Advertisement

Seminars in Immunopathology

, Volume 34, Issue 6, pp 847–861 | Cite as

Immunopathogenesis of lymphatic filarial disease

  • Subash Babu
  • Thomas B. Nutman
Review

Abstract

Although two thirds of the 120 million people infected with lymph-dwelling filarial parasites have subclinical infections, ∼40 million have lymphedema and/or other pathologic manifestations including hydroceles (and other forms of urogenital disease), episodic adenolymphangitis, tropical pulmonary eosinophilia, lymphedema, and (in its most severe form) elephantiasis. Adult filarial worms reside in the lymphatics and lymph nodes and induce changes that result in dilatation of lymphatics and thickening of the lymphatic vessel walls. Progressive lymphatic damage and pathology results from the summation of the effect of tissue alterations induced by both living and nonliving adult parasites, the host inflammatory response to the parasites and their secreted antigens, the host inflammatory response to the endosymbiont Wolbachia, and those seen as a consequence of secondary bacterial or fungal infections. Inflammatory damage induced by filarial parasites appears to be multifactorial, with endogenous parasite products, Wolbachia, and host immunity all playing important roles. This review will initially examine the prototypical immune responses engendered by the parasite and delineate the regulatory mechanisms elicited to prevent immune-mediated pathology. This will be followed by a discussion of the proposed mechanisms underlying pathogenesis, with the central theme being that pathogenesis is a two-step process—the first initiated by the parasite and host innate immune system and the second propagated mainly by the host's adaptive immune system and by other factors (including secondary infections).

Keywords

Filariasis Pathology Lymphedema Hydrocele Cytokines Immunity 

Notes

Acknowledgements

This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Conflict of interest disclosure

Because S. Babu and T. B. Nutman are government employees and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U.S. subject to a government use license.

