Abstract
Initiation of an innate and/or adaptive immune response involves the coordinated function of multiple cells as well as numerous signaling and effector molecules, all supported by a stromal framework that may provide additional immunomodulatory signals. Signaling and effector molecules of the immune system have been the focus of intense investigation in recent decades, resulting in a massive accumulation of relevant information. The aim of this chapter is to provide an overview of the major groups of signaling and effector molecules, and to provide a general framework whereby these molecules function in the initiation, modulation, and dissolution of immune responses. Particular interest is given to those molecules and processes that represent targets for possible pharmacological intervention.
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References
Aggarwal S, Xie MH, Maruoka M, Foster J, Gurney AL (2001) Acinar cells of the pancreas are a target of interleukin-22. J Interferon Cytokine Res 21(12):1047–1053. doi:10.1089/107999001317205178
Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285(5428):727–729
Behnsen J, Jellbauer S, Wong CP, Edwards RA, George MD, Ouyang W, Raffatellu M (2014) The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity 40(2):262–273. doi:10.1016/j.immuni.2014.01.003
Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, Shirakawa AK, Farber JM, Segal DM, Oppenheim JJ, Kwak LW (2002) Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 298(5595):1025–1029. doi:10.1126/science.1075565
Blumberg H, Conklin D, Xu WF, Grossmann A, Brender T, Carollo S, Eagan M, Foster D, Haldeman BA, Hammond A, Haugen H, Jelinek L, Kelly JD, Madden K, Maurer MF, Parrish-Novak J, Prunkard D, Sexson S, Sprecher C, Waggie K, West J, Whitmore TE, Yao L, Kuechle MK, Dale BA, Chandrasekher YA (2001) Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104(1):9–19
Boruchov AM, Heller G, Veri MC, Bonvini E, Ravetch JV, Young JW (2005) Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J Clin Invest 115(10):2914–2923. doi:10.1172/JCI24772
Braud V, Jones EY, McMichael A (1997) The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9. Eur J Immunol 27(5):1164–1169. doi:10.1002/eji.1830270517
Braud VM, Allan DS, O’Callaghan CA, Soderstrom K, D’Andrea A, Ogg GS, Lazetic S, Young NT, Bell JI, Phillips JH, Lanier LL, McMichael AJ (1998) HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391(6669):795–799. doi:10.1038/35869
Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3(3):238–250. doi:10.1038/nrmicro1098
Brooks AG, Posch PE, Scorzelli CJ, Borrego F, Coligan JE (1997) NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor. J Exp Med 185(4):795–800
Brubaker SW, Bonham KS, Zanoni I, Kagan JC (2015) Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 33:257–290. doi:10.1146/annurev-immunol-032414-112240
Bruhns P, Jonsson F (2015) Mouse and human FcR effector functions. Immunol Rev 268(1):25–51. doi:10.1111/imr.12350
Call ME, Wucherpfennig KW (2007) Common themes in the assembly and architecture of activating immune receptors. Nat Rev Immunol 7(11):841–850. doi:10.1038/nri2186
Campbell KS, Purdy AK (2011) Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology 132(3):315–325. doi:10.1111/j.1365-2567.2010.03398.x
Cannons JL, Tangye SG, Schwartzberg PL (2011) SLAM family receptors and SAP adaptors in immunity. Annu Rev Immunol 29:665–705. doi:10.1146/annurev-immunol-030409-101302
Carayannopoulos LN, Naidenko OV, Fremont DH, Yokoyama WM (2002) Cutting edge: murine UL16-binding protein-like transcript 1: a newly described transcript encoding a high-affinity ligand for murine NKG2D. J Immunol 169(8):4079–4083
Cerwenka A, Bakker AB, McClanahan T, Wagner J, Wu J, Phillips JH, Lanier LL (2000) Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity 12(6):721–727
Chang C, Dietrich J, Harpur AG, Lindquist JA, Haude A, Loke YW, King A, Colonna M, Trowsdale J, Wilson MJ (1999) Cutting edge: KAP10, a novel transmembrane adapter protein genetically linked to DAP12 but with unique signaling properties. J Immunol 163(9):4651–4654
