibroblast growth factor
INHIBITS INFLAMMATION (along with IL-10)
Secreted by macrophages
Platelet Derived Growth Factor
From Platelets
Growth Factor for Endothelium, Smooth Muscle and Fibroblasts
Fibroblast Growth Factor
Sort Of A Misnomer: IMPORTANT FOR ANGIOGENESIS
VEGF
Important for Angiogenesis
Primary Intention
Wound edges are brought together ( like suturing)
Minimal scar formation
Secondary intention
Edges of wound not approximated. Repair and Regenertion –> Granulation tissue which fills the defect
Myofibroblasts contract the wound –> Scar
What is the most common cause of delayed wound healing ?
INFECTION
S.aureus is the most common offender
Vitamin C deficiency leads to delayed wound healing because it is an important factor for what process ?
Hydroxylation of Proline and Lysine Procollagen Residues needed for collagen cross linking.
Copper deficiency leads to delayed wound healing because it is an important factor for what process ?
Cofactor for Lysly oxidase which cross links lysine and hydroxylysine to form stable collagen.
Zinc deficiency leads to delayed wound healing because it is an important factor for what process ?
Cofactor for Collagenase which is necessary for replacing Type III with Type I Collagen in granulation tissue
What is the most commonly seen site of Dehiscence (wound rupture) ?
Abdominal (after surgery)
This scar deformity is due to an Excess of Type I collagen being put down
Hypertrophic Scar
This scar deformity is due to an Excess of Type III collagen being put down
Keloid
Which scar deformity is seen most often in african americans and often involves the earlobes, face and upper extremities ?
Keloid
