Determinants for resistance and susceptibility to microfilaraemia in Litomosoides sigmodontis filariasis

Hoffmann, W. H.; Pfaff, Alexander W.; Schulz‐Key, H.; Soboslav, P. T.

doi:10.1017/s0031182001007892

Cited by 58 publications

(58 citation statements)

References 33 publications

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“…To understand how the established L. sigmodontis infection mediated suppression of Th cells, we focused on Treg and IL-10 because there is accumulating evidence that these are central mediators of L. sigmodontis-induced suppression of the immune response toward itself (26)(27)(28)(29)43) and to third-party Ags (30-32, 44, 45) in different systems. Also, human studies strongly support the notion that IL-10 is a key mediator of nematode-induced immune suppression (46)(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

“…The power of this suppression was demonstrated by the fact that implantation of a single L. sigmodontis female adult into resistant DBA/1 mice inhibited the clearance of MF, which under normal circumstances occurs within 3 d in this mouse strain (29). This suppression was not restricted to filarial-specific immune responses but acted on unrelated thirdparty Ags as well.…”

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confidence: 95%

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Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

Hartmann

Haben

Fleischer

et al. 2011

The Journal of Immunology

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One third of the human population is infected with helminth parasites. To promote their longevity and to limit pathology, helminths have developed several strategies to suppress the immune response of their host. As this immune suppression also acts on unrelated third-party Ags, a preexisting helminth infection may interfere with vaccination efficacy. In this study, we show that natural infection with Litomosoides sigmodontis suppressed the humoral response to thymus-dependent but not to thymus-independent model Ags in C57BL/6 mice. Thereby, we provide evidence that reduced humoral responses were mediated by interference with Th cell function rather than by direct suppression of B cells in L. sigmodontis-infected mice. We directly demonstrate suppression of Ag-specific proliferation in OVA-specific Th cells after adoptive transfer into L. sigmodontis-infected mice that led to equally reduced production of OVA-specific IgG. Transferred Th cells displayed increased frequencies of Foxp3+ after in vivo stimulation within infected but not within naive mice. Helminth-mediated suppression was induced by established L. sigmodontis infections but was completely independent of the individual worm burden. Using DEREG mice, we rule out a central role for host-derived regulatory T cells in the suppression of transferred Th cell proliferation. In contrast, we show that L. sigmodontis-induced, host-derived IL-10 mediated Foxp3 induction in transferred Th cells and significantly contributed to the observed Th cell hypoproliferation within infected mice.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

Hartmann

Haben

Fleischer

et al. 2011

The Journal of Immunology

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“…Similarly, a population of peritoneal exudate cells capable of inhibiting the proliferative responses of spleen cells to mitogen is recruited following implantation of adult L. sigmondontis worms (22). To determine whether a similarly suppressive cell population is recruited to the pleural cavity during a natural L. sigmodontis infection, we isolated the adherent PleC from BALB/c mice 40 days (prepatency) and 60 days (postpatency) postinfection.…”

Section: Sigmodontis Infection Recruits a Suppressive Cell Populatmentioning

confidence: 99%

“…injected microfilariae (Mf) (22). Similarly, implantation of B. malayi adults into the peritoneal cavity recruits NeM that profoundly inhibit the proliferative responses of T cells (23).…”

mentioning

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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“…1 Evidence for its immunosuppressive activity has been based on the observations that (i) increased production of IL-10 ex vivo and in animal models was associated with states of immunosuppression, 2,3 (ii) neutralizing antibodies to IL-10 reversed hyporesponsiveness of T cells ex vivo, 4,5 and (iii) deletion of the IL-10 gene rendered mice more resistant to tumors or infection and more susceptible to infection pathology or autoimmune disease. [6][7][8][9] Substantial interindividual variability has been noted in several studies with humans, and heritability of high or low IL-10 secretion was observed. 10,11 Polymorphisms in the putative promoter region of the human IL-10 gene were identified and correlated to high or low IL-10 production of peripheral blood cells (PBCs) upon in vitro stimulation with lipopolysacharide (LPS) or concanavalin A (ConA).…”

Section: Introductionmentioning

confidence: 99%

Promoter haplotypes of the interleukin-10 gene influence proliferation of peripheral blood cells in response to helminth antigen

et al. 2004

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Since interleukin (IL)-10 is a key mediator of immunosuppression, and immunosuppression is considered an important element of helminth infection, we studied variants of the putative IL-10 gene promoter in 337 individuals from 130 families heavily exposed to infection by the tissue nematode Onchocerca volvulus. As shown by transmission disequilibrium tests, variants of the IL-10 promoter at positions -1082(G/A), -819(C/T), and -592(C/A) in the haplotype of ATA were significantly associated with high peripheral blood cell (PBC) proliferative responses to O. volvulus antigen (OvAg). No associations were observed using phytohemagglutinin-induced PBC proliferation or with qualitative or quantitative phenotypes of onchocerciasis or onchocerciasis-related skin disease. The findings are compatible with the hypothesis that the ATA haplotype causes a decrease in IL-10 production by OvAg-reactive type-1 regulatory T-lymphocytes, thereby alleviating the suppression of other T cells. To our knowledge, this is the first time that an influence of IL-10 promoter variants is shown on the adaptive immune response.

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Determinants for resistance and susceptibility to microfilaraemia in Litomosoides sigmodontis filariasis

Cited by 58 publications

References 33 publications

Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

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

Promoter haplotypes of the interleukin-10 gene influence proliferation of peripheral blood cells in response to helminth antigen

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