Immuno Complement/Inflammation (9, 10)

• a series of proteins that work in a cascading fashion to generate important host defense mechanisms
• can be activated in 3 ways:
• 1. classical
• 2. alternative
• 3. MBL (mannan binding ligand)

• triggered by antibodies bound to antigens on the microbial surface
• results in the recruitment of inflammatory cells

• antigen-antibody complexes
• this pathway is a major effector pathway of the humoral adaptive immune response

• 1. when an antibody binds an antigen fragment, a region on it's Fc (heavy chain) becomes exposed & C1q may bind to it
• 2. immediately C1r & C1s bind to C1q (q --> r & s)
• 3. this triad = the enzyme C1 esterase
• 4. C1 esterase cleaves C4 --> C4a (released) & C4b (stays covalently bound)
• 5. C14b complex binds C2, which is cleaved by the C1 esterase --> C2a (released) & C2b (stays bound)
• 6. C14b2b splits C3 --> C3a & C3b
• 7. C14b2b3b splits C5 --> C5a and C5b
• 8. C5b stays attached to C14b2b3b & from there binds to C6
• 9. this initiates the formation of the MAC: C14b2b3b5b + C6, C7, C8, & C9
• ORDER: 1, 4, 2, 3, 5, 6-9

inhibits the binding of C1 to the Fc region of an antibody bound to an antigen

• made up of C14b2b3b5b + late components C6-9
• triggered by C3b attaching to membrane surfaces & cleaving C5 --> C5b sticks & the late components stick to IT

• 1. production of opsonins: coating infected cells w/ Ig & C3b enhances the ability of macrophages + neutrophils to phagocytose them
• 2. chemotaxis of cells toward injury & production of anaphylatoxins: C3a & C5a induce local & systemic inflammatory responses
• 3. c8 & c9 direct killing/lysis of organisms

• stimulate inflammation by
• 1) attracting neutrophil polymorphs chemotactically to the site of infection
• 2) stimulating the release of anaphylatoxin (eg. histamine) by degranulating basophils + mast cells

• late components/part of the MAC
• protein that forms pores in a pathogen's membrane through which fluid can rush, lysing the foreign cell

• triggered by C3b binding directly to bacterial/viral products, especially lipopolysaccharide (LPS) aka endotoxin from the cell walls of gram - bacteria & some yeasts
• results in the opsonization of pathogens

• UNIQUE: the serum factors B & D, and properdin (factor P)
• shared: C3, C3b, C5, C6, C7, C8, & C9

because C3b is normally present in the circulation in small amounts as a result of spontaneous hydrolysis of C3 - it's always primed & ready to go

two inhibitory proteins that constantly inactivate C3b, inhibiting the alternative complement pathway

C3 convertase formed during activation of the alternative complement pathway after C3b has detected a foreign particle (eg. LPS) and complexed with/undergone a series of reactions involving factors B & D, properdin

• or mannan binding ligand complement pathway
• initiated when mannan-binding lectin binds to carbohydrates on the surface of microbes
• results in lysis & death of pathogens
• activation results in the cleavage of the classical complement pathway components C4 & C2 to form C4b2b

• MBL (mannose binding lectin)
• MASP 1
• MASP 2
• C4
• C2

• gram positive
• they DO NOT have mannose on their surface

they are both effector arms of the INNATE immune system b/c they occurs in the absence of antibody

C3 - because it functions in ALL 3 complement systems

• caused by an absence of C1q, C2 or C4
• deficiency of these tend to cause autoimmunity due to an impaired ability to process & clear immune complexes
• bacterial infection is not an issue b/c the 2 nonclassical pathways can combat such immune disruptions

severe recurrent bacterial infections - none of the complement pathways can function

• bacterial infections (LESS severe than C3 deficiency)
• won't be able to make C5a --> can't punch holes in bacteria membranes

• an absence of C5b --> C6, C7 or C8
• N. meningitidis & N. gonorrhea (gram -) cause an overwhelming infection because holes can't be punched in bacteria
• are normally disposed of by complement when they enter blood stream by formation of transmembrane pores
• without C5b --> C6, C7 or C8, bacteria can spread & infection may manifest in abnormal areas
• chemotaxis, anaphylaxis, opsonization still function normally, which is why these people are mostly not immunocompromised

recurrent bacterial infections

absence of Lectin pathway proteins

• also a deficiency of the alternative pathway component properdin, or of factors B or D
• pyogenic = bacteria that cause pus

