Brugia pahangi: Effects of duration of infection and parasite burden on lymphatic lesion severity, granulomatous hypersensitivity, and immune responses in jirds (Meriones unguiculatus)

Klei, Thomas R.; McVay, Catherine S.; Dennis, Vida A.; Coleman, Sharon U.; Enright, Frederick M.; Casey, Harold W.

doi:10.1016/0014-4894(90)90065-k

Cited by 53 publications

(46 citation statements)

References 14 publications

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“…There is clear evidence during human infection that APC function is compromised (11,12), and rodent models of filarial infection have demonstrated a variety of mechanisms by which filarial parasites immunosuppress their host (13)(14)(15)(16)(17)(18)(19). Mosquito-borne Brugia malayi L3 larvae are able to down-regulate expression of MHC class I and class II on human Langerhans cells and to inhibit their ability to activate T cells in vitro (20), whereas the same parasites, if injected into the murine peritoneal cavity, induce suppressive nematode-elicited macrophages (NeM) 3 that are able to block T cell proliferative responses (21).…”

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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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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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“…Relative standard curves were constructed from cDNA prepared from RNA isolated from cells stimulated with either concanavalin A (10 g/ml, 24 h) (10,22) or lipopolysaccharide (LPS) (10 g/ml) (22). The concanavalin A-stimulated cDNA was used as a standard for IL-4 and IFN-␥, and the LPS-stimulated cDNA was used for TNF-␣ and IL-6.…”

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confidence: 99%

Inflammatory Responses to Migrating Brugia pahangi Third-Stage Larvae

et al. 2006

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Despite being central to parasite establishment and subsequent host pathological and immunologic responses, host-parasite interactions during early third-stage filarial larva (L3) migration are poorly understood. These studies aimed to define early tissue migration of Brugia pahangi L3 in the gerbil (Meriones unguiculatus) and measure host cellular responses during this period. Gerbils were intradermally inoculated in the hind limb with 100 B. pahangi L3, and necropsies were performed at various times. At 3 h, most L3 (96.3%) were recovered from tissues associated with the infection site, with marked L3 migration occurring by 24 h. Larvae were dispersed throughout the lymphatics at 7 days postinfection (dpi), and at 28 dpi, most parasites were recovered from the spermatic cord lymphatics. Parasites were identified histologically at all time points. Inflammatory cells, primarily neutrophils, were frequently observed around larvae in the dermis and muscle near the injection site at 3 h and 24 h. Levels of interleukin-6 (IL-6) and tumor necrosis factor-␣ mRNA peaked at 3 h in all tissues, with IL-6 levels also high in the spleen at 28 dpi. Levels of IL-4 mRNA were elevated in all tissues at 28 dpi. These observations demonstrate that L3 migrate quickly through various tissues and into lymph nodes in a predictable pattern. Migrating L3 induce an early acute inflammatory response that is modulated as parasites establish in the lymphatics. Polarization of the host response towards a dominant Th2-like profile is present at 7 dpi and is well established by 28 dpi in this permissive host.It is generally accepted that third-stage filarial nematode infective larvae (L3) emerge from the mosquito labia during feeding, accumulate in a pool of hemolymph, and enter the host through the wound left by the mosquito vector (13). While the L3 are apparently unable to penetrate intact skin, their early migrations require movements through the connective tissues of the skin to lymphatic vessels and, in some cases, the blood vascular system. These events have been demonstrated experimentally by feeding Brugia-infected mosquitoes on cats (14, 17) and gerbils (3) and by in vivo studies involving the application of L3 to punctured skin (14). Furthermore, previous studies by Ah et al. (1) have clearly shown that L3 can actively and rapidly migrate through a variety of complex tissues following placement on the surface of the gerbil eyeball. The mechanisms utilized by the larvae during this early migratory phase through these various tissues have not been defined.Early migrations of L3 through the tissues of the skin not only are central to the successful establishment of parasites but are also likely to be important in the initial induction of the host response. It is expected that these responses are involved in the elimination or inhibition of incoming L3 during early migrations. The migration of L3 into the skin may also be uniquely involved in defining the nature of subsequent immune responses to parasite antigens. Based on various in ...

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“…19,20 This inflammatory response can be systemically measured by determining granuloma areas that form around Sepharose 4B (Sigma, St. Louis, MO) beads coated with parasite proteins and subsequently embolized in the lungs. [21][22][23] A differential induction of this granulomatous response in infected animals has been demonstrated using high-performance liquid chromatography fractions of soluble worm extracts. 5 More recently, the kinetics of lymphoproliferative responses of cells from renal lymph nodes that drain lymphatics harboring parasites have been shown to mimic that of the pulmonary granulomatous inflammatory response (PGRN).…”

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confidence: 99%

“…The methods used to couple the beads were essentially followed as previously described. 23 To confirm that these proteins were bound to the beads, protein determination on beads coated with these proteins was performed with Bio-Rad (Hercules, CA) protein detection assay. The absorbance values indicated that similar amounts of recombinant proteins and MBP were coupled to the surface of all coated beads.…”

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confidence: 99%

“…The results presented here indicate that gp29 is capable of eliciting a similar immune response that induces this type of lesion. 23 Antibody responses to gp29 have been detected early during infection of cats with B. pahangi 38 and of monkeys with Wuchereria bancrofti. 39 However, the isotypic character of these antibodies is not known and cellular responses of animals or human patients to this protein have not been described.…”

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confidence: 99%

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Granulomatous inflammatory response to recombinant filarial proteins of Brugia species.

Rao

Nasarre²,

Coleman³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. The lymphatic inflammatory response in Brugia-infected jirds peaks early during primary infections and then decreases in severity as judged by the numbers of lymph thrombi present within these vessels. Antigenspecific hypersensitivity reactions in these animals was measured by a pulmonary granulomatous inflammatory response (PGRN) induced by somatic adult worm antigen (SAWA)-coated beads, and by cellular proliferative responses of renal lymph node cells. The kinetics of these responses temporally correspond to lymphatic lesion formation. The importance of any single antigen to the induction of this inflammatory response has not been elucidated. In this study, the PGRN was used to measure the cellular immune response to four recombinant filarial proteins during the course of a primary B. pahangi infection. These proteins were BpL4, glycoprotein (glutathione peroxidase) gp29, heat shock protein (hsp) 70, and filarial chitinase. All were fusion proteins of maltose-binding protein (MBP). Control beads included those coated with diethanolamine (DEA), SAWA, or MBP. The measurements of PRGN were made at 14, 28, 56, and Ͼ 150 days postinfection (PI) in infected jirds, in jirds sensitized with SAWA, and in uninfected jirds. The secretory homolog of glutathione peroxidase gp29 was the only recombinant protein tested that induced a significantly greater PGRN (P Ͻ 0.05) than controls. This was seen at 28 days PI. These observations indicate that gp29 may be part of the worm antigen complex that induces an early inflammatory response, a response similar to that observed with SAWA. These studies indicate that this approach is useful in investigating the functional ability of specific proteins in the induction and down-regulation of immune-mediated inflammatory responses elicited by filarial parasites. Absence of a granulomatous response to the other recombinant proteins used may be related to the nature and sensitivity of the assay used or the character of recombinant proteins tested.

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Brugia pahangi: Effects of duration of infection and parasite burden on lymphatic lesion severity, granulomatous hypersensitivity, and immune responses in jirds (Meriones unguiculatus)

Cited by 53 publications

References 14 publications

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

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

Inflammatory Responses to Migrating Brugia pahangi Third-Stage Larvae

Granulomatous inflammatory response to recombinant filarial proteins of Brugia species.

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