What are Toll-like receptors?
TLRs are surface receptors that respond to patterns on extracellular microbes. Activation leads to release of TNF.
What are inflammasomes
Inflammasomes are intracellular receptors that detect fragments of dead cells and some microbes. Activation of the inflammasome leads to activation of caspase-1, which in turn activates release of IL-1.
Vasodilation is mediated by what?
Histamine and nitric oxide (NO)
Vascular permeability is mediated by what?
histamine and bradykinin
Histamine: what is it released by and what does it mediate?
Released by: mast cells (stimulated by IL-1 and other inflammatory cytokines) Produces vasodilation and increases vascular permeability
Nitric oxide: what is it released by and what does it mediate?
Released by: endothelial cells in response to injury Increases vasodilation
Bradykinin: what is it released by and what does it mediate?
Bradykinin is a plasma protein produced by the liver. It is activated by factors expressed on injured epithelial cells. Bradykinin increases vasodilation, increases vascular permeability, and causes pain
excess fluid in the interstitium
Compare/contrast: Trasudate vs. Exudate
Transudate: SG < 1.012, protein-poor ultrafiltrate of blood plasma due to increased hydrostatic pressure or lowered plasma osmotic pressure. Non-inflammatory. Exudate: SG > 1.02, protein and inflammatory cell rich fluid released due to increased vascular permeability. Due to inflammatory process.
What is pus?
Purulent exudate -> exudate rich in neutrophils (PMNs)
List the major steps in leukocyte recruitment
Name the receptor associated with each of the following steps of leukocyte recruitment:
- PECAM-1 (CD31)
Selectins are expressed on endothelial cells in response to what?
Histamine, thrombin, etc
ICAM-1 is expressed on endothelial cells in response to what?
TNF and IL-1 secreted by macrophages at the site of injury
What is diapedesis?
Movement of a leukocyte through the epi/endothelial barrier
Killing and degradation of microbes/tissues at the site of injury is driven by what two processes?
- ROS (within phagolysosome)
- Enzyme release (example: elastase, extracellular)
Name the principal mediators of the following features of inflammation:
- Increased vascular permeability
- Chemotaxis and leukocyte recruitment
- Tissue damage
- histamine and nitric oxide
- histamine and bradykinin
- TNF, IL-1, bacterial products
- TNF, IL-1
- ROS, NO, lysosomal enzymes
Name four major morphologies of acute inflammation
Describe serous acute inflammation
- mildest form of acute inflammation
- consists mostly of transudate from injured serious tissues
- example: pleural/pericardial/peritoneal effusion due to chronic heart failure or fluid overload
- example: skin blistering from friction, burn, trauma, or viral infection due to leaky epi/endothelia
Describe fibrinous acute inflammation
- usually secondary to a more severe injury
- larger vascular leaks, allowing passage of fibrinogen and conversion to fibrin
- examples: fibrous pericarditis, fibrous peritonitis with ascites, acute rheumatoid fever (ARF)
Describe suppurative acute inflammation
- suppurative = purulent (pus)
- S. aureus is common
- formation of an abscess: central necrotic tissue with PMNs enclosed by fibroblasts
- examples: acute appendicitis, acute bronchopneumonia, acute meningitis
Describe ulcerative acute inflammation
- local defect on surface of organ or tissue
- sloughing of surface and necrotic tissue
- examples: peptic ulcer, skin ulceration (common with diabetes)
A friction rub on cardiac auscultation may be indiciative of what type of inflammation?
Acute appendicities is usually an example of what type of acute inflammation?
Tissue macrophages are a hallmark sign of what type of inflammation?
What is polymyositis?
Chronic inflammation (autoimmune) characterized by CTL destruction of skeletal myofibers
What type of inflammation is defined by the presence of epithelioid macrophages?
example: sarcoidosis is defined by the presence of granulomatous inflammation
What is a multinucleate giant cell?
Fused epithelioid macrophages, induced by IFN-gamma
Caseous necrosis with multinucleated giant cells is definitively what disease until proven otherwise?
What is SIRS?
a.k.a. Acute Phase reaction
Systemic reaction to inflammation that may include the following:
- Fever: in response to bacterial lipopolysaccharides (endotoxin), elevated endogenous pyrogens (IL-1, TNF), and increased release of prostaglandins (PGE2, increases setpoint of HT)
- Elevated acute phase protein release from the liver, stimulated by IL-6. Includes: c-reactive protein, fibrinogen, serum amyloid A protein, etc. Produces increased sedimentation (sed) rate.
- Leukocytosis: stimulated by TNF and IL-1. Produces accelerated release of leukocytes from bone marrow.
What is the "sed rate"
Fibrinogen released in response to inflammation binds to erythrocytes (RBCs), forming stacks. In lab tests, these stacks (due to their mass) 'sediment' faster.
Inflammation may increase sed rate (part of SIRS)
What is a leukemoid reaction?
Extreme leukocytosis (>20,000)
What is a "left-shift"?
