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Clin J Am Soc Nephrol 2: S2-S5, 2007
© 2007 American Society of Nephrology
doi: 10.2215/CJN.00020107
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Viruses and Diseases of the Kidney

Virus-Induced Cellular Immune Mechanisms of Injury to the Kidney

Jason R. Faulhaber*, and Peter J. Nelson{dagger}

* Division of Infectious Diseases and {dagger} Division of Nephrology, New York University School of Medicine, New York, New York

Address correspondence to: Dr. Peter J. Nelson, Division of Nephrology, New York University School of Medicine, Smilow Research Center, 522 First Avenue, New York, NY 10016. Phone: 212-263-7681; Fax: 212-263-7683; E-mail: nelsop02{at}med.nyu.edu


   Abstract
Top
 Abstract
Introduction
 Bystander Injury
 Direct Injury: Targeting by...
 Conclusion
 Disclosures
 References
 
Cellular immune systems play an important role in determining renal outcomes in virus-induced kidney diseases. Highlighted briefly are five different locations along the development of adaptive immune responses to viral infection that may promote injury to the renal parenchyma and the loss of renal function. This may occur because adaptive immune cells directly target infected renal parenchymal cells or because the kidney becomes a bystander organ of adaptive immune cell–mediated injury. Examples from recent studies are provided to illustrate how this may lead to clinically relevant renal disease.


   Introduction
Top
 Abstract
 Introduction
Bystander Injury
 Direct Injury: Targeting by...
 Conclusion
 Disclosures
 References
 
Cellular immune responses that are effective at combating viral infections often result from the coordinated action of both the innate and adaptive arms of the immune system (1). If a virus breaches physical barriers to infection that normally are provided by the skin and the mucosa, then the activity of immune cells (e.g., natural killer cells, granulocytes) and extracellular factors (e.g., lysozyme, complement) of the innate immune system may be sufficient to halt any further infection by the virus. If the virus escapes these innate immune responses, then adaptive immune responses are induced to try to contain the virus. In contrast to innate immune responses, these adaptive immune responses demonstrate specificity, discrimination, and acquired "memory" for distinct viral molecules (i.e., viral antigens), and the ability to respond more vigorously after repeated exposure to these same viral antigens. The effector phases of adaptive immune responses are coordinated by lymphocytes and their products, and may eliminate the virus from the host, primarily by generating neutralizing antibody that is specific for the virus and CD8+ cytotoxic T lymphocytes (CTL) that directly kill virally infected cells. These adaptive immune responses may also prevent future infections by the same virus.

In the following brief discussion, we highlight specific cellular immune mechanisms of injury to the kidney that can occur during the development of adaptive immune responses to viral infections. Figure 1 depicts a simplified schema of an adaptive immune response to viral infection and five different locations along this coordinated response where activation of adaptive cellular immunity can cause bystander or direct injury to the renal parenchyma. This injury may occur irrespective of the outcome for the virus (i.e., elimination, or induction of abortive, latent, restricted, or productive infection) as a result of adaptive immune responses. The following discussion and the accompanying illustrative examples are not intended to encompass the entirety of how cellular immune systems may injure the kidney, an extensive topic, and the reader may find other recent reviews on virus-induced kidney diseases informative as well (2,3).


