ANCAs are also antimonocyte cytoplasmic autoantibodies.

Names can be misleading. The term ANCA is a misnomer, because ANCAs recognize antigens that are in not only the primary granules of neutrophils but also, the peroxidase-positive lysosomes of monocytes, including both proteinase 3 (PR3) and myeloperoxidase (MPO). The first published article on ANCA was in 1982 by Davies et al. (1), who reported eight patients with segmental necrotizing GN who all “had in their serum a factor that stained the cytoplasm of neutrophil leucocytes by indirect immunofluorescence” (1). This article was largely overlooked, and widespread recognition of ANCA awaited the publication in 1985 of an article in The Lancet by van derWoude et al. (2), which “found antibodies reacting with the cytoplasm of ethanol-fixed granulocytes and monocytes (anticytoplasmic antibodies, ACPA)” in patients with active granulomatosis with polyangiitis (2). This report clearly showed that ANCAs react with both neutrophils and monocytes and used the more generic term anticytoplasmic antibodies (ACPAs) rather than ANCAs (2). For several years after the discovery of ANCAs, there were many advocates for using the termACPA rather than ANCA; however, the term ANCA prevailed, and ACPA was relegated to becoming the acronym for anticitrullinated protein antibody (3). Although ANCAs react with monocytes, they do not react with macrophages. Using indirect immunofluorescence microscopy assays, Charles et al. (4) observed that normal human peripheral blood monocytes have well defined cytoplasmic staining with MPO-ANCA and PR3-ANCA. However, monocytes that are cultured in vitro progressively lose reactivity with MPO-ANCA and PR3-ANCA as they differentiate into macrophages, which have no reactivity using this method. Patient alveolar macrophages obtained by bronchoalveolar gavage and peritoneal macrophages obtained during dialysis also do not react with MPO-ANCA or PR3-ANCA. These observations indicate that ANCA can directly interact only with monocytes before and shortly after activation but not with mature macrophages. Initial in vitro studies of the pathogenic potential of ANCA showed that primed neutrophils can be activated byANCAtoundergo respiratoryburst anddegranulation (5). This has been confirmed by numerous additional in vitro studies (reviewed in ref. 6). A lesser number of in vitro studies clearly show that ANCA also can activate monocytes (6–10). Multiple animal models support a pathogenic role for ANCA in vivo (11). These studies have not delineated the respective pathogenic roles of neutrophils versus monocytes, although one study indicated that selective depletion of neutrophils was sufficient to prevent acute necrotizing glomerular injury in a mouse model of ANCAGN induced by anti-MPO antibodies (12). In this issue of CJASN, Zhao et al. (13) show that, at the time of biopsy, monocytes/macrophages are the most frequent leukocytes in very early segmental necrotizing lesions in patients with ANCAGN,with lesser numbers of neutrophils. Zhao et al. (13) also identified increasednumbersofmacrophages innormal-appearing glomeruli in specimens with ANCAGN. Zhao et al. (13) conclude that activated macrophages are important in the induction of acute lesions and potential targets for therapy. A technical limitation of the studywas the identification of neutrophils by histologic appearance alone, whereas monocytes and macrophages were detected by immunohistochemical markers (13). Zhao et al. (13) used CD68 as a marker for monocytes/macrophages, which may result in an overestimation of monocytes/ macrophages and an underestimation of neutrophils, becauseCD68 is innot only the lysosomesormonocytes/ macrophages but also, the primary granules of neutrophils. Nevertheless, the observations are valuable and warrant careful consideration. The results of the work by Zhao et al. (13) are in accord with those reported in the work by Weidner et al. (14), which also showed thatmonocytes/macrophages and to a lesser extent, neutrophils were the predominant leukocytes in glomeruli in renal biopsies from patients withANCAGN,with 4.767.4monocytes/macrophages compared with 3.267.4 neutrophils per glomerular cross-section (14). Neither study identified substantial numbers of T lymphocytes or B lymphocytes (13,14). This latterfindingdiffers from the studybyCunningham et al. (15), which reported 7.366.1 macrophages, 3.762.5 T lymphocytes, and 2.861.7 neutrophils per glomerular cross-section in patients with pauci-immune crescentic GN. This discrepancy could be the result of the timing of the biopsy relative to the stage of the glomerular injury if there are more neutrophils and monocytes in earlier lesions and more macrophages and T lymphocytes in later lesions. Neutrophils are evanescent at sites of Department of Pathology and Laboratory Medicine and University of North Carolina Kidney Center, University of North Carolina, Chapel Hill, North Carolina