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Biomedical subjects

G Rook

Publications and source records attributed to G Rook.

At least 19 recordsLinked to original sources
PubMed2001

The molecular mechanisms of severe typhoid fever.

Salmonella typhi continues to cause severe disease in many parts of the world, its most feared complication being perforation of ulcerated Peyer's patches within the small intestine, leading to peritonitis with associated mortality. The pathogenesis of this process is not well understood. In this article, we present a theoretical mechanism as to how bacterial factors and host immunological mediators within infected tissue might contribute to the observed intestinal pathology, and propose that necrosis of the Peyer's patches observed in typhoid is caused by a mechanism similar to the Shwartzman and Koch reactions.

Enterotoxins↗
PubMed2000

Cytokine analysis at the single cell level and lymphoproliferative responses to mycobacterial antigens in HIV-1 patients with successful virologic response to potent antiretrovirals.

Immunologic parameters, known to be grossly abnormal in HIV-1-infected subjects, were analyzed in 22 patients with sustained viral load suppression (<200 copies/ml) following long-term highly active antiretroviral therapy (HAART). Responses were compared with those from 18 HIV-seronegative healthy controls. Persistent phenotypic alterations in patients' blood mononuclear cells were minimal, though the percentages of lymphocytes that could be activated to produce interleukin-2 (IL-2) remained severely depressed. Using lymphoproliferative assays, a striking deficit in the capacity of patients to respond to the common mycobacterial antigens and particularly to recombinant heat-shock proteins paralleled the absence of responses to virus p24 antigen. In view of the important immunoregulatory role of stress proteins, these findings reveal profound functional deficiencies and persistent immune dysregulation in HIV-1 patients, despite successful HAART and a considerable recovery of CD4+ lymphocyte numbers. Rational immunotherapeutic approaches should be aimed to correct the characterized immune abnormalities.

Antigens, Bacterial↗
PubMed2000

Treatment with BB-94, a broad spectrum inhibitor of zinc-dependent metalloproteinases, causes deviation of the cytokine profile towards type-2 in experimental pulmonary tuberculosis in Balb/c mice.

BB-94 (batimastat) is a broad- spectrum hydroxamic acid-based zinc metalloproteinase inhibitor that inhibits both the matrix metalloproteinases (MMP) and members of the ADAM family of enzymes such as Tumour Necrosis Factor-alpha Cleaving Enzyme (TACE). These enzymes are involved in the regulation of inflammatory processes in tuberculosis. Balb/c mice infected with M. tuberculosis via the intratracheal route were treated with BB-94 for 1 month, starting on the day of infection. Immunohistochemistry, semiquantitative RT-PCR and ELISA assays for cytokines revealed a deficit in IL-1 and IL-2 expression and a premature bias towards IL-4 expression, accompanied by a delay in granuloma formation and more rapid progression of disease in BB-94-treated animals. This situation corrected itself after the drug was withdrawn at 28 days. In contrast, when BB-94 was administered only after 1 month there were no significant changes apart from the presence of amyloid, and a paradoxically increased expression of IL-1alpha. These results cast light on mechanisms of immunity in tuberculosis and also indicate that in patients treated with similar broad-spectrum MMP inhibitors there may be a risk of inappropriate deviation of some immune responses towards a Type-2 cytokine profile.

Animals↗
PubMed2000

Local regulation of glucocorticoid activity in sites of inflammation. Insights from the study of tuberculosis.

In sites of inflammation there is a change in the equilibrium between the enzymes that inactivate cortisol by conversion to cortisone and those that reactivate cortisone by conversion to cortisol. Current evidence suggests that during an immune response with a Type 1 cytokine profile such as tuberculosis, there is locally enhanced reductase activity with locally increased cortisol concentrations due to recruitment of cortisone. This results in enhanced cortisol mediated feedback on the inflammatory process, and deviation of the response towards Type 2. Preliminary data suggest that eventually, in the presence of Type 2 cytokine polarization, the enzyme equilibrium may reverse again and cortisol is then locally inactivated to cortisone. Together with changes in glucocorticoid receptor expression and function this may result in local cortisol resistance and susceptibility to tissue damage mediated by proinflammatory cytokines. These observations help to explain the sequence of events in several infectious, inflammatory and autoimmune diseases.

Animals↗
PubMed1997

Pathogenesis of tuberculosis in mice exposed to low and