Chen L, Flies DB (2013) Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 13(4):227–242. doi:10.1038/nri3405
Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL (2007) Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med 13(7):851–856. doi:10.1038/nm1603
Chow KT, Gale M Jr (2015) SnapShot: interferon signaling. Cell 163(7):1808–1808 . doi:10.1016/j.cell.2015.12.008e1801
Clynes R, Maizes JS, Guinamard R, Ono M, Takai T, Ravetch JV (1999) Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors. J Exp Med 189(1):179–185
Coeshott C, Ohnemus C, Pilyavskaya A, Ross S, Wieczorek M, Kroona H, Leimer AH, Cheronis J (1999) Converting enzyme-independent release of tumor necrosis factor alpha and IL-1beta from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3. Proc Natl Acad Sci U S A 96(11):6261–6266
Cohen I, Rider P, Carmi Y, Braiman A, Dotan S, White MR, Voronov E, Martin MU, Dinarello CA, Apte RN (2010) Differential release of chromatin-bound IL-1alpha discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc Natl Acad Sci U S A 107(6):2574–2579. doi:10.1073/pnas.0915018107
Cole JL, Housley GA Jr, Dykman TR, MacDermott RP, Atkinson JP (1985) Identification of an additional class of C3-binding membrane proteins of human peripheral blood leukocytes and cell lines. Proc Natl Acad Sci U S A 82(3):859–863
Colobran R, Pedrosa E, Carretero-Iglesia L, Juan M (2010) Copy number variation in chemokine superfamily: the complex scene of CCL3L-CCL4L genes in health and disease. Clin Exp Immunol 162(1):41–52. doi:10.1111/j.1365-2249.2010.04224.x
Cosman D, Mullberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, Kubin M, Chalupny NJ (2001) ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14(2):123–133
Croft M, Benedict CA, Ware CF (2013) Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12(2):147–168. doi:10.1038/nrd3930
Daeron M (2014) Fc receptors as adaptive immunoreceptors. Curr Top Microbiol Immunol 382:131–164. doi:10.1007/978-3-319-07911-0_7
Dalton DK, Pitts-Meek S, Keshav S, Figari IS, Bradley A, Stewart TA (1993) Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science 259(5102):1739–1742
Dawson TC, Lentsch AB, Wang Z, Cowhig JE, Rot A, Maeda N, Peiper SC (2000) Exaggerated response to endotoxin in mice lacking the Duffy antigen/receptor for chemokines (DARC). Blood 96(5):1681–1684
Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT (1996) C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271(5247):348–350
DeVries ME, Kelvin AA, Xu L, Ran L, Robinson J, Kelvin DJ (2006) Defining the origins and evolution of the chemokine/chemokine receptor system. J Immunol 176(1):401–415
Diefenbach A, Tomasello E, Lucas M, Jamieson AM, Hsia JK, Vivier E, Raulet DH (2002) Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nat Immunol 3(12):1142–1149. doi:10.1038/ni858
Dubois S, Mariner J, Waldmann TA, Tagaya Y (2002) IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. Immunity 17(5):537–547
Dudakov JA, Hanash AM, van den Brink MR (2015) Interleukin-22: immunobiology and pathology. Annu Rev Immunol 33:747–785. doi:10.1146/annurev-immunol-032414-112123
Elliott JM, Yokoyama WM (2011) Unifying concepts of MHC-dependent natural killer cell education. Trends Immunol 32(8):364–372. doi:10.1016/j.it.2011.06.001
Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S, Cianfarani F, Odorisio T, Traidl-Hoffmann C, Behrendt H, Durham SR, Schmidt-Weber CB, Cavani A (2009) Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest 119(12):3573–3585. doi:10.1172/JCI40202
Fantuzzi G, Ku G, Harding MW, Livingston DJ, Sipe JD, Kuida K, Flavell RA, Dinarello CA (1997a) Response to local inflammation of IL-1 beta-converting enzyme- deficient mice. J Immunol 158(4):1818–1824
Fantuzzi G, Sacco S, Ghezzi P, Dinarello CA (1997b) Physiological and cytokine responses in IL-1 beta-deficient mice after zymosan-induced inflammation. Am J Physiol 273(1 Pt 2):R400–R406
Fernandes-Alnemri T, Yu JW, Juliana C, Solorzano L, Kang S, Wu J, Datta P, McCormick M, Huang L, McDermott E, Eisenlohr L, Landel CP, Alnemri ES (2010) The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nat Immunol 11(5):385–393. doi:10.1038/ni.1859
