Interferon-α and -β in kidney inflammation

Type I interferons, interferon-α and interferon-β, are central regulators of antiviral immunity and autoimmunity, but little is known about their role in renal inflammation. Recent work documents that viral nucleic acids are potent inducers of interferon-α and interferon-β in mesangial cells and glomerular endothelial cells. This review discusses the available evidence on the role of interferon-α and interferon-β in viral nephropathies, in kidney diseases triggered by extrarenal infections, in lupus nephritis, and in other kidney disease entities. Finally, we propose areas of research that may help unravel the roles of type I interferons and interferon-related genes in the renal field. Type I interferons, interferon-α and interferon-β, are central regulators of antiviral immunity and autoimmunity, but little is known about their role in renal inflammation. Recent work documents that viral nucleic acids are potent inducers of interferon-α and interferon-β in mesangial cells and glomerular endothelial cells. This review discusses the available evidence on the role of interferon-α and interferon-β in viral nephropathies, in kidney diseases triggered by extrarenal infections, in lupus nephritis, and in other kidney disease entities. Finally, we propose areas of research that may help unravel the roles of type I interferons and interferon-related genes in the renal field. Fifty years after the discovery of interferon-alpha (IFN-α) and interferon-beta (IFN-β), which are type I IFNs, renal science has largely neglected this antiviral cytokine family.1.Borden E.C. Sen G.C. Uze G. et al.Interferons at age 50: past, current and future impact on biomedicine.Nat Rev Drug Discov. 2007; 6: 975-990Crossref PubMed Scopus (797) Google Scholar This is surprising because there are good reasons to study the role of IFNs in kidney diseases. For example, type I IFNs are central mediators of antiviral immunity and many types of kidney diseases are directly or indirectly related to viral infection (Table 1).2.Berns J.S. Bloom R.D. Viral nephropathies: core curriculum 2008.Am J Kidney Dis. 2008; 52: 370-381Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,3.Waldman M. Marshall V. Whitby D. et al.Viruses and kidney disease: beyond HIV.Semin Nephrol. 2008; 28: 595-607Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Second, textbooks declare that all cells can produce type I IFNs during viral infection but respective data for renal cell populations barely exist. Third, type I IFNs are central mediators of systemic lupus erythematosus (SLE), which should include lupus nephritis. Beyond basic science that may help better understand the pathogenesis of kidney diseases, additional reasons exist from a clinical point of view. Recombinant IFNs are approved and efficient drugs in clinical use, for example, for the treatment of chronic hepatitis C in renal transplantation or renal cell carcinoma. As a future perspective, IFN-α-neutralizing antibodies are now in clinical trials for the treatment of SLE. Thus, its time for nephrologists and kidney researchers to catch up with the field of IFN research.Table 1Viral infections that trigger kidney diseaseVirusPrimary manifestation in the kidneyOther possible manifestation in the kidneyHepatitis C virusMembrano-proliferative GNIgA nephropathy, membranous nephropathy, FSGS, postinfectious GN, immunotactoid glomerulopathy, fibrillary GNHepatitis B virusMembranous nephropathyMesangioproliferative GN, membrano-proliferative GN, renal vasculitisHIVCollapsing nephropathyFSGS, mesangioproliferative GNParvovirus B19Tubulointerstitial nephritisPostinfectious GN, FSGS, thrombotic microangiopathyPolyomavirusesTubulointerstitial nephritisCytomegalovirusTubulointerstitial nephritisThrombotic microangiopathyEBVAcute GN, acute kidney injuryHantavirusAcute interstitial nephritisInterstitial hemorrhageHepatitis A virusAcute kidney injuryAdenovirusAcute interstitial nephritisMumpsAcute interstitial nephritisMeaslesAcute interstitial nephritisDengue feverAcute interstitial nephritisAbbreviations: EBV, Epstein–Barr virus; FSGS, focal segmental glomerulosclerosis; GN, glomerulonephritis; HIV, human immunodeficiency