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Biomedical subjects

D W Dunne

Publications and source records attributed to D W Dunne.

At least 19 recordsLinked to original sources
PubMed2006

Characterization of immunoglobulin binding by schistosomes.

Although controversial, schistosomes are believed to cloak themselves in antibody through non-specific interactions with the immunoglobulin (Ig) molecule. The acquisition of host Ig by the schistosome may mask its foreign status and/or interfere with Fc-dependent functions. We report experiments aimed at characterizing the interaction between Ig-Fc and paramyosin, a schistosome Fc-receptor previously reported to bind human IgG. We show that certain Ig classes, in particular murine IgG2b and IgG3, are not only able to bind recombinant paramyosin, but also associate with other parasite proteins. The Fc region of IgG contains four hydrophobic patches, two of which are known to interact with distinct molecules: one in the Cgamma2-Cgamma3 interdomain region bound by protein G, mannose binding lectin (MBL), and the neonatal Fc-receptor (FcRn), and one at the top of the Cgamma2 domain bound by phagocytic FcgammaRs and C1q. We provisionally discounted the involvement of these regions, since IgG binding by paramyosin did not inhibit FcgammaR-mediated NADPH respiratory bursts, and protein G was unable to block IgG binding to paramyosin. Given their apparent low affinity, we postulate hydrogen bonding between reactive residues in a hydrophobic patch at the bottom of the Cgamma3 domain and negatively charged Glu or Asp amino acids in paramyosin.

Amino Acid Sequence↗
PubMed2006

Parasitic worms and inflammatory diseases.

The debate on whether infection precipitates or prevents autoimmunity remains a contentious one. Recently the suggestion that some unknown microbe can be at the origin of some chronic inflammatory diseases has been countered by accumulating evidence that decreasing infection rates might have an important role to play in the rising prevalence of autoimmune disorders. The 'Hygiene Hypothesis' was initially postulated to explain the inverse correlation between the incidence of infections and the rise of allergic diseases, particularly in the developed world. Latterly, the Hygiene Hypothesis has been extended to also incorporate autoimmune diseases in general. Amongst the various infectious agents, a particular emphasis has been put on the interaction between parasitic worms and humans. Worm parasites have co-evolved with the mammalian immune system for many millions of years and during this time, they have developed extremely effective strategies to modulate and evade host defences and so maintain their evolutionary fitness. It is therefore reasonable to conclude that the human immune system has been shaped by its relationship with parasitic worms and this may be a necessary requirement for maintaining our immunological health. Fully understanding this relationship may lead to novel and effective treatments for a host of deleterious inflammatory reactions.

Animals↗
PubMed2006

Comparative epidemiology of Chlamydia trachomatis infection among men attending sexually transmitted disease clinics with and without indication for testing.

Understanding the epidemiology of Chlamydia trachomatis infection in men without indication for testing (without symptoms, signs, or a report of sexual contact with an infected partner) is of crucial importance to reduce the heavy burden of this infection, particularly because this group of men is not usually offered testing in different clinical settings. Using electronic medical records of two STD clinics in Connecticut, 2000-02, this study identified the risk factors of C. trachomatis infection in men with and without indication for testing. In both groups, men who were younger than 30, African-American, or had a prior history of C. trachomatis infection were significantly more likely to be infected. Since a system for routine reproductive health care of young men does not currently exist, health-care providers need to promote an increased awareness of C. trachomatis infection among their male patients who are at increased risk of infection.

Adult↗
PubMed2005

Condom effectiveness for prevention of Chlamydia trachomatis infection.

