# Granulomata

# Granulomata

section 21  Disorders of the kidney and urinary tract
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Experimental studies have demonstrated unequivocally that ANCA 
induce neutrophil activation, superoxide and cytokine release, and 
can cause neutrophil-​mediated endothelial cytotoxicity. ANCA re-
quire neutrophil priming with TNF, which leads to translocation of 
PR3 or MPO from primary cytoplasmic granules to the cell mem-
brane. In addition to binding to cell surface autoantigens, ligation 
of the Fc component of the ANCA antibody to neutrophil Fc re-
ceptors is necessary for intracellular signalling and cell activation. 
Both spontaneous and induced animal models have demonstrated 
the ability of ANCA to cause a pauci-​immune renal vasculitis in sus-
ceptible animal strains. There is increased glomerular deposition 
of alternative complement components, and complement factor 5 
receptor inhibition has abrogated experimental MPO-​ANCA vas-
culitis. A positive feedback loop between neutrophil and alterna-
tive complement pathway activation has been proposed. Neutrophil 
extracellular traps (NETs) containing PR3 and MPO are found in 
the circulation and renal lesions and promote autoantigen presenta-
tion to the immune system; penicillamine promotes NET formation 
that has led to vasculitis in experimental models.
Pathology
AAV predominantly affects small blood vessels, capillaries, arteri-
oles, and venules, but may also affect muscular arteries and (rarely) 
larger arteries and the heart. Capillaritis in the glomerular tuft re-
sults in capillary thrombosis and infarction. This appears on biopsy 
as segmental fibrinoid necrosis and a secondary crescentic reaction 
within Bowman’s capsule, containing monocytes and epithelial cells 
(Figs. 21.10.2.1a and 21.10.2.1b), which progresses to involve the 
whole tuft and destroy the glomerulus (Fig. 21.10.2.1c). In addition, 
there is periglomerular and tubulointerstitial inflammation, which 
may contain giant cells (Fig. 21.10.2.1d). Extraglomerular arter-
itis is seen in 15% of cases and frank granulomata occur rarely in 
GPA. There is considerable variety in the severity and proportion 
of fibrotic lesions between glomeruli. Obsolescent glomeruli and fi-
brotic crescents reflect previous vasculitic events and are associated 
with tubulointerstitial scarring. Capillaritis in pulmonary alveoli 
causes capillary rupture and haemorrhage into the alveolar space.
Granulomata
The ANCA autoantigen PR3 is abundantly expressed in granuloma-
tous lesions in close proximity to mature dendritic cells capable of 
antigen presentation. The inflammatory infiltrate at such foci is neu-
trophil rich, and interventions which deplete neutrophils, including 
experimental chemokine blockade or the drugs cyclophospha-
mide and deoxyspergualin, are effective therapies. T cells in granu-
lomatous lesions are over-​represented by a CD4+, CD28− subset 
which release γ-​interferon and TNFα and have cytotoxic potential. 
A pathogenetic role for cytotoxic T cells has been shown in larger-​
vessel arteritis, and similar mechanisms are likely to be important in 
smaller-​vessel disease. Circulating markers of T-​cell activation are 
elevated, including the soluble interleukin-​2 receptor. The efficacy 
of B-​cell-​depleting therapies has focused attention on B cells, which 
(b)
(a)
(d)
(c)
Fig. 21.10.2.1  Glomerular histology of ANCA-​associated vasculitis. (a) A glomerulus showing focal necrosis 
with an early crescentic reaction (arrow). (b) Glomerular macrophage infiltration (brown) illustrated by CD68 
staining. (c) Severe glomerular involvement with widespread necrosis, a circumferential crescent, and collapse of 
the glomerular tuft. (d) Massive periglomerular leucocyte infiltration occurring around an affected glomerulus.