Figure 1
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  		Figure 1. Simplified schema of an adaptive immune response to a viral infection. A dendritic cell (DC) that has captured viral antigen migrates from the periphery into a secondary lymphoid organ such as the spleen or a lymph node. The DC presents the viral antigen for recognition by naïve CD4+ and CD8+ lymphocytes to initiate a T helper type 1 (Th1) immune response to the virus. Naïve CD4+ lymphocytes that recognize the antigen proliferate and differentiate into CD4+ Th1 lymphocytes, which can further stimulate viral antigen–specific B lymphocytes and CD8+ lymphocytes to differentiate into plasma cells and cytotoxic T lymphocytes (CTL), respectively. CD4+ Th1 lymphocytes will also activate mononuclear phagocytes (M{theta}) that present viral antigen in the periphery. Five locations marked by the boxed numbers 1 through 5 along this adaptive immune response have been implicated in promoting bystander or direct injury to the renal parenchyma and include the following: 1, pattern recognition of viral products by dendritic cells; 2, B lymphocyte/plasma cell responses; 3, activation of mononuclear phagocytes; 4, encountering viral antigen in the periphery by T lymphocyte effectors; and 5, CTL responses. The mechanisms of bystander injury to the renal parenchyma, represented by 1 through 3, can initiate within and/or outside the kidney, whereas the bystander injury, represented by 4, occurs within the kidney. The mechanism of direct injury to the renal parenchyma, represented by 5, occurs within the kidney.

 

   Bystander Injury
Top
 Abstract
 Introduction
 Bystander Injury
Direct Injury: Targeting by...
 Conclusion
 Disclosures
 References
 
Pattern Recognition of Viral Products
Viruses encode products that can be recognized by immune and nonimmune cells as pathogen-associated molecular patterns (PAMP), structural motifs that serve as "danger" signals to the host indicating the presence of virus (1,4,5). PAMP also exist on a diverse repertoire of other nonviral molecules, including factors that are elaborated by damaged or stressed cells (e.g., heat-shock proteins) and by other microbes (e.g., LPS from bacteria), and play a similar role in alarming the host to environmental insults (4). The best characterized receptors for PAMP are the Toll-like receptors (TLR) (1,4,5). At least four TLR can recognize viral PAMP (1,4,5). TLR3 can recognize double-stranded viral RNA, TLR7 and TLR8 can recognize single-stranded viral RNA, and TLR9 can recognize unmethylated dinucleotide motifs in viral DNA (1,4,5). Engagement of these and other TLR on dendritic cells (DC) is an important step in determining whether DC will induce T helper type 1 (Th1) adaptive immune responses to viral infections (Figure 1) (6). Some of these TLR are expressed by nonimmune renal cells (4,5). It is the engagement of TLR on immune cells, however, and the subsequent inflammatory response that occurs that may be particularly important in inducing inflammatory injury to the kidney (1,4–6).

Multiples studies have now demonstrated that TLR-mediated activation of immune cells both within and outside the kidney by viral products can induce bystander injury to the renal parenchymal in renal diseases that are not conventionally considered to be of viral origin (4,5). One recent study nicely illustrates this (7). Administration of CpG-DNA, a ligand for TLR9, was capable alone of triggering proliferative lupus nephritis (i.e., a "lupus flare") in mice that were prone to the disease (7). Because TLR9 was not detected on intrinsic renal parenchymal cells, the induction of proliferative lupus nephritis was thought to occur via a TLR9-mediated proinflammatory response by immune cells that resided within and outside the kidney (7). This mechanism of injury contrasts with the direct effect that some PAMP may have on intrinsic renal parenchymal cells, such as the proposed ability of LPS to activate TLR4 on podocytes, inducing alterations in the morphology of podocytes and proteinuria (8). Thus, viral PAMP can play a role in inducing bystander injury in the kidney by activating damaging immune responses, even in heterologous (i.e., nonviral) renal diseases.

Hyperactive B Lymphocyte Responses
The ability of B lymphocytes to produce neutralizing antibodies against viruses is an important determinant of adaptive immune responses to control, eliminate, and protect from viral infections (1). CD4+ Th1 lymphocytes that recognize viral antigen that is presented by B lymphocytes in the context of their surface Ig secrete cytokines that will promote the proliferation and Ig class switching of these B lymphocytes (Figure 1). If effective, then the result is plasma cells that produce high-affinity, neutralizing, opsonizing, and complement-activating antibody that is directed against viral epitopes.