BACKGROUND/OBJECTIVES: A growing body of evidence is increasingly demonstrating the effectiveness of condoms for sexually transmitted infection (STI) prevention. The purpose of the present analysis was to provide a disease specific estimate for the effectiveness of condoms in preventing Chlamydia trachomatis infection while controlling for known exposure to infection. METHODS: Condom effectiveness for C trachomatis was estimated using a medical record database from a public sexually transmitted disease clinic (n = 1455). Clients were classified as having known exposure to C trachomatis if they presented to the clinic as a contact to an infected partner. RESULTS: Among clients with known exposure, 13.3% of consistent condom users were diagnosed with C trachomatis infection compared to 34.4% of inconsistent condom users (adjusted odds ratio = 0.10; 95% CI: 0.01 to 0.83). Among clients with unknown exposure, there was no observed protective effect of condoms. CONCLUSIONS: This study provides further evidence that condoms are effective in preventing C trachomatis infection by reporting a disease specific estimate and restricting analyses to individuals with known exposure.

Adult↗
PubMed2004

Hepatosplenic morbidity in two neighbouring communities in Uganda with high levels of Schistosoma mansoni infection but very different durations of residence.

Peri-portal fibrosis can be a serious sequelae of Schistosoma mansoni infection. Age or duration of exposure have been identified as important risk factors, but their relative importance cannot be easily separated. Here, we have compared two cohorts, aged 6-50 years and resident for ten years or since birth, from two neighbouring villages (Booma and Bugoigo) on the eastern shore of Lake Albert, Uganda. Parasitological measurements were similar, whereas the prevalence of peri-portal fibrosis was 5-fold higher in Booma. Data from the cohorts were pooled to assess the relative contribution of age and duration of residency on the risk of disease. Amongst adults, duration of residency was the critical risk factor--individuals aged 17-31 years resident for more 22 years had an almost 12-fold increased risk of fibrosis than those resident for less than 15 years. Height-standardised Splenic Vein Diameter (SVD), Portal Vein Diameter (PVD), Para-sternal Liver Length (PLL) and Spleen Length (SL) values were all higher in Booma, and each organometric parameter except PLL increased with the severity of fibrosis. Our results clearly demonstrate that duration of exposure is a critical risk factor for the development of peri-portal fibrosis and its sequelae in adults. This parameter should therefore be a routine measurement during epidemiological surveys of S. mansoni.

Adolescent↗
PubMed2001

Defective in vivo induction of functional type 2 cytokine responses in aged mice.

Aged mice have various defects in their immune system. We report that following in vivo challenge with type 2 cytokine-inducing Schistosoma mansoni eggs, aged mice fail to produce type 2 cytokines and also have impaired antigen-specific antibody production. Using two separate type 2 cytokine-dependent in vivo models, the synchronous pulmonary schistosome egg granuloma model and infection with the gastro-intestinal nematode Nippostrongylus brasiliensis, aged mice were shown to have a dramatically impaired capacity to elicit a functional type 2 response, i. e. respectively, impaired pulmonary granulomas and delayed rejection of intestinal worms. Aged mice did not develop eosinophilia and had impaired production of antigen specific IgE. Defective induction of type 2 responses was associated with negligible IL-2 and elevated IFN-gamma production by cells from aged mice. Naive aged mice had increased numbers of Th1, Th2 and Tc1 cells compared to young animals. In vivo type 2 challenge increased the frequencies of Th1 and Tc1 cells and reducing Th2 cell numbers in aged mice. These data demonstrate that a consequence of ageing is a profound in vivo defect in the capacity to elicit type 2 cytokine responses and such an impairment in type 2 responsiveness may account for the increased incidence of various type 1 cytokine-mediated diseases in aged individuals.

Aging↗
PubMed2000

Elevated type 1, diminished type 2 cytokines and impaired antibody response are associated with hepatotoxicity and mortalities during Schistosoma mansoni infection of CD4-depleted mice.

