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

Abstract

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 anti-PR3 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][6][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][9][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 ANCAassociated 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-pos...