References

  1. 1.
    Fenwick A (2012) The global burden of neglected tropical diseases. Public Health 126:233–236PubMedCrossRefGoogle Scholar
  2. 2.
    2007. Global programme to eliminate lymphatic filariasis. Wkly Epidemiol Rec 82: 361-80Google Scholar
  3. 3.
    1992. Lymphatic filariasis: the disease and its control. Fifth report of the WHO Expert Committee on Filariasis. World Health Organ Tech Rep Ser 821: 1-71Google Scholar
  4. 4.
    Freedman DO, de Almeida Filho PJ, Besh S, Maia e Silva MC, Braga C, Maciel A (1994) Lymphoscintigraphic analysis of lymphatic abnormalities in symptomatic and asymptomatic human filariasis. J Infect Dis 170:927–933PubMedCrossRefGoogle Scholar
  5. 5.
    Freedman DO, de Almeido Filho PJ, Besh S, Maia e Silva MC, Braga C, Maciel A, Furtado AF (1995) Abnormal lymphatic function in presymptomatic bancroftian filariasis. J Infect Dis 171:997–1001PubMedCrossRefGoogle Scholar
  6. 6.
    Noroes J, Addiss D, Amaral F, Coutinho A, Medeiros Z, Dreyer G (1996) Occurrence of living adult Wuchereria bancrofti in the scrotal area of men with microfilaraemia. Trans R Soc Trop Med Hyg 90:55–56PubMedCrossRefGoogle Scholar
  7. 7.
    Noroes J, Addiss D, Santos A, Medeiros Z, Coutinho A, Dreyer G (1996) Ultrasonographic evidence of abnormal lymphatic vessels in young men with adult Wuchereria bancrofti infection in the scrotal area. J Urol 156:409–412PubMedCrossRefGoogle Scholar
  8. 8.
    Dreyer G, Ottesen EA, Galdino E, Andrade L, Rocha A, Medeiros Z, Moura I, Casimiro I, Beliz F, Coutinho A (1992) Renal abnormalities in microfilaremic patients with Bancroftian filariasis. Am J Trop Med Hyg 46:745–751PubMedGoogle Scholar
  9. 9.
    Partono F (1987) The spectrum of disease in lymphatic filariasis. CIBA Found Symp 127:15–31PubMedGoogle Scholar
  10. 10.
    Srividya A, Pani SP, Rajagopalan PK, Bundy DA, Grenfell BT (1991) The dynamics of infection and disease in bancroftian filariasis. Trans R Soc Trop Med Hyg 85:255–259PubMedCrossRefGoogle Scholar
  11. 11.
    Pani SP, Srividya A (1995) Clinical manifestations of bancroftian filariasis with special reference to lymphoedema grading. Indian J Med Res 102:114–118PubMedGoogle Scholar
  12. 12.
    Dreyer G, Medeiros Z, Netto MJ, Leal NC, de Castro LG, Piessens WF (1999) Acute attacks in the extremities of persons living in an area endemic for bancroftian filariasis: differentiation of two syndromes. Trans R Soc Trop Med Hyg 93:413–417PubMedCrossRefGoogle Scholar
  13. 13.
    Dreyer G, Noroes J, Figueredo-Silva J, Piessens WF (2000) Pathogenesis of lymphatic disease in bancroftian filariasis: a clinical perspective. Parasitol Today 16:544–548PubMedCrossRefGoogle Scholar
  14. 14.
    Figueredo-Silva J, Noroes J, Cedenho A, Dreyer G (2002) The histopathology of bancroftian filariasis revisited: the role of the adult worm in the lymphatic-vessel disease. Ann Trop Med Parasitol 96:531–541PubMedCrossRefGoogle Scholar
  15. 15.
    Olszewski WL, Jamal S, Manokaran G, Lukomska B, Kubicka U (1993) Skin changes in filarial and non-filarial lymphoedema of the lower extremities. Trop Med Parasitol 44:40–44PubMedGoogle Scholar
  16. 16.
    Ong RK, Doyle RL (1998) Tropical pulmonary eosinophilia. Chest 113:1673–1679PubMedCrossRefGoogle Scholar
  17. 17.
    Ottesen EA, Nutman TB (1992) Tropical pulmonary eosinophilia. Annu Rev Med 43:417–424PubMedCrossRefGoogle Scholar
  18. 18.
    Melrose WD (2002) Lymphatic filariasis: new insights into an old disease. Int J Parasitol 32:947–960PubMedCrossRefGoogle Scholar
  19. 19.
    Adebajo AO (1996) Rheumatic manifestations of tropical diseases. Curr Opin Rheumatol 8:85–89PubMedCrossRefGoogle Scholar
  20. 20.
    Allen JE, Maizels RM (2011) Diversity and dialogue in immunity to helminths. Nat Rev Immunol 11:375–388PubMedCrossRefGoogle Scholar
  21. 21.
    Maizels RM, Yazdanbakhsh M (2003) Immune regulation by helminth parasites: cellular and molecular mechanisms. Nat Rev Immunol 3:733–744PubMedCrossRefGoogle Scholar
  22. 22.
    Lawrence RA, Devaney E (2001) Lymphatic filariasis: parallels between the immunology of infection in humans and mice. Parasite Immunol 23:353–361PubMedCrossRefGoogle Scholar
  23. 23.
    Chandrashekar R, Rao UR, Subrahmanyam D (1985) Serum dependent cell-mediated immune reactions to Brugia pahangi infective larvae. Parasite Immunol 7:633–641PubMedCrossRefGoogle Scholar
  24. 24.
    Rajan B, Ramalingam T, Rajan TV (2005) Critical role for IgM in host protection in experimental filarial infection. J Immunol 175:1827–1833PubMedGoogle Scholar