During murine Schistosoma mansoni infections parasite eggs evoke a type 2 cytokine-dependent and CD4(+) T cell-mediated granulomatous response in the liver. In this study CD4(+) T cell-depleted CBA / Ca mice developed hepatic steatosis and had high mortalities during early acute schistosome infection. CD4-depleted mice had smaller liver granulomas and reduced hepatic fibrosis. The hepatocytotoxicity was characterized by microvesicular steatosis and neutrophil infiltration. The livers of depleted mice had similar levels of apoptosis as control infected mice but had a marked increase in lipid peroxidation indicative of their livers being under oxidative stress. CD4-depleted mice had impaired egg excretion and exacerbated intestinal pathology. A type 1 cytokine-dominated response was present in infected CD4-depleted mice and relatively reduced production of type 2 cytokines. Antibody responses to parasite antigens were also substantially reduced. Transfer of immune serum or IgG significantly delayed mortalities in depleted mice and prevented hepatocyte damage. Although biasing the cytokine dichotomy to a type 1-dominated response during murine schistosome infection is desirable with respect to certain pathological processes, i. e. it will reduce the granulomatous inflammation and hepatic fibrosis, these effects contribute to fatal pathology if there is reduced protective type 2 cytokines and a defect in antibody responses.

Animals↗
PubMed2000

Immune responses during the acute stages of infection with the intestinal trematode Echinostoma caproni.

This study investigated the nature of the immune response of C57BL/6 mice infected with the trematode Echinostoma caproni. To determine the preferential development of either a Th1 or Th2 cytokine pattern during early stages of infection, cytokine production by spleen and mesenteric lymph node (MLN) cells during the first 3 weeks of infection was followed. Whereas spleen cells failed to respond to antigen stimulation, MLN cells produced IFN-gamma and to a lesser extent IL-4. IL-5 levels were elevated throughout the period studied. The humoral response was consistent with a Th1 cytokine pattern as antigen-specific IgG2a antibodies were preferentially developed. We investigated whether IFN-gamma is critical for establishment of E. caproni infection. Worm burden in infected mice treated with a single injection of anti-IFN-gamma mAb was significantly reduced compared to that of animals treated with a control antibody.

Animals↗
PubMed2000

Expression of interleukin-9 leads to Th2 cytokine-dominated responses and fatal enteropathy in mice with chronic Schistosoma mansoni infections.

Mice infected with Schistosoma mansoni develop Th2 cytokine-mediated granulomatous pathology that is focused on the liver and intestines. In this study, transgenic mice constitutively expressing IL-9 were infected with S. mansoni and the outcome of infection was determined. Eight weeks after infection, transgenic mice with acute infections had a moderate increase in Th2 cytokine production but were overtly normal with respect to parasite infection and pathological responses. Transgenic mice with chronic infections died 10 weeks after infection, with 86% of transgenic mice dead by week 12 of infection, compared to 7% mortality in infected wild-type mice. Stimulation of mesenteric lymph node cells from infected transgenic mice with parasite antigen elicited elevated interleukin-4 (IL-4) and IL-5 production and reduced gamma interferon and tumor necrosis factor alpha production compared to the responses in wild-type mice. Morbid transgenic mice had substantial enlargement of the ileum, which was associated with muscular hypertrophy, mastocytosis, eosinophilia, goblet cell hyperplasia, and increased mucin expression. We also observed that uninfected transgenic mice exhibited alterations in their intestines. Although there was hepatic mastocytosis and eosinophilia in infected transgenic mice, there was no hepatocyte damage. Death of transgenic mice expressing IL-9 during schistosome infection was primarily associated with enteropathy. This study highlights the pleiotropic in vivo activity of IL-9 and demonstrates that an elevated Th2 cytokine phenotype leads to death during murine schistosome infection.

Animals↗
PubMed1999

Nitric oxide and the Th2 response combine to prevent severe hepatic damage during Schistosoma mansoni infection.