This T lymphocyte–dependent B lymphocyte response, however, may become hyperactive and, in some cases, cause a loss in tolerance through mechanisms such as molecular mimicry and epitope spreading (9). In the former possibility, a nonspecific polyclonal hypergammaglobulinemia of viral infection can occur (9), leading to sequelae in the kidney such as distal renal tubular acidosis (10) or the renal disease manifestations of cryoglobulinemia. In the latter possibility, antibody that is directed against self-antigen may be produced (9), as was recently found in some HIV-infected patients who developed antibodies that were directed against extracellular components of the glomerular basement membrane (11). Thus, in response to a viral infection, hyperactive or aberrant B lymphocyte responses may produce antibody that induces bystander injury to the kidney.

Excessive Activation of Mononuclear Phagocytes
Th1 lymphocytes that encounter mononuclear phagocytes (M{theta}) that present viral antigen in the periphery (Figure 1) will classically activate these M{theta} to perform their own effector functions (1). This includes the production of reactive oxygen intermediates, nitric oxide, and lysosomal enzymes; the secretion of several proinflammatory cytokines and growth factors; and the upregulation of co-stimulatory molecules. These effector functions can play an important role in inactivating virus that is sequestered with M{theta}, in amplifying adaptive immune responses, and in promoting tissue repair. However, if excessive or poorly resolving, then tissue injury may result from these M{theta} effector functions.

A dramatic example of the potential for bystander injury to the kidney by M{theta} is presented by the hemophagocytic syndrome (HPS), a severe inflammatory state that is caused by the excessive activation, proliferation, and infiltration of multiple tissues by nonmalignant M{theta} (12,13). HPS can be genetic in origin, or it may develop secondary to infection, malignancy, or autoimmune disease (12,13). HPS is a recognized complication of infection by several viruses, including Epstein-Barr virus, cytomegalovirus, herpes simplex virus, varicella zoster virus, HIV, and parvovirus B19 (12,13). Renal sequelae can include acute renal failure secondary to acute tubular necrosis, and, recently, an association between HPS and podocyte injury was found (14). Several patients with HPS and proteinuria were discovered to have minimal-change disease, FSGS, or collapsing glomerulopathy on kidney biopsy (14). This podocyte injury may have occurred secondary to the cytokine storm that often develops in patients with HPS (12–14).

Encountering Viral Antigen in the Kidney
T lymphocyte effectors that have been generated during the adaptive immune response will exit secondary lymphoid organs to traffic in search of viral antigen (Figure 1) (1). This viral antigen may be associated with and presented by nonimmune and/or immune cells that reside anywhere in the periphery. CD4+ Th1 lymphocytes that recognize viral antigen that is presented by MHC class II molecules, which in the kidney are expressed by endothelial cells in glomeruli but have not been consistently detected on other renal parenchymal cells, will be activated to perform localized effector functions that are designed to eliminate virus at the site of antigen encounter. CTL that recognize viral antigen that is presented by MHC class I molecules, which in the kidney can be expressed by all renal parenchymal cells, will directly kill the cell that presents the viral antigen (discussed next).

The recent discovery of the contiguous renal DC network raised the possibility that viral antigen may be encountered by T lymphocyte effectors within the kidney apart from the parenchymal cells of the nephron (15). One major immunologic function of tissue-resident DC is to survey for, scavenge, and present foreign antigen, whether produced locally or arriving from distant sources, in the context of surface MHC class II molecules (16,17). DC may also present foreign antigen that is produced via intracellular synthetic pathways in the context of surface MHC class I molecules. In contrast to conventional models (Figure 1), however, antigen-bearing renal DC may not receive cues to traffic out of the kidney after taking up foreign antigen (18). Thus, renal DC may scavenge and present viral antigen for recognition within the interstitial compartment of the kidney. This may be a potent recipe for organizing "nephron-associated lymphoid tissue" if trafficking T lymphocyte effectors encounter these renal DC, a potentially causative mechanism for acute and chronic virus-associated interstitial nephritis. Indeed, this phenomenon has already been demonstrated in the lung, where marked lymphoid organization within the interstitial spaces between the airways and the blood vessels can occur (19).