  25. 25.
    Spencer LA, Porte P, Zetoff C, Rajan TV (2003) Mice genetically deficient in immunoglobulin E are more permissive hosts than wild-type mice to a primary, but not secondary, infection with the filarial nematode Brugia malayi. Infect Immun 71:2462–2467PubMedCrossRefGoogle Scholar
  26. 26.
    Rajan TV, Porte P, Yates JA, Keefer L, Shultz LD (1996) Role of nitric oxide in host defense against an extracellular, metazoan parasite, Brugia malayi. Infect Immun 64:3351–3353PubMedGoogle Scholar
  27. 27.
    Taylor MJ, Cross HF, Mohammed AA, Trees AJ, Bianco AE (1996) Susceptibility of Brugia malayi and Onchocerca lienalis microfilariae to nitric oxide and hydrogen peroxide in cell-free culture and from IFN gamma-activated macrophages. Parasitology 112(Pt 3):315–322PubMedCrossRefGoogle Scholar
  28. 28.
    Hussain R, Hamilton RG, Kumaraswami V, Adkinson NF Jr, Ottesen EA (1981) IgE responses in human filariasis. I. Quantitation of filaria-specific IgE. J Immunol 127:1623–1629PubMedGoogle Scholar
  29. 29.
    Mitre E, Nutman TB (2006) IgE memory: persistence of antigen-specific IgE responses years after treatment of human filarial infections. J Allergy Clin Immunol 117:939–945PubMedCrossRefGoogle Scholar
  30. 30.
    Geha RS, Jabara HH, Brodeur SR (2003) The regulation of immunoglobulin E class-switch recombination. Nat Rev Immunol 3:721–732PubMedCrossRefGoogle Scholar
  31. 31.
    Ottesen EA, Skvaril F, Tripathy SP, Poindexter RW, Hussain R (1985) Prominence of IgG4 in the IgG antibody response to human filariasis. J Immunol 134:2707–2712PubMedGoogle Scholar
  32. 32.
    Nutman TB, Kumaraswami V (2001) Regulation of the immune response in lymphatic filariasis: perspectives on acute and chronic infection with Wuchereria bancrofti in South India. Parasite Immunol 23:389–399PubMedCrossRefGoogle Scholar
  33. 33.
    Maizels RM, Balic A, Gomez-Escobar N, Nair M, Taylor MD, Allen JE (2004) Helminth parasites—masters of regulation. Immunol Rev 201:89–116PubMedCrossRefGoogle Scholar
  34. 34.
    King CL, Nutman TB (1991) Regulation of the immune response in lymphatic filariasis and onchocerciasis. Immunol Today 12:A54–A58PubMedCrossRefGoogle Scholar
  35. 35.
    van Riet E, Hartgers FC, Yazdanbakhsh M (2007) Chronic helminth infections induce immunomodulation: consequences and mechanisms. Immunobiology 212:475–490PubMedCrossRefGoogle Scholar
  36. 36.
    Hewitson JP, Grainger JR, Maizels RM (2009) Helminth immunoregulation: the role of parasite secreted proteins in modulating host immunity. Mol Biochem Parasitol 167:1–11PubMedCrossRefGoogle Scholar
  37. 37.
    Harnett W, Harnett MM (2010) Helminth-derived immunomodulators: can understanding the worm produce the pill? Nat Rev Immunol 10:278–284PubMedCrossRefGoogle Scholar
  38. 38.
    Maizels RM, Gomez-Escobar N, Gregory WF, Murray J, Zang X (2001) Immune evasion genes from filarial nematodes. Int J Parasitol 31:889–898PubMedCrossRefGoogle Scholar
  39. 39.
    Taylor MD, van der Werf N, Maizels RM (2012) T cells in helminth infection: the regulators and the regulated. Trends Immunol 33:181–189PubMedCrossRefGoogle Scholar
  40. 40.
    King CL, Kumaraswami V, Poindexter RW, Kumari S, Jayaraman K, Alling DW, Ottesen EA, Nutman TB (1992) Immunologic tolerance in lymphatic filariasis. Diminished parasite-specific T and B lymphocyte precursor frequency in the microfilaremic state. J Clin Invest 89:1403–1410PubMedCrossRefGoogle Scholar
  41. 41.
    Taylor MD, LeGoff L, Harris A, Malone E, Allen JE, Maizels RM (2005) Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo. J Immunol 174:4924–4933PubMedGoogle Scholar
  42. 42.
    Steel C, Nutman TB (2003) CTLA-4 in filarial infections: implications for a role in diminished T cell reactivity. J Immunol 170:1930–1938PubMedGoogle Scholar
  43. 43.
    Babu S, Blauvelt CP, Kumaraswami V, Nutman TB (2006) Regulatory networks induced by live parasites impair both Th1 and Th2 pathways in patent lymphatic filariasis: implications for parasite persistence. J Immunol 176:3248–3256PubMedGoogle Scholar
  44. 44.
    Babu S, Kumaraswami V, Nutman TB (2005) Transcriptional control of impaired Th1 responses in patent lymphatic filariasis by T-box expressed in T cells and suppressor of cytokine signaling genes. Infect Immun 73:3394–3401PubMedCrossRefGoogle Scholar
  45. 45.
    Semnani RT, Law M, Kubofcik J, Nutman TB (2004) Filaria-induced immune evasion: suppression by the infective stage of Brugia malayi at the earliest host–parasite interface. J Immunol 172:6229–6238PubMedGoogle Scholar