During infection with Schistosoma mansoni, NO production increases following the deposition of parasite eggs in the liver. In wild-type C57BL/6 mice, NO levels peak during the sixth week of infection and are subsequently down-regulated. Inducible NO synthase (iNOS) mRNA was found in diseased liver tissue along with TNF-alpha and IFN-gamma, which are known promoters of iNOS expression. Mice treated with aminoguanidine, a selective inhibitor of iNOS, exhibited cachexia and exacerbated liver pathology, suggesting that NO limits hepatocyte damage when the liver is first exposed to eggs. Hepatic iNOS is up-regulated in SCID mice, indicating that NO production is part of an innate response. Studies with infected highly susceptible IL-4-/- mice revealed that prolonged NO production is in itself deleterious and that a major function of the Th2 response, which is severely compromised in the absence of IL-4, is to regulate NO production. In these animals, plasma NO levels are high compared with those in infected wild-type mice and remain elevated until death. Nevertheless, the underlying importance of NO is illustrated by the finding that aminoguanidine treatment leads to more severe liver disease and reduced time to death in infected IL-4-/- mice.

Animals↗
PubMed1999

Tolerization of mice to Schistosoma mansoni egg antigens causes elevated type 1 and diminished type 2 cytokine responses and increased mortality in acute infection.

The granuloma that surrounds the Schistosoma mansoni egg is the cause of pathology in murine schistosomiasis, and its formation is driven by egg Ag-stimulated type 1 and type 2 cytokines. To determine the role of egg-driven immune responses during schistosome infection we rendered CBA/Ca mice unresponsive to schistosome eggs by combined cyclophosphamide treatment and thymectomy. In the early acute stages of schistosome infection, egg-tolerized mice suffered high mortalities. Granuloma size and deposition of collagen in the liver were significantly reduced in egg-tolerized mice. Similarly, limited granuloma responses were detected in the intestines of these mice, and this was associated with a >90% reduction in egg excretion. Histologically, egg-tolerized mice had exacerbated hepatocyte damage, with extensive microvesicular steatosis. Elevated plasma transaminase levels confirmed the damage to hepatocytes. Infected egg-tolerized mice had impaired proliferation responses to egg Ag but intact responses to worm Ag. Tolerized mice had diminished Ab responses to egg Ag and had a type 1 cytokine isotype pattern to worm Ag, with elevated IgG2a and diminished IgG1 and IgE. Egg-tolerized mice failed to down-regulate type 1 cytokines that are normally elicited during early schistosome infection. Hepatic granuloma cells from egg-tolerized mice were also type 1 cytokine dominated, with elevated frequencies of Tc1/Th1 and reduced Tc2/Th2 cells. This study demonstrates that mice tolerized to schistosome eggs have elevated type 1 cytokine responses with diminished type 2 responses and reduced anti-egg Ab during schistosome infection, and these effects are detrimental to the host.

Animals↗
PubMed1999

Selectin and Lewis(x) are required as co-receptors in antibody-dependent cell-mediated cytotoxicity of human eosinophils to Schistosoma mansoni schistosomula.

Killing of Schistosoma mansoni larvae by human eosinophils via antibody-dependent cell-mediated cytotoxicity (ADCC) mechanisms requires adherence between effector cells and parasite targets. The role of adhesion molecules in this mechanism was investigated using blocking monoclonal antibodies (mAb) and soluble ligands. We show that, along with the Mac-1 alpha chain, interactions between selectins and LewisX-related structures, both expressed by eosinophils and parasite targets, play a critical part in the antibody-dependent cytotoxic function of eosinophils. To further elucidate the interactions between adhesion molecules and eosinophil Fc receptors, ADCC was performed with IgG1 or IgA mAb. We found that mAb directed against Mac-1 alpha chain or against LewisX could significantly inhibit the IgG1-, but not IgA cytotoxicity. This result might be explained, at least in part, by the inhibitory effect of these mAb on the release by eosinophils of eosinophil cationic protein, one of the major mediators involved in target killing. Taken together, these results suggest novel interactions between Fc receptors and selectins and LewisX-related structures which might act as co-receptors for eosinophil-mediated cytotoxicity.

Animals↗
PubMed1999

Adult resistance to schistosomiasis mansoni: age-dependence of reinfection remains constant in communities with diverse exposure patterns.

