Coming of Age--CC Chemokine Ligand 18 in ANCA-Associated Vasculitis.

The management of pauci–immune focal necrotizing GN (FNGN) remains a challenge, with morbidity and mortality remaining stubbornly high. Well powered controlled clinical trials have optimized older treatments and introduced new ones, but substantial numbers of those affected still die of active disease or from the toxicity of the drugs used to treat it.1,2 Current strategies for tailoring therapy to disease activity are clearly inadequate because of the lack of biomarkers that accurately reflect the underlying pathogenesis and can be used to anticipate clinical relapses. The need for new approaches provided the starting point for a study from the laboratory of Stahl and colleagues in this issue of JASN.3 Brix et al.3 suggest that the CC chemokine ligand 18 (CCL18) contributes to the pathogenesis of ANCA–associated crescentic GN and that its serum concentration may be a clinically relevant marker of disease intensity. It was originally assumed that assays for autoantibodies to myeloperoxidase (MPO) and proteinase 3 (PR3) would be ideal biomarkers for ANCA–associated disease activity. Unfortunately, although positive assays for anti-MPO and antiPR3 have a .90% sensitivity and specificity for diagnosing pauci–immune FNGN and in vitro studies, experimental models, and genetic studies provide a compelling case for their pathogenicity,4 recent evidence from controlled trials as well as meta-analyses show that this is not the case.5–7 Indeed, assays for ANCA and autoantibodies to MPO or PR3 reflect disease activity poorly and cannot be used to predict disease relapses in those treated with either traditional immunosuppressive drugs or rituximab. Alternative biomarkers currently being explored include developing more pathogenetically relevant assays for antibodies to MPO and PR3,8–10 monitoring titers of more recently described autoantibodies in ANCA associated vasculitis,11 and monitoring injury using targeted circulating or urinary biomarkers.12,13 Although promising, none of these have yet led to the development of a robust biomarker; hence, there is interest in the different strategy by Stahl and colleagues.3 Brix et al.3 optimized methods for extracting mRNA from paraffin–embedded renal biopsies before using array technology to analyze the genes expressed in renal biopsies from a representative group of 30 patients with ANCA– associated crescentic GN. Brix et al.3 identified just over 1300 gene transcripts that were robustly overexpressed, whereas 342 were downregulated in patients’ biopsies compared with healthy control kidneys. Brix et al.3 then focused on chemokine genes, because they were among the most highly expressed and because of their known importance for renal injury by recruiting and activating specific leukocyte subsets.14 Of the many chemokine genes that were upregulated in patients’ biopsies, CCL18 was the most highly expressed of all, with approximately 100-fold higher levels than in normal kidneys. The source of the CCL18 was shown by immunohistology to be a subset of CD68–positive mononuclear phagocytes (that is, macrophages or dendritic cells). These were far more frequent in the patients’ biopsies and clustered around glomeruli and in foci of interstitial inflammation. Both the abundance ofCCL18mRNAand the number of CCL18-positive cells correlated with cellular crescents and the extent of interstitial inflammation but not fibrosis of tubular atrophy. As a group, the serum CCL18 concentration in patients’ sera was significantly raised at the time of the biopsy and decreased toward normal after immunosuppressive drugs were started, but it was again increased during disease relapses. Interestingly, the group of patients who relapsed had significantly higher concentrations of CCL18 at presentation. Thus, CCL18 expression reflected acute injury in ANCA associated vasculitis, and it is important to put it into the context of what is currently known about CCL18 and its involvement in disease. The chemokine CCL18 is present in relatively high concentrations in human serum, and it is one of a group of cytokines that has a role in tissue homeostasis and inflammation.15 CCL18 has no murine equivalent, probably because it arose from a gene fusion event that occurred after the evolutionary separation of rodents and primates.16 It was described independently by a number of groups in the late 1990s and given different names, reflecting the circumstances of its discovery16: pulmonaryand activation-regulated chemokine, alternative macrophage activation–associated chemokine-1, dendritic cell chemokine-1, and macrophage inflammatory peptide-4. Macrophages and dendritic cells are the major sources of CCL1817,18: it is expressed constitutively by alveolar macrophages in the lung and to a lesser extent, dermal dendritic cells in the skin. Much still needs to be Published online ahead of print. Publication date available at www.jasn.org.