• a rare autosomal dominant genetic disorder caused by an inherited deficiency or dysfunction of the C1 inhibitor (C1-INH)
• C1 binding to Ig Fc is NOT inhibited
• there is uncontrolled cleavage of C2 & C4
• characterized by recurrent episodes of angioedema that most often affect the skin & the mucosal tissues of the upper respiratory and gastrointestinal tracts

• the immediate and early response of vascularized, living tissue to injury
• in order for a tissue to be inflamed it has to be vascularized/living

• anything that causes tissue damage will invoke an acute inflammatory response; exposure to:
• pathogens (eg. bacteria, viruses, fungi)
• trauma
• extreme heat or cold (eg. burn/frostbite)
• caustic chemicals
• radiation (eg. UV light, sunburn)
• an aberrant immune response

• redness, heat, swelling, pain, loss of function
• 1. Rubor: caused by vasodilation
• 2. Calor: as vessels dilate, more warm core blood from inside can move to the periphery
• 3. Tumor: swelling's caused by increased vascular permeability at the site of inflammation
• 4. Dolor
• 5. Functio laesa

• the ENDOTHELIUM lining the vasculature
• modulates things such as blood flow, leukocyte adhesion, & leukocyte transmigration

• 1. vasoconstriction: mediated by sensory nerve impulses to smooth muscle in blood vessel; only transient, lasts a few seconds
• 2. vasodilation: promoted by inflammatory mediators
• 3. increased blood flow: b/c of vasodilation there's less resistance & the BV has a larger lumed --> more warm core blood enters vessels at inflammation site
• 4. increased vascular permeability: promoted by inflammatory mediators, endothelial cells separate from each other
• 5. hemoconcentration + slowing of flow (stasis): blood is a liquid; with the endothelial cells separated from one another, plasma (liquid) leaks from the BV lumen to the surrounding interstitium, & remaining RBCs to sludge within the vessel
• 6. leukocyte trafficking: WBCs in blood vessel lumen attack to endoth. tissues & migrate into site of inflammation

• 1. capture
• 2. rolling
• 3. slow rolling
• 4. arrest
• 5. adhesion/strengthening/ spreading
• 6. intravascular crawling
• 7. transcellular migration
• 8. paracellular migration
• leukocyte trafficking is controlled by coordinated expression of soluble mediators and adhesion molecules
• these events occur sequentially; interruption of any ONE of these steps (w/ drugs, genetic mutation, or missing mediator) may decrease or halt inflammatory response
• 

• plasma proteins: activated by proteolytic cleavage reactions
• synthesized by cells: pre-formed or synthesized de novo when needed

• pre-formed in granules: histamine, serotonin [vasoactive amines]
• de novo: nitric oxide [NO], prostaglandins, leukotrienes

• promotes vaso/veno/post-capillary dilation & increased vascular permeability
• activates endothelial cells to upregulate adhesion molecules
• is a vasoactive amine
• pre-formed mainly by mast cells (& basophils)
• is rapidly released upon cell activation
• by itself can cause most of the symptoms of acute inflammation
• *is an important mediator of type I hypersensitivity

• the interaction of an antigen w/ specific IgE molecules bound to the surface of mast cells or circulating basophils
• C5a or C3a binding to their individual receptors
• trauma
• temperature extremes

• promotes venodilation + increased vascular permeability
• activates capillary endothelial cells to upregulate adhesion molecules
• is a vasoactive amine
• pre-formed in platelet cells & stored in granules
• by itself can cause most of the symptoms of acute inflammation
• released during platelet activation

Serotonin

• constitutively expressed by endothelial cells
• causes vascular smooth muscle relaxation - allows blood vessels to dilated

• local vasoconstriction --> atherosclerosis
• drug used for treatment: nitroglycerine

• leukocytes infiltrating inflamed tissues
• iNOS (inducible nitric oxide synthase) is produced by activated macrophages
• results in additional vasodilation at an infected site; participates in acute inflammation as well*

• 1. complement system
• 2. kinin system
• 3. clotting system
• certain cleavage products of each system have important roles in acute inflammation