In a fishing community on Lake Albert in Uganda the pattern of intensity of Schistosoma mansoni infection 6 months after treatment with praziquantel was found to be very similar to reinfection patterns seen in previously studied endemic communities: the profile peaks sharply at around the age of 10 years falling away rapidly to much lower levels in adults. This is in stark contrast to the patterns of water contact, which differ greatly between fishing and non-fishing communities. On Lake Albert, adults appear to be more heavily exposed than children. From these observations we conclude that adults are physiologically (perhaps immunologically) more resistant to infection after treatment than children.

Adolescent↗
PubMed1999

Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice.

The spontaneous development of insulin dependent diabetes mellitus in non-obese diabetic (NOD) mice has been shown to be mediated by a Th1 response against beta cell antigens. It is known that in murine models of Schistosoma mansoni infection, egg production is associated with a switch from a Th1 to Th2 response. This subsequent dominance of a Th2 response in S.mansoni infected mice has been shown to influence the response to other infectious agents or antigens. We therefore determined whether infection with S.mansoni could influence the spontaneous incidence of insulin dependent diabetes mellitus (IDDM) in NOD mice. Infection with this helminth significantly reduced the spontaneous incidence of IDDM. IDDM was also prevented by injecting parasite eggs alone. Because until relatively recently humans might expect to succumb to a variety of infectious agents, the current freedom from infection might permit the expression of a genetic predisposition to autoimmune pathology and be responsible for the increased incidence of IDDM.

Animals↗
PubMed1999

Paramyosin is a major target of the human IgA response against Schistosoma japonicum.

Human resistance and susceptibility to schistosomiasis is associated with age and specific antibody isotype responses against worm (SWAP) and egg (SEA) antigens. In a cross-sectional study of 176 individuals infected with Schistosoma japonicum in the Philippines, strikingly similar isotype response patterns against SWAP and SEA was observed when compared to other endemic areas. Interestingly, IgA titres to SWAP correlated with older age among S. japonicum-infected individuals (n = 176, P < 0.01), suggesting a role for this isotype in protective immunity. To identify the molecular targets of human IgA, 17 high-IgA/SWAP responders were identified from the said population. IgA antibodies from the majority (14/17) of these individuals recognized a band of 97 kDa (Sj97), comigrating in immunoblots with the myofibrillar protein paramyosin. The antigen was confirmed as paramyosin by expressed sequence tag (EST)-analysis of four clones obtained by screening an adult S. japonicum cDNA library with pooled IgA antisera and mouse antiparamyosin polyclonal antibodies. The identification of paramyosin as a major target of human IgA raises its potential as a vaccine candidate that targets mucosal immune responses. Since this antigen is exposed on the parasite surface only during the lung stages, we propose that human IgA contributes to parasite attrition during schistosome migration in the lungs.

Adolescent↗
PubMed1999

Development of antibody isotype responses to Schistosoma mansoni in an immunologically naive immigrant population: influence of infection duration, infection intensity, and host age.

We have identified the influence of host and parasite factors that give rise to characteristic antibody isotype profiles with age seen in human populations living in different areas of schistosomiasis endemicity. This is important in the immunobiology of this disease. It is also of interest in the context of human responses to chronic antigen stimulation, vaccines, allergens, and other pathogens. In populations exposed to endemic schistosomiasis, factors such as intensity and duration of infection are age dependent. They therefore confound the influence of host age on antiparasite responses. Here, we resolved these confounding factors by comparing the developing antibody responses of an immunologically naive immigrant population as they acquired the infection for the first time with those of chronically infected resident inhabitants of the same region of Schistosoma mansoni endemicity in Kenya. Recent arrival in the area strongly favored immunoglobulin G3 (IgG3) responses against the parasite. The antibody isotype responses associated with human susceptibility to reinfection after chemotherapy were elevated in those suffering high intensities of infection (IgG4 responses against worm and egg antigens) or were characteristic responses of young children irrespective of the intensity or duration of infection (IgG2 responses against egg antigen). IgE responses against the adult worm, a response associated with resistance to reinfection after chemotherapy, increased with the ages of infected individuals and were also favored in those currently suffering higher intensities of infection.

Adult↗