Innate Immunity and Dendritic Cells in Kidney Disease and the Nobel Prize

EDITORIALS www.jasn.org

Innate Immunity and Dendritic nately, Janeway died in 2003 and was no longer eligible to receive the prize. Cells in Kidney Disease and the The discoveries of Hoffmann and Janeway alerted immunologists all over the world to the possibility of a new signal- Nobel Prize ing pathway, and in 1998, Bruce Beutler and colleagues at the

† Howard Hughes Medical Institute in Dallas first identified Hans-Joachim Anders* and Christian Kurts TLR4 as recognizing bacterial endotoxin.5 Beutler’s approach *Medizinische Poliklinik, Klinikum der Universita¨t Mu¨ nchen-LMU, Campus Innenstadt, Munich, Germany; and †Institutes of Molecu- was as clever as simple. He took advantage of two well-known lar Medicine and Experimental Immunology (IMMEI), University lipopolysaccharide-resistant mouse strains to map the newly Clinic of Bonn, Bonn, Germany discovered loci of the Toll genes. In doing so, he realized that

J Am Soc Nephrol 22: ●●●–●●●, 2011. endotoxin resistance was linked to loss-of-function muta- doi: 10.1681/ASN.2011100975 tions in the Tlr4 gene. Two more circumstances encouraged researchers from many disciplines to rush into this new area of science, pro- On December 10, 2011, the Nobel Prize for Physiology or ducing more than 18,000 related publications within the last Medicine will honor the work of Jules Hoffmann, Bruce 15 years: first, Tlr4 mutant mice as well as suitable immuno- Beutler, and Ralph Steinman for their landmark discoveries stimulatory compounds, now discovered as agonists for dis- in the field of immunology. This recognition brings wide at- tinct TLRs, became available at relatively low costs to every- tention to a paradigm shift in understanding how multicel- one, and second, Shizou Akira, in Osaka, produced null mice lular organisms sense and interpret their external and inter- for most TLRs and many other related genes, and did not nal environments in maintaining homeostasis or initiating hesitate to share them with collaborators and competitors. host defense in case of pathogen danger and infection.1,2 Un- His generous attitude enormously pushed the field forward raveling these fundamental processes not only allowed a bet- in short time.6 But what has this all to do with the kidney? ter understanding of how pathology develops but also offered The kidney is a sterile organ but well equipped with TLRs novel possibilities for disease prevention and cure, including and other innate pattern recognition receptors ready to signal kidney diseases. danger upon the entry of pathogens. For example, in infective It was the previous Nobel laureate, Christiane Nu¨sslein- pyelonephritis, ascending uropathogenic Escherichia coli Volhard, that unexpectedly set the stage for a piece of this provide endotoxin from their bacterial wall to engage TLR4 year award. Nu¨sslein-Volhard had induced random mu- on tubular epithelial cells and intrarenal dendritic cells, a tagenesis in Drosophila to search for unknown genotype- process triggering the release of cytokines and chemokines phenotype associations. In 1984, one such mutant attracted leading to renal inflammation involving the rapid recruit- her attention so much that she shouted the German word ment of neutrophils into the kidney and the tubular lumen Toll, meaning “great”. Obviously, her joy encouraged her noted on urinalysis. Tlr4 mutant mice cannot recognize bac- postdoctoral fellows to name the mutated gene as such. Dur- terial endotoxin inside the kidney; hence, uropathogenic E. ing the following decade, a few papers were published on the coli no longer induce chemokines and neutrophil recruit- role of Toll for dorsal-ventral polarity of flies. This changed ment.7 Insufficient immune recognition, however, is Janus- dramatically when Jules Hoffmann’s group in Strasbourg re- faced, and failing local pathogen control allows potentially ported in 1996 that Toll-deficient flies succumb to fungal fatal systemic spreading through immunodeficiency reminis- infection, which established a role for Toll in host defense.3 cent of urosepsis. On the other hand, lack of TLR4 prevents One year later, the Janeway Laboratory at Yale described the immunopathology such as renal abscesses in E. coli pyelone- human homologue Toll-like receptor (TLR) genes.4 Unfortu- phritis. Meanwhile, it is clear that TLRs more than guard against

Published online ahead of print. Publication date available at www.jasn.org. pathogens as a potential source of danger in tissue homeostasis. Dying cells in that environment release intracellular fac- Correspondence: Dr. Hans-Joachim Anders, Medizinische Poliklinik, Klini- kum der Universita¨t Mu¨ nchen, Campus Innenstadt, Pettenkoferstr. 8a, tors with comparable potential to trigger local inflammation 80336 Mu¨nchen, Germany. Phone: ϩ49-89-218075855; Fax: ϩ49-89- through TLRs.8 This means innate immunity not only signals 218075860; E-mail: [email protected]; or Dr. Christian pathogen entry but also monitors tissue integrity, which can Kurts, Institutes of Molecular Medicine and Experimental Immunology (IMMEI) Friedrich-Wilhelms University, Sigmund-Freud-Str. 25, 53105 be disrupted by any type of injury. Thus, renal cell necrosis Bonn, Germany. Phone: ϩ49–228-287–11050; Fax: ϩ49–228-287–11052; involves additional immunopathology by activating innate E-mail: [email protected] immunity. Numerous studies now document that too much Copyright © 2011 by the American Society of Nephrology TLR signaling causes additional renal damage in acute kidney