virus. Open table in a new tab Abbreviations: EBV, Epstein–Barr virus; FSGS, focal segmental glomerulosclerosis; GN, glomerulonephritis; HIV, human immunodeficiency virus. This review provides a short overview on type I IFN biology and recent data on their expression in renal cells. We further discuss the potential roles of type I IFN in viral nephropathies, in kidney diseases triggered by extrarenal infections, in lupus nephritis, and in other kidney diseases. Finally, we suggest areas of research that may help unravel the potential roles of type I IFN in the renal field. IFNs are pleiotropic cytokines that have broad effects on innate and adaptive immunity. The IFN family is divided into type I and type II IFNs. Type I IFNs include IFN-α, IFN-β, IFN-ω, IFN-τ, IFN-δ, IFN-κ, and IFN-ε.4.Platanias L.C. Mechanisms of type-I- and type-II-interferon-mediated signalling.Nat Rev Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2029) Google Scholar The predominant members are the multiple separate protein variants of IFN-α and a single IFN-β. IFN-γ is the only member of type II IFN.4.Platanias L.C. Mechanisms of type-I- and type-II-interferon-mediated signalling.Nat Rev Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2029) Google Scholar All type I IFNs bind a common cell-surface receptor, known as the type I IFN receptor (IFNAR), whereas IFN-γ ligates a different cell-surface receptor, that is, type II IFN receptor.1.Borden E.C. Sen G.C. Uze G. et al.Interferons at age 50: past, current and future impact on biomedicine.Nat Rev Drug Discov. 2007; 6: 975-990Crossref PubMed Scopus (797) Google Scholar A detailed description of the structural aspects of IFN–IFN receptor interactions, the IFN signaling pathways, and their pleiotropic biologic effects have been reviewed elsewhere4.Platanias L.C. Mechanisms of type-I- and type-II-interferon-mediated signalling.Nat Rev Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2029) Google Scholar, 5.Biron C.A. Interferons alpha and beta as immune regulators—a new look.Immunity. 2001; 14: 661-664Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar, 6.Theofilopoulos A.N. Baccala R. Beutler B. et al.Type I interferons (alpha/beta) in immunity and autoimmunity.Annu Rev Immunol. 2005; 23: 307-336Crossref PubMed Scopus (962) Google Scholar and are only briefly outlined in this review. The IFNAR is composed of two multichain structured distinct subunits, IFNAR1 and IFNAR2. Each of the receptor subunits interacts with members of the JAK (Janus-activated kinase) family (Figure 1). The IFNAR1 subunit is associated with TYK2 (tyrosine kinase 2), whereas IFNAR2 is associated with JAK1. In general, the binding of type I IFNs leads to heterodimerization of IFNAR1 and IFNAR2 inducing both autophosphorylation and transphosphorylation of JAK1 and TYK2. However, the various forms of IFN-α and IFN-β have different binding affinities to each of the receptor subunits, which might serve as an explanation for some different biological effects of IFN-α and IFN-β. This leads to the activation of signal transducers and activators of transcription (STAT)1, STAT2, STAT3, and STAT5, which form homodimers or heterodimers that translocate to the nucleus. Further binding of IFN-regulated factor (IRF)9 to the activated heterodimer of STAT1 and STAT2 forms an important transcriptional complex known as ISGF (IFN-stimulated genes factor)3.7.Taniguchi T. Ogasawara K. Takaoka A. et al.IRF family of transcription factors as regulators of host defense.Annu Rev Immunol. 2001; 19: 623-655Crossref PubMed Scopus (1218) Google Scholar ISGF3 binds to IFN-stimulated response elements in the promoters of related genes and initiates transcription.4.Platanias L.C. Mechanisms of type-I- and type-II-interferon-mediated signalling.Nat Rev Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2029) Google Scholar Type I IFNs can also induce several other pathways, for example, STAT1 homodimers stimulate the transcription of genes containing the IFN-γ-activated sequence.6.Theofilopoulos A.N. Baccala R. Beutler B. et al.Type I interferons (alpha/beta) in immunity and autoimmunity.Annu Rev Immunol. 