  46. 46.
    Semnani RT, Liu AY, Sabzevari H, Kubofcik J, Zhou J, Gilden JK, Nutman TB (2003) Brugia malayi microfilariae induce cell death in human dendritic cells, inhibit their ability to make IL-12 and IL-10, and reduce their capacity to activate CD4+ T cells. J Immunol 171:1950–1960PubMedGoogle Scholar
  47. 47.
    Loke P, Nair MG, Parkinson J, Guiliano D, Blaxter M, Allen JE (2002) IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol 3:7PubMedCrossRefGoogle Scholar
  48. 48.
    Nair MG, Cochrane DW, Allen JE (2003) Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro. Immunol Lett 85:173–180PubMedCrossRefGoogle Scholar
  49. 49.
    Nair MG, Gallagher IJ, Taylor MD, Loke P, Coulson PS, Wilson RA, Maizels RM, Allen JE (2005) Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun 73:385–394PubMedCrossRefGoogle Scholar
  50. 50.
    Allen JE, Wynn TA (2011) Evolution of Th2 immunity: a rapid repair response to tissue destructive pathogens. PLoS Pathog 7:e1002003PubMedCrossRefGoogle Scholar
  51. 51.
    Jenson JS, O'Connor R, Osborne J, Devaney E (2002) Infection with Brugia microfilariae induces apoptosis of CD4(+) T lymphocytes: a mechanism of immune unresponsiveness in filariasis. Eur J Immunol 32:858–867PubMedCrossRefGoogle Scholar
  52. 52.
    Babu S, Blauvelt CP, Nutman TB (2007) Filarial parasites induce NK cell activation, type 1 and type 2 cytokine secretion, and subsequent apoptotic cell death. J Immunol 179:2445–2456PubMedGoogle Scholar
  53. 53.
    Dreyer G, Noroes J, Addiss D, Santos A, Medeiros Z, Figueredo-Silva J (1999) Bancroftian filariasis in a paediatric population: an ultrasonographic study. Trans R Soc Trop Med Hyg 93:633–636PubMedCrossRefGoogle Scholar
  54. 54.
    Amaral F, Dreyer G, Figueredo-Silva J, Noroes J, Cavalcanti A, Samico SC, Santos A, Coutinho A (1994) Live adult worms detected by ultrasonography in human Bancroftian filariasis. Am J Trop Med Hyg 50:753–757PubMedGoogle Scholar
  55. 55.
    Dreyer G, Amaral F, Noroes J, Medeiros Z (1994) Ultrasonographic evidence for stability of adult worm location in bancroftian filariasis. Trans R Soc Trop Med Hyg 88:558PubMedCrossRefGoogle Scholar
  56. 56.
    Connor DH, Palmieri JR, Gibson DW (1986) Pathogenesis of lymphatic filariasis in man. Z Parasitenkd 72:13–28PubMedCrossRefGoogle Scholar
  57. 57.
    von Lichtenberg F (1987) The Wellcome Trust lecture. Inflammatory responses to filarial connective tissue parasites. Parasitology 94(Suppl):S101–S122CrossRefGoogle Scholar
  58. 58.
    Olszewski WL, Jamal S, Manokaran G, Pani S, Kumaraswami V, Kubicka U, Lukomska B, Dworczynski A, Swoboda E, Meisel-Mikolajczyk F (1997) Bacteriologic studies of skin, tissue fluid, lymph, and lymph nodes in patients with filarial lymphedema. Am J Trop Med Hyg 57:7–15PubMedGoogle Scholar
  59. 59.
    Shenoy RK, Kumaraswami V, Suma TK, Rajan K, Radhakuttyamma G (1999) A double-blind, placebo-controlled study of the efficacy of oral penicillin, diethylcarbamazine or local treatment of the affected limb in preventing acute adenolymphangitis in lymphoedema caused by brugian filariasis. Ann Trop Med Parasitol 93:367–377PubMedCrossRefGoogle Scholar
  60. 60.
    Vickery AC, Albertine KH, Nayar JK, Kwa BH (1991) Histopathology of Brugia malayi-infected nude mice after immune-reconstitution. Acta Trop 49:45–55PubMedCrossRefGoogle Scholar
  61. 61.
    Vincent AL, Vickery AC, Lotz MJ, Desai U (1984) The lymphatic pathology of Brugia pahangi in nude (athymic) and thymic mice C3H/HeN. J Parasitol 70:48–56PubMedCrossRefGoogle Scholar
  62. 62.
    Nelson FK, Greiner DL, Shultz LD, Rajan TV (1991) The immunodeficient scid mouse as a model for human lymphatic filariasis. J Exp Med 173:659–663PubMedCrossRefGoogle Scholar
  63. 63.
    Vincent AL, Ash LR, Rodrick GE, Sodeman WA Jr (1980) The lymphatic pathology of Brugia pahangi in the Mongolian jird. J Parasitol 66:613–620PubMedCrossRefGoogle Scholar
  64. 64.
    Grenfell BT, Michael E, Denham DA (1991) A model for the dynamics of human lymphatic filariasis. Parasitol Today 7:318–323PubMedCrossRefGoogle Scholar
  65. 65.
    Rogers R, Denham DA, Nelson GS, Guy F, Ponnudurai T (1975) Studies with Brugia pahangi. III: histological changes in the affected lymph nodes of infected cats. Ann Trop Med Parasitol 69:77–84PubMedGoogle Scholar
  66. 66.
    Orton S, Weinstock D, Hammerberg B (1998) Association of elevated lymph node cell release of histamine and tumor necrosis factor with genetic predisposition to limb edema formation in dogs infected with Brugia pahangi. Am J Trop Med Hyg 58:695–704PubMedGoogle Scholar