Fishelson Z, Pangburn MK, Muller-Eberhard HJ (1984) Characterization of the initial C3 convertase of the alternative pathway of human complement. J Immunol 132(3):1430–1434
Ford ML, Adams AB, Pearson TC (2014) Targeting co-stimulatory pathways: transplantation and autoimmunity. Nat Rev Nephrol 10(1):14–24. doi:10.1038/nrneph.2013.183
Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E, Lipp M (1999) CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99(1):23–33
Frank DN, Robertson CE, Hamm CM, Kpadeh Z, Zhang T, Chen H, Zhu W, Sartor RB, Boedeker EC, Harpaz N, Pace NR, Li E (2011) Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases. Inflamm Bowel Dis 17(1):179–184. doi:10.1002/ibd.21339
Freigang S, Ampenberger F, Weiss A, Kanneganti TD, Iwakura Y, Hersberger M, Kopf M (2013) Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1alpha and sterile vascular inflammation in atherosclerosis. Nat Immunol 14(10):1045–1053. doi:10.1038/ni.2704
Fruh K, Yang Y (1999) Antigen presentation by MHC class I and its regulation by interferon gamma. Curr Opin Immunol 11(1):76–81
Fujita T, Inoue T, Ogawa K, Iida K, Tamura N (1987) The mechanism of action of decay-accelerating factor (DAF). DAF inhibits the assembly of C3 convertases by dissociating C2a and Bb. J Exp Med 166(5):1221–1228
Griffith JW, Sokol CL, Luster AD (2014) Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol 32:659–702. doi:10.1146/annurev-immunol-032713-120145
Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T (1996) Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci U S A 93(22):12445–12450
Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, Knoblaugh S, Cado D, Greenberg NM, Raulet DH (2008) NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28(4):571–580. doi:10.1016/j.immuni.2008.02.016
Guma M, Ronacher L, Liu-Bryan R, Takai S, Karin M, Corr M (2009) Caspase 1-independent activation of interleukin-1beta in neutrophil-predominant inflammation. Arthritis Rheum 60(12):3642–3650. doi:10.1002/art.24959
Guo RF, Ward PA (2005) Role of C5a in inflammatory responses. Annu Rev Immunol 23:821–852. doi:10.1146/annurev.immunol.23.021704.115835
Ha H, Han D, Choi Y (2009) TRAF-mediated TNFR-family signaling. In: John E Coligan et al. (eds) Current protocols in immunology (Chapter 11:Unit11 19D). doi:10.1002/0471142735.im1109ds87
Hayden MS, Ghosh S (2012) NF-kappaB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev 26(3):203–234. doi:10.1101/gad.183434.111
Herzog C, Haun RS, Kaushal V, Mayeux PR, Shah SV, Kaushal GP (2009) Meprin A and meprin alpha generate biologically functional IL-1beta from pro-IL-1beta. Biochem Biophys Res Commun 379(4):904–908. doi:10.1016/j.bbrc.2008.12.161
Hoesel B, Schmid JA (2013) The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer 12:86. doi:10.1186/1476-4598-12-86
Hogarth PM (2002) Fc receptors are major mediators of antibody based inflammation in autoimmunity. Curr Opin Immunol 14(6):798–802
Holers VM (2014) Complement and its receptors: new insights into human disease. Annu Rev Immunol 32:433–459. doi:10.1146/annurev-immunol-032713-120154
Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, Vilcek J, Zinkernagel RM, Aguet M (1993) Immune response in mice that lack the interferon-gamma receptor. Science 259(5102):1742–1745
Ichinohe T, Lee HK, Ogura Y, Flavell R, Iwasaki A (2009) Inflammasome recognition of influenza virus is essential for adaptive immune responses. J Exp Med 206(1):79–87. doi:10.1084/jem.20081667
Janeway CA Jr (1989) Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 54(Pt 1):1–13
John B, Rajagopal D, Pashine A, Rath S, George A, Bal V (2002) Role of IL-12-independent and IL-12-dependent pathways in regulating generation of the IFN-gamma component of T cell responses to Salmonella typhimurium. J Immunol 169(5):2545–2552
Joosten LA, Netea MG, Fantuzzi G, Koenders MI, Helsen MM, Sparrer H, Pham CT, van der Meer JW, Dinarello CA, van den Berg WB (2009) Inflammatory arthritis in caspase 1 gene-deficient mice: contribution of proteinase 3 to caspase 1-independent production of bioactive interleukin-1beta. Arthritis Rheum 60(12):3651–3662. doi:10.1002/art.25006
