Modulation of Dendritic Cells and Regulatory T Cells by Naturally Occurring Antibodies

  • Jaap Kwekkeboom
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 750)


Most studies on the effects of naturally occurring autoantibodies (NAbs) on immune cells have been performed in the context of research on the immunomodulatory effects of intravenous immunoglobulin (IVIG). Among others, IVIG inhibits the differentiation, maturation and functions of dendritic cells (DC), thereby suppressing T-cell activation. In addition, IVIG stimulates expansion and suppressive function of regulatory T cells (Treg) carrying the antigens CD4, CD25 and Foxp3. Current data on the immunomodulatory effects of IVIG on DC and Treg are summarized, and possible molecular interactions between NAbs and DC or Treg that mediate these effects are discussed.


Dendritic Cell Experimental Autoimmune Encephalomyelitis Kawasaki Disease Intravenous Immunoglobulin Immune Thrombocytopenic Purpura 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Imbach P, Barandun S, d’Apuzzo V et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981; 1:1228–31. PMID:6112565 doi:10.1016/S0140-6736(81)92400-4PubMedCrossRefGoogle Scholar
  2. 2.
    Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001; 345:747–55. PMID:11547745 doi:10.1056/NEJMra993360PubMedCrossRefGoogle Scholar
  3. 3.
    Negi VS, Elluru S, Siberil S et al. Intravenous immunoglobulin: an update on the clinical use and mechanisms of action. J Clin Immunol 2007; 27:233–45. PMID:17351760 doi:10.1007/sl0875-007-9088-9PubMedCrossRefGoogle Scholar
  4. 4.
    Tha-In T, Bayry J, Metselaar HJ et al. Modulation of the cellular immune system by intravenous immunoglobulin. Trends Immunol 2008; 29:608–15. PMID:18926775 doi:10.1016/ Scholar
  5. 5.
    Sokos DR, Berger M, Lazarus HM. Intravenous immunoglobulin: appropriate indications and uses in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2002; 8:117–30. PMID: 11939601 doi: 10.1053/bbmt.2002.v8.pml 1939601PubMedCrossRefGoogle Scholar
  6. 6.
    Luke PP, Scantlebury VP, Jordan ML et al. Reversal of steroid-and anti-lymphocyte antibody-resistant rejection using intravenous immunoglobulin (IVIG) in renal transplant recipients. Transplantation 2001; 72:419–22. PMID:11502969 doi: 10.1097/00007890-200108150-00010PubMedCrossRefGoogle Scholar
  7. 7.
    Casadei DH, del C Rial M, Opelz G et al. A randomized and prospective study comparing treatment with high-dose intravenous immunoglobulin with monoclonal antibodies for rescue of kidney grafts with steroid-resistant rejection. Transplantation 2001; 71:53–8. PMID:11211195 doi: 10.1097/00007890-200101150-00009PubMedCrossRefGoogle Scholar
  8. 8.
    Kwekkeboom J, Tha-In T, Tra WM et al. Hepatitis B immunoglobulins inhibit dendritic cells and T cells and protect against acute rejection after liver transplantation. Am J Transplant 2005; 5:2393–402. PMID:16162187 doi:10.1111/j.l600-6143.2005.01029.xPubMedCrossRefGoogle Scholar
  9. 9.
    Bucuvalas JC, Anand R. Treatment with immunoglobulin improves outcome for pediatric liver transplant recipients. Liver Transpl 2009; 15:1564–9. PMID:19877216 doi: 10.1002/lt.21843PubMedCrossRefGoogle Scholar
  10. 10.
    Bayry J, Lacroix-Desmazes S, Donkovax-Petrini V et al. Natural antibodies sustain differentiation and maturation of human dendritic cells. Proc Natl Acad Sci USA 2004; 101:14210–5. PMID:15381781 doi:10.1073/pnas.0402183101PubMedCrossRefGoogle Scholar
  11. 11.