  67. 67.
    Rao UR, Vickery AC, Kwa BH, Nayar JK (1996) Regulatory cytokines in the lymphatic pathology of athymic mice infected with Brugia malayi. Int J Parasitol 26:561–565PubMedCrossRefGoogle Scholar
  68. 68.
    Porthouse KH, Chirgwin SR, Coleman SU, Taylor HW, Klei TR (2006) Inflammatory responses to migrating Brugia pahangi third-stage larvae. Infect Immun 74:2366–2372PubMedCrossRefGoogle Scholar
  69. 69.
    Sakamoto M, Meier JL, Folse DS, Ewert A (1985) Perturbation of lymphatic endothelial cells in experimental Brugia malayi infections. Microcirc Endothelium Lymphatics 2:487–498PubMedGoogle Scholar
  70. 70.
    Sakamoto M, Shimada M, Fujimaki Y, Ewert A (1988) Degenerative changes in lymphatic endothelium of jirds infected with Brugia pahangi. J Parasitol 74:731–734PubMedCrossRefGoogle Scholar
  71. 71.
    Lal RB, Dhawan RR, Ramzy RM, Farris RM, Gad AA (1991) C-reactive protein in patients with lymphatic filariasis: increased expression on lymphocytes in chronic lymphatic obstruction. J Clin Immunol 11:46–53PubMedCrossRefGoogle Scholar
  72. 72.
    Das BK, Sahoo PK, Ravindran B (1996) A role for tumour necrosis factor-alpha in acute lymphatic filariasis. Parasite Immunol 18:421–424PubMedCrossRefGoogle Scholar
  73. 73.
    Satapathy AK, Sartono E, Sahoo PK, Dentener MA, Michael E, Yazdanbakhsh M, Ravindran B (2006) Human bancroftian filariasis: immunological markers of morbidity and infection. Microbes Infect 8:2414–2423PubMedCrossRefGoogle Scholar
  74. 74.
    el-Sharkawy IM, Haseeb AN, Saleh WA (2001) Serum levels of endothelin-1 (ET-1), interleukin-2 (IL-2) and amino-terminal propeptide type III procollagen (PIII NP) in patients with acute and chronic filariasis. J Egypt Soc Parasitol 31:169–176PubMedGoogle Scholar
  75. 75.
    Babu S, Blauvelt CP, Kumaraswami V, Nutman TB (2005) Chemokine receptors of T cells and of B cells in lymphatic filarial infection: a role for CCR9 in pathogenesis. J Infect Dis 191:1018–1026PubMedCrossRefGoogle Scholar
  76. 76.
    Olszewski WL, Jamal S, Lukomska B, Manokaran G, Grzelak I (1992) Immune proteins in peripheral tissue fluid-lymph in patients with filarial lymphedema of the lower limbs. Lymphology 25:166–171PubMedGoogle Scholar
  77. 77.
    Babu S, Kumaraswami V, Nutman TB (2009) Alternatively activated and immunoregulatory monocytes in human filarial infections. J Infect Dis 199:1827–1837PubMedCrossRefGoogle Scholar
  78. 78.
    Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483PubMedCrossRefGoogle Scholar
  79. 79.
    Senbagavalli P, Anuradha R, Ramanathan VD, Kumaraswami V, Nutman TB, Babu S (2011) Heightened measures of immune complex and complement function and immune complex-mediated granulocyte activation in human lymphatic filariasis. Am J Trop Med Hyg 85:89–96PubMedCrossRefGoogle Scholar
  80. 80.
    Semnani RT, Nutman TB (2004) Toward an understanding of the interaction between filarial parasites and host antigen-presenting cells. Immunol Rev 201:127–138PubMedCrossRefGoogle Scholar
  81. 81.
    Semnani RT, Mahapatra L, Dembele B, Konate S, Metenou S, Dolo H, Coulibaly ME, Soumaoro L, Coulibaly SY, Sanogo D, Seriba Doumbia S, Diallo AA, Traore SF, Klion A, Nutman TB, Mahanty S (2010) Expanded numbers of circulating myeloid dendritic cells in patent human filarial infection reflect lower CCR1 expression. J Immunol 185:6364–6372PubMedCrossRefGoogle Scholar
  82. 82.
    Witte MH, Way DL, Witte CL, Bernas M (1997) Lymphangiogenesis: mechanisms, significance and clinical implications. EXS 79:65–112PubMedGoogle Scholar
  83. 83.
    Bennuru S, Nutman TB (2009) Lymphatics in human lymphatic filariasis: in vitro models of parasite-induced lymphatic remodeling. Lymphat Res Biol 7:215–219PubMedCrossRefGoogle Scholar
  84. 84.
    Rao UR, Zometa CS, Vickery AC, Kwa BH, Nayar JK, Sutton ET (1996) Effect of Brugia malayi on the growth and proliferation of endothelial cells in vitro. J Parasitol 82:550–556PubMedCrossRefGoogle Scholar
  85. 85.
    Bennuru S, Nutman TB (2009) Lymphangiogenesis and lymphatic remodeling induced by filarial parasites: implications for pathogenesis. PLoS Pathog 5:e1000688PubMedCrossRefGoogle Scholar
  86. 86.
    Pfarr KM, Debrah AY, Specht S, Hoerauf A (2009) Filariasis and lymphoedema. Parasite Immunol 31:664–672PubMedCrossRefGoogle Scholar
  87. 87.
    Debrah AY, Mand S, Specht S, Marfo-Debrekyei Y, Batsa L, Pfarr K, Larbi J, Lawson B, Taylor M, Adjei O, Hoerauf A (2006) Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis. PLoS Pathog 2:e92PubMedCrossRefGoogle Scholar
