1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Immunology
  4. Volume 41, 2023
  5. Article

Annual Review of Immunology

Volume 41, 2023

IgE, IgE Receptors and Anti-IgE Biologics: Protein Structures and Mechanisms of Action

Abstract

The evolution of IgE in mammals added an extra layer of immune protection at body surfaces to provide a rapid and local response against antigens from the environment. The IgE immune response employs potent expulsive and inflammatory forces against local antigen provocation, at the risk of damaging host tissues and causing allergic disease. Two well-known IgE receptors, the high-affinity FcεRI and low-affinity CD23, mediate the activities of IgE. Unlike other known antibody receptors, CD23 also regulates IgE expression, maintaining IgE homeostasis. This mechanism evolved by adapting the function of the complement receptor CD21. Recent insights into the dynamic character of IgE structure, its resultant capacity for allosteric modulation, and the potential for ligand-induced dissociation have revealed previously unappreciated mechanisms for regulation of IgE and IgE complexes. We describe recent research, highlighting structural studies of the IgE network of proteins to analyze the uniquely versatile activities of IgE and anti-IgE biologics.

Keyword(s): allergy, allostery, CD23, Fc receptors, FcεRI, immunoglobulin E, immunoglobulins
Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-061020-053712
2023-04-26
2024-04-28
Loading full text...

Full text loading...