    Bayry J, Lacroix-Desmazes S, Hermine O et al. Amelioration of differentiation of dendritic cells from CVID patients by intravenous immunoglobulin. Am J Med 2005; 118:1439–40. PMID: 16378810 doi: 10.1016/j. amjmed.2005.06.028PubMedCrossRefGoogle Scholar
  12. 12.
    Bayry J, Lacroix-Desmazes S, Kazatchkine MD et al. Common variable immunodeficiency is associated with defective functions of dendritic cells. Blood 2004; 104:2441–3. PMID:15226176 doi:10.1182/blood-2004-04-1325PubMedCrossRefGoogle Scholar
  13. 13.
    Bayry J, Lacroix-Desmazes S, Carbonneil C et al. Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood 2003; 101:758–65. PMID: 12393386 doi: 10.1182/blood-2002-05-1447PubMedCrossRefGoogle Scholar
  14. 14.
    Bayry J, Lacroix-Desmazes S, Delignat S et al. Intravenous immunoglobulin abrogates dendritic cell differentiation induced by interferon-alpha present in serum from patients with systemic lupus erythematosus. Arthritis Rheum 2003; 48:3497–502. PMID: 14674000 doi: 10.1002/art. 11346PubMedCrossRefGoogle Scholar
  15. 15.
    Tha-In T, Metselaar HJ, Tilanus HW et al. Superior immunomodulatory effects of intravenous immunoglobulins on human T-cells and dendritic cells: comparison to calcineurin inhibitors. Transplantation 2006; 81:1725–34. PMID:16794540 doi:10.1097/ Scholar
  16. 16.
    Smed-Sorensen A, Moll M, Cheng TY et al. IgG regulates the CD1 expression profile and lipid antigen presenting function in human dendritic cells via Fc{gamma}RIIa. Blood 2008; ll:5037–46 PMID:18337560 doi: 10.1182/blood-2007-07-099549.CrossRefGoogle Scholar
  17. 17.
    Aubin E, Lemieux R, Bazin R. Indirect inhibition of in vivo and in vitro T-cell responses by intravenous immunoglobulins due to impaired antigen presentation. Blood 2010; 115:1727–34. PMID: 19965673 doi: 10.1182/blood-2009-06-225417PubMedCrossRefGoogle Scholar
  18. 18.
    Bayry J, Bansal K, Kazatchkine MD et al. DC-SIGN and alpha2,6-sialylated IgG Fc interaction is dispensable for the anti-inflammatory activity of IVIG on human dendritic cells. Proc Natl Acad Sci U S A. 2009; 106:E24; author reply E25.PubMedCrossRefGoogle Scholar
  19. 19.
    Geijtenbeek TB, Gringhuis SI. Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol 2009; 9:465–79. PMID:19521399 doi:10.1038/nri2569PubMedCrossRefGoogle Scholar
  20. 20.
    Requena M, Bouhlal H, Nasreddine N et al. Inhibition of HIV-1 transmission in trans from dendritic cells to CD4+ T lymphocytes by natural antibodies to the CRD domain of DC-SIGN purified from breast milk and intravenous immunoglobulins. Immunology 2008; 123:508–18. PMID: 17999675 doi: 10.1111/j.l365-2567.2007.02717.xPubMedCrossRefGoogle Scholar
  21. 21.
    Geijtenbeek TB, Van Vliet SJ, Koppel EA et al. Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med 2003; 197:7–17. PMID: 12515809 doi: 10.1084/jem.20021229PubMedCrossRefGoogle Scholar
  22. 22.
    Gringhuis SI, den Dunnen J, Litjens M et al. Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nat Immunol 2009; 10:1081–8. PMID:19718030 doi:10.1038/ni.1778PubMedCrossRefGoogle Scholar
  23. 23.
    Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 2006; 313:670–3. PMID:16888140 doi:10.1126/science. 1129594PubMedCrossRefGoogle Scholar
  24. 24.