  88. 88.
    Bennuru S, Maldarelli G, Kumaraswami V, Klion AD, Nutman TB (2010) Elevated levels of plasma angiogenic factors are associated with human lymphatic filarial infections. Am J Trop Med Hyg 83:884–890PubMedCrossRefGoogle Scholar
  89. 89.
    Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA (1998) Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A 95:548–553PubMedCrossRefGoogle Scholar
  90. 90.
    Aranda C, Aponte JJ, Saute F, Casimiro S, Pinto J, Sousa C, Rosario VD, Petrarca V, Dgedge M, Alonso P (2005) Entomological characteristics of malaria transmission in Manhica, a rural area in southern Mozambique. J Med Entomol 42:180–186PubMedCrossRefGoogle Scholar
  91. 91.
    Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K (1997) Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423–1425PubMedCrossRefGoogle Scholar
  92. 92.
    Debrah AY, Mand S, Toliat MR, Marfo-Debrekyei Y, Batsa L, Nurnberg P, Lawson B, Adjei O, Hoerauf A, Pfarr K (2007) Plasma vascular endothelial growth factor-A (VEGF-A) and VEGF-A gene polymorphism are associated with hydrocele development in lymphatic filariasis. Am J Trop Med Hyg 77:601–608PubMedGoogle Scholar
  93. 93.
    McLaren DJ, Worms MJ, Laurence BR, Simpson MG (1975) Micro-organisms in filarial larvae (Nematoda). Trans R Soc Trop Med Hyg 69:509–514PubMedCrossRefGoogle Scholar
  94. 94.
    Kozek WJ (1977) Transovarially-transmitted intracellular microorganisms in adult and larval stages of Brugia malayi. J Parasitol 63:992–1000PubMedCrossRefGoogle Scholar
  95. 95.
    Taylor MJ, Cross HF, Bilo K (2000) Inflammatory responses induced by the filarial nematode Brugia malayi are mediated by lipopolysaccharide-like activity from endosymbiotic Wolbachia bacteria. J Exp Med 191:1429–1436PubMedCrossRefGoogle Scholar
  96. 96.
    Hise AG, Daehnel K, Gillette-Ferguson I, Cho E, McGarry HF, Taylor MJ, Golenbock DT, Fitzgerald KA, Kazura JW, Pearlman E (2007) Innate immune responses to endosymbiotic Wolbachia bacteria in Brugia malayi and Onchocerca volvulus are dependent on TLR2, TLR6, MyD88, and Mal, but not TLR4, TRIF, or TRAM. J Immunol 178:1068–1076PubMedGoogle Scholar
  97. 97.
    Debrah AY, Mand S, Marfo-Debrekyei Y, Batsa L, Pfarr K, Lawson B, Taylor M, Adjei O, Hoerauf A (2009) Reduction in levels of plasma vascular endothelial growth factor-A and improvement in hydrocele patients by targeting endosymbiotic Wolbachia sp. in Wuchereria bancrofti with doxycycline. Am J Trop Med Hyg 80:956–963PubMedGoogle Scholar
  98. 98.
    Esterre P, Plichart C, Huin-Blondey MO, Nguyen LN (2005) Soluble cellular adhesion molecules, selectins, VEGF and endothelin-1 in patients with Wuchereria bancrofti infection and association with clinical status. Parasite Immunol 27:9–16PubMedCrossRefGoogle Scholar
  99. 99.
    Babu S, Blauvelt CP, Kumaraswami V, Nutman TB (2005) Diminished expression and function of TLR in lymphatic filariasis: a novel mechanism of immune dysregulation. J Immunol 175:1170–1176PubMedGoogle Scholar
  100. 100.
    Babu S, Blauvelt CP, Kumaraswami V, Nutman TB (2006) Cutting edge: diminished T cell TLR expression and function modulates the immune response in human filarial infection. J Immunol 176:3885–3889PubMedGoogle Scholar
  101. 101.
    Semnani RT, Venugopal PG, Leifer CA, Mostbock S, Sabzevari H, Nutman TB (2008) Inhibition of TLR3 and TLR4 function and expression in human dendritic cells by helminth parasites. Blood 112:1290–1298PubMedCrossRefGoogle Scholar
  102. 102.
    Venugopal PG, Nutman TB, Semnani RT (2009) Activation and regulation of toll-like receptors (TLRs) by helminth parasites. Immunol Res 43:252–263PubMedCrossRefGoogle Scholar
  103. 103.
    Babu S, Bhat SQ, Pavan Kumar N, Lipira AB, Kumar S, Karthik C, Kumaraswami V, Nutman TB (2009) Filarial lymphedema is characterized by antigen-specific Th1 and th17 proinflammatory responses and a lack of regulatory T cells. PLoS Negl Trop Dis 3:e420PubMedCrossRefGoogle Scholar
  104. 104.
    Babu S, Anuradha R, Kumar NP, George PJ, Kumaraswami V, Nutman TB (2011) Filarial lymphatic pathology reflects augmented toll-like receptor-mediated, mitogen-activated protein kinase-mediated proinflammatory cytokine production. Infect Immun 79:4600–4608PubMedCrossRefGoogle Scholar
  105. 105.
    Babu S, Anuradha R, Kumar NP, George PJ, Kumaraswami V, Nutman TB (2012) Toll-like receptor- and filarial antigen-mediated, mitogen-activated protein kinase- and NF-κB-dependent regulation of angiogenic growth factors in filarial lymphatic pathology. Infect Immun. doi: 10.1128/IAI.06179-11