/deliver/fulltext/immunol/41/1/annurev-immunol-061020-053712.html?itemId=/content/journals/10.1146/annurev-immunol-061020-053712&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Gould HJ, Sutton BJ. 2008. IgE in allergy and asthma today. Nat. Rev. Immunol. 8:3205–17
     [Google Scholar]
  2. 2.
    Sutton BJ, Davies AM. 2015. Structure and dynamics of IgE-receptor interactions: FcεRI and CD23/FcεRII. Immunol. Rev. 268:1222–35
     [Google Scholar]
  3. 3.
    Sutton BJ, Davies AM, Bax HJ, Karagiannis SN. 2019. IgE antibodies: from structure to function and clinical translation. Antibodies 8:1E19
     [Google Scholar]
  4. 4.
    Wan T, Beavil RL, Fabiane SM, Beavil AJ, Sohi MK et al. 2002. The crystal structure of IgE Fc reveals an asymmetrically bent conformation. Nat. Immunol. 3:7681–86
     [Google Scholar]
  5. 5.
    Price NE, Price NC, Kelly SM, McDonnell JM. 2005. The key role of protein flexibility in modulating IgE interactions. J. Biol. Chem. 280:32324–30
     [Google Scholar]
  6. 6.
    Harwood NE, McDonnell JM. 2007. The intrinsic flexibility of IgE and its role in binding FcεRI. Biomed. Pharmacother. 61:161–67
     [Google Scholar]
  7. 7.
    Kinet JP. 1999. The high-affinity IgE receptor (FcεRI): from physiology to pathology. Annu. Rev. Immunol. 17:931–72
     [Google Scholar]
  8. 8.
    Garman SC, Kinet JP, Jardetzky TS. 1998. Crystal structure of the human high-affinity IgE receptor. Cell 95:7951–61
     [Google Scholar]
  9. 9.
    Mallamaci MA, Chizzonite R, Griffin M, Nettleton M, Hakimi J et al. 1993. Identification of sites on the human Fc epsilon RI alpha subunit which are involved in binding human and rat IgE. J. Biol. Chem. 268:2922076–83
     [Google Scholar]
  10. 10.
    Keown MB, Ghirlando R, Mackay GA, Sutton BJ, Gould HJ. 1997. Basis of the 1:1 stoichiometry of the high affinity receptor Fc epsilon RI-IgE complex. Eur. Biophys. J. 25:5–6471–76
     [Google Scholar]
  11. 11.
    Garman SC, Wurzburg BA, Tarchevskaya SS, Kinet JP, Jardetzky TS. 2000. Structure of the Fc fragment of human IgE bound to its high-affinity receptor FcεRIα. Nature 406:6793259–66
     [Google Scholar]
  12. 12.
    Radaev S, Sun P. 2002. Recognition of immunoglobulins by Fcγ receptors. Mol. Immunol. 38:141073–83
     [Google Scholar]
  13. 13.
    Wurzburg BA, Jardetzky TS. 2009. Conformational flexibility in immunoglobulin E-Fc3–4 revealed in multiple crystal forms. J. Mol. Biol. 393:1176–90
     [Google Scholar]
  14. 14.
    Holdom MD, Davies AM, Nettleship JE, Bagby SC, Dhaliwal B et al. 2011. Conformational changes in IgE contribute to its uniquely slow dissociation rate from receptor FcεRI. Nat. Struct. Mol. Biol. 18:5571–76
     [Google Scholar]
  15. 15.
    Wurzburg BA, Garman SC, Jardetzky TS. 2000. Structure of the human IgE-Fc Cε3-Cε4 reveals conformational flexibility in the antibody effector domains. Immunity 13:3375–85
     [Google Scholar]
  16. 16.
    Doré KA, Davies AM, Drinkwater N, Beavil AJ, McDonnell JM, Sutton BJ. 2017. Thermal sensitivity and flexibility of the Cε3 domains in immunoglobulin E. Biochim. Biophys. Acta Proteins Proteom. 1865:11 Part A1336–47
     [Google Scholar]
  17. 17.
    Borthakur S, Andrejeva G, McDonnell JM. 2011. Basis of the intrinsic flexibility of the Cε3 domain of IgE. Biochemistry 50:214608–14
     [Google Scholar]
  18. 18.
    Feige MJ, Walter S, Buchner J. 2004. Folding mechanism of the CH2 antibody domain. J. Mol. Biol. 344:1107–18
     [Google Scholar]
  19. 19.
    Fink AL. 2005. Natively unfolded proteins. Curr. Opin. Struct. Biol. 15:135–41
     [Google Scholar]
  20. 20.
    Harwood NE, Price NC, McDonnell JM. 2006. Catalytic folding of the Cε3 domain by its high affinity receptor. FEBS Lett 580:82129–34
     [Google Scholar]
  21. 21.
    McDonnell JM, Calvert R, Beavil RL, Beavil AJ, Henry AJ et al. 2001. The structure of the IgE Cε2 domain and its role in stabilizing the complex with its high-affinity receptor FcεRIα. Nat. Struct. Biol. 8:5437–41