• they promote increased vascular permeability and vasodilation by binding to specific complement receptors on mast cells --> releasing histamine
• *C5a is also a chemotactic for leukocytes: promotes their adhesion to endothelium

• potent vasoactive peptides are generated by a cascade of enzymatic reactions following activation of clotting Factor XIIa (12a)
• Factor XII activates Kallekrein which cleaves heavy molecular weight kininogen (HMWK) --> bradykinin
• *activation of individual pathways activates each other

• a protein that causes vasodilation and PAIN at a site of inflammation
• made from the cleavage of HMWK by Kallekrein

• after mechanical, physical or biochemical cell stimulation phospholipase A2 is activated and cleaves arachidonic acid from the plasma membrane
• AA is precursor for both inflammatory mediators PG & LT

• corticosteroids
• therefore no arachidonic acid is cleaved from the phospholipids of the PM, & neither PGs or LTs are made

• 1.Cyclooxygenase pathway: produces prostaglandins
• 2. Lipoxygenase pathway: produces leukotrienes & lipoxins

• in general cause vasodilation & increased vascular permeability
• PGE2: also causes hyperalgesia (increased sensitivity to pain)
• made from arachidonic acid via the cyclooxygenase pathway

• cause vasoconstriction & bronchospasm
• typically involved with asthma
• made from arachidonic acid via the lipoxygenase pathway

• enzyme responsible for inducing the lipoxygenase pathway resulting in leukotriene production
• blocking it's activity doesn't completely get rid of asthma because it's a complex disease

• 1. COX 1
• 2. COX 2
• make prostaglandins

• cyclooxygenase pathway enzyme constitutively expressed in most tissues (principally by endothelium and to a lesser extent, vascular smooth muscle)
• is thought to be involved in the production of physiologic levels of prostaglandins

• cyclooxygenase pathway enzymes produced principally by endothelial cells & vascular smooth muscle WITHIN sites of inflammation and tissue trauma
• only produced at sites of trauma because it's upregulated BY WBCs

• ns-NSAIDS
• s-NSAIDS

• block BOTH COX-1 AND COX-2
• eg. aspirin, indomethacin, ibuprofen
• take care of inflammation, but also decrease physiologic amounts of PGs

• Specific for COX-2 and have the benefit of relieving symptoms of acute inflammation WITHOUT the undesirable side effects of
• gastrointestinal ulceration and potential renal damage
• eg. Vioxx and Celebrex

• type of leukotriene chemotactic for neutrophils & ACTIVATES them
• (remember, general leukotrienes promote vasoconstriction, increased vascular permeability (venules) and bronchospasm

main examples of leukotrienes responsible for vasoconstriction & increased vascular permeability

• causes vasodilation and increased vascular permeability
• promotes leukocyte adhesion and extravascular trafficking
• *made by activated/infiltrating leukocytes (& other cell types) at the site of inflammation
• may be involved in Type I hypersensitivity reactions

PAF is 10,000 times more potent than histamine

• one way in which cells communicate with each other
• orchestrate + amplify acute inflammatory response locally & systemically
• can exert autocrine, paracrine, & endocrine effects

• dendritic cells and macrophages (innate immune system)
• & other cell types at the site of tissue damage

• autocrine: IL-1 and TNF-α secreted from a given macrophage may bind its receptors causing more production of itself
• paracrine: bind on endothelial cell receptors in the immediate vicinity of the secreting cell, causing endothelial activation
• endocrine: can be absorbed systemically & promote fever, loss of appetite, neutrophilia, ACTH, & corticosteroid release; induce the formation of acute phase reactant proteins by the liver

• besides being particularly important in inducing acute inflammation...
• it indirectly promotes the symptoms of endotoxic shock including hypotension, decreased blood pressure, & increased heart rate
• it's seen especially in arthritic joints during fare ups; can help alleviate inflammation by making TNF-α antibodies OR decoy receptors which bind TNF-α & render it unable to have any affect on a target cell
• *people can be more susceptible to infection on such treatment

a chemokine that promotes neutrophil recruitment & activation within acutely damaged tissues - is largely responsible for the wave of neutrophils that move to an injured site

• quiescently IL-8 is made by endothelial cells and stored pre-formed in Weibel-Palade bodies for immediate release upon endothelial cell activation
• it can also be synthesized de novo by macrophages, epithelial cells, or other cells including fibroblasts at the site of tissue injury