   Direct Injury: Targeting by CTL
Top
 Abstract
 Introduction
 Bystander Injury
 Direct Injury: Targeting by...
Conclusion
 Disclosures
 References
 
A robust CTL response is required to eliminate cells that harbor infectious virus (1). The interaction between CTL and infected cells is MHC restricted. If a CTL recognizes viral antigen that is presented in the context of MHC class I molecules on the surface of an infected cell, then the CTL will directly target the infected cell by elaborating perforin, granzymes, and other factors that directly kill the infected cell. It is interesting that despite the number of different viruses that have been detected within renal parenchymal cells, little is known about the role of CTL responses in targeting these cells during adaptive immune responses.

Polyomavirus-associated nephropathy is a major cause of kidney allograft dysfunction, and recent studies indicate that CTL responses may play a "paradoxic" role in causing allograft failure (20,21). Under immunosuppressive drug regimens that commonly are used to prevent rejection of kidney allografts by the host, reactivated BK virus can induce cytopathic and inflammatory injury to the renal epithelium that closely mimics rejection (20,21). One recent study found that during the tapering of immunosuppression to allow adaptive immune responses to mount against reactivated virus, allografts that were more closely matched to the host at MHC class I loci fared worse than those that were not as closely matched (22). This suggested that CTL responses were more effective at killing infected renal epithelial cells and paradoxically promoting a further loss of renal function in MHC class I–matched allografts with polyomavirus (22). This is reminiscent of immune restoration inflammatory syndromes that can occur after initiation of antiretroviral therapy in HIV-infected patients, in which reconstituted adaptive immune responses to an existing burden of foreign antigen (e.g., from mycobacterium tuberculosis) can lead to inflammatory injury to organs, including to the kidney (23).


   Conclusion
Top
 Abstract
 Introduction
 Bystander Injury
 Direct Injury: Targeting by...
 Conclusion
Disclosures
 References
 
In attempting to contain viral infections, adaptive immune responses can promote injury to the kidney. We have discussed in this brief overview several ways whereby adaptive immunity can directly and indirectly cause the loss of renal function. Future research should provide approaches to prevent, limit, or reverse this immunologic injury to the kidney in patients who are infected with viruses.


   Disclosures
Top
 Abstract
 Introduction
 Bystander Injury
 Direct Injury: Targeting by...
 Conclusion
 Disclosures
References
 
None.


   Acknowledgments
 
P.J.N. is supported by National Institutes of Health grant DK065498.

The discussion was presented at the symposium "Basic Science for Clinical Nephrologists—Mechanisms of Viral Injury to the Kidney" at the 39th Annual Meeting of the American Society of Nephrology.


   References
Top
 Abstract
 Introduction
 Bystander Injury
 Direct Injury: Targeting by...
 Conclusion
 Disclosures
 References
 