2005; 23: 307-336Crossref PubMed Scopus (962) Google Scholar Thus, type I IFNs induce different combinations of STATs to regulate transcription of functionally distinct genes, but the mechanisms defining such differential STAT usage and specificity are not well understood. Negative regulation of type I IFN signaling is mediated by receptor internalization and degradation, dephosphorylation of JAKs and STATs by phosphatases, by inducing SOCS (suppressors of cytokine signaling), and by repression of STAT-mediated gene activation by PIAS (protein inhibitors of activated STAT).6.Theofilopoulos A.N. Baccala R. Beutler B. et al.Type I interferons (alpha/beta) in immunity and autoimmunity.Annu Rev Immunol. 2005; 23: 307-336Crossref PubMed Scopus (962) Google Scholar Multiple ISGs contribute to the antiviral activity of type I IFN. For example, the myxovirus resistance gene is a guanosine triphosphatase that sequesters viral ribonucleoproteins to specific subcellular compartments. 2′–5′-Oligoadenylate synthetases activate ribonuclease-L that degrades cellular and viral RNA.8.Garcia-Sastre A. Biron C.A. Type 1 interferons and the virus-host relationship: a lesson in detente.Science. 2006; 312: 879-882Crossref PubMed Scopus (668) Google Scholar Type I IFNs also modulate innate and adaptive immune responses and regulate the expression and function of multiple cytokines. They enhance interleukin-6 signaling and induce chemokines (especially CXCL10, formerly known as IFN-inducible protein 10), chemokine receptors, transforming growth factor-β, interleukin-1 receptor antagonist, and soluble tumor necrosis factor receptors.6.Theofilopoulos A.N. Baccala R. Beutler B. et al.Type I interferons (alpha/beta) in immunity and autoimmunity.Annu Rev Immunol. 2005; 23: 307-336Crossref PubMed Scopus (962) Google Scholar Type I IFNs promote natural killer cell cytotoxicity, as well as macrophage development, maturation, and inducible nitric oxide synthase production.7.Taniguchi T. Ogasawara K. Takaoka A. et al.IRF family of transcription factors as regulators of host defense.Annu Rev Immunol. 2001; 19: 623-655Crossref PubMed Scopus (1218) Google Scholar They also directly activate immature dendritic cells (DCs) to upregulate the major histocompatibility complex I and the costimulatory molecules CD40, CD80, CD86, which fosters the presentation of viral (as well as auto) antigens in secondary lymphoid organs and the priming of antigen-specific T cells.9.Le Bon A. Etchart N. Rossmann C. et al.Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon.Nat Immunol. 2003; 4: 1009-1015Crossref PubMed Scopus (639) Google Scholar Type I IFNs exert potent antiproliferative and proapoptotic effects on T cells, by inducing cyclin kinase inhibitors and several proapoptotic molecules (such as Fas/FasL, p53, Bax, Bak), as well as activation of procaspases 8 and 3.6.Theofilopoulos A.N. Baccala R. Beutler B. et al.Type I interferons (alpha/beta) in immunity and autoimmunity.Annu Rev Immunol. 2005; 23: 307-336Crossref PubMed Scopus (962) Google Scholar Furthermore, type I IFNs regulate the development and function of B cells. They enhance B cell receptor-dependent mature B-cell responses and increase survival and resistance to Fas-mediated apoptosis.6.Theofilopoulos A.N. Baccala R. Beutler B. et al.Type I interferons (alpha/beta) in immunity and autoimmunity.Annu Rev Immunol. 2005; 23: 307-336Crossref PubMed Scopus (962) Google Scholar IFN-α upregulates the expression of the two major B-cell survival factors, the B lymphocyte stimulator and the A proliferation-inducing ligand in DCs and monocytes, a finding that might explain the antiapoptotic effect of type I IFNs on B cells. An integrated view shows that type I IFNs orchestrate antiviral immunity at all levels of the innate and adaptive immune response, and thereby contribute to cell death and tissue inflammation as part of the antiviral host defense.6.Theofilopoulos A.N. Baccala R. Beutler B. et al.Type I interferons (alpha/beta) in immunity and autoimmunity.Annu Rev Immunol. 2005; 23: 307-336Crossref PubMed Scopus (962) Google Scholar Viral nucleic acids are the most potent inducers of type I IFN and they are being recognized by two major pathways: the endosomal Toll-like receptor (TLR) pathway and by cytosolic sensors (Figure 1). TLR3 detects double-stranded RNA (dsRNA), for example, from RNA viruses.10.Alexopoulou L. Holt A.C. Medzhitov R. et al.Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.Nature. 2001; 413: 732-738Crossref PubMed Scopus (4615) Google Scholar TLR7 and TLR8 sense single-stranded RNA (ssRNA), as well as viruses containing ssRNA genomes.11.Diebold S.S. Kaisho T. Hemmi H. et al.Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.Science. 2004; 303: 1529-1531Crossref PubMed Scopus (2412) Google Scholar,12.Heil F. Hemmi H. Hochrein H. et al.Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.Science. 2004; 303: 1526-1529Crossref PubMed Scopus (2799) Google Scholar TLR9 in plasmacytoid DCs and B cells recognizes unmethylated CpG DNA motifs which are common in bacteria and in some DNA viruses.13.Hemmi H. Takeuchi O. Kawai T. et al.A Toll-like receptor recognizes bacterial DNA.Nature. 2000; 408: 740-745Crossref PubMed Scopus (5105) Google Scholar TLR4 recognizes viral proteins at the plasma membrane and activates type I IFN production through the TRIF (Toll/interleukin (IL)-1 receptor domain-containing adaptor-protein inducing interferon beta) pathway.14.Takeuchi O. Akira S. Innate immunity to virus infection.Immunol Rev. 2009; 227: 75-86Crossref PubMed Scopus (816) Google Scholar Recently, it was shown that TLR2 also recognizes vaccinia virus in an MyD88-dependent and MyD88-independent manner resulting in type I IFN release.15.Barbalat R. Lau L. Locksley R.M. et al.Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands.Nat Immunol. 2009; 10: 1200-1207Crossref PubMed Scopus (313) Google Scholar The cytosolic and MyD88-independent pathway that leads to type I IFN induction is initiated by the caspase recruitment domain-containing RNA helicases retinoic acid inducible gene-I (RIG-I) and MDA5 (melanoma differentiation antigen 5).14.Takeuchi O. Akira S. Innate immunity to virus infection.Immunol Rev. 2009; 227: 75-86Crossref PubMed Scopus (816) Google Scholar Both helicases induce the production of IFN through the adaptor protein MAVS (mitochondrial-associated adaptor protein) (also known as IPS-1, VISA, Cardif). dsRNA and picornaviruses are detected by MDA5, whereas the 5′-triphosphate ends of ssRNA are important for the binding to RIG-I. Recently, it was discovered that DNA viruses also trigger IFN through RIG-I as polymerase III converts viral DNA into 5′-triphosphate ssRNA within the cytosol.16.Chiu Y.H. Macmillan J.B. Chen Z.J. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway.Cell. 2009; 138: 576-591Abstract Full Text Full Text PDF PubMed Scopus (803) Google Scholar The search for cytosolic DNA receptors is ongoing. The DNA-dependent activator of IFN-regulatory factor/DNA sensor Z-DNA binding protein (ZBP1) has been proposed as one of these receptors.17.Takaoka A. Wang Z. Choi M.K. et al.DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response.Nature. 2007; 448: 501-505Crossref PubMed Scopus (1170) Google Scholar IFN induction by viral infections is controlled at the transcriptional level. The transcription factors IRF3 and IRF7 synergize all upstream receptor pathways. Once being phosphorylated by the kinases TBK1 and IKKε, they transfer into the nucleus and locate to IRF-binding elements in IFN-α and IFN-β promoters.14.Takeuchi O. Akira S. Innate immunity to virus infection.Immunol Rev. 2009; 227: 75-86Crossref PubMed Scopus (816) Google Scholar Although IRF3 and IRF7 binding is sufficient to activate IFN-α expression, the induction of IFN-β also requires nuclear factor-κB binding.18.Genin P. Vaccaro A. Civas A. The role of differential expression of human interferon—a genes in antiviral immunity.Cytokine Growth Factor Rev. 2009; 20: 283-295Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Secreted IFN-α and IFN-β act in a paracrine and in an autocrine manner to signal viral infection by the host. A positive feedback loop is created because IFNAR activation induces IRF7 and the aforementioned viral nucleic sensors.6.Theofilopoulos A.N. Baccala R. Beutler B. et al.Type I interferons (alpha/beta) in immunity and autoimmunity.Annu Rev Immunol. 