Kahlenberg JM, Kaplan MJ (2013) Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease. J Immunol 191(10):4895–4901. doi:10.4049/jimmunol.1302005
Kaiser BK, Pizarro JC, Kerns J, Strong RK (2008) Structural basis for NKG2A/CD94 recognition of HLA-E. Proc Natl Acad Sci U S A 105(18):6696–6701. doi:10.1073/pnas.0802736105
Kamada N, Chen GY, Inohara N, Nunez G (2013) Control of pathogens and pathobionts by the gut microbiota. Nat Immunol 14(7):685–690. doi:10.1038/ni.2608
Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD (1998) Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A 95(13):7556–7561
Kim YU, Kinoshita T, Molina H, Hourcade D, Seya T, Wagner LM, Holers VM (1995) Mouse complement regulatory protein Crry/p65 uses the specific mechanisms of both human decay-accelerating factor and membrane cofactor protein. J Exp Med 181(1):151–159
Klett J, Reeves J, Oberhauser N, Perez-Regidor L, Martin-Santamaria S (2014) Modulation of toll-like receptor 4. Insights from x-ray crystallography and molecular modeling. Curr Top Med Chem 14(23):2672–2683
Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Kohl J (2009) The role of the anaphylatoxins in health and disease. Mol Immunol 46(14):2753–2766. doi:10.1016/j.molimm.2009.04.027
Kone-Paut I, Piram M (2012) Targeting interleukin-1beta in CAPS (cryopyrin-associated periodic) syndromes: what did we learn? Autoimmun Rev 12(1):77–80. doi:10.1016/j.autrev.2012.07.026
Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, Langer JA, Sheikh F, Dickensheets H, Donnelly RP (2003) IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol 4(1):69–77. doi:10.1038/ni875
Kruse PH, Matta J, Ugolini S, Vivier E (2014) Natural cytotoxicity receptors and their ligands. Immunol Cell Biol 92(3):221–229. doi:10.1038/icb.2013.98
Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75(2):263–274
Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, Tripp RA, Walsh EE, Freeman MW, Golenbock DT, Anderson LJ, Finberg RW (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 1(5):398–401. doi:10.1038/80833
Lanier LL, Corliss B, Wu J, Phillips JH (1998) Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity 8(6):693–701
Lara-Tejero M, Sutterwala FS, Ogura Y, Grant EP, Bertin J, Coyle AJ, Flavell RA, Galan JE (2006) Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J Exp Med 203(6):1407–1412. doi:10.1084/jem.20060206
Lazear HM, Nice TJ, Diamond MS (2015) Interferon-lambda: Immune Functions at Barrier Surfaces and Beyond. Immunity 43(1):15–28. doi:10.1016/j.immuni.2015.07.001
Li P, Morris DL, Willcox BE, Steinle A, Spies T, Strong RK (2001) Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nat Immunol 2(5):443–451. doi:10.1038/87757
Li J, Kim SG, Blenis J (2014) Rapamycin: one drug, many effects. Cell Metab 19(3):373–379. doi:10.1016/j.cmet.2014.01.001
Liechty KW, Kim HB, Adzick NS, Crombleholme TM (2000) Fetal wound repair results in scar formation in interleukin-10-deficient mice in a syngeneic murine model of scarless fetal wound repair. J Pediatr Surg 35(6):866–872 . doi:10.1053/jpsu.2000.6868discussion 872-863
Limon JJ, Fruman DA (2012) Akt and mTOR in B Cell Activation and Differentiation. Front Immunol 3:228. doi:10.3389/fimmu.2012.00228
Liu W, Sohn HW, Tolar P, Pierce SK (2010) It’s all about change: the antigen-driven initiation of B-cell receptor signaling. Cold Spring Harb Perspect Biol 2(7):a002295. doi:10.1101/cshperspect.a002295
Liu J, Xiao Z, Ko HL, Shen M, Ren EC (2014) Activating killer cell immunoglobulin-like receptor 2DS2 binds to HLA-A*11. Proc Natl Acad Sci U S A 111(7):2662–2667. doi:10.1073/pnas.1322052111
Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104(4):487–501
Makou E, Herbert AP, Barlow PN (2013) Functional anatomy of complement factor H. Biochemistry 52(23):3949–3962. doi:10.1021/bi4003452
Malek TR, Castro I (2010) Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 33(2):153–165. doi:10.1016/j.immuni.2010.08.004
