7. Type III Hypersensitivity Flashcards
Type III Hypersensitivity – immune complex mediated hyp
• Pathogenesis:
– Formation of ____
– Deposition of ____
– IC and complement mediated ____
• Morphologic and functional changes:
– Vasculitis with ____ necrosis due to inflammation
– Platelet aggregation > microthrombi > ____ necrosis
• Examples of disease: – Systemic: • \_\_\_\_ sickness • \_\_\_\_ glomerulonephritis • \_\_\_\_ nodosa
– Localized disease:
• ____, hypersensitivity pneumonitides
• ____ reaction
* Immune complex > \_\_\_\_ * BV > inflammation > vasculitis, along with fibrinoid necrosis in walls (morphologic term involving inflammation, and accumulation of protein material > typically \_\_\_\_ protein that leaked out of vessel) * Vasculitits > death of BV > \_\_\_\_ vasculitis * Necrotizing vasculitis and ischemic necrosis * Top image: starts off as immune response, here, invididual produce \_\_\_\_ and \_\_\_\_ as antigen and sees it as foreign and wants to remove > tissue injury > hypersensitivity
immune complexes
immune complexes
inflammation
fibrinoid
ischemic
serum
poststreptococcal
polyarteritis
lung
arthus
soluble
plasma
necrotizing
IgG
IgM
Induction of immune-complex mediated disease involves small to intermediate size aggregates deposited within blood vessels> accumulate on ____ and between ____ cells; trapped by ____ membrane
• Antibody + antigen > interact • Take antibody in lower half of test tube, and overlay with antigen > over time, at interface > \_\_\_\_ material due to precipitate > key to disease ○ Too large to stay in solution and precipitate out • To each tube add increasing antigen > measure precipitate, amount of \_\_\_\_ is the same ○ Red line is amount of antigen??? ○ Low levels of antigen > \_\_\_\_ complexes > do not \_\_\_\_ > remain soluble > zone of antibody \_\_\_\_ ○ Increase antigen > zone of \_\_\_\_ > a lot of precipitate > formation of a \_\_\_\_ ○ Add antigen > past zone of equivalence > antigen excess > \_\_\_\_ complexes, similar to antibody excess, and some of \_\_\_\_ size (none that are as large as equivalence) • The soluble and small complexes > \_\_\_\_; large complexes that precipitate are removed by \_\_\_\_, or filtered by spleen
walls
endothelial
basement membrane
flocculent
ab
small
corss-link
excess
equivalence
complex/lattice
small
intermediate
hypersensitivity
phagocytosis
Factors Affecting IC deposition
• \_\_\_\_ of complex • Impaired \_\_\_\_ • Hemodynamic factors: – Alterations in local vascular \_\_\_\_ – Turbulent flow—branch points of vessels – Areas of filtration/fenestration
• Commonly affected tissue:
– ____ and ____: tissue where blood is filtered under ____ pressure to generate fluids (____, ____) concentrates complexes
• Size - complex big - precipitates, readily removed; smaller - soluble and stays in solution > eventually localizes (areas of vasc perm, turbulent flow) • Smaller complexes can be cleared by \_\_\_\_ • \_\_\_\_ is a target > a lot of bifurcation in microcirculation, and lung • When accumulate > complexes form, accumulate within BV > not bound to EC, just sitting there (sticky, not actually bound) > activate complement** > two things: generate \_\_\_\_ mediators (C3, C5a > inc vascperm), C5a,6,7 attract inflam cells (neutrophils); complexes don't escape the BV, neutrophils cannot degrade bc it's too \_\_\_\_ • Hallmark: \_\_\_\_ activation and neutrophil activation > damage to tissue is due to \_\_\_\_ ○ Enzymes from neutrophil destroy endothelium > \_\_\_\_ > leading to necrotizing vasc; some BV > amorphous staining material (would look pink/red) > \_\_\_\_ necrosis (due to plasma protein)
size
clearance
permeability
glomeruli joints high urine synovial
spleen
skin
inflam
smaller
complement
neutrophil
vasculitits
fibrinoid
• Sensitized > produce AB > immune rxn in lymphoid tissue; when antibody encounters antigen > complex formed, if not in equiv zone > small, soluble > accumulate in areas absed upon factors from previous slide
○ Complexes do not bind directly to ____
• Activate complement (complement fixation) > formation of gap, but complexes cannot go anywhere > neutrophils arrive > wants to engulf complexes, releases lysosomal enzymes (sometimes macro’s involved) > bc of enzymes by neutrophils, and formation of ____ > EC begins to get damaged