     [Google Scholar]
  22. 22.
    Beavil AJ, Young RJ, Sutton BJ, Perkins SJ. 1995. Bent domain structure of recombinant human IgE-Fc in solution by X-ray and neutron scattering in conjunction with an automated curve fitting procedure. Biochemistry 34:4414449–61
     [Google Scholar]
  23. 23.
    Zheng Y, Shopes B, Holowka D, Baird B. 1992. Dynamic conformations compared for IgE and IgG1 in solution and bound to receptors. Biochemistry 31:337446–56
     [Google Scholar]
  24. 24.
    Jensen RK, Jabs F, Miehe M, Mølgaard B, Pfützner W et al. 2020. Structure of intact IgE and the mechanism of ligelizumab revealed by electron microscopy. Allergy 75:81956–65
     [Google Scholar]
  25. 25.
    Zelensky AN, Gready JE. 2005. The C-type lectin-like domain superfamily. FEBS J 272:246179–217
     [Google Scholar]
  26. 26.
    Kijimoto-Ochiai S. 2002. CD23 (the low-affinity IgE receptor) as a C-type lectin: a multidomain and multifunctional molecule. Cell Mol. Life Sci. 59:4648–64
     [Google Scholar]
  27. 27.
    Natarajan K, Dimasi N, Wang J, Mariuzza RA, Margulies DH. 2002. Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination. Annu. Rev. Immunol. 20:853–85
     [Google Scholar]
  28. 28.
    Beavil AJ, Edmeades RL, Gould HJ, Sutton BJ. 1992. Alpha-helical coiled-coil stalks in the low-affinity receptor for IgE (Fc epsilon RII/CD23) and related C-type lectins. PNAS 89:2753–57
     [Google Scholar]
  29. 29.
    Cooper AM, Hobson PS, Jutton MR, Kao MW, Drung B et al. 2012. Soluble CD23 controls IgE synthesis and homeostasis in human B cells. J. Immunol. 188:73199–207
     [Google Scholar]
  30. 30.
    McCloskey N, Hunt J, Beavil RL, Jutton MR, Grundy GJ et al. 2007. Soluble CD23 monomers inhibit and oligomers stimulate IGE synthesis in human B cells. J. Biol. Chem. 282:3324083–91
     [Google Scholar]
  31. 31.
    Hibbert RG, Teriete P, Grundy GJ, Beavil RL, Reljic R et al. 2005. The structure of human CD23 and its interactions with IgE and CD21. J. Exp. Med. 202:6751–60
     [Google Scholar]
  32. 32.
    Weskamp G, Ford JW, Sturgill J, Martin S, Docherty AJP et al. 2006. ADAM10 is a principal “sheddase” of the low-affinity immunoglobulin E receptor CD23. Nat. Immunol. 7:121293–98
     [Google Scholar]
  33. 33.
    Weis WI, Taylor ME, Drickamer K. 1998. The C-type lectin superfamily in the immune system. Immunol. Rev. 163:19–34
     [Google Scholar]
  34. 34.
    Marcelletti JF, Richards ML, Katz DH. 1989. The emerging importance of IgE and Fc receptors for IgE (Fc epsilon R) in the regulation of B cell activity. Contrib. Microbiol. Immunol. 11:188–205
     [Google Scholar]
  35. 35.
    Vercelli D, Helm B, Marsh P, Padlan E, Geha RS, Gould H. 1989. The B-cell binding site on human immunoglobulin E. Nature 338:6217649–51
     [Google Scholar]
  36. 36.
    Aubry JP, Pochon S, Graber P, Jansen KU, Bonnefoy JY. 1992. CD21 is a ligand for CD23 and regulates IgE production. Nature 358:6386505–7
     [Google Scholar]
  37. 37.
    Szakonyi G, Guthridge JM, Li D, Young K, Holers VM, Chen XS. 2001. Structure of complement receptor 2 in complex with its C3d ligand. Science 292:55221725–28
     [Google Scholar]
  38. 38.
    Nemerow GR, Houghten RA, Moore MD, Cooper NR. 1989. Identification of an epitope in the major envelope protein of Epstein-Barr virus that mediates viral binding to the B lymphocyte EBV receptor (CR2). Cell 56:3369–77
     [Google Scholar]
  39. 39.
    Delcayre AX, Salas F, Mathur S, Kovats K, Lotz M, Lernhardt W. 1991. Epstein Barr virus/complement C3d receptor is an interferon alpha receptor. EMBO J 10:4919–26
     [Google Scholar]
  40. 40.
    Wurzburg BA, Tarchevskaya SS, Jardetzky TS. 2006. Structural changes in the lectin domain of CD23, the low-affinity IgE receptor, upon calcium binding. Structure 14:61049–58