J Am Soc Nephrol 22: ●●●–●●●, 2011 ISSN : 1046-6673/2212-●●● 1 EDITORIALS www.jasn.org

injury and that blocking TLR signaling protects kidneys from initiated about 10 years ago.20 Since then, it has become clear inappropriate immunopathology.8 This amplification of in- that kidney dendritic cells act as sentinels against injury after jury not only involves TLRs; RIG-like helicases, the inflam- renal obstruction or ischemia/reperfusion,22 in that they sup- masome, small leucine–rich proteoglycans, and lectin recep- press unwanted intrarenal immune responses. However, in tors add to the complexity of innate pattern recognition.9–11 chronic kidney inflammation, they mature and drive progres- The other half of the 2011 Nobel Prize was awarded to the sion of renal disease.23 Notably, they also orchestrate innate late Ralph Steinman, for his discovery of dendritic cells and defenses against bacterial pyelonephritis by recruiting neutro- their unique capacity to activate and regulate adaptive immu- phils into the kidney.24 The potential of kidney dendritic cells nity.12,13 Dendritic cells are not immune effectors themselves; to affect renal inflammation makes them highly promising they instruct other immune cells, especially T lymphocytes. To therapeutic candidates. this end, dendritic cells exist in virtually all tissues as immune Only a few hours before the Nobel committee decided to sentinels. Once they sense pathogens using pattern receptors award the prize to him, Ralph Steinman lost his long battle to like TLR, they become activated and gather and carry suspi- cancer, a cancer that was treated successfully for 4 years using cious antigenic material to lymph nodes to activate T lympho- immunization protocols that depend on dendritic cell func- cytes,14 another immune cell type originally identified by tion. Although the Nobel Prize is not awarded posthumously, Jacques Miller in the early 1960s.15 These T cells in turn be- exceptions can be made, and the committee decided to do so in come activated to perform various immune responses, such as this special case. The president of the British Royal Society, Sir cytotoxicity, delayed-type hypersensitivity, or stimulating B Paul Nurse—himself a Nobel laureate—commented: “This is lymphocytes to produce antibodies. a great tragedy. Ralph Steinman’s work was ahead of its time Lymphocytes do not simply calm down after performing and he waited too long for the Nobel Prize. To die just days their immune engagement. Some of them persist as so-called before its announcement is almost too much to bear. He will be memory cells, which are capable of faster, stronger, and more remembered as one of the great immunologists of our time.” specific responses, such as when pathogens reinfect an organ- Jules Hoffman, Bruce Beutler, and Ralph Steinman were ism. Such immunologic memory is the basis of all vaccinations awarded the Nobel Prize 2011 because their discoveries ad- and of immunity in its original meaning. After the Nobel com- vance our understanding of immunopathology. It remains our mittee in 1996 had honored the complicated mechanism by task to bring this to the benefit of patients with kidney disease. which T cells are activated by dendritic cells, so-called MHC restriction,16 this year’s prize pays tribute to the immune cells that engage this mechanism, and their discoverer. ACKNOWLEDGMENTS Ralph Steinman discovered dendritic cells in 1973 as a postdoctoral fellow with Zanvil Cohn at the Rockefeller University. H.J.A. is supported by grants from the Deutsche Forschungsgemein- Dendritic cells are characterized by numerous branched pro- schaft (AN372/9-2, 10-1, 14-1, and GRK 1202). C.K. is supported by jections, the dendrites from the Greek word, Dendron, mean- grants from the Deutsche Forschungsgemeinschaft (KFO228, SFB ing tree. He described these cells as motile, continuously ex- TR57, SFB704, SFB645) and by the EU Consortium Intricate. tending, retracting, and reorienting their dendritic processes, but comparatively poor in endocytosis.17 Before the discovery of MHC restriction, this functionality appeared bewildering, DISCLOSURES and it took a long time to appreciate its exquisite suitability for None. T cell activation. Dendritic cells use small amounts of captured antigen extremely efficiently for T cell activation, taking advantage of unique intracellular mechanisms such as cross-pre- REFERENCES sentation.18 In addition to antigens from pathogens, dendritic cells also present self-antigens. The latter antigens normally 1. Matzinger P: The danger model: A renewed sense of self. Science 296: engage autoreactive T cells, which otherwise would lead to au- 301–305, 2002 toimmunity, but instead induces their apoptosis. In other 2. Medzhitov R: Origin and physiological roles of inflammation. 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Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, behind.20 Initial descriptions of renal tubulointerstitial cells Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, with morphologic characteristics of dendritic cells date back to Layton B, Beutler B: Defective LPS signaling in C3H/HeJ and C57BL/ the early 1990s,21 but studies of their functional roles were only 10ScCr mice: Mutations in Tlr4 gene. Science 282: 2085–2088, 1998

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