MacDonald AS et al. (1999) Pathobiology "Suppressive antigen-presenting cells in Helminth infection."

Allen JE, Loke P, MacDonald AS

[Pathobiology, 1999]

Infection with filarial nematodes is commonly associated with a failure of T cells to proliferate in response to parasite antigen. We have investigated the possibility that antigen-presenting cells recruited during filarial infection are responsible for impairment of T cell function. We have found that the human filarial parasite Brugia malayi, when implanted into the peritoneal cavity of mice, recruits a population of adherent cells that actively block the proliferation of T cells. Phenotypic analysis of the recruited cells reveals large numbers of both macrophages and eosinophils and cell sorting experiments demonstrate that these antiproliferative cells are Mac-1-positive. Studies in gene-deficient mice have demonstrated that proliferative suppression is dependent on the in vivo production of IL-4 but not IL-5 or IL-10, while suppression in vitro is not mediated by any known antiproliferative factor. Our results suggest that helminth infection can lead to the development and/or recruitment of an IL-4-dependent macrophage population that mediates suppression via a novel mechanism.

MacDonald AS et al. (1998) J Immunol "Requirement for in vivo production of IL-4, but not IL-10, in the induction of proliferative suppression by filarial parasites."

Dransfield I, Allen JE, Lawrence RA, Maizels RM, MacDonald AS

[J Immunol, 1998]

Loss of T lymphocyte proliferation and the emergence of a host response that is dominated by a Th2-type profile are well-established features of human filariasis. We have previously reported that adherent peritoneal exudate cells (PEC) from mice transplanted with adult Brugia malayi parasites suppress the proliferation of lymphocytes without blocking Ag-cytokine production in vitro. We now show that infection of mice with the infective larval (L3) stage of B. malayi generates a similar population of PEC. Suppressive cells are generated within 7 days of infection and mediate their effects through a nitric oxide-independent pathway. Both L3 and adult infection elicit high levels of host IL-4 whereas the microfilarial stage of the parasite induces IFN-gamma production and does not generate a similar form of suppression. Production of host IL-4 was necessary to allow the generation of suppressive PEC, given that IL-4-deficient mice implanted with adult parasites failed to induce proliferative block. However, IL-10-deficient mice implanted with adult parasites resulted in T cell suppression, indicating that IL-10 is not essential for the induction of hyporesponsiveness. Neither IL-4 nor IL-10 were directly responsible for ablating cellular proliferation in vitro, as the addition of neutralizing Ab to either cytokine did not reverse the proliferative block. Thus, IL-4 produced in vivo in response to filarial L3 and adult parasites is essential for the induction of proliferative suppression but is not itself the suppressive factor.

MacDonald AS et al. (1998) J Immunol "Requirement for in vivo production of IL-4, but not IL-10, in the induction of proliferative suppression by filarial parasites."

MacDonald AS, Dransfield I, Allen JE, Maizels RM, Lawrence RA

[J Immunol, 1998]

Loss of T lymphocyte proliferation and the emergence of a host response that is dominated by a Th2-type profile are well-established features of human filariasis. We have previously reported that adherent peritoneal exudate cells (PEC) from mice transplanted with adult Brugia malayi parasites suppress the proliferation of lymphocytes without blocking Ag-cytokine production in vitro. We now show that infection of mice with the infective larval (L3) stage of B. malayi generates a similar population of PEC. Suppressive cells are generated within 7 days of infection and mediate their effects through a nitric oxide-independent pathway. Both L3 and adult infection elicit high levels of host IL-4 whereas the microfilarial stage of the parasite induces IFN-gamma production and does not generate a similar form of suppression. Production of host IL-4 was necessary to allow the generation of suppressive PEC, given that IL-4-deficient mice implanted with adult parasites failed to induce proliferative block. However, IL-10-deficient mice implanted with adult parasites resulted in T cell suppression, indicating that IL-10 is not essential for the induction of hyporesponsiveness. Neither IL-4 nor IL-10 were directly responsible for ablating cellular proliferation in vitro, as the addition of neutralizing Ab to either cytokine did not reverse the proliferative block. Thus, IL-4 produced in vivo in response to filarial L3 and adult parasites is essential for the induction of proliferative suppression but is not itself the suppressive factor.