    Anthony RM, Nimmerjahn F, Ashline DJ et al. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science 2008; 320:373–6. PMID: 18420934 doi: 10.1126/science.1154315PubMedCrossRefGoogle Scholar
  25. 25.
    Anthony RM, Wermeling F, Karlsson MC et al. Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci USA 2008; 105:19571–8. PMID: 19036920 doi: 10.1073/pnas.0810163105PubMedCrossRefGoogle Scholar
  26. 26.
    Geijtenbeek TB, Groot PC, Nolte MA et al. Marginal zone macrophages express a murine homologue of DC-SIGN that captures blood-borne antigens in vivo. Blood 2002; 100:2908–16. PMID:12351402 doi: 10.1182/blood-2002-04-1044PubMedCrossRefGoogle Scholar
  27. 27.
    Pöhlmann S, Soilleux EJ, Baribaud F et al. DC-SIGNR, a DC-SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans. Proc Natl Acad Sci USA 2001; 98:2670–5. PMID:11226297 doi:10.1073/pnas.051631398PubMedCrossRefGoogle Scholar
  28. 28.
    Anthony RM, Kobayashi T, Wermeling F et al. Intravenous gammaglobulin suppresses inflammation through anovel T(H)2 pathway. Nature 2011; 475:110–3. PMID:21685887 doi:10.1038/nature 10134PubMedCrossRefGoogle Scholar
  29. 29.
    Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001; 291:484–6. PMID: 11161202 doi: 10.1126/science.291.5503.484PubMedCrossRefGoogle Scholar
  30. 30.
    Bruhns P, Samuelsson A, Pollard JW et al. Colony-stimulating factor-1-dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity 2003; 18:573–81. PMID:12705859 doi:10.1016/S1074-7613(03)00080-3PubMedCrossRefGoogle Scholar
  31. 31.
    Kaneko Y, Nimmerjahn F, Madaio MP et al. Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors. J Exp Med 2006; 203:789–97. PMID:16520389 doi:10.1084/jem.20051900PubMedCrossRefGoogle Scholar
  32. 32.
    Siragam V, Brine D, Crow AR et al. Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease? J Clin Invest 2005; 115:155–60. PMID: 15630455PubMedGoogle Scholar
  33. 33.
    Siragam V, Crow AR, Brine D et al. Intravenous immunoglobulin ameliorates ITP via activating Fc gamma receptors on dendritic cells. Nat Med 2006; 12:688–92. PMID:16715090 doi:10.1038/nml416PubMedCrossRefGoogle Scholar
  34. 34.
    Dhodapkar KM, Kaufman JL, Ehlers M et al. Selective blockade of inhibitory Fcgamma receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells. Proc Natl Acad Sci USA 2005; 102:2910–5. PMID:15703291 doi:10.1073/pnas.0500014102PubMedCrossRefGoogle Scholar
  35. 35.
    Dhodapkar KM, Banerjee D, Connolly J et al. Selective blockade of the inhibitory Fcgamma receptor (FcgammaRIIB) in human dendritic cells and monocytes induces a type I interferon response program. J Exp Med 2007; 204:1359–69. PMID: 17502666 doi:10.1084/jem.20062545PubMedCrossRefGoogle Scholar
  36. 36.
    Boruchov AM, Heller G, Veri MC et al. Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J Clin Invest 2005; 115:2914–23. PMID:16167082 doi:10.1172/JCI24772PubMedCrossRefGoogle Scholar
  37. 37.
    Tackenberg B, Jelcic I, Baerenwaldt A et al. Impaired inhibitory Fcgamma receptor IIB expression on B cells in chronic inflammatory demyelinatingpolyneuropathy. ProcNatl Acad Sci USA 2009; 106:4788–92. PMID:19261857 doi:10.1073/pnas.0807319106CrossRefGoogle Scholar
  38. 38.
