Pathoma Inflammation, inflammatory disorders, wound healing Flashcards
Inflammation allows what to happen?
Inflammatory cells, plasma proteins, and fluid to exit from vessel to enter interstitial space
Cells seen in acute inflammation
Neutrophil
Cells in chronic inflammation
Lymphocytes
Acute inflammation characterized by
Edema and neutrophils
Acute inflammation arises in response to what 2 things
Infection or tissue necrosis - eliminate pathogen or clear necrotic debris
What is included in innate immunity
epithelium, mucus secreted by cells, complement system, cells (mast, macrophages, neutrophils, eosinophils, basophils)
Acute inflammation mediated by what factors?
TLRs: present on cells of innate immunity
AA: from phospholipase A2 (acted on by COX/5-lipooxygease)
What do TLRs recognize?
PAMPs - pathogen associated molecular patterns
What TLR is found on macrophages and recognizes LPS on outer membrane of G- bacteria
CD14
TLR activation results in upregulation of?
NF-kappaB
activates immune response genes
COX pathway produces what?
PG
I2, D2, E2
Mediate vasodilation (arteriole) and vascular permeability (post-capillary venule)
E2 - also mediates fever and pain
5-lipooxygenase produces?
LT
B4 - attracts and activates neutrophils
C4, D4, E4 - vasoconstriction, bronchospasm, increased vascular permeability - contract smooth muscle
What attracts/activates neutrophils?
LTB4, C5A, IL8, bacterial products
mast cells activated by
tissue trauma
complement proteins C3a, C5a
Crosslinking of cell surface IgE by antigen
what does histamine do
mediates vasodilation of arterioles and increase vascular permeability
Delayed response of mast cell
production of AA metabolites - leukotrienes to maintain inflammatory response
Complement for acute inflammation activation
classical pathway (C1) binds IgG/IgM bound to antigen "GM makes classic cars"
alternative pathway - microbial products directly activate complement
mannose binding lectin pathway - MBL binds mannose on microorganisms and activates complement.
complement pathways result in
C3 convertase: C3 - C3a/b which activates
C5 convertase: C5 - C5a/b which creates formation of MAC
Binds with C6-9 to form MAC complex
C3a and C5a trigger what?
Mast cell degranulation
C5a is chemotactic for what?
neutrophils
C3b action
opsonin for phagocytosis
MAC complex does what?
Lyses microbes by creating holes in cell membrane
Hageman Factor
Activated up subendothelial or tissue collage
Produced in liver - important role in DIC (Gram - Sepsis)
What does Hegeman factor activate?
Coagulation and fibrinolytic systems
Complement
Kinin system (cleave HMWK to bradykinin - mediates vasodilation, vascular permeability, pain
Cardinal signs of inflammation
Rubor, calor, tumor, swelling, dolor, fever
Redness - d/t vasodilation (arteriole) resulting in increased blood flow
Relaxation of arteriolar smooth muscle
Leakage of fluid from postcapillary venules
Key mediators of rubor and color
Histamine, PG, bradykinin
Key mediators of swelling (tumor)
histamine, tissue damage
Key mediators of pain
Bradykinin and PGE2 by sensitizing nerve endings
Key mediators of fever
Pyrogens cause macrophages to release IL-1 & TNF
Increase in COX (perivascular cells of hypothalamus)
PGE2 - raise temp set point
Neutrophil phase peaks at what time?
24 hours
Macrophage phase peaks at what time?
2-3 days
Step 1 of neutrophil arrival
Margination
Vasodilation slows blood flow in postpapillary venule
Cells marginate from center to periphery
Step 2 of neutrophil arrival
Rolling
Selectin - speed bumps upregulates
P selectin from Weibel Palade bodies (histamine)
E selectin by TNF and IL-1
Where does P selectin come from
Weibel Palade bodies
What are 2 key proteins from Weibel Palade body
vWF
P selectin
E selectin induced by
TNF & IL-1
What do selectins bind?
