Granulomata

Granulomata

section 21  Disorders of the kidney and urinary tract 4990 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.