title: Activated innate immunity and the involvement of CX3CR1-fractalkine in promoting hematuria in patients with IgA nephropathy.
abstract: A hallmark of immunoglobulin A nephropathy (IgAN) is episodes of gross hematuria coinciding with mucosal infections that can represent the disease-triggering event. Here we performed a whole genomic screen of IgAN patients during gross hematuria to clarify the link between mucosal antigens and glomerular hematuria. Modulated genes showed a clear involvement of the intracellular interferon signaling, antigen-presenting pathway, and the immunoproteasome. The mRNA and protein level of the chemokine receptor characterizing cytotoxic effector lymphocytes, CX3CR1, was upregulated. In vitro antigenic stimulation of peripheral blood mononuclear cells from IgAN patients, healthy blood donors, and other nephropathies with microscopic hematuria showed that only in IgAN patients was CX3CR1 enhanced in a dose-dependent manner. A significantly higher amount of glomerular and urinary fractalkine, the only ligand of CX3CR1, was also found in IgAN patients with recurrent episodes of gross hematuria compared with other patients with microscopic or no hematuria. This suggests a predisposition for cytotoxic cell extravasation only in patients with recurrent gross hematuria. Thus, we found a defect in antigen handling in peripheral blood mononuclear cells of IgAN patients with a specific increase of CX3CR1. This constitutive upregulation of glomerular and urinary fractalkine suggests an involvement of the CX3CR1-fractalkine axis in the exacerbation of gross hematuria.
authors.affiliation: Department of Emergency and Organ Transplantation, Nephrology Dialysis and Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Sharon N
authors.initials: SN
authors.lastname: Cox
authors.forename: Fabio
authors.initials: F
authors.lastname: Sallustio
authors.forename: Grazia
authors.initials: G
authors.lastname: Serino
authors.forename: Antonia
authors.initials: A
authors.lastname: Loverre
authors.forename: Francesco
authors.initials: F
authors.lastname: Pesce
authors.forename: Margherita
authors.initials: M
authors.lastname: Gigante
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zaza
authors.forename: Patrizia F
authors.initials: PF
authors.lastname: Stifanelli
authors.forename: Nicola
authors.initials: N
authors.lastname: Ancona
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Schena
mesh_terms: D000328:Adult; D000073883:CX3C Chemokine Receptor 1; D016022:Case-Control Studies; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000378:metabolism* / Q000652:urine; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D005922:Glomerulonephritis, IGA / Q000150:complications / Q000235:genetics / Q000276:immunology*; D006417:Hematuria / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007558:Italy; D007678:Kidney Glomerulus / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D012008:Recurrence; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D008024:Ligands; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human