2005; 23: 307-336Crossref PubMed Scopus (962) Google Scholar Interestingly, both plasmacytoid DCs and conventional DCs differ in terms of their predominant use of viral sensors. Conventional DCs require viral replication in the cytosol to activate the cytosolic helicases and IFN production.19.Kumagai Y. Kumar H. Koyama S. et al.Cutting edge: TLR-dependent viral recognition along with type I IFN positive feedback signaling masks the requirement of viral replication for IFN-{alpha} production in plasmacytoid dendritic cells.J Immunol. 2009; 182: 3960-3964Crossref PubMed Scopus (75) Google Scholar Hence, conventional DCs trigger antiviral immunity only when being directly infected at the tissue level. This mechanism should contribute to viral nephropathies because the intrarenal DC network comprises conventional DCs. Plasmacytoid DCs rather localize to the intravascular compartment and use the TLR system to induce type I IFN.19.Kumagai Y. Kumar H. Koyama S. et al.Cutting edge: TLR-dependent viral recognition along with type I IFN positive feedback signaling masks the requirement of viral replication for IFN-{alpha} production in plasmacytoid dendritic cells.J Immunol. 2009; 182: 3960-3964Crossref PubMed Scopus (75) Google Scholar This mechanism allows plasmacytoid DCs to sense viral infection independent of viral replication. The endosomal TLRs rather recognize ingested viral particles that had reached the circulation. This includes IFN induction upon the recognition of immune complexes containing viral nucleic acids. This mechanism is of particular interest in immune complex nephropathies such as lupus nephritis or hepatitis C virus-associated glomerulonephritis as discussed later in this review. The kidney is a sterile organ, still—similar to other cells—kidney cells recognize and respond to pathogen-associated molecular patterns, because they express TLRs and other recognition molecules in intrarenal DCs and in intrinsic renal parenchymal cells (reviewed in detail in Anders20.Anders H.J. Innate pathogen recognition in the kidney: Toll-like receptors, NOD-like receptors, and RIG-like helicases.Kidney Int. 2007; 72: 1051-1056Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Nucleic acids are the most potent type I IFN inducers, and among the TLRs, TLR3 is expressed on intrinsic renal cells and on intrarenal conventional DCs.20.Anders H.J. Innate pathogen recognition in the kidney: Toll-like receptors, NOD-like receptors, and RIG-like helicases.Kidney Int. 2007; 72: 1051-1056Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar However, dsRNA induces IFN-α and IFN-β through TLR3 in DCs but not in mesangial cells or glomerular endothelial cells.21.Flur K. Allam R. Zecher D. et al.Viral RNA induces type I interferon-dependent cytokine release and cell death in mesangial cells via melanoma-differentiation-associated gene-5: implications for viral infection-associated glomerulonephritis.Am J Pathol. 2009; 175: 2014-2022Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,22.Hagele H. Allam R. Pawar R.D. et al.Double-stranded RNA activates type I interferon secretion in glomerular endothelial cells via retinoic acid-inducible gene (RIG)-1.Nephrol Dial Transplant. 2009; 24: 3312-3318Crossref PubMed Scopus (50) Google Scholar Interestingly, dsRNA turned out to be a potent inducer of IFN-α and IFN-β in these glomerular cells when being transfected into the cytosol where it ligates RIG-like helicases, that is, RIG-I in endothelial cells and MDA5 in mesangial cells.21.Flur K. Allam R. Zecher D. et al.Viral RNA induces type I interferon-dependent cytokine release and cell death in mesangial cells via melanoma-differentiation-associated gene-5: implications for viral infection-associated glomerulonephritis.Am J Pathol. 2009; 175: 2014-2022Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,22.Hagele H. Allam R. Pawar R.D. et al.Double-stranded RNA activates type I interferon secretion in glomerular endothelial cells via retinoic acid-inducible gene (RIG)-1.Nephrol Dial Transplant. 2009; 24: 3312-3318Crossref PubMed Scopus (50) Google Scholar 5′-Triphosphate RNA induces type I IFNs in mesangial cells through RIG-I.23.Allam R. Lichtnekert J. Moll A. et al.Viral RNA and DNA sense common antiviral responses including type I interferons in mesangial cells.J Am Soc Nephrol. 