     [Google Scholar]
  41. 41.
    Bettler B, Texido G, Raggini S, Rüegg D, Hofstetter H. 1992. Immunoglobulin E-binding site in Fc epsilon receptor (Fc epsilon RII/CD23) identified by homolog-scanning mutagenesis. J. Biol. Chem. 267:1185–91
     [Google Scholar]
  42. 42.
    Hoppe HJ, Reid KB. 1994. Trimeric C-type lectin domains in host defence. Structure 2:121129–33
     [Google Scholar]
  43. 43.
    Yuan D, Keeble AH, Hibbert RG, Fabiane S, Gould HJ et al. 2013. Ca2+-dependent structural changes in the B-cell receptor CD23 increase its affinity for human immunoglobulin E. J. Biol. Chem. 288:3021667–77
     [Google Scholar]
  44. 44.
    Dhaliwal B, Pang MOY, Yuan D, Yahya N, Fabiane SM et al. 2013. Conformational plasticity at the IgE-binding site of the B-cell receptor CD23. Mol. Immunol. 56:4693–97
     [Google Scholar]
  45. 45.
    Dhaliwal B, Yuan D, Pang MOY, Henry AJ, Cain K et al. 2012. Crystal structure of IgE bound to its B-cell receptor CD23 reveals a mechanism of reciprocal allosteric inhibition with high affinity receptor FcεRI. PNAS 109:3112686–91
     [Google Scholar]
  46. 46.
    Borthakur S, Hibbert RG, Pang MOY, Yahya N, Bax HJ et al. 2012. Mapping of the CD23 binding site on immunoglobulin E (IgE) and allosteric control of the IgE-FcεRI interaction. J. Biol. Chem. 287:3731457–61
     [Google Scholar]
  47. 47.
    Shi J, Ghirlando R, Beavil RL, Beavil AJ, Keown MB et al. 1997. Interaction of the low-affinity receptor CD23/FcεRII lectin domain with the Fcε3–4 fragment of human immunoglobulin E. Biochemistry 36:82112–22
     [Google Scholar]
  48. 48.
    Dhaliwal B, Pang MOY, Keeble AH, James LK, Gould HJ et al. 2017. IgE binds asymmetrically to its B cell receptor CD23. Sci. Rep. 7:45533
     [Google Scholar]
  49. 49.
    Kelly AE, Chen BH, Woodward EC, Conrad DH. 1998. Production of a chimeric form of CD23 that is oligomeric and blocks IgE binding to the FcεRI. J. Immunol. 161:126696–704
     [Google Scholar]
  50. 50.
    Jégouzo SAF, Feinberg H, Morrison AG, Holder A, May A et al. 2019. CD23 is a glycan-binding receptor in some mammalian species. J. Biol. Chem. 294:4114845–59
     [Google Scholar]
  51. 51.
    Ilkow VF, Davies AM, Dhaliwal B, Beavil AJ, Sutton BJ, McDonnell JM. 2021. Reviving lost binding sites: exploring calcium-binding site transitions between human and murine CD23. FEBS Open Biol 11:71827–40
     [Google Scholar]
  52. 52.
    Karagiannis SN, Warrack JK, Jennings KH, Murdock PR, Christie G et al. 2001. Endocytosis and recycling of the complex between CD23 and HLA-DR in human B cells. Immunology 103:3319–31
     [Google Scholar]
  53. 53.
    Ohman S, Larsson L. 1978. Higher values for ionized calcium with a new type of electrode for Orion SS-20. Clin. Chem. 24:112070–71
     [Google Scholar]
  54. 54.
    Andersen CBF, Moestrup SK. 2014. How calcium makes endocytic receptors attractive. Trends Biochem. Sci. 39:282–90
     [Google Scholar]
  55. 55.
    Gilbert HE, Asokan R, Holers VM, Perkins SJ. 2006. The 15 SCR flexible extracellular domains of human complement receptor type 2 can mediate multiple ligand and antigen interactions. J. Mol. Biol. 362:51132–47
     [Google Scholar]
  56. 56.
    Prota AE, Sage DR, Stehle T, Fingeroth JD. 2002. The crystal structure of human CD21: implications for Epstein-Barr virus and C3d binding. PNAS 99:1610641–46
     [Google Scholar]
  57. 57.
    Carter RH, Fearon DT. 1992. CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256:5053105–7
     [Google Scholar]
  58. 58.
    Dempsey PW, Fearon DT. 1996. Complement: instructing the acquired immune system through the CD21/CD19 complex. Res. Immunol. 147:271–75; discussion 119–120
    [Google Scholar]
  59. 59.
    Hannan JP. 2016. The structure-function relationships of complement receptor type 2 (CR2; CD21). Curr. Protein Pept. Sci. 17:5463–87
