Vasculitis Flashcards
vasculitis definition
a heterogenous group of immune mediated disorders that causes inflammation and damage to blood vessel walls leading to tissue ischemia and organ failure
pathogenesis of vasculitis
starts with infiltration of blood vessel walls by leukocytes or immune complex deposition on the vessel walls, which triggers leukocyte infiltration. This triggers an inflammatory cascade that damages the vessel, causes lumenal occlusion and ischemia/inflammation, ultimately leading to organ failure
which vessels are targeted in vasculitis?
all arteries, microcirculation, and venues & small veins (medium and large veins are spared)
large vessel vasculitis
any inflammatory disease that affects the aorta and or its major branches to the head, neck, and extremities
medium vessel vasculitis
everything else on the arterial side (not aorta and main branches). Includes not only medium, but small muscular arteries as well
small vessel vasculitis
largest group of vasculitis. microcirculation, intraparenchymal arteries and veins.
two subtypes of small vessel vasculitis
ANCA associated vasculitides (pauci-immune) & Immune complex mediated
ANCA associated vasculitis (AAV)
serum antibody in blood (ANCA) causes disease. Immune complexes aren’t found in vessel walls (pauci-immune)
Immune complex mediated vasculitis
immune complex deposition in vessel walls. no ANCAs
primary diagnostic procedure for vasculitis
biopsy of affected tissue
if you can’t get a tissue biopsy, how can you diagnose vasculitis?
angiogram
cardinal features of vasculitis
leukocyte infiltration (inflammation) of vessel wall
damage to vessel wall
possibly deposition of immune complex in vessel wall for IC mediated small vessel vasculitis
what is the damage to the vessel wall in vasculitis?
lumenal narrowing, fibrinoid necrosis, disruption of the internal and external elastic laminae
polyarteritis nodosum (PAN)
medium (occasionally small) artery vasculitis that targets the gut, kidneys, nervous system, heart, muscles, joints, testes, and skin.
what organs are specifically spared in PAN?
lungs and glomeruli (doesn’t affect microcirculation)
diagnostic test for PAN
angiogram
cardinal features of PAN
narrowing, dilation, aneurysm
a case where PAN affects small muscular arteries
digital gangrene
test for digital gangrene
MRI angiogram
3 cellular layers of artery (luminal to outer)
intima (single lining of epithelial cells)
Media (smooth muscle cells)
Adventitia (outer layer of connective tissue)
2 membranes of arteries
internal elastic lamina (between intima and media)
external elastic lamina (between media and adventitia)
how does nutrition reach small arteries?
diffusion
how does nutrition reach larger arteries?
vasa vasorum (vessels of the vessel) in adventitia.
pathology of PAN
mixed transmural inflammatory cell infiltrate (intima, media, adventitia). fibrinoid necrosis, lumen obliteration
specific details of vessel damage in PAN
destruction of internal and external elastic laminae, intimal proliferation that causes lumen narrowing, fibrosis
renal involvement in PAN
narrowing of renal arteries causes decreased blood supply, which causes the kidney to activate renin and angiotensin hormonal system, which causes increased salt/H2O retention, which leads to hypertension
where do aneurysms and inflammation occur in PAN?
branch points of arteries (sites of increased shear stress)
how is shear stress associated with inflammation in PAN?
induces expression of endothelial cell adhesion molecules like ICAM and increases the expression of pro inflammatory transcription factors (NFkB)
what does ANCA stand for?
Antineutrophil cytoplasm antibodies
what are ANCAs?
serum autoantibodies that bind neutrophil cytoplasmic granules
how do we detect ANCAs?
indirect immunofluorescence. add patients serum to slides coated with neutrophils that have been fixed with ethanol and have disrupted membranes. if ANCAs are present, they will bind to granules. Wash away unbound antibody and add anti human IgG that is conjugated with fluorescein
ANCA fluorescent patterns
C-ANCA and P-ANCA
C-ANCA
cytoplasmic staining, most specific for AAV, least common, recognizes proteinase-3, must be confirmed via ELISA
P-ANCA
perinuclear staining, least specific for AAV, most common, recognizes MPO, must be confirmed by ELISA
tropism for AAV
microcirculation in respiratory tract and kidneys (commonly causes pulmonary hemorrhage and acute renal failure)
sign of kidney involvement in AAV
cresentic glomerulonephritis
pathogenesis of crescentic glomerulonephritis
injury to glomerular capillary wall causes leakage of plasma proteins into bowman’s space. This triggers the influx of inflammatory cells that release pro inflammatory cytokines (IL-1, TNFa), fibroblasts are triggered to secrete collagen that forms crescents.
consequence of glomerulonephritis
hematurua, proteinuria, anasarca
anasarca
whole body edema due to renal involvement from AAV
role of ANCAs in AAV
markers of the disease and bind to/activate neutrophil granule antigens, which makes them more adherent to endothelium and then they release lytic enzymes that cause free radical endothelial damage in vessels
how can infection be linked to AAV?
proinflammatory cytokines from infection primes the neutrophils, which causes migration of the ANCA antigens to the cell surface.
immune complex mediated small vessel vasculitis
most common and most benign, usually presents as a skin rash.
tropism for IC mediated SVV
dermal vessels, especially venules
what determines immungenicity of IC mediated SSV?
IC size and solubility, which is determined by Ab:Ag ratio. Equal=large ICs=removed by RES, Excess Ab=small ICs=soluble, Excess Ag=ICs precipitate and deposit
common clinical manifestation of IC mediated SSV
palpable purpura
most common pattern of IC mediated SSV
leukocytoclasis (WBC fragmentation, predominantly PMNs)
name of nuclear debris from fragmentation in leukocytoclastic vasculitis
karyorrhexis
how can we test for IC deposition?
immunofluorescent staining of biopsy
pathogenesis of IC mediated SVV
antigen excess causes IC deposition in vessel walls. complement binds IC and is cleaved in C3/5a that then attracts other inflammatory cells. Neutrophils try to phagocytose ICs and become activated to start causing damage via lysosomal enzyme release
endothelial cell activation in IC-SVV
activated in response to various stimuli to up regulate adhesion proteins which allow for further neutrophil containment
role of C3a and C5a in IC-SVV
attract inflammatory cells and trigger histamine release which widens the EC junctions, allowing plasma/cells/fluid to leak out causing palpable purpura
what infection is PAN commonly associated with?
Heo B
ANCA priming
migration of ANCA antigens to neutrophil surface