MacDonald AS et al. (2003) Med Microbiol Immunol "Cytokine-dependent inflammatory cell recruitment patterns in the peritoneal cavity of mice exposed to the parasitic nematode Brugia malayi."

Dransfield I, Loke P, MacDonald AS, Allen JE, Martynoga R

[Med Microbiol Immunol, 2003]

Mice exposed intraperitoneally to either adult or first larval stage (microfilaria) of the human nematode parasite Brugia malayi display polarized cytokine responses. We have used this model to investigate the impact of altered cytokine profiles on inflammatory cell recruitment patterns in vivo. Here we demonstrate that Th2-inducing adult parasites drive the recruitment of eosinophils and macrophages after implant into the murine peritoneal cavity whereas Th1-inducing microfilaria do not. The underlying mechanism of recruitment was further defined by use of mice deficient in the key Th2 cytokines IL-4 or IL5 and mice that lack T cells (nude mice). Recruitment dynamics differed in IL-4 and IL-5 deficient mice, showing reduced or absent eosinophilia. These data emphasize the pivotal role of these cytokines in shaping the cellular profile of inflammatory responses. Surprisingly, the absence of T cells failed to influence inflammatory cell recruitment indicating that recruitment signals are provided by other cell types.

Macdonald LD et al. (2008) Genetics "Proteasomal regulation of the proliferation vs. meiotic entry decision in the Caenorhabditis elegans germ line."

Hansen D, Knox A, Macdonald LD

[Genetics, 2008]

Reproductive fitness in many animals relies upon a tight balance between the number of cells that proliferate in the germ line, and the number of cells that enter meiosis and differentiate as gametes. In the C. elegans germ line, the GLP-1/Notch signaling pathway controls this balance between proliferation and meiotic entry. Here we describe the identification of the proteasome as an additional regulator of this balance. We show that a decrease in proteasome activity, either through genetic mutation or RNAi to core components of the proteasome, shifts this balance towards excess germline proliferation. We further demonstrate that there are likely two or more proteasome targets that contribute to excess germline proliferation when proteasome activity is reduced. One of these targets is likely a component or regulator of the Notch signaling pathway, while the other functions on one of the two major redundant genetic pathways downstream of GLP-1/Notch signaling. We propose a model in which the proteasome degrades proteins that are necessary for proliferation as cells switch from proliferation to meiotic entry.

Macdonald BA et al. (2006) Blood "Zebrafish to humans: evolution of the alpha3-chain of type IV collagen and emergence of the autoimmune epitopes associated with Goodpasture syndrome."

Kalluri R, Sund M, Zon LI, Pfaff KL, Holthaus K, Macdonald BA, Grant MA

[Blood, 2006]

Goodpasture''s syndrome is an autoimmune vascular disease associated with kidney and lung failure, with pathogenic circulating autoantibodies targeted to a set of discontinuous epitope sequences within the non-collagenous domain-1 (NC1) of the alpha3 chain of type IV collagen [alpha3(IV)NC1], the Goodpasture''s autoantigen. We demonstrate that basement membrane extracted NC1 domain preparations from C. elegans, Drosophila melanogaster and Danio rerio do not bind Goodpasture''s autoantibodies, while Xenopus laevis, chicken, mouse and human alpha3(IV)NC1 domains bind autoantibodies. The alpha3(IV)-chain is not present in C. elegans and Drosophila melanogaster, but is first detected in the Danio rerio. Interestingly, native Danio rerio alpha3(IV)NC1 does not bind Goodpasture''s autoantibodies. Next, we cloned, sequenced and generated recombinant Danio rerio alpha3(IV)NC1 domain. In contrast to recombinant human alpha3(IV)NC1 domain, there was complete absence of autoantibody binding to recombinant Danio rerio alpha3(IV)NC1. 3D molecular modeling from existing x-ray co-ordinates of human NC1 domain suggest that evolutionary alteration of electrostatic charge and polarity due to the emergence of critical serine, aspartic acid and lysine residues, accompanied by the loss of asparagine and glutamine contributes to the emergence of the two major Goodpasture''s epitopes on the human alpha3(IV)NC1 domain, as it evolved from the Danio rerio over 450 million years.