    Nimmerjahn F, Ravetch JV. Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol 2008; 26:513–33. PMID:18370923 doi:10.1146/annurev.immunol.26.021607.090232PubMedCrossRefGoogle Scholar
  39. 39.
    Huang HS, Sun DS, Lien TS et al. Dendritic cells modulate platelet activity in IVIG-mediated amelioration of ITP in mice. Blood 2010; 116:5002–9. PMID:20699442 doi: 10.1182/blood-2010-03-275123PubMedCrossRefGoogle Scholar
  40. 40.
    Park-Min KH, Serbina NV, Yang W et al. FcgammaRIII-dependent inhibition of interferon-gamma responses mediates suppressive effects of intravenous immune globulin. Immunity 2007; 26:67–78. PMID: 17239631 doi:10.1016/j.immuni.2006.11.010PubMedCrossRefGoogle Scholar
  41. 41.
    van Mirre E, Teeling JL, van der Meer JW et al. Monomeric IgG in intravenous Ig preparations is a functional antagonist of FcgammaRII and FcgammaRIIIb. J Immunol 2004; 173:332–9. PMID: 15210791PubMedGoogle Scholar
  42. 42.
    Tankersley DL. Dimer formation in immunoglobulin preparations and speculations on the mechanism of action of intravenous immune globulin in autoimmune diseases. Immunol Rev 1994; 139:159–72. PMID:7927410 doi:10.1111/j.l600-065X.1994.tb00861.xPubMedCrossRefGoogle Scholar
  43. 43.
    Vassilev TL, Bineva IL, Dietrich G et al. Variable region-connected, dimeric fraction of intravenous immunoglobulin enriched in natural autoantibodies. J Autoimmun 1995; 8:405–13. PMID:7576001 doi: 10.1006/jaut. 1995.0032PubMedCrossRefGoogle Scholar
  44. 44.
    Tha-In T, Metselaar HJ, Tilanus HW et al. Intravenous immunoglobulins suppress T-cell priming by modulating the bidirectional interaction between dendritic cells and natural killer cells. Blood 2007; 110:3253–62. PMID: 17673603 doi:10.1182/blood-2007-03-077057PubMedCrossRefGoogle Scholar
  45. 45.
    Andersson UG, Bjork L, Skansen-Saphir U et al. Down-regulation of cytokine production and interleukin-2 receptor expression by pooled human IgG. Immunology 1993; 79:211–6. PMID:8344700PubMedGoogle Scholar
  46. 46.
    Amran D, Renz H, Lack G et al. Suppression of cytokine-dependent human T-cell proliferation by intravenous immunoglobulin. Clin Immunol Immunopathol 1994; 73:180–6. PMID:7523013 doi: 10.1006/clin. 1994.1186PubMedCrossRefGoogle Scholar
  47. 47.
    Modiano JF, Amran D, Lack G et al. Posttranscriptional regulation of T-cell IL-2 production by human pooled immunoglobin. Clin Immunol Immunopathol 1997; 83:77–85. PMID:9073539 doi: 10.1006/clin. 1997.4329PubMedCrossRefGoogle Scholar
  48. 48.
    MacMillan HF, Lee T, Issekutz AC. Intravenous immunoglobulin G-mediated inhibition of T-cell proliferation reflects an endogenous mechanism by which IgG modulates T-cell activation. Clin Immunol 2009; 132:222–33. PMID: 19447680 doi:10.1016/j.clim.2009.04.002PubMedCrossRefGoogle Scholar
  49. 49.
    Marchalonis JJ, Kaymaz H, Dedeoglu F et al. Human autoantibodies reactive with synthetic autoantigens from T-cell receptor beta chain. ProcNatl Acad Sci USA 1992; 89:3325–9. PMID: 1565623 doi: 10.1073/pnas.89.8.3325CrossRefGoogle Scholar
  50. 50.