Sialyl Lewis X on leukocytes - results in rolling of leukocytes along vessel wall
Step 3 of neutrophil arrival
Adhesion
binding to wall by cellular adhesion molecules (upregulated by TNF and IL-1)
Bind integrins on leukocytes (upregulated by C5a, LTB4)
Results in firm adhesion to vessel wall
Leukocyte adhesion deficiency
CD18 subunit
Ar defect integrin - can’t be drawn into tissue
Delayed separation of umbilical cord - (normally neutrophils destroy tissue to allow separation)
Increased circulating neutrophils
Recurrent bacterial infections that lack pus formation (pus is dead neutrophils)
Step 4 neutrophil arrival
Transmigration and chemotaxis
Leukocyte transmigrate across endothelium of postcapillary venule
Move toward chemical attractants (C5a, LTB4, bacterial products, IL-8)
Step 5 neutrophil arrival
Phagocytosis
Enhanced by opsonins (IgG & C3b)
Chediak Higashi Syndrome
Protein trafficking defect - impaired phagolysosome formation (microtubule defect so can’t merge phagosome + lysosome)
- Increased risk pyogenic infection
- Neutropenia - (can’t divide properly)
- Giant granules in leukocytes (can’t be moved)
- Defective primary hemostasis - dependent on platelets - granules not properly distributed
- Albinism
- Peripheral neuropathy - can’t move proteins from nucleus to nerves
Step 6 of neutrophil arrival
Destrocion of phagocytosed material
O2 dependent
- most effective
- HOCl generated by oxidative burst in phagolysosomes
O2 independent
- enzyme present in leukocytes
Which is more effective? O2 dependent or independent killing?
O2 dependent
O2 - to O2.- to H2O2 to HOCl
O2 to O2.- by NADPH oxidase
O2.- to H2O2 by superoxide dismutate
H2O2 to HOCl (bleach) by myeloperoxidase
CGD (chronic granulomatous dz)
poor O2 dependent killing
D/T NADPH oxidase defect
can’t generate bleach: granuloma infections with catalase + organisms
Catalase + organism associated with CGD (chronic granulomatous dz)
Catalase destroys H2O2 so can’t produce bleach
S aureus
Pseudomonas cepacia
Test to screen for CGD?
Nitroblue tetrazolium
Is O2 to O2.- intact by NADPH oxidase? NO - dye remains colorless
MPO deficiency
can’t produce bleach but most pt will be asymptomatic
Increase risk in candida infections
what will happen in NBP (nitroblue tetrazolium) test in MPO deficiency?
It will turn blue because the O2 to O2.- reaction is intact
Step 7 neutrophil arrival
Resolution
Neutrophil undergoes apoptosis
Disappear within 24 hours after resolution of inflammatory stimulus
Monocytes arrive how?
Same as neutrophils:
margination, rolling, adhesion, transmigration
What is primary enzyme in macrophages?
Lysozyme
What are anti-inflammatory cytokines?
IL-10 and TGF-beta
What cytokine continues inflammation?
IL-8 - macrophages call in neutrophils
Does time or response define acute inflammation?
RESPONSE - IL-8 Secreted calling more macrophages, production of pus
What characterizes chronic inflammation
Lymphocytes and plasma cells in tissue
CD4+ T cell actiavtion
Extracellular antigen phagocytosed, processed, presented to MCH class II
B7 on APC binds CD28 on CD4+ T cells providing 2nd activation signal
28/7=4
What do CD4+ T cells secrete?
cytokines
TH1: IL-2 (T cell GF and CD8+ T cell activator) INF- gamma (marcophages activator)
TH2: B cells IL-4 - class switching to IgG and IgE IL-5 - eosinphilia chemotaxis and activation, maturation of B cells to plasma cells, class switching to IgA IL-10 - inhibits TH1 phenotype
CD8+ T cell activation
MHC I - intracelluar antigen
IL-2 from CD4+ TH1 cell produces 2nd activation signal
Cytotoxic T cells activated for killing (kill cell)
CD8+ kills cells how?
Perforins & granzyme inducing apoptosis
(caspase is key mediator)
Express FasL bind Fas activating apoptosis
B cell activation
Antigen binding by IgM or IgD
B cell antigen presentation to CD4+ helper T cell via MHC II
CD40 receptor on B cell binds CD40L on helper T cell providing 2nd activation signal
Defining feature of granuloma
Epitheloid histocyte! macrophages with abundant pink cytoplasm
Noncaseating granulomas lack what? and what are the causes
Central necrosis
Reaction to foreign material Sacroidosis Beryllium exposure Crohn dz (noncaseating dz) Cat scratch dz
Differential dx for caseating granuloma
TB & FUNGAL
AFB for TB
GMS (silver stain) for Fungal infection
Steps in granuloma formation
Macrophage and CD4+TH1 helper T cell interaction
Find antigen on present via MCH II
IL-12 secreted from macrophages -> CD4+ helper cells to TH1 subtype which secrete TNF-gamma to convert macrophages into epithelioid histocytes
DiGeorge - failure of what pharyngeal pouches and what deletion?
3rd/4th pouch
22q11 microdeletion
DiGeorge presents with what?