MacDonald D et al. (2004) J Ethnopharmacol "Ascaridole-less infusions of Chenopodium ambrosioides contain a nematocide(s) that is(are) not toxic to mammalian smooth muscle."

Rosenfeld J, Rangachari PK, Sorger G, Warren C, MacDonald D, VanCrey K, Harrison P

[J Ethnopharmacol, 2004]

Infusions of Chenopodium ambrosioides (L.) have been used for centuries in the Americas as a popular remedy against intestinal worm infections. The essential oil of Chenopodium ambrosioides contains high levels of ascaridole, which is a potent anthelmintic, but which has also been responsible for human fatalities, leading to its disuse. Almost 90% of the nematocidal activity of Chenopodium ambrosioides infusions was due to a hydrophilic component different from ascaridole. Synthetic ascaridole and the ascaridole from infusions, extracted into hexane, caused a reduction of carbachol-induced contractions in rat gastrointestinal smooth muscle at concentrations required to kill Caenorhabditis elegans (L.). The herbal infusion and the ascaridole-free hexane-extracted aqueous residue of the above infusion, at nematocidal concentrations, had no detectable effect on smooth muscle contraction in the above system. It would appear that the traditional form of usage of Chenopodium ambrosioides infusions as a vermifuge is safer than the use of the herb's essential oil.

MacDonald AJ et al. (2002) Infect Immun "Differential cytokine and antibody responses to adult and larval stages of Onchocerca volvulus consistent with the development of concomitant immunity."

MacDonald AJ, Bennett KE, Simonek SC, Enyong PA, Lustigman S, Harmon-Brown C, Tierney TJ, McCarthy MC, Turaga PS, Moukatte DW

[Infect Immun, 2002]

The possibility of concomitant immunity and its potential mechanisms in Onchocerca volvulus infection were examined by analyzing cytokine and antibody responses to infective larval (third-stage larvae [L3] and molting L3 [mL3]), adult female worm (F-OvAg), and skin microfilaria (Smf) antigens in infected individuals in a region of hyperendemicity in Cameroon as a function of age. Peripheral blood mononuclear cell interleukin 5 (IL-5) responses to F-OvAg and Smf declined significantly with age (equivalent to years of exposure to O. volvulus). In contrast, IL-5 secretion in response to L3 and mL3 remained elevated with increasing age. Gamma interferon responses to L3, mL3, and F-OvAg were low or suppressed and unrelated to age, except for responses to Smf in older subjects. IL-10 levels were uniformly elevated, regardless of age, in response to L3, mL3, and F-OvAg but not to Smf, for which levels declined with age. A total of 49 to 60% of subjects had granulocyte-macrophage colony-stimulating factor responses to all O. volvulus antigens unrelated to age. Analysis of levels of stage-specific immunoglobulin G3 (IgG3) and IgE revealed a striking, age-dependent dissociation between antibody responses to larval antigens (L3 and a recombinant L3-specific protein, O. volvulus ALT-1) which were significantly increased or maintained with age and antibody responses to F-OvAg, which decreased. Levels of IgG1 to L3 and F-OvAg were elevated regardless of age, and levels of IgG4 increased significantly with age, although not to O. volvulus ALT-1, which may have unique L3-specific epitopes. Immunofluorescence staining of whole larvae showed that total anti-L3 immunoglobulin levels also increased with the age of the serum donor. The separate and distinct cytokine and antibody responses to adult and infective larval stages of O. volvulus which are age related are consistent with the acquisition of concomitant immunity in infected individuals.

MACDONALD WW (1963) Ann Trop Med Parasitol "A PRELIMINARY CROSS-OVER VALUE BETWEEN THE GENE FM (FILARIAL SUSCEPTIBILITY, BRUGIA MALAYI) AND THE SEX LOCUS IN AEDES AEGYPTI."

MACDONALD WW

[Ann Trop Med Parasitol, 1963]

MACDONALD WW et al. (1965) Ann Trop Med Parasitol "THE INFLUENCE OF THE GENE FM (FILARIAL SUSCEPTIBILITY, BRUGIA MALAYI) ON THE SUSCEPTIBILITY OF AEDES AEGYPTI TO SEVEN STRAINS OF BRUGIA, WUCHERERIA AND DIROFILARIA."

MACDONALD WW, RAMACHANDRAN CP

[Ann Trop Med Parasitol, 1965]