Mansour SC, Pena OM, Hancock RE (2014) Host defense peptides: front-line immunomodulators. Trends Immunol 35(9):443–450. doi:10.1016/j.it.2014.07.004
Mariathasan S, Weiss DS, Dixit VM, Monack DM (2005) Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis. J Exp Med 202(8):1043–1049. doi:10.1084/jem.20050977
Masopust D, Schenkel JM (2013) The integration of T cell migration, differentiation and function. Nat Rev Immunol 13(5):309–320. doi:10.1038/nri3442
Mathern DR, Heeger PS (2015) Molecules great and small: the complement system. Clin J Am Soc Nephrol 10(9):1636–1650. doi:10.2215/CJN.06230614
McGaha TL, Sorrentino B, Ravetch JV (2005) Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 307(5709):590–593. doi:10.1126/science.1105160
Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila toll protein signals activation of adaptive immunity. Nature 388(6640):394–397. doi:10.1038/41131
Mencacci A, Bacci A, Cenci E, Montagnoli C, Fiorucci S, Casagrande A, Flavell RA, Bistoni F, Romani L (2000) Interleukin 18 restores defective Th1 immunity to Candida albicans in caspase 1-deficient mice. Infect Immun 68(9):5126–5131
Migone TS, Rodig S, Cacalano NA, Berg M, Schreiber RD, Leonard WJ (1998) Functional cooperation of the interleukin-2 receptor beta chain and Jak1 in phosphatidylinositol 3-kinase recruitment and phosphorylation. Mol Cell Biol 18(11):6416–6422
Miknis ZJ, Magracheva E, Li W, Zdanov A, Kotenko SV, Wlodawer A (2010) Crystal structure of human interferon-lambda1 in complex with its high-affinity receptor interferon-lambdaR1. J Mol Biol 404(4):650–664. doi:10.1016/j.jmb.2010.09.068
Moore KW, de Waal MR, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765. doi:10.1146/annurev.immunol.19.1.683
Morgan BP, Berg CW, Harris CL (2005) “Homologous restriction” in complement lysis: roles of membrane complement regulators. Xenotransplantation 12(4):258–265. doi:10.1111/j.1399-3089.2005.00237.x
Mouchess ML, Arpaia N, Souza G, Barbalat R, Ewald SE, Lau L, Barton GM (2011) Transmembrane mutations in Toll-like receptor 9 bypass the requirement for ectodomain proteolysis and induce fatal inflammation. Immunity 35(5):721–732. doi:10.1016/j.immuni.2011.10.009
Muta T, Kurosaki T, Misulovin Z, Sanchez M, Nussenzweig MC, Ravetch JV (1994) A 13-amino-acid motif in the cytoplasmic domain of Fc gamma RIIB modulates B-cell receptor signalling. Nature 369(6478):340. doi:10.1038/369340a0
Napetschnig J, Wu H (2013) Molecular basis of NF-kappaB signaling. Annu Rev Biophys 42:443–468. doi:10.1146/annurev-biophys-083012-130338
Navid F, Boniotto M, Walker C, Ahrens K, Proksch E, Sparwasser T, Muller W, Schwarz T, Schwarz A (2012) Induction of regulatory T cells by a murine beta-defensin. J Immunol 188(2):735–743. doi:10.4049/jimmunol.1100452
Nijnik A, Hancock RE (2009) The roles of cathelicidin LL-37 in immune defences and novel clinical applications. Curr Opin Hematol 16(1):41–47
Nomiyama H, Osada N, Yoshie O (2010) The evolution of mammalian chemokine genes. Cytokine Growth Factor Rev 21(4):253–262. doi:10.1016/j.cytogfr.2010.03.004
O’Callaghan CA, Cerwenka A, Willcox BE, Lanier LL, Bjorkman PJ (2001) Molecular competition for NKG2D: H60 and RAE1 compete unequally for NKG2D with dominance of H60. Immunity 15(2):201–211
O’Connor GM, Vivian JP, Gostick E, Pymm P, Lafont BA, Price DA, Rossjohn J, Brooks AG, McVicar DW (2015) Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1. J Virol 89(10):5213–5221. doi:10.1128/JVI.03586-14
Ogasawara K, Benjamin J, Takaki R, Phillips JH, Lanier LL (2005) Function of NKG2D in natural killer cell-mediated rejection of mouse bone marrow grafts. Nat Immunol 6(9):938–945. doi:10.1038/ni1236
Omoto Y, Tokime K, Yamanaka K, Habe K, Morioka T, Kurokawa I, Tsutsui H, Yamanishi K, Nakanishi K, Mizutani H (2006) Human mast cell chymase cleaves pro-IL-18 and generates a novel and biologically active IL-18 fragment. J Immunol 177(12):8315–8319
Paul, W.E., Fundamental immunology. 2013, Wolters Kluwer Health/Lippincott Williams & Wilkins,: Philadelphia. p. 1 online resource (xviii, 1283 p.)