     [Google Scholar]
  60. 60.
    Babu KS, Holgate ST. 2002. The role of anti-IgE therapies in the treatment of asthma. Hosp. Med. 63:8483–86
     [Google Scholar]
  61. 61.
    Guntern P, Eggel A. 2020. Past, present, and future of anti-IgE biologics. Allergy 75:102491–502
     [Google Scholar]
  62. 62.
    Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. 2004. Omalizumab-induced reductions in mast cell FcεRI expression and function. J. Allergy Clin. Immunol. 114:3527–30
     [Google Scholar]
  63. 63.
    Vichyanond P. 2011. Omalizumab in allergic diseases, a recent review. Asian Pac. J. Allergy Immunol. 29:3209–19
     [Google Scholar]
  64. 64.
    Schulman ES. 2001. Development of a monoclonal anti-immunoglobulin E antibody (omalizumab) for the treatment of allergic respiratory disorders. Am. J. Respir. Crit. Care Med. 164:8 Part 2S6–11
     [Google Scholar]
  65. 65.
    Pennington LF, Tarchevskaya S, Brigger D, Sathiyamoorthy K, Graham MT et al. 2016. Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange. Nat. Commun. 7:11610
     [Google Scholar]
  66. 66.
    Davies AM, Allan EG, Keeble AH, Delgado J, Cossins BP et al. 2017. Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab. J. Biol. Chem. 292:249975–87
     [Google Scholar]
  67. 67.
    Gasser P, Tarchevskaya SS, Guntern P, Brigger D, Ruppli R et al. 2020. The mechanistic and functional profile of the therapeutic anti-IgE antibody ligelizumab differs from omalizumab. Nat. Commun. 11:1165
     [Google Scholar]
  68. 68.
    Cohen ES, Dobson CL, Käck H, Wang B, Sims DA et al. 2014. A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma. mAbs 6:3756–64
     [Google Scholar]
  69. 69.
    Jabs F, Plum M, Laursen NS, Jensen RK, Mølgaard B et al. 2018. Trapping IgE in a closed conformation by mimicking CD23 binding prevents and disrupts FcεRI interaction. Nat. Commun. 9:17
     [Google Scholar]
  70. 70.
    Drinkwater N, Cossins B, Keeble AH, Wright M, Cain K et al. 2014. Human immunoglobulin E flexes between acutely bent and extended conformations. Nat. Struct. Mol. Biol. 21:4397–404
     [Google Scholar]
  71. 71.
    Chen J-B, Ramadani F, Pang MOY, Beavil RL, Holdom MD et al. 2018. Structural basis for selective inhibition of immunoglobulin E-receptor interactions by an anti-IgE antibody. Sci. Rep. 8:111548
     [Google Scholar]
  72. 72.
    Stumpp MT, Dawson KM, Binz HK. 2020. Beyond antibodies: the DARPin® drug platform. BioDrugs 34:4423–33
     [Google Scholar]
  73. 73.
    Kim B, Eggel A, Tarchevskaya SS, Vogel M, Prinz H, Jardetzky TS. 2012. Accelerated disassembly of IgE-receptor complexes by a disruptive macromolecular inhibitor. Nature 491:7425613–17
     [Google Scholar]
  74. 74.
    Miyajima H, Watanabe N, Ovary Z, Okumura K, Hirano T. 2002. Rat monoclonal anti-murine IgE antibody removes IgE molecules already bound to mast cells or basophilic leukemia cells, resulting in the inhibition of systemic anaphylaxis and passive cutaneous anaphylaxis. Int. Arch. Allergy Immunol. 128:124–32
     [Google Scholar]
  75. 75.
    Meerts P, Cornelis S, Hermans G, Vercammen J, Verdonck FKD. 2011. Immunoglobulin single variable domains directed against IgE WO Patent 2012175740A1
  76. 76.
    Rinaldi M, Denayer T, Thiolloy S, Perez Tosar L, Buyse M-A et al. 2013. ALX-0962, an anti-IgE nanobody with a dual mode of action. Eur. Respir. J. 42:1765
     [Google Scholar]
  77. 77.
    Eggel A, Baravalle G, Hobi G, Kim B, Buschor P et al. 2014. Accelerated dissociation of IgE-FcεRI complexes by disruptive inhibitors actively desensitizes allergic effector cells. J. Allergy Clin. Immunol. 133:61709–19.e8
     [Google Scholar]
  78. 78.
    MacGlashan D. 2015. Facilitated dissociation of IgE versus cell replacement. J. Allergy Clin. Immunol. 135:1294–95
     [Google Scholar]
  79. 79.