  106. 106.
    Brenchley JM, Douek DC (2012) Microbial translocation across the GI tract. Annu Rev Immunol 30:149–173PubMedCrossRefGoogle Scholar
  107. 107.
    Anuradha R, George PJ, Pavan Kumar N, Fay MP, Kumaraswami V, Nutman TB, Babu S (2012) Circulating microbial products and acute phase proteins as markers of pathogenesis in lymphatic filarial disease. PLoS Pathog. doi: 10.1371/journal.ppat.1002749
  108. 108.
    Amalinei C, Caruntu ID, Giusca SE, Balan RA (2010) Matrix metalloproteinases involvement in pathologic conditions. Rom J Morphol Embryol 51:215–228PubMedGoogle Scholar
  109. 109.
    Wynn TA (2007) Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 117:524–529PubMedCrossRefGoogle Scholar
  110. 110.
    Anuradha R, George JP, Pavankumar N, Kumaraswami V, Nutman TB, Babu S (2012) Altered circulating levels of matrix metalloproteinases and inhibitors associated with elevated type 2 cytokines in lymphatic filarial disease. PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0001681
  111. 111.
    Piessens WF, Partono F, Hoffman SL, Ratiwayanto S, Piessens PW, Palmieri JR, Koiman I, Dennis DT, Carney WP (1982) Antigen-specific suppressor T lymphocytes in human lymphatic filariasis. N Engl J Med 307:144–148PubMedCrossRefGoogle Scholar
  112. 112.
    Nutman TB, Kumaraswami V, Ottesen EA (1987) Parasite-specific anergy in human filariasis. Insights after analysis of parasite antigen-driven lymphokine production. J Clin Invest 79:1516–1523PubMedCrossRefGoogle Scholar
  113. 113.
    Lal RB, Kumaraswami V, Krishnan N, Nutman TB, Ottesen EA (1989) Lymphocyte subpopulations in Bancroftian filariasis: activated (DR+) CD8+ T cells in patients with chronic lymphatic obstruction. Clin Exp Immunol 77:77–82PubMedGoogle Scholar
  114. 114.
    Freedman DO, Horn TD, Maia e Silva CM, Braga C, Maciel A (1995) Predominant CD8+ infiltrate in limb biopsies of individuals with filarial lymphedema and elephantiasis. Am J Trop Med Hyg 53:633–638PubMedGoogle Scholar
  115. 115.
    Freedman DO, Parker-Cook S, Maia e Silva MC, Braga C, Maciel A (1996) Very late antigen-4/vascular cell adhesion molecule-1 (VLA-4/VCAM-1) pathway is involved in the transendothelial migration of lymphocytes in bancroftian filariasis. J Immunol 156:2901–2908PubMedGoogle Scholar
  116. 116.
    Freedman DO, Nutman TB, Jamal S, Kumaraswami V, Ottesen EA (1989) Selective up-regulation of endothelial cell class I MHC expression by cytokines from patients with lymphatic filariasis. J Immunol 142:653–658PubMedGoogle Scholar
  117. 117.
    Freedman DO, Plier DA, de Almeida A, Miranda J, Braga C, Maia e Silva MC, Tang J, Furtado A (1999) Biased TCR repertoire in infiltrating lesional T cells in human Bancroftian filariasis. J Immunol 162:1756–1764PubMedGoogle Scholar
  118. 118.
    King CL, Mahanty S, Kumaraswami V, Abrams JS, Regunathan J, Jayaraman K, Ottesen EA, Nutman TB (1993) Cytokine control of parasite-specific anergy in human lymphatic filariasis. Preferential induction of a regulatory T helper type 2 lymphocyte subset. J Clin Invest 92:1667–1673PubMedCrossRefGoogle Scholar
  119. 119.
    de Almeida AB, Silva MC, Braga C, Freedman DO (1998) Differences in the frequency of cytokine-producing cells in antigenemic and nonantigenemic individuals with bancroftian filariasis. Infect Immun 66:1377–1383PubMedGoogle Scholar
  120. 120.
    Ravichandran M, Mahanty S, Kumaraswami V, Nutman TB, Jayaraman K (1997) Elevated IL-10 mRNA expression and downregulation of Th1-type cytokines in microfilaraemic individuals with Wuchereria bancrofti infection. Parasite Immunol 19:69–77PubMedCrossRefGoogle Scholar
  121. 121.
    Bluestone JA, Mackay CR, O'Shea JJ, Stockinger B (2009) The functional plasticity of T cell subsets. Nat Rev Immunol 9:811–816PubMedCrossRefGoogle Scholar
  122. 122.
    Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA, Rudensky AY (2007) Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445:771–775PubMedCrossRefGoogle Scholar
  123. 123.
    Belkaid Y, Tarbell K (2009) Regulatory T cells in the control of host-microorganism interactions (*). Annu Rev Immunol 27:551–589PubMedCrossRefGoogle Scholar
  124. 124.
    Mahanty S, Mollis SN, Ravichandran M, Abrams JS, Kumaraswami V, Jayaraman K, Ottesen EA, Nutman TB (1996) High levels of spontaneous and parasite antigen-driven interleukin-10 production are associated with antigen-specific hyporesponsiveness in human lymphatic filariasis. J Infect Dis 173:769–773PubMedCrossRefGoogle Scholar