2009; 20: 1986-1996Crossref PubMed Scopus (48) Google Scholar Transfection of dsDNA has the same IFN-inducing effect but the cytosolic DNA receptors in renal cells remain obscure.23.Allam R. Lichtnekert J. Moll A. et al.Viral RNA and DNA sense common antiviral responses including type I interferons in mesangial cells.J Am Soc Nephrol. 2009; 20: 1986-1996Crossref PubMed Scopus (48) Google Scholar,24.Hagele H. Allam R. Pawar R.D. et al.Double-stranded DNA activates glomerular endothelial cells and enhances albumin permeability via a toll-like receptor-independent cytosolic DNA recognition pathway.Am J Pathol. 2009; 175: 1896-1904Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Type I IFN secretion is associated with a coordinated induction of >200 ISGs in mesangial cells which is a consequence of an autocrine-activation loop involving the IFNAR.21.Flur K. Allam R. Zecher D. et al.Viral RNA induces type I interferon-dependent cytokine release and cell death in mesangial cells via melanoma-differentiation-associated gene-5: implications for viral infection-associated glomerulonephritis.Am J Pathol. 2009; 175: 2014-2022Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,23.Allam R. Lichtnekert J. Moll A. et al.Viral RNA and DNA sense common antiviral responses including type I interferons in mesangial cells.J Am Soc Nephrol. 2009; 20: 1986-1996Crossref PubMed Scopus (48) Google Scholar Disrupting this autocrine loop also reduced the capacity of dsRNA to induce interleukin-6 in mesangial cells,21.Flur K. Allam R. Zecher D. et al.Viral RNA induces type I interferon-dependent cytokine release and cell death in mesangial cells via melanoma-differentiation-associated gene-5: implications for viral infection-associated glomerulonephritis.Am J Pathol. 2009; 175: 2014-2022Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar indicating that IFN signaling is generally necessary to mount the nucleic acid-induced expression of inflammatory cytokines in mesangial cells. The immunology literature negates TLR7/8/9 expression in nonimmune cells,14.Takeuchi O. Akira S. Innate immunity to virus infection.Immunol Rev. 2009; 227: 75-86Crossref PubMed Scopus (816) Google Scholar but few reports describe their induction in tubular epithelial cells or podocytes in disease. The functional contribution of this observation remains unclear but the dense network of intrarenal conventional DCs as well as infiltrating macrophages and B cells anyway assure intrarenal IFN signaling upon activation of these receptors.25.Patole P.S. Pawar R.D. Lech M. et al.Expression and regulation of Toll-like receptors in lupus-like immune complex glomerulonephritis of MRL-Fas(lpr) mice.Nephrol Dial Transplant. 2006; 21: 3062-3073Crossref PubMed Scopus (98) Google Scholar On the basis of the above observations, one would predict that type I IFN should contribute to the immunopathology of viral nephropathies when viruses replicate in kidney cells. Surprisingly, hardly any data are yet available to support this concept probably because we lack good viral nephropathy models in rodents. For example, human immunodeficiency virus (HIV)-1 transgenic mice are used as a model for HIVAN (human deficiency virus-associated nephropathy), but this model is based on transgenes encoding for HIV proteins. Hence, HIV-1 transgenic mice do not represent a model of viral replication that would be required to study type I IFN responses to HIV virions. Research with human renal biopsy samples is especially important in this field. One study reported increased intrarenal IFN-α production in human HIVAN biopsies as compared with non-HIV focal-segmental glomerulosclerosis.26.Kimmel P.L. Cohen D.J. Abraham A.A. et al.Upregulation of MHC class II, interferon-alpha and interferon-gamma receptor protein expression in HIV-associated nephropathy.Nephrol Dial Transplant. 