  1. Cellular and Molecular Immunology, 5th Ed., edited by Abbas AK, Lichtman AH, Boston, Elsevier Saunders,2005
  2. Kotton CN, Fishman JA: Viral infection in the renal transplant recipient. J Am Soc Nephrol16 :1758 –1774,2005[Abstract/Free Full Text]
  3. Lai AS, Lai KN: Viral nephropathy. Nat Clin Pract Nephrol2 :254 –262,2006[CrossRef][Medline]
  4. El-Achkar TM, Dagher PC: Renal Toll-like receptors: Recent advances and implications for disease. Nat Clin Pract Nephrol2 :568 –581,2006[CrossRef][Medline]
  5. Pawar RD, Patole PS, Wornle M, Anders HJ: Microbial nucleic acids pay a Toll in kidney disease. Am J Physiol Renal Physiol291 :F509 –F516,2006[Abstract/Free Full Text]
  6. Mazzoni A, Segal DM: Controlling the Toll road to dendritic cell polarization. J Leukoc Biol75 :721 –730,2004[Abstract/Free Full Text]
  7. Pawar RD, Patole PS, Ellwart A, Lech M, Segerer S, Schlondorff D, Anders HJ: Ligands to nucleic acid-specific toll-like receptors and the onset of lupus nephritis. J Am Soc Nephrol17 :3365 –3373,2006[Abstract/Free Full Text]
  8. Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, Rastaldi MP, Calvaresi N, Watanabe H, Schwarz K, Faul C, Kretzler M, Davidson A, Sugimoto H, Kalluri R, Sharpe AH, Kreidberg JA, Mundel P: Induction of B7–1 in podocytes is associated with nephrotic syndrome. J Clin Invest113 :1390 –1397,2004[CrossRef][Medline]
  9. Hunziker L, Recher M, Macpherson AJ, Ciurea A, Freigang S, Hengartner H, Zinkernagel RM: Hypergammaglobulinemia and autoantibody induction mechanisms in viral infections. Nat Immunol4 :343 –349,2003[CrossRef][Medline]
  10. Laing CM, Roberts R, Summers S, Friedland JS, Lightstone L, Unwin RJ: Distal renal tubular acidosis in association with HIV infection and AIDS. Nephrol Dial Transplant21 :1420 –1422,2006[Free Full Text]
  11. Szczech LA, Anderson A, Ramers C, Engeman J, Ellis M, Butterly D, Howell DN: The uncertain significance of anti-glomerular basement membrane antibody among HIV-infected persons with kidney disease. Am J Kidney Dis48 :e55 –e59,2006[CrossRef][Medline]
  12. Imashuku S: Differential diagnosis of hemophagocytic syndrome: Underlying disorders and selection of the most effective treatment. Int J Hematol66 :135 –151,1997[CrossRef][Medline]
  13. Larroche C, Mouthon L: Pathogenesis of hemophagocytic syndrome (HPS). Autoimmun Rev3 :69 –75,2004[CrossRef][Medline]
  14. Thaunat O, Delahousse M, Fakhouri F, Martinez F, Stephan JL, Noel LH, Karras A: Nephrotic syndrome associated with hemophagocytic syndrome. Kidney Int69 :1892 –1898,2006[CrossRef][Medline]
  15. Soos TJ, Sims TN, Barisoni L, Lin K, Littman DR, Dustin ML, Nelson PJ: CX3CR1+ interstitial dendritic cells form a contiguous network throughout the entire kidney. Kidney Int70 :591 –596,2006[Medline]
  16. Granucci F, Foti M, Ricciardi-Castagnoli P: Dendritic cell biology. Adv Immunol88 :193 –233,2005[CrossRef][Medline]
  17. Adams S, O'Neill DW, Bhardwaj N: Recent advances in dendritic cell biology. J Clin Immunol25 :177 –188,2005[Medline]
  18. Sozzani S: Dendritic cell trafficking: More than just chemokines. Cytokine Growth Factor Rev16 :581 –592,2005[CrossRef][Medline]
  19. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Pare PD: The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med350 :2645 –2653,2004[Abstract/Free Full Text]
  20. Randhawa P, Brennan DC: BK virus infection in transplant recipients: An overview and update. Am J Transplant6 :2000 –2005,2006[CrossRef][Medline]
  21. Drachenberg CB, Papadimitriou JC: Polyomavirus-associated nephropathy: Update in diagnosis. Transpl Infect Dis8 :68 –75,2006[CrossRef][Medline]
  22. Drachenberg CB, Papadimitriou JC, Mann D, Hirsch HH, Wali R, Ramos E: Negative impact of human leukocyte antigen matching in the outcome of polyomavirus nephropathy. Transplantation80 :276 –278,2005[CrossRef][Medline]
  23. Daugas E, Plaisier E, Boffa J, Guiard-Schmid JB, Pacanowski J, Mougenot B, Ronco P: Acute renal failure associated with immune restoration inflammatory syndrome. Nat Clin Pract Nephrol2 :594 –598,2006[CrossRef][Medline]




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