  125. 125.
    Metenou S, Dembele B, Konate S, Dolo H, Coulibaly SY, Coulibaly YI, Diallo AA, Soumaoro L, Coulibaly ME, Sanogo D, Doumbia SS, Traore SF, Mahanty S, Klion A, Nutman TB (2010) At homeostasis filarial infections have expanded adaptive T regulatory but not classical Th2 cells. J Immunol 184:5375–5382PubMedCrossRefGoogle Scholar
  126. 126.
    Mitre E, Chien D, Nutman TB (2008) CD4(+) (and not CD25+) T cells are the predominant interleukin-10-producing cells in the circulation of filaria-infected patients. J Infect Dis 197:94–101PubMedCrossRefGoogle Scholar
  127. 127.
    Rajan TV (2007) Neonatal tolerance and patent filarial infection. Trends Parasitol 23:459–462PubMedCrossRefGoogle Scholar
  128. 128.
    Steel C, Guinea A, McCarthy JS, Ottesen EA (1994) Long-term effect of prenatal exposure to maternal microfilaraemia on immune responsiveness to filarial parasite antigens. Lancet 343:890–893PubMedCrossRefGoogle Scholar
  129. 129.
    Malhotra I, Mungai PL, Wamachi AN, Tisch D, Kioko JM, Ouma JH, Muchiri E, Kazura JW, King CL (2006) Prenatal T cell immunity to Wuchereria bancrofti and its effect on filarial immunity and infection susceptibility during childhood. J Infect Dis 193:1005–1013PubMedCrossRefGoogle Scholar
  130. 130.
    Ottesen EA, Mendell NR, MacQueen JM, Weller PF, Amos DB, Ward FE (1981) Familial predisposition to filarial infection—not linked to HLA-A or-B locus specificities. Acta Trop 38:205–216PubMedGoogle Scholar
  131. 131.
    Terhell AJ, Houwing-Duistermaat JJ, Ruiterman Y, Haarbrink M, Abadi K, Yazdanbakhsh M (2000) Clustering of Brugia malayi infection in a community in South-Sulawesi, Indonesia. Parasitology 120(Pt 1):23–29PubMedCrossRefGoogle Scholar
  132. 132.
    Wahyuni S, Houwing-Duistermaat JJ, Syafruddin ST, Yazdanbakhsh M, Sartono E (2004) Clustering of filarial infection in an age-graded study: genetic, household and environmental influences. Parasitology 128:315–321PubMedCrossRefGoogle Scholar
  133. 133.
    Chan SH, Dissanayake S, Mak JW, Ismail MM, Wee GB, Srinivasan N, Soo BH, Zaman V (1984) HLA and filariasis in Sri Lankans and Indians. Southeast Asian J Trop Med Public Health 15:281–286PubMedGoogle Scholar
  134. 134.
    Yazdanbakhsh M, Sartono E, Kruize YC, Kurniawan A, Partono F, Maizels RM, Schreuder GM, Schipper R, de Vries RR (1995) HLA and elephantiasis in lymphatic filariasis. Hum Immunol 44:58–61PubMedCrossRefGoogle Scholar
  135. 135.
    Choi EH, Zimmerman PA, Foster CB, Zhu S, Kumaraswami V, Nutman TB, Chanock SJ (2001) Genetic polymorphisms in molecules of innate immunity and susceptibility to infection with Wuchereria bancrofti in South India. Genes Immun 2:248–253PubMedCrossRefGoogle Scholar
  136. 136.
    Cuenco KT, Halloran ME, Lammie PJ (2004) Assessment of families for excess risk of lymphedema of the leg in a lymphatic filariasis-endemic area. Am J Trop Med Hyg 70:185–190PubMedGoogle Scholar
  137. 137.
    Cuenco KT, Halloran ME, Louis-Charles J, Lammie PJ (2004) A family study of lymphedema of the leg in a lymphatic filariasis-endemic area. Am J Trop Med Hyg 70:180–184PubMedGoogle Scholar
  138. 138.
    Hise AG, Hazlett FE, Bockarie MJ, Zimmerman PA, Tisch DJ, Kazura JW (2003) Polymorphisms of innate immunity genes and susceptibility to lymphatic filariasis. Genes Immun 4:524–527PubMedCrossRefGoogle Scholar
  139. 139.
    Meyrowitsch DW, Simonsen PE, Garred P, Dalgaard M, Magesa SM, Alifrangis M (2010) Association between mannose-binding lectin polymorphisms and Wuchereria bancrofti infection in two communities in North-Eastern Tanzania. AmJ Trop Med Hyg 82:115–120PubMedCrossRefGoogle Scholar
  140. 140.
    Junpee A, Tencomnao T, Sanprasert V, Nuchprayoon S (2010) Association between Toll-like receptor 2 (TLR2) polymorphisms and asymptomatic bancroftian filariasis. Parasitol Res 107:807–816PubMedCrossRefGoogle Scholar
  141. 141.
    Panda AK, Sahoo PK, Kerketta AS, Kar SK, Ravindran B, Satapathy AK (2011) Human lymphatic filariasis: genetic polymorphism of endothelin-1 and tumor necrosis factor receptor II correlates with development of chronic disease. J Infect Dis 204:315–322PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.NIAID/TRC (now NIRT) ICERChennaiIndia
  2. 2.Helminth Immunology Section, Laboratory of Parasitic DiseasesNational Institute of Allergy and Infectious DiseasesBethesdaUSA
  3. 3.National Institute for Research in TuberculosisChennaiIndia

Personalised recommendations