Immunology

inflammation: response by vascularized tissues to deliver leukocytes and proteins from circulation to sites of infection and cell damage in order to eliminate offending agents that develops through a series of 5 steps

• recognition

• recruitment

• removal

• regulation

• repair

exudate vs transudate

• exudate: high protein and contains cellular debris

  1. implies ↑vascular permeability 2/2 inflammation

• transudate: low protein and little-to-no cellular debris

  1. implies oncotic and/or hydrostatic imbalance (ie non-inflammatory)

acute inflammation has 3 major components

1. post-capillary venule vasodilation

-MOA: histamine and prostaglandins → ↓tone of vascular smooth muscle

-produces warmth and erythema

2. ↑vascular permeability

-MOA: histamine, bradykinin, LTs → endothelial cell contraction → opening of inter-endothelial gaps

-produces edema

3. leukocyte extravasation, phagocytosis

leukocyte extravasation

1. margination (in lumen)

a. post-capillary venule vasodilation → blood flow slows (stasis) → leukocytes assume peripheral positions

2. rolling (in lumen)

endothelium

a. TNF and IL-1 → ↑E-selectin and Sialyl-Lewis X

b. histamine and thrombin → Weibel-Palade bodies redistribute P-selectin to surface

leukocytes

c. ↑L-selectin and Sialyl-Lewis X

3. adhesion (in lumen)

endothelium

a. TNF and IL-1 → ↑ligands for integrins (eg ICAM-1, VCAM-1)

leukocytes

b. rolling → low-affinity integrins (eg LFA-1, MAC-1, VLA-4) assume high-affinity state

4. transmigration (across endothelial wall)

a. chemokines/adhesion molecules → adherent leukocytes migrate via interendothelial gaps

5. chemotaxis (in tissue)

a. exogenous (fMet, lipid A) and endogenous (IL-8, C5a, LT-B₄) chemoattractants

morphology: acute inflammation

1. small vessel dilation

2. tissue edema

3. polymorphonuclear infiltrate

a. neutrophils infiltrate first 6-24h

b. replaced by monocytes w/in 24-48h

phagocytosis occurs in 3 sequential steps

1. recognition/attachment of particle to be ingested

a. mannose receptor

b. scavenger receptor

c. receptors for opsonins (IgG, C3b, MBL)

2. engulfment w/formation of phagocytic vacuole

a. cytoplasm extends → intra-cellular vesicle (phagosome) → fusion w/lysosome (phagolysosome)

3. killing/degradation of ingested material

a. ROS

1) NADPH oxidase: O₂ → superoxide

2) spontaneous: superoxide → H₂O₂

3) MPO: H₂O₂ → bleach

b. reactive nitrogen species

1) iNOS: arginine → NO

2) NO + superoxide → peroxynitrite

c. lysosomal enzymes

1) regulated by anti-proteases (esp. α₁-antitrypsin)

cytokines??

resolution

1. macrophage-mediated resolution of acute inflammation occurs by production of IL-10 and TGF-β

1. the richest source of histamine is in mast cells

TNF and IL-1 are cytokines produced by macrophages (primarily) that activate endothelium, other leukocytes, and acute phase responses

IL-8 is a chemokine produced by macrophages and endothelial cells that induces neutrophil chemotaxis

prostaglandins

1. PG-E₂

a. produced by many cells

b. induces vasodilation

c. ↑vascular permeability

2. PG-D₂

a. produced by mast cells

b. induces vasodilation

c. ↑vascular permeability

3. PG-F_2a

a. produced by uterine cells

b. induces labor in response to oxytocin

4. PG-I₂

a. produced by endothelium

b. inhibits platelet aggregation

c. induces vasodilation

5. TxA₂

a. produced by platelets

b. induces platelet aggregation

c. induces vasoconstriction

6. ASA/NSAIDs

a. aspirin irreversibly acetylates COX → ↓PGs

b. NSAIDs reversibly inhibit COX → ↓PGs

c. selective COX-2 inhibitors ↑risk MI/stroke 2/2 inhibiting PG-I₂ while leaving intact TxA₂

leukotrienes

1. LT-B₄

a. produced by leukocytes and mast cells

b. induces chemotaxis

c. activates leukocytes

2. LT-C₄, LT-D₄, LT-E₄

a. produced by leukocytes and mast cells

b. induce vasoconstriction

c. induce bronchospasm

d. ↑vascular permeability

complement

1. classic: initiates w/C1qrs binding to only IgG or IgM

2. alternative: initiates w/C3b binding to functional groups common to pathogens

3. lectin: initiates w/MBL binding to mannose on microorganisms

4. all 3 pathways lead to formation C3 convertase that cleaves C3

5. 3 main functions

a. inflammation (C5a > C3a > C4a)

b. opsonization (C3b)

c. cell lysis (MAC)

6. complement control proteins

a. C1-inh

1) sequesters C1r/C1s (classic) and MBL proteins (lectin)

2) inherited deficiency causes hereditary angioedema

b. DAF

1) sequesters C4b (classic) and C3b (alternative)

2) acquired deficiency causes PNH

c. factor H

1) binds self-cell membrane sialic acid → degrades C3 convertase

Components of the Immune System

Immune Response to Injury and Infection

Surgery and Surgical Conditions in Immunocompromised Hosts

Transplant Immunology