    Hurez V, Kaveri SV, Mouhoub A et al. Anti-CD4 activity of normal human immunoglobulin G for therapeutic use. (Intravenous immunoglobulin, IVIG). Ther Immunol 1994; 1:269–77. PMID:7584501PubMedGoogle Scholar
  51. 51.
    Kersh GJ, Allen PM. Structural basis for T cell recognition of altered peptide ligands: a single T cell receptor can productively recognize a large continuum of related ligands. J Exp Med 1996; 184:1259–68. PMID:8879197 doi:10.1084/jem.l84.4.1259PubMedCrossRefGoogle Scholar
  52. 52.
    Kersh GJ, Allen PM. Essential flexibility in the T-cell recognition of antigen. Nature 1996; 380:495–8. PMID:8606766 doi:10.1038/380495a0PubMedCrossRefGoogle Scholar
  53. 53.
    Germain RN, Stefanova I. The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu Rev Immunol 1999; 17:467–522. PMID:10358766 doi:10.1146/annurev.immunol. 17.1.467PubMedCrossRefGoogle Scholar
  54. 54.
    Kessel A, Ammuri H, Peri R et al. Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol 2007; 179:5571–5. PMID: 17911644PubMedGoogle Scholar
  55. 55.
    Ephrem A, Chamat S, Miquel C et al. Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood 2008; 111:715–22. PMID:17932250 doi:10.1182/blood-2007-03-079947PubMedCrossRefGoogle Scholar
  56. 56.
    Tha-In T, Metselaar HJ, Bushell AR et al. Intravenous immunoglobulins promote skin allograft acceptance by triggering functional activation of CD4+Foxp3+T cells. Transplantation 2010; 89:1446–55. PMID:20463648 doi:10.1097/TP.0b013e3181dd6bflPubMedCrossRefGoogle Scholar
  57. 57.
    Furuno K, Yuge T, Kusuhara K et al. CD25+CD4+ regulatory T cells in patients with Kawasaki disease. J Pediatr 2004; 145:385–90. PMID:15343196 doi:10.1016/j.jpeds.2004.05.048PubMedCrossRefGoogle Scholar
  58. 58.
    Olivito B, Taddio A, Simonini G et al. Defective FOXP3 expression in patients with acute Kawasaki disease and restoration by intravenous immunoglobulin therapy. Clin Exp Rheumatol 2010; 28:93–7. PMID:20412712PubMedGoogle Scholar
  59. 59.
    Chi LJ, Wang HB, Zhang Y et al. Abnormality of circulating CD4(+)CD25(+) regulatory T cell in patients with Guillain-Barre syndrome. J Neuroimmunol 2007; 192:206–14. PMID: 17997492 doi: 10.1016/j. jneuroim.2007.09.034PubMedCrossRefGoogle Scholar
  60. 60.
    De Groot AS, Moise L, McMurry JA et al. Activation of natural regulatory T cells by IgG Fc-derived peptide “Tregitopes”. Blood 2008; 112:3303–11. PMID:18660382 doi: 10.1182/blood-2008-02-138073PubMedCrossRefGoogle Scholar
  61. 61.
    Becker C, Kubach J, Wijdenes J et al. CD4-mediated functional activation of human CD4+CD25+regulatory T cells. Eur J Immunol 2007; 37:1217–23. PMID:17407195 doi:10.1002/eji.200636480PubMedCrossRefGoogle Scholar
  62. 62.
    Bayry J, Kazatchkine MD, Kaveri SV. Shortage of human intravenous immunoglobulin-reasons and possible solutions. Nat Clin PractNeurol 2007; 3:120–1. PMID:17342189 doi:10.1038/ncpneuro0429CrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Jaap Kwekkeboom
    • 1
  1. 1.Laboratory of Gastroenterology and HepatologyErasmus MC — University Medical Centre RotterdamRotterdamThe Netherlands

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