title: CD163+ M2c-like macrophages predominate in renal biopsies from patients with lupus nephritis.
abstract: BACKGROUND
  The role of macrophages in the pathogenesis of lupus nephritis, in particular their differentiation to a certain subtype (e.g., M1- or M2-like) modulating the inflammatory reaction, is unknown. Here we investigated whether the differentiation in M1- or M2-like macrophages depends on the stage of lupus nephritis and whether this correlates with clinical parameters.
  
  
  METHODS
  Using immunohistochemical analysis we analyzed renal biopsies from 68 patients with lupus nephritis (ISN/RPS classes II-V) for infiltration with M1-like (iNOS+/CD68+), M2a-like (CD206+/CD68+), M2c-like macrophages (CD163+/CD68+), and FoxP3+ regulatory T-cells. In addition, clinical parameters at the time of renal biopsy, i.e., blood pressure, proteinuria and serum urea were correlated with the macrophage infiltration using the Spearman test.
  
  
  RESULTS
  The mean number of CD68+ macrophages was related to the diagnosed ISN/RPS class, showing the highest macrophage infiltration in biopsies with diffuse class IV and the lowest number in ISN/RPS class V. In all ISN/RPS classes we detected more M2c-like CD163+/CD68+ than M2a-like CD206+/CD68+ cells, while M1-macrophages played only a minor role. Cluster analysis using macrophage subtype numbers in different renal compartments revealed three main clusters showing cluster 1 dominated by class V. Clusters 2 and 3 were dominated by lupus class IV indicating that this class can be further differentiated by its macrophage population. The number of tubulointerstitial FoxP3+ cells correlated with all investigated macrophage subtypes showing the strongest association to numbers of M2a-like macrophages. Kidney function, as assessed by serum creatinine and serum urea, correlated positively with the number of total CD68+, M2a-like and M2c-like macrophages in the tubulointerstitium. In addition, total CD68+ and M2c-like macrophage numbers highly correlated with Austin activity score. Interestingly, in hypertensive lupus patients only the number of M2a-like macrophages was significantly increased compared to biopsies from normotensive lupus patients.
  
  
  CONCLUSIONS
  M2-like macrophages are the dominant subpopulation in human lupus nephritis and particularly, M2a subpopulations were associated with disease progression, but their role in disease progression remains unclear.
authors.affiliation: Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Krankenhausstr. 8-10, 91054, Erlangen, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Olmes
authors.affiliation: Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Krankenhausstr. 8-10, 91054, Erlangen, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Büttner-Herold
authors.affiliation: Institute of Human Genetics, FAU Erlangen-Nürnberg, 91054, Erlangen, Germany.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Ferrazzi
authors.affiliation: Department of Radiation Oncology, FAU Erlangen-Nürnberg, 91054, Erlangen, Germany.
authors.forename: Luitpold
authors.initials: L
authors.lastname: Distel
authors.affiliation: Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Krankenhausstr. 8-10, 91054, Erlangen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.affiliation: Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Krankenhausstr. 8-10, 91054, Erlangen, Germany. Christoph.Daniel@uk-erlangen.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Daniel
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D001706:Biopsy; D002454:Cell Differentiation / Q000276:immunology; D016000:Cluster Analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D011956:Receptors, Cell Surface
keywords: Lupus nephritis; Macrophage subtypes; Macrophages; T-reg-cells