Immune responses in human infections with Brugia malayi: specific cellular unresponsiveness to filarial antigens.

Piessens, Willy F.; McGreevy, P. B.; Piessens, P W; McGreevy, M.; Koiman, Iskak; Saroso, J. Sulianti; Dennis, David T.

doi:10.1172/jci109648

Cited by 139 publications

(80 citation statements)

References 12 publications

(18 reference statements)

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“…Lymphatic filariasis covers a spectrum of disease states from asymptomatic carrier (microfilaremic) to chronic lymphatic dysfunction and elephantiasis (3,4). Notably, the asymptomatic subjects, who carry high levels of circulating transmissionstage microfilariae, display a muted immunological response (5)(6)(7)(8), failing to mount parasite-specific T cell proliferative and cytokine responses. The degree of suppression is accentuated with higher parasite loads (9), and can be reversed by anti-filarial chemotherapy (10,11).…”

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confidence: 99%

Expansion of Foxp3+ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi

McSorley

Harcus

Murray

et al. 2008

The Journal of Immunology

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Many helminths, including Brugia malayi, are able to establish long-lived infections in immunocompetent hosts. Growing evidence suggests that the immune system’s failure to eliminate parasites is at least partially due to the effects of regulatory T cells (Tregs). To test whether parasites may directly stimulate host regulatory activity, we infected mice with two key stages of B. malayi. Both mosquito-borne infective larvae and mature adults i.p. introduced were found to preferentially expand the proportion of CD25+Foxp3+ cells within the CD4+ T cell population. The induction of Foxp3 was accompanied by raised CD25, CD103, and CTLA-4 expression, and was shown to be an active process, which accompanied the introduction of live, but not dead parasites. CTLA-4 expression was also markedly higher on Foxp3− cells, suggesting anergized effector populations. Peritoneal lavage CD4+CD25+ cells from infected mice showed similar suppressive activity in vitro to normal splenic “natural” Tregs. Both B. malayi larvae and adults were also able to induce Foxp3 expression in adoptively transferred DO11.10 T cells, demonstrating that filarial infection can influence the development of T cells specific to a third party Ag. In addition, we showed that induction was intact in IL-4R-deficient animals, in the absence of a Th2 or alternatively activated macrophage response. We conclude that filarial infections significantly skew the balance of the host immune system toward Treg expansion and activation, in a manner dependent on live parasites but independent of a concomitant Th2 response.

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confidence: 99%

Expansion of Foxp3+ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi

McSorley

Harcus

Murray

et al. 2008

The Journal of Immunology

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“…This response has led to the hypothesis that the long-lived survival of filarial worms within immunocompetent hosts is due to the parasites' ability to suppress protective immune responses (1)(2)(3). In human infection, this effect is evident in a loss of Ag-specific T cell proliferative responses (4,5) and lowered production of both Th1 (IFN-␥) and Th2 (IL-5) effector cytokines (6,7). The isolation of T cells with regulatory characteristics from humans infected with Onchocerca volvulus, Loa loa, and Wuchereria bancrofti indicates that regulatory T cells are involved in filarial suppression (8,9), and during Litomosoides sigmodontis infection of mice, they play an important role in promoting filarial survival (10).…”

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confidence: 99%

“…In human studies, filarial immunosuppression is most marked in microfilaremic individuals who carry healthy adult worms and circulating Mf (5). The time of onset of microfilaremia is also associated with maximal immune suppression in a range of animal models (17,(25)(26)(27)(28).…”

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confidence: 99%

F4/80+ Alternatively Activated Macrophages Control CD4+ T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection

Taylor

Harris

Nair

et al. 2006

The Journal of Immunology

105

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Both T cells and APC have been strongly implicated in the immune suppression observed during filarial nematode infections, but their relative roles are poorly understood, particularly in regard to timing and locality of action. Using Litomosoides sigmodontis infection of susceptible BALB/c mice, we have studied the progression of filarial immunosuppression leading to patent infection with blood microfilaremia. Patent infection is associated with decreased immune responsiveness in the draining thoracic lymph nodes (tLN) and intrinsically hyporesponsive CD4+ T cells at the infection site. We now show that we are able to separate, both in time and space, different suppressive mechanisms and cell populations that contribute to filarial hyporesponsiveness. L. sigmodontis infection recruited a F4/80+ population of alternatively activated macrophages that potently inhibited Ag-specific CD4+ T cell proliferative responses even in the presence of competent naive APC. T cell responsiveness was partially restored by neutralizing TGF-β, but not by blocking IL-10 or CTLA-4 signaling. During prepatent infection, the macrophage population was restricted to the infection site. However, once infection became patent with systemic release of microfilariae, the suppressive macrophage activity extended peripherally into the tLN. In contrast, the hyporesponsive CD4+ T cell phenotype remained localized at the infection site, and the tLN CD4+ T cell population recovered full Ag responsiveness in the absence of suppressive macrophages. Filarial immunosuppression, therefore, evolves over time at sites increasingly distal to infection, and the mechanisms of filarial down-regulation are dependent on proximity to the infection site.

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“…The events that lead to these conditions are poorly characterized, but immune and/or inflammatory responses to the parasites are believed to play a significant role in mediating some of these serious clinical manifestations. [2][3][4][5] Because both Wb and Bm harbor the intracellular Wolbachia endosymbiont, previous studies have implicated Wolbachia as an inducer of VEGF-C that, in turn, could affect the lymphatic vessels. 6 In addition, treatment with doxycycline, an antibiotic that targets Wolbachia , in patients with LF has been shown to reduce plasma VEGF-C/VEGFR-3 levels and improve pathology.…”

Section: Introductionmentioning

confidence: 99%

Elevated Levels of Plasma Angiogenic Factors Are Associated with Human Lymphatic Filarial Infections

Bennuru¹,

Maldarelli²,

Kumaraswami³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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Lymphatic dilatation, dysfunction, and lymphangiogenesis are hallmarks of patent lymphatic filariasis, observed even in those with subclinical microfilaremia, through processes associated, in part, by vascular endothelial growth factors (VEGFs). A panel of pro-angiogenic factors was measured in the plasma of subjects from filaria-endemic regions using multiplexed immunological assays. Compared with endemic normal control subjects, those with both subclinical microfilaremia, and those with longstanding lymphedema had significantly elevated levels of VEGF-A, VEGF-C, VEGF-D, and angiopoeitins (Ang-1/Ang-2), with only levels of basic fibroblast growth factor (bFGF) and placental growth factor (PlGF) being elevated only if lymphedema was evident. Furthermore, levels of these factors 1-year post-treatment with doxycycline were similar to pretreatment levels suggesting a minimal role, if any, for Wolbachia. Our data support the concept that filarial infection per se is associated with elevated levels of most of the known pro-angiogenic factors, with only a few being associated with the serious pathologic consequences associated with Wuchereria bancrofti infection.

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Immune responses in human infections with Brugia malayi: specific cellular unresponsiveness to filarial antigens.

Cited by 139 publications

References 12 publications

Expansion of Foxp3+ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi

Expansion of Foxp3+ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi

F4/80+ Alternatively Activated Macrophages Control CD4+ T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection

Elevated Levels of Plasma Angiogenic Factors Are Associated with Human Lymphatic Filarial Infections

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