2003; 18: 285-292Crossref PubMed Scopus (27) Google Scholar The local release of IFN-α should also account for tubuloreticular inclusions, an ultrastructural hallmark of HIV-infected podocytes (Figure 2).27.Strauss J. Abitbol C. Zilleruelo G. et al.Renal disease in children with the acquired immunodeficiency syndrome.N Engl J Med. 1989; 321: 625-630Crossref PubMed Scopus (194) Google Scholar Tubuloreticular inclusions in HIVAN resemble those seen in blood leukocytes of patients under treatment with recombinant IFN-α. Polyomavirus infection of tubular cells in renal allografts should induce type I IFN expression through polyomavirus DNA. An appropriate mouse model was established but no data on the induction or functional role of type I IFN have yet been reported. Unpublished data from our laboratory suggest that cytosolic DNA sensors recognize polyomavirus DNA and induce IFN-α and IFN-β expression in cultured tubular epithelial cells once the DNA is transfected into the cytosol similar to mesangial cells or glomerular endothelial cells.23.Allam R. Lichtnekert J. Moll A. et al.Viral RNA and DNA sense common antiviral responses including type I interferons in mesangial cells.J Am Soc Nephrol. 2009; 20: 1986-1996Crossref PubMed Scopus (48) Google Scholar,24.Hagele H. Allam R. Pawar R.D. et al.Double-stranded DNA activates glomerular endothelial cells and enhances albumin permeability via a toll-like receptor-independent cytosolic DNA recognition pathway.Am J Pathol. 2009; 175: 1896-1904Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar However, this observation needs to be validated by replicating BK virus infection in vitro or in vivo. Yet, nothing is known about the role of endogenous type I IFN during Hantaan nephropathy. Thus, it is likely that the proinflammatory and proapoptotic effects of IFN-α contribute to the immunopathology of HIVAN, BK nephropathy, or Hantaan virus infection. Much remains to be discovered about type I IFN in these viral nephropathies. Extrarenal viral infections can cause immune complex glomerulonephritis (Table 1). For example, chronic hepatitis C virus infection of the liver can trigger membrano-proliferative glomerulonephritis, a disease in which glomerular deposition of viral particles in immune complexes is associated with increased glomerular IFN-α mRNA expression (our unpublished data in collaboration with Markus Wörnle and Detlef Schlöndorff). Transient viral infections also trigger flares of IgA nephropathy, lupus nephritis, or renal vasculitis. It is believed that this clinical association refers mainly to a transient immunostimulatory effect on the production of pathogenic autoantibodies at the DC, B cell, or plasma cell level.28.Munz C. Lunemann J.D. Getts M.T. et al.Antiviral immune responses: triggers of or triggered by autoimmunity?.Nat Rev Immunol. 2009; 9: 246-258Crossref PubMed Scopus (331) Google Scholar Whether type I IFN, among other cytokine signals, contributes to this transient immune activation is difficult to assess in patients also because renal flares manifest after some delay. Some evidence comes from studies with nephritic mice. Few injections with imiquimod, a viral ssRNA mimic that ligates TLR7 in DCs and B cells, aggravated lupus-like immune complex glomerulonephritis by inducing plasma IFN-α, DNA autoantibody levels, as well as glomerular IgG and C3 deposition.29.Pawar R.D. Patole P.S. Zecher D. et al.Toll-like receptor-7 modulates immune complex glomerulonephritis.J Am Soc Nephrol. 2006; 17: 141-149Crossref PubMed Scopus (111) Google Scholar The role of IFN-α induction in this context is supported by Fairhurst et al.30.Fairhurst A.M. Mathian A. Connolly J.E. et al.Systemic IFN-alpha drives kidney nephritis in B6.Sle123 mice.Eur J Immunol. 2008; 38: 1948-1960Crossref PubMed Scopus (72) Google Scholar who observed aggravation of immune complex glomerulonephritis after injecting nephritic B6.Sle123 mice with an adenovirus expression vector containing a recombinant IFN-α gene cassette. IFN-α activated DCs, plasma cells, and T cells, enhanced lymphoproliferation, and aggravated immune complex glomerulonephritis.30.Fairhurst A.M. Mathian A. Connolly J.E. et al.Systemic IFN-alpha drives kidney nephritis in B6.Sle123 mice.Eur J Immunol. 2008; 38: 1948-1960Crossref PubMed Scopus (72) Google Scholar Interestingly, injecting recombinant IFN-β has opposite effects on lupus nephritis of MRL(Fas)lpr/lpr mice.31.Schwarting A. Paul K. Tschirner S. et al.Interferon-beta: a therapeutic for autoimmune lupus in MRL-Faslp