Filarial Lymphedema is Characterized by Antigen-specific Th1 and Th17 Proinflammatory Responses and a Lack of Regulatory T Cells

Overview

Journal PLoS Negl Trop Dis

Specialties Infectious Diseases
Tropical Medicine

Date 2009 Apr 22

PMID 19381284

Citations 78

Authors

Subash Babu

Sajid Q Bhat

N Pavan Kumar

Angelo B Lipira

Sanath Kumar

C Karthik

V Kumaraswami

Thomas B Nutman

Affiliations

Soon will be listed here.

Abstract

Background: Lymphatic filariasis can be associated with development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients.

Methods And Findings: To elucidate the role of CD4(+) T cell subsets in the development of lymphatic pathology, we examined specific sets of cytokines in individuals with filarial lymphedema in response to parasite antigen (BmA) and compared them with responses from asymptomatic infected individuals. We also examined expression patterns of Toll-like receptors (TLR1-10) and Nod-like receptors (Nod1, Nod2, and NALP3) in response to BmA. BmA induced significantly higher production of Th1-type cytokines-IFN-gamma and TNF-alpha-in patients with lymphedema compared with asymptomatic individuals. Notably, expression of the Th17 family of cytokines-IL-17A, IL-17F, IL-21, and IL-23-was also significantly upregulated by BmA stimulation in lymphedema patients. In contrast, expression of Foxp3, GITR, TGFbeta, and CTLA-4, known to be expressed by regulatory T cells, was significantly impaired in patients with lymphedema. BmA also induced significantly higher expression of TLR2, 4, 7, and 9 as well Nod1 and 2 mRNA in patients with lymphedema compared with asymptomatic controls.

Conclusion: Our findings implicate increased Th1/Th17 responses and decreased regulatory T cells as well as regulation of Toll- and Nod-like receptors in pathogenesis of filarial lymphedema.

Citing Articles

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References

Rutitzky L, Lopes da Rosa J, Stadecker M . Severe CD4 T cell-mediated immunopathology in murine schistosomiasis is dependent on IL-12p40 and correlates with high levels of IL-17. J Immunol. 2005; 175(6):3920-6. DOI: 10.4049/jimmunol.175.6.3920. View

Taylor M, LeGoff L, Harris A, Malone E, Allen J, Maizels R . Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo. J Immunol. 2005; 174(8):4924-33. DOI: 10.4049/jimmunol.174.8.4924. View

Takeda K, Kaisho T, Akira S . Toll-like receptors. Annu Rev Immunol. 2003; 21:335-76. DOI: 10.1146/annurev.immunol.21.120601.141126. View

Lal R, Kumaraswami V, Krishnan N, Nutman T, Ottesen E . Lymphocyte subpopulations in Bancroftian filariasis: activated (DR+) CD8+ T cells in patients with chronic lymphatic obstruction. Clin Exp Immunol. 1989; 77(1):77-82. PMC: 1541923. View

Weaver C, Harrington L, Mangan P, Gavrieli M, Murphy K . Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity. 2006; 24(6):677-688. DOI: 10.1016/j.immuni.2006.06.002. View

Figueredo-Silva J, Noroes J, Cedenho A, Dreyer G . The histopathology of bancroftian filariasis revisited: the role of the adult worm in the lymphatic-vessel disease. Ann Trop Med Parasitol. 2002; 96(6):531-41. DOI: 10.1179/000349802125001348. View

Vickery A, Albertine K, NAYAR J, Kwa B . Histopathology of Brugia malayi-infected nude mice after immune-reconstitution. Acta Trop. 1991; 49(1):45-55. DOI: 10.1016/0001-706x(91)90029-j. View

Gavin M, Rudensky A . Control of immune homeostasis by naturally arising regulatory CD4+ T cells. Curr Opin Immunol. 2003; 15(6):690-6. DOI: 10.1016/j.coi.2003.09.011. View

Li M, Flavell R . Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity. 2008; 28(4):468-76. DOI: 10.1016/j.immuni.2008.03.003. View

10.

Saint Andre A, Blackwell N, Hall L, Hoerauf A, Brattig N, Volkmann L . The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness. Science. 2002; 295(5561):1892-5. DOI: 10.1126/science.1068732. View

11.

Freedman D, Horn T, Maia e Silva C, Braga C, Maciel A . Predominant CD8+ infiltrate in limb biopsies of individuals with filarial lymphedema and elephantiasis. Am J Trop Med Hyg. 1995; 53(6):633-8. View

12.

Taylor M, Bandi C, Hoerauf A . Wolbachia bacterial endosymbionts of filarial nematodes. Adv Parasitol. 2005; 60:245-84. DOI: 10.1016/S0065-308X(05)60004-8. View

13.

Freedman D, Plier D, de Almeida A, Miranda J, Braga C, Maia e Silva M . Biased TCR repertoire in infiltrating lesional T cells in human Bancroftian filariasis. J Immunol. 1999; 162(3):1756-64. View

14.

Numasaki M, Lotze M, Sasaki H . Interleukin-17 augments tumor necrosis factor-alpha-induced elaboration of proangiogenic factors from fibroblasts. Immunol Lett. 2004; 93(1):39-43. DOI: 10.1016/j.imlet.2004.01.014. View

15.

Esterre P, Plichart C, Huin-Blondey M, Nguyen L . Soluble cellular adhesion molecules, selectins, VEGF and endothelin-1 in patients with Wuchereria bancrofti infection and association with clinical status. Parasite Immunol. 2005; 27(1-2):9-16. DOI: 10.1111/j.1365-3024.2005.00732.x. View

16.

Ouyang W, Kolls J, Zheng Y . The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008; 28(4):454-67. PMC: 3424508. DOI: 10.1016/j.immuni.2008.03.004. View

17.

Taylor M, Cross H, Bilo K . Inflammatory responses induced by the filarial nematode Brugia malayi are mediated by lipopolysaccharide-like activity from endosymbiotic Wolbachia bacteria. J Exp Med. 2000; 191(8):1429-36. PMC: 2193140. DOI: 10.1084/jem.191.8.1429. View

18.

Debrah A, Mand S, Specht S, Marfo-Debrekyei Y, Batsa L, Pfarr K . Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis. PLoS Pathog. 2006; 2(9):e92. PMC: 1564427. DOI: 10.1371/journal.ppat.0020092. View

19.

MacMicking J, Xie Q, Nathan C . Nitric oxide and macrophage function. Annu Rev Immunol. 1997; 15:323-50. DOI: 10.1146/annurev.immunol.15.1.323. View

20.

Brattig N, Bazzocchi C, Kirschning C, Reiling N, Buttner D, Ceciliani F . The major surface protein of Wolbachia endosymbionts in filarial nematodes elicits immune responses through TLR2 and TLR4. J Immunol. 2004; 173(1):437-45. DOI: 10.4049/jimmunol.173.1.437. View