Paulmann M, Arnold T, Linke D, Ozdirekcan S, Kopp A, Gutsmann T, Kalbacher H, Wanke I, Schuenemann VJ, Habeck M, Burck J, Ulrich AS, Schittek B (2012) Structure-activity analysis of the dermcidin-derived peptide DCD-1L, an anionic antimicrobial peptide present in human sweat. J Biol Chem 287(11):8434–8443. doi:10.1074/jbc.M111.332270
Pegram HJ, Andrews DM, Smyth MJ, Darcy PK, Kershaw MH (2011) Activating and inhibitory receptors of natural killer cells. Immunol Cell Biol 89(2):216–224. doi:10.1038/icb.2010.78
Pepys MB (1974) Role of complement in induction of antibody production in vivo. Effect of cobra factor and other C3-reactive agents on thymus-dependent and thymus-independent antibody responses. J Exp Med 140(1):126–145
Pestka S, Krause CD, Walter MR (2004) Interferons, interferon-like cytokines, and their receptors. Immunol Rev 202:8–32. doi:10.1111/j.0105-2896.2004.00204.x
Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282(5396):2085–2088
Pruenster M, Mudde L, Bombosi P, Dimitrova S, Zsak M, Middleton J, Richmond A, Graham GJ, Segerer S, Nibbs RJ, Rot A (2009) The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity. Nat Immunol 10(1):101–108. doi:10.1038/ni.1675
Rahim MM, Makrigiannis AP (2015) Ly49 receptors: evolution, genetic diversity, and impact on immunity. Immunol Rev 267(1):137–147. doi:10.1111/imr.12318
Raupach B, Peuschel SK, Monack DM, Zychlinsky A (2006) Caspase-1-mediated activation of interleukin-1beta (IL-1beta) and IL-18 contributes to innate immune defenses against Salmonella enterica serovar Typhimurium infection. Infect Immun 74(8):4922–4926. doi:10.1128/IAI.00417-06
Ravetch JV, Nimmerjahn F (2013) Fc receptors and their role in immune regulation and inflammation. In: Paul WE (ed) Fundamental immunology, 7th edn, vol 24. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia, pp. 583–605
Rider P, Carmi Y, Guttman O, Braiman A, Cohen I, Voronov E, White MR, Dinarello CA, Apte RN (2011) IL-1alpha and IL-1beta recruit different myeloid cells and promote different stages of sterile inflammation. J Immunol 187(9):4835–4843. doi:10.4049/jimmunol.1102048
Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD, Hood LE, Aderem A (2005) The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci U S A 102(27):9577–9582. doi:10.1073/pnas.0502272102
Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SG (2015) The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Res 43(Database issue):D423–D431. doi:10.1093/nar/gku1161
Rosenzweig SD, Holland SM (2005) Defects in the interferon-gamma and interleukin-12 pathways. Immunol Rev 203:38–47. doi:10.1111/j.0105-2896.2005.00227.x
Rutz S, Wang X, Ouyang W (2014) The IL-20 subfamily of cytokines--from host defence to tissue homeostasis. Nat Rev Immunol 14(12):783–795. doi:10.1038/nri3766
Sadler AJ, Williams BR (2008) Interferon-inducible antiviral effectors. Nat Rev Immunol 8(7):559–568. doi:10.1038/nri2314
Scheller J, Chalaris A, Garbers C, Rose-John S (2011) ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol 32(8):380–387. doi:10.1016/j.it.2011.05.005
Schoenborn JR, Wilson CB (2007) Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41–101. doi:10.1016/S0065-2776(07)96002-2
Scott LJ (2014) Etanercept: a review of its use in autoimmune inflammatory diseases. Drugs 74(12):1379–1410. doi:10.1007/s40265-014-0258-9
Sharma P, Allison JP (2015) The future of immune checkpoint therapy. Science 348(6230):56–61. doi:10.1126/science.aaa8172
Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J, Ostrander C, Dong D, Shin J, Presnell S, Fox B, Haldeman B, Cooper E, Taft D, Gilbert T, Grant FJ, Tackett M, Krivan W, McKnight G, Clegg C, Foster D, Klucher KM (2003) IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol 4(1):63–68. doi:10.1038/ni873
Shimobayashi M, Hall MN (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15(3):155–162. doi:10.1038/nrm3757
Shinkai K, McCalmont TH, Leslie KS (2008) Cryopyrin-associated periodic syndromes and autoinflammation. Clin Exp Dermatol 33(1):1–9. doi:10.1111/j.1365-2230.2007.02540.x
Simonian PL, Wehrmann F, Roark CL, Born WK, O’Brien RL, Fontenot AP (2010) Gammadelta T cells protect against lung fibrosis via IL-22. J Exp Med 207(10):2239–2253. doi:10.1084/jem.20100061
Sims JE, Nicklin MJ, Bazan JF, Barton JL, Busfield SJ, Ford JE, Kastelein RA, Kumar S, Lin H, Mulero JJ, Pan J, Pan Y, Smith DE, Young PR (2001) A new nomenclature for IL-1-family genes. Trends Immunol 22(10):536–537
Sonnenberg GF, Monticelli LA, Alenghat T, Fung TC, Hutnick NA, Kunisawa J, Shibata N, Grunberg S, Sinha R, Zahm AM, Tardif MR, Sathaliyawala T, Kubota M, Farber DL, Collman RG, Shaked A, Fouser LA, Weiner DB, Tessier PA, Friedman JR, Kiyono H, Bushman FD, Chang KM, Artis D (2012) Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336(6086):1321–1325. doi:10.1126/science.1222551
Spitzer D, Mitchell LM, Atkinson JP, Hourcade DE (2007) Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly. J Immunol 179(4):2600–2608
Stapleton NM, Einarsdottir HK, Stemerding AM, Vidarsson G (2015) The multiple facets of FcRn in immunity. Immunol Rev 268(1):253–268. doi:10.1111/imr.12331
Stewart CA, Laugier-Anfossi F, Vely F, Saulquin X, Riedmuller J, Tisserant A, Gauthier L, Romagne F, Ferracci G, Arosa FA, Moretta A, Sun PD, Ugolini S, Vivier E (2005) Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors. Proc Natl Acad Sci U S A 102(37):13224–13229. doi:10.1073/pnas.0503594102
Stienstra R, Tack CJ, Kanneganti TD, Joosten LA, Netea MG (2012) The inflammasome puts obesity in the danger zone. Cell Metab 15(1):10–18. doi:10.1016/j.cmet.2011.10.011
Strainic MG, Liu J, Huang D, An F, Lalli PN, Muqim N, Shapiro VS, Dubyak GR, Heeger PS, Medof ME (2008) Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity 28(3):425–435. doi:10.1016/j.immuni.2008.02.001
Sugawara S, Uehara A, Nochi T, Yamaguchi T, Ueda H, Sugiyama A, Hanzawa K, Kumagai K, Okamura H, Takada H (2001) Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cells. J Immunol 167(11):6568–6575
Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA (2007) Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J Exp Med 204(13):3235–3245. doi:10.1084/jem.20071239
Sziksz E, Pap D, Lippai R, Beres NJ, Fekete A, Szabo AJ, Vannay A (2015) Fibrosis related inflammatory mediators: role of the IL-10 cytokine family. Mediators Inflamm 2015:764641. doi:10.1155/2015/764641
Tai X, Van Laethem F, Sharpe AH, Singer A (2007) Induction of autoimmune disease in CTLA-4-/- mice depends on a specific CD28 motif that is required for in vivo costimulation. Proc Natl Acad Sci U S A 104(34):13756–13761. doi:10.1073/pnas.0706509104
Takai S, Kasama M, Yamada K, Kai N, Hirayama N, Namiki H, Taniyama T (1994) Human high-affinity Fc gamma RI (CD64) gene mapped to chromosome 1q21.2-q21.3 by fluorescence in situ hybridization. Hum Genet 93(1):13–15
Thielens A, Vivier E, Romagne F (2012) NK cell MHC class I specific receptors (KIR): from biology to clinical intervention. Curr Opin Immunol 24(2):239–245. doi:10.1016/j.coi.2012.01.001