    Pennington LF, Gasser P, Kleinboelting S, Zhang C, Skiniotis G et al. 2021. Directed evolution of and structural insights into antibody-mediated disruption of a stable receptor-ligand complex. Nat. Commun. 12:17069
     [Google Scholar]
  80. 80.
    Pennington LF, Gasser P, Brigger D, Guntern P, Eggel A, Jardetzky TS. 2021. Structure-guided design of ultrapotent disruptive IgE inhibitors to rapidly terminate acute allergic reactions. J. Allergy Clin. Immunol. 148:41049–60
     [Google Scholar]
  81. 81.
    Paramanathan T, Reeves D, Friedman LJ, Kondev J, Gelles J. 2014. A general mechanism for competitor-induced dissociation of molecular complexes. Nat. Commun. 5:5207
     [Google Scholar]
  82. 82.
    Abdiche YN, Yeung AY, Ni I, Stone D, Miles A et al. 2017. Antibodies targeting closely adjacent or minimally overlapping epitopes can displace one another. PLOS ONE 12:1e0169535
     [Google Scholar]
  83. 83.
    Gromadski KB, Wieden H-J, Rodnina MV. 2002. Kinetic mechanism of elongation factor Ts-catalyzed nucleotide exchange in elongation factor Tu. Biochemistry 41:1162–69
     [Google Scholar]
  84. 84.
    Freistroffer DV, Pavlov MY, MacDougall J, Buckingham RH, Ehrenberg M. 1997. Release factor RF3 in E. coli accelerates the dissociation of release factors RF1 and RF2 from the ribosome in a GTP-dependent manner. EMBO J 16:134126–33
     [Google Scholar]
  85. 85.
    De Meyts P, Whittaker J 2002. Structural biology of insulin and IGF1 receptors: implications for drug design. Nat. Rev. Drug Discov. 1:10769–83
     [Google Scholar]
  86. 86.
    He MM, Smith AS, Oslob JD, Flanagan WM, Braisted AC et al. 2005. Small-molecule inhibition of TNF-alpha. Science 310:57501022–25
     [Google Scholar]
  87. 87.
    Chen T-Y, Cheng Y-S, Huang P-S, Chen P 2018. Facilitated unbinding via multivalency-enabled ternary complexes: new paradigm for protein-DNA interactions. Acc. Chem. Res. 51:4860–68
     [Google Scholar]
  88. 88.
    Prinz H, Striessnig J. 1993. Ligand-induced accelerated dissociation of (+)-cis-diltiazem from L-type Ca2+ channels is simply explained by competition for individual attachment points. J. Biol. Chem. 268:2518580–85
     [Google Scholar]
  89. 89.
    Xolair® [package insert] Dublin, Ireland: Novartis Europharm Ltd.; 2005.
  90. 90.
    Cooper A, Dryden DT. 1984. Allostery without conformational change: a plausible model. Eur. Biophys. J. 11:2103–9
     [Google Scholar]
  91. 91.
    Cook JP, Henry AJ, McDonnell JM, Owens RJ, Sutton BJ, Gould HJ. 1997. Identification of contact residues in the IgE binding site of human FcεRIα. Biochemistry 36:5015579–88
     [Google Scholar]
  92. 92.
    Henry AJ, Cook JP, McDonnell JM, Mackay GA, Shi J et al. 1997. Participation of the N-terminal region of Cε3 in the binding of human IgE to its high-affinity receptor FcεRI. Biochemistry 36:5015568–78
     [Google Scholar]
  93. 93.
    Sayers I, Cain SA, Swan JR, Pickett MA, Watt PJ et al. 1998. Amino acid residues that influence FcεRI-mediated effector functions of human immunoglobulin E. Biochemistry 37:4616152–64
     [Google Scholar]
  94. 94.
    Ortega E, Schweitzer-Stenner R, Pecht I. 1991. Kinetics of ligand binding to the type 1 Fc epsilon receptor on mast cells. Biochemistry 30:143473–83
     [Google Scholar]
  95. 95.
    Kolkhir P, Altrichter S, Munoz M, Hawro T, Maurer M. 2020. New treatments for chronic urticaria. Ann. Allergy Asthma Immunol. 124:12–12
     [Google Scholar]
/content/journals/10.1146/annurev-immunol-061020-053712
Loading
IgE, IgE Receptors and Anti-IgE Biologics: Protein Structures and Mechanisms of Action
Annual Review of Immunology 41, 255 (2023); https://doi.org/10.1146/annurev-immunol-061020-053712
/content/journals/10.1146/annurev-immunol-061020-053712
/content/journals/10.1146/annurev-immunol-061020-053712
Loading

Data & Media loading...

Supplemental Material

Supplementary Data

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error