T cell deficiency d/t lack of thymus
Hypocalcemia d/t lack of parathyroids
Abnormalities of heart, great vessels, face
SCID
What are the etiologies
defective cell mediated and humoral immunity
- cytokine receptor defects
- Adenosine deaminase deficiency*** (enzyme for deamination of adenosine and deoxyadenosine - build up is toxic to lymphocytes)
- MHC class II deficiency
What enzyme is can be deficient in SCID?
Adenoside deaminase
SCID characteristics
Fungal, viral, bacteria, protozal infection
Opportunistic infection & live vaccines
SCID tx
Sterile isolation and stem cell transplant - can generate normal B & T cells
X linked agammaglobulinemia
Lack Ig in blood - x linked
Disordered B cell maturation so Niave B cell can’t mature into plasma cels
What is Bruton tyrosine kinase mutation associated with
X linked agammaglobinemia
Signal for B cell to become plasma cell normally
X linked agammaglobulinemia presentation
After 6 mo Recurrent bacterial (can't opsonize), enterovirus (no IgA) and Giardia infections (no IgA)
Live vaccines must be avoided
Common Variable Immunodeficieny (CVID)
Low immunoglobin d/t B cell or helper T cell defect
Risk for bacterial, enterovirus, Giardia late in childhoood
Increase risk for AI dz and Lymphoma
Common Variable Immunodeficieny (CVID) has increased risk for what 2 things
Autoimmune
Lymphoma
IgA def
Mucosal infection risk
Most asymptomatic
Celiac dz association
Hyper IgM syndrome
Too much IgM
Mutation in CD40L or CD40 receptor (B cells)
Can’t produce IL4/IL5
Low IgA, IgG, IgE
Recurrent pyogenic infections especially at mucosal sites
Wiskott Aldrich Syndrome Triad
Thrombocytopenia
Eczema
Recurrent Infections
what is the defect in wiskott aldrich syndrome and inheritance?
WASP gene and X linked
Complement deficiency
C5-C9 - at risk for Neisseria infection
C1 inhibitor - edema of skin and mucosal surfaces (called hereditary edema) - especially periorbital
What is the etiology of autoimmune?
Loss of self tolerance
Central tolerance occurs where?
Thymus & Bone marrow
Stem cells from bone marrow to thymus to Double + cells (CD4 & CD8 & T cell receptor) then turn to Single + cells which progress to niave mature T cells
Undergo check points
DP+ cell undergo + or - selection?
+ selection
Need to recognize MHC and antigen
If they can recognize MHC they turn to SP+ cells
If not undergo apoptosis
SP+ cell undergo + or - selection?
- selection
If recognize self antigen, they will undergo apoptosis
Remove self reactive lymphocytes
Central tolerance in Thymus for t Cells
AIRE mutation results in?
AI polyendocrine syndrome - destroys endocrine glands
Can’t express some subset of self antigen so some self recognizing antigens escape and go into the periphery
- hypoparathyroidism
- Adrenal failure
- candida infection (chronic)
Where does negative and positive selection occur in thymus?
Negative in medulla
Positive in cortex
Central tolerance for B cells occurs where?
Bone marrow
Stem cell in bone marrow changes to immature (Ig) then escapes bone marrow to naive mature b cell
If B cell recognizes self antigen what happens?
Ig - undergo
1. B cell receptor editing (Rag genes will be re-expressed and edit the light chain so won’t bind self antigen)
OR
2. undergo apoptosis thru mito pathway
Peripheral tolerance
If central tolerance failed - then peripheral tolerance - antigen recognized without co-stimulatory signal - then lymphocyte will undergo anergy (shut down) or undergo apoptosis
CD4+ T cell has CD95 present known as what?
FAS- expressed when recognizes self-antigen & binds FAS Ligand inducing apoptosis
ALPS
AI Lymphoproliferative Syndrome
mutation in FAS apoptosis pathway
Need FAS, FAS L & caspases (particularly 10)
Can’t undergo apoptotic pathway so self reactive lymphocytes can survive
AI: IgG production (self reactive) - cytopenia, anemia
LP - can’t get rid of self reactive lymphocytes - so lymph node enlargement, HSM (can get lymphoma)
Regulatory T cells: CD4+ T cells
Block T cell activation
Needs second signal - CTLA4 can bind B7 decreasing second signal so cell undergoes anergy
Cytokines - IL-10 & TGF-beta - IL10 inhibits macrophages/dendritic cell limiting TCR, limit B7, TGF-beta inhibits macrophages
CD4+ CD25+ FOXP3+
Regulatory T cells
CD25+ = IL-2R
FOXP3+ transcription factor
CD25 polymorphisms are related to?
AI (MS & DM1)
Essential for regulatory T Cells
FOXP3 mutations related to?