Thome M, Charton JE, Pelzer C, Hailfinger S (2010) Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harb Perspect Biol 2(9):a003004. doi:10.1101/cshperspect.a003004
Tough DF (2012) Modulation of T-cell function by type I interferon. Immunol Cell Biol 90(5):492–497. doi:10.1038/icb.2012.7
Tzeng SJ, Bolland S, Inabe K, Kurosaki T, Pierce SK (2005) The B cell inhibitory Fc receptor triggers apoptosis by a novel c-Abl family kinase-dependent pathway. J Biol Chem 280(42):35247–35254. doi:10.1074/jbc.M505308200
Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H (2002) HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem 277(17):15107–15112. doi:10.1074/jbc.M111204200
Valmiki MG, Ramos JW (2009) Death effector domain-containing proteins. Cell Mol Life Sci 66(5):814–830. doi:10.1007/s00018-008-8489-0
Vance RE, Jamieson AM, Raulet DH (1999) Recognition of the class Ib molecule Qa-1(b) by putative activating receptors CD94/NKG2C and CD94/NKG2E on mouse natural killer cells. J Exp Med 190(12):1801–1812
Vincent FB, Saulep-Easton D, Figgett WA, Fairfax KA, Mackay F (2013) The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity. Cytokine Growth Factor Rev 24(3):203–215. doi:10.1016/j.cytogfr.2013.04.003
Volkmann ER, Chang YL, Barroso N, Furst DE, Clements PP, Gorn AH, Roth BE, Conklin JL, Getzug T, Borneman J, McGovern DP, Tong M, Jacobs JP, Braun J (2016) Systemic sclerosis is associated with a unique colonic microbial consortium. Arthritis Rheumatol. doi:10.1002/art.39572
Wang H, Coligan JE, Morse HC 3rd (2016) Emerging functions of natural IgM and its Fc receptor FCMR in immune homeostasis. Front Immunol 7:99. doi:10.3389/fimmu.2016.00099
Ware CF (2005) Network communications: lymphotoxins, LIGHT, and TNF. Annu Rev Immunol 23:787–819. doi:10.1146/annurev.immunol.23.021704.115719
Ware CF (2013) Tumor necrosis factor-related cytokines in immunity. In: Paul WE (ed) Fundamental immunology, 7th edn, vol 24. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia, pp. 659–680
Wills-Karp M, Finkelman FD (2008) Untangling the complex web of IL-4- and IL-13-mediated signaling pathways. Sci Signal 1(51):pe55. doi:10.1126/scisignal.1.51.pe55
Wu J, Song Y, Bakker AB, Bauer S, Spies T, Lanier LL, Phillips JH (1999) An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285(5428):730–732
Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, Anderson M, Schroder JM, Wang JM, Howard OM, Oppenheim JJ (1999) Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286(5439):525–528
Yoshimura T (2015) Discovery of IL-8/CXCL8 (The story from Frederick). Front Immunol 6:278. doi:10.3389/fimmu.2015.00278
Zeeuwen PL, Kleerebezem M, Timmerman HM, Schalkwijk J (2013) Microbiome and skin diseases. Curr Opin Allergy Clin Immunol 13(5):514–520. doi:10.1097/ACI.0b013e328364ebeb
Zenewicz LA, Yin X, Wang G, Elinav E, Hao L, Zhao L, Flavell RA (2013) IL-22 deficiency alters colonic microbiota to be transmissible and colitogenic. J Immunol 190(10):5306–5312. doi:10.4049/jimmunol.1300016
Zhang LJ, Guerrero-Juarez CF, Hata T, Bapat SP, Ramos R, Plikus MV, Gallo RL (2015) Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science 347(6217):67–71. doi:10.1126/science.1260972
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Milone, M.C. (2017). Signaling and Effector Molecules in Immunity. In: Parker, G. (eds) Immunopathology in Toxicology and Drug Development. Molecular and Integrative Toxicology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-47377-2_3
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