Accelerated release of immature neutrophils
Give the conditions of the following leukocytoses:
- bacterial infection -> may produce a left-shift
- viral infection
- allergy, asthma, parasites
- WBC sequestration in lymph nodes due to certain infections (examples: rickettsia, typhoid, etc)
Name the four types of hypersensitivity
- Type I: Immediate, IgE-mediated
- Type II: direct antibody-mediated cytolytic
- Type III: immune-complex-mediated
- Type IV: delayed type cell-mediated
What type of hypersensitivity reaction is Rhus Dermatitis?
Describe the sensitization stage of Type I hypersensitivity
- Specific antigen taken up and presented by APC
- Presentation to Th2 cell
- Th2 cell secretes IL-4 and IL-6, inducing B-cell class-switching to IgE
- B-cell produces IgE against specific antigen
- Specific antigen IgE is taken up by mast cells
What is the difference between an allergen and an irritant?
- Allergen: not dose-dependent, does not affect all individuals, IgE-mediated, affects only those previously sensitized
- Irritant: dose-dependent effet, affects all individuals, not Ig-E mediated, tends to be a small molecule
What products are secreted by mast cells in the early phase of type I hypersensitivity reactions?
What products are released during the late phase of Type I hypersensitivity reactions?
- LTB4, LTC4
- PGD2, PGE2, PGF2-alpha
- histamine (lower load than early phase)
- GM-CSF, IL-5
- Eosinophil products: MBP, ECP, EPO, etc
Testing for what mast cell product is a good diagnostic indicator of Type-I hypersensitivity reaction?
Lasts for ~4 hours
What is the difference between alpha-tryptase and beta-tryptase? What does tryptase do?
- Alpha: released constituitively
- Beta: released upon mast cell activation
Tryptase triggers remodeling of connective tissue in the ECM
What class of drugs are likely to produce a false-negative skin test?
Name the drug(s) that blocks leukotriene synthesis by blocking the action of 5-lipoxygenase
Name the drug(s) that block leukotriene receptors
montelukast / zafirlukast
Does psychological stress lower or raise the mast cell sensitivity threshold?
Name 3 drugs or classes of drug that raise the sensitivity threshold of mast cells?
- Cromolyn sodium
Describe the cytokines released by mast cells during the late phase reaction
- IL-4 and IL-13: stimulate Th2 cells and IgE class switching
- IL-3, IL-5, GM-CSF: activate and promote survival of eosinophils
- TNF: endothelium activation and adhesion expression
Describe the major chemokines released by mast cells during the late phase
- CCL3: macrophage and leukocyte chemotaxis
- RANTES (CCL5) and eotaxin (CCL11): T-cell and eosinophil chemotaxis
Describe the major lipid mediators released by mast cells during the late phase reaction
- LTC4, LTD4, LTE4: eosinophil migration, smooth muscle contraction, increased vascular permeability, mucus hypersecretion
- PAF: attracts leukocytes, activates eosinophils/neutrophils/platelets
Name 5 major caused of increased eosinophil count (eosinophilia)
- connective tissue disease
Describe the mechanism by which corticosteroids suppress eosinophils
- Directly block IL-5, reducing eosinophil release from bone marrow and promoting eosinophil apoptosis
- Bind GR-alpha, inhibiting AP-1 and NFkB
Give 4 clinical examples of Type I hypersensitivity
- Allergic rhinitis
Why is early life viral infection significant in the context of hypersensitivity reactions?
Early childhood viral infections increases the risk of development of allergies
What cells type(s) infiltrates are commonly seen in asthma? Sudden-death asthma?
Asthma: eosinophils and lymphocytes
Sudden-death asthma: neutrophils
What is denudation?
Destruction of airway epithelium
Give the 5 major morphological features of asthma
- Mucus gland hyperplasia and hypersecretion
- smooth muscle hyperplasia
- submucosal edema and vascular dilation
- fibrin deposition and airway remodeling
Why must administration of a skin test wait 4-6 weeks after an allergic event?
Mast cells need time to 'reload'
What type of hypersensitivity reaction is Myasthenia Gravis?
What is the name for the Type II hypersensitivity reaction caused by Rh-factor mismatch between mother and child?
What type of hypersensitivity reaction generally features a soluble antigen? A matrix-bound antigen?
- Type III
- Type II
Name 4 major sites of immune complex deposition in Type III hypersensitivity reactions
- blood vessels
What is the Arthus Reaction?
Skin reaction when sensitized individuals are exposed to a specific antigen. The reaction is caused by leukocyte activation via FC(gamma)III receptors with no complement involvement - therefore Type III
What is serum sickness?
Systemic reaction following injection of a large quantity of foreign antigen. Reaction occurs 7-10 days post-exposure (sweet spot of Ab:Ag complex formation).
Symptoms: flu-like condition (fever, vasculitis, arthritis, nephritis)
Farmer's Lung features what type of hypersensitivity reaction?
Type III - reaction to hay dust and mold spores
Systemic Lupus Erthematosus is what type of hypersensitivity reaction?
Describe Type IV hypersensitivity
- Delayed-type, cell-mediated, does not generally involve antibodies
- Process: antigen enters skin and binds self-protein, antigen-protein complex is presented to T-cells, resulting in T-cell proliferation
- Cellular response is mediated by CD4+ Th1 cells and/or CD8+ CTLs
Name the plant-based chemical involved in Rhus Dermatitis?