• Platelets also aggregate > ____ > areas of ischema (ischemic necrosis)
endothelial cells
free radicals
microthrombi
- In kidney, primarily the glomerulis (folding and bending of cap’s, and fenestrated allowing filtration)
- Same process overall
- Inflammation of kidney due to immune mediated > ____
glomerular nephritis
Type III Hypersensitivity: Serum sickness
• Late 1800s pts treated for
diptheria infections by ____ immunization
• Some pts developed
arthritis, skin rash and fever
• Proteins in horse serum induced antibody response leading to ____ formation
• Pathogenesis
– ____ formation
– Histopathology: ____ vasculitis, ____ necrosis, ____ and ischemia
Clinical signs and symptoms: – Skin: \_\_\_\_ or purpuric lesions – Joints: \_\_\_\_ and swelling – Renal: \_\_\_\_ and \_\_\_\_ in urine – Constitutional: \_\_\_\_
passive immune complex necrotizing fibrinoid microthrombi
papular pain protein blood fever
Type III Hypersensitivity: Serum sickness
• Diptheria - life thtreatning > how fast patient produced ab's (because toxins were lethal) ○ Passive immunization - serum from idnividual, hyperimmune, injected into recipitent with infection and abs from donor combat the disease § From horses, sometimes § Today, derived IgG in serum is isolated and injected, or monoclonal abs from mouse/rat/rabbit § Neutralize snake venom, need quick ab's • Serum - protein - serve as antigen • Inject serum at T0 > serum increase > first few days \_\_\_\_ (due to distribution throughout body, and normal clearance) > week out: rapid decline in free \_\_\_\_ ○ Track presence of ab to injected serum; nothing for week, then antibody increases (around time where patient develops clinical manifestations - this is the point of \_\_\_\_ formation due to antigen excess) ◦ Critical: \_\_\_\_ of period that immune complexes are formed / how much damage was done to kidney, joint, vasculature, etc. • As antibody titers go up, antigen goes down, start to clear the antigen, disease would be short lived • Patient will eventually form ab's to diphtheria, but we're not looking at that here [READ KIM's TRANSCRIPTION FOR THIS!!!]
gradual decline
soluble antigen
immune complex
length
- ____ lesions > slightly raised > occur all over body
- ____ play a role > activating; histamine from basophil is more important because happening in BC/blood column
- Why doesn’t comp activation result in direct lytic action of endothelium? > not physically ____, has to be activated on surface of target cell (antibody and antigen must both be there)
papular
basophils
attached
• Same happens in glomerulus
LEFT = normal ____, fine network of capillaries
MIDDLE = early stage, ____ glomerulus, smudgey material (circled) = combination of ____ and ____
C = immune complexes forming anywhere but accumulating in the glomerulus, activating complement, recruiting neutrophils, neutrophils release lysosomal elements / proteases / free radicals which cause destruction of capillaries in the glomerulus
Difference bt left/middle:
• Destruction of capillaries > blood ends up in ____ (via bowman’s capsule and tubules) (____ and ____ protein)
glomerulus
hypercellular
immune complexes
plasma proteins
urine
blood
plasma
Immunofluorescence
• Tool to detect of molecular structure in tissue, in a cell (protein) > antibody to entity, and if antigen in tissue it would bind
• In order to see it, couple antiboyd with ____ (substance that when under fluorescent micro ands tim with wavelength > fluoresce)
• Take reagent, incubate with biopsy > if binding > observe under microscope, will see ____ fluorescen and ____ of fluroensce (two pieces of info)
○ Punctae fluoro - ____ distribution; not continuous and regular**
• Indirect fluoro - similar to direct, but it’s done in two stages:
○ First expose to tissue to ____ antibody (to the specific antigen) - no fluorochrome
○ Secondary ____ recgonizes Ig of all sorts (doesn’t care about ____ of antibody) has fluorochrome on it; and you get saem info as direct
○ Why two? Clinical lab > 100 diff antibodies each conjugated (short half-life); economic purposes; only need ____ conjugated antibody to recognize all primary antiobdy
• Autoimmunity: take advantage of direct vs indirect fluoro [???]
fluorochrome
positive
pattern
lumpy/bumpy primary antibody specificity one
• Immune complexes - not bound to ____ - randomly accumulated (that’s why it’s lumpy-bumpy)
endothelium
- Reaction can occur in lung - develop ____ vasc in lung
- Left: normal
- Middle: accumulate in lung > destruction of lung (starts within ____, but bc BV in ____ > they get destroy and alveolar destroyed)
- Right: high-power
necrotizing
BV
alveolar septa
• Left: severely inflamed
• Right - looking at presence of immune complexes via immunofluorescence; white = positive fluorescence
○ See ____ irregular pattern b/c immune complexes present w/ IgG present within that
* What else could we stain for in these complexes so that we'd see positive fluorescence? * \_\_\_\_ * We would see a similar pattern as shown in E
lumpy/bump
C3 complement
Localized form of this disease = Arthus reaction
• This happens when you inject an antigen into a pt that already has ____ to that antigen
• If we were talking about serum sickness, if the patient got a second or third injection of the horse serum and they were starting to amount an immune response to it, not only would they develop a systemic reaction, but they’d develop a ____ reaction at the site of injection where immune complexes will form (when you inject, you break some blood vessels, antibody will leak out, immune complexes will form, leading to complement activation, in this case, activation of mast cells via complement and same reactions (but local).
- We will get vasculitis, the rxn may start outside the blood vessel, as the vessels become ____ the antigen will seep into the vessels, complexes will form,
- Lead to ____ vasculitis, erymatous / purpuric lesion of the skin
- Same lesion as serum sickness but due to ____ rxn
antibody local leaky necrotizing localized
Type III Hypersensitivity: Poststreptococcal glomerulonephritis
Antigen: ____ antigens (types ____, 49, ____-hemoytic streptococci)
Pathogenesis:
- 1-4 weeks following infection of ____ or skin (____)
- Immune complex mediated (high ____ titers)
- Hypercellularity of ____
Clinical Manifestations:
- ____
- Red cell casts
- ____
- Mild hypertension
- ____
- Malaise
- ____• Disease that occurs following a ____ infection
• Infection of pharynx - pharyngitis, sore throat; impetigo - infection of ____
• Develop infection, and overtime develop high titers to the pathogen and eliminate it > some strep antigens remain (but bacteria is dead) > immune complex formed under high-Ab titer conditions
• Bottom right: hypercellular glomerulus > ____ proceed to destroy glomerulus
• Glomerulus > hypercellular > destruction
○ Develops ____ > (next slide), as blood leaves glomerulus into kidney ends up in tubules > bc of inflammation going on > ____ and ____ are compacted and become adherent > leave the kidney (as a cast of tubule they formed in)
○ Mild hypertension > glomerulus inflamed > affects ____ rate > releases renin-angiotensin-aldosterone > increase blood volume through ____ retention, raises blood pressure; as aldosterone / angiotensin II produced will lead to ____ = which will all RAISE blood pressure
○ Oliguria - ____ urine output
streptococcas 12 alpha beta pharynx impetigo Ab glomerulus
hematuria
proteinuria
oliguria
fever
strep
skin
neutrophils
red cell casts
red cells
debris
filtration
sodium
vasoconstriction
decreased