IPEX
Immune dysfunction Polyendocrinopathy Enteropathy
Thryoiditis, DM1 (islet of pancreas), Diarrhea, Skin
X linked
What might be the effect of estrogen on B cells?
decrease apoptosis
AI gene associations
HLA subtypes (code for MHC) Strongest is HLA-B27 (anklyosising spondylitis)
PTPN22 - tyrosine phosphatase - gain of function decreasing signaling for tolerance
2 ethnicities in LUPUS
Af Am/Hispanics
What complement deficiency is associated with lupus?
Early complement
C1a, C4, C2
*Most commonly C2
what are the 11 criteria of Lupus?
* is a characteristic but not diagnostic
- Malar “butterfly” rash
- Discoid rash - circle, erythematous, scaling - scars
- Rash upon exposure to sunlight
- Oral/nasopharyngeal ulcers
- Arthritis
- Serositis
- Psychosis/seizures
- Renal damage (Most common/most damaging - Diffuse proliferative glomerulonephritis or membranous glomerulonephritis)
- Antibodies to cells in blood: anemia, thrombocytopenia, leukopenia (Type II specifically even though Lupus is type III Hypersensitivity)
* Libman-sacks endocarditis - small vegetations of both sides of mitral valve - Antinuclear antibodies
- Anti-dsDNA or Anti-Sm antibodies/Antiphospholipid Ab
what are the 3 antiphospholipid antibodies generally tested?
Anticardiolipin (False + VDRL & RPR - false positive for Syphillis) Lupus anticoagulant (falsely elevates PTT test) Anti-Beta2-glycoprotein I
APA syndrome
Anitphospholipid antibody + hypercoagulable state
DV, hepatic vein, placental, cerebral thrombosis
Requires lifelong anticoagulant
Drug induced Lupus causing drus + antibody
Hydralazine, procainamide, isoniazid
ANA+
Most common causes of death in Lupus
Renal failure and infection
- from immunosuppressions
- antibodies to WBC
Late common cause of death in Lupus
Accelerated coronary atherosclerosis
Sjrogren syndrome - destruction of what glands?
lacrimal - dry eyes
salivary glands - dry mouth/dental caries
Type IV hypersensitivity
Antibodies in sjrogen syndrome
ANA
anti-ribonucleoprotein (anti-SSA/SSB) - related to extraglandular associations
SSA can cross placenta and develop neonatal lupus
Neonatal lupus - develop what condition?
Heart block
Additional diagnostic criteria for Sjrogen - what biopsy and what are you looking for?
Lymphocytic sialadenitis (on lip biopsy of minor salivary glands)
Increase risk of what cancer with Sjrogens
B cell lymphoma
Systemic sclerosis - sclerodoma
Deposition of collagen by fibroblasts
Limited scleroderma has limited skin involvement
What does CREST mean?
C:alcinosis/anti-Centromere bodies R:aynaud E:sophageal dysmotility S:clerodactyly T:elangiectasias of skin
Diffuse type scleroderma
Early visceral involvement
Vessels GI Lungs Kidney Heart DNA topo 1 antibodies
Wound healing beings when?
Initiated when inflammation beings
Regeneration or repair (scarring)
What are the 3 types of regenerative capacity?
Labile - continuously regenerating = stem cells
(BONE: CD34 hematopoietic stem cell)
Stable - quiescent (Go - re-enter cell cycle)
Permanent - lack significant regenerative potential
What are the permanant tissues in the body?
Myocardium
Skeletal muscle
Neurons
Repair places damage with?
fibrous scar
What is the initial phase of repair?
Granulation tissue…
Firborblasts (deposit collagen type III)
Capallaries
Myofibroblasts
In a scar what collagen replaces the initial collage III deposition?
Collagen I removed by collegenase (requires Zn cofactor)
Collagen I
Bone
B”one”
Strong tensile strenght
Collagen II
Cartilage
Car”two”lage
Collagen III
pliable
BV, granulation tissue, embryonic tissue
Collagen IV
Basement membrane
What type of signaling mediates regeneration and repair?
Paracrine signlaing by GR
TFG-alpha
epithelial and fibroblast GF
TGF-beta
fibroblast GF
Inhibits inflammation
PDGF
endotheilum, SM, fibroblast GF
FGF
angiogensis
Skeletal development
VEGF
angiogenesis
Secondary intention of wound healing
Granulation tissue fills in defect so scar will from
Cause contraction of wound - by myofibroblasts
Most common cause of delayed wound healing
Infection
Less common:
Vit C, Copper, Zn def
Foreign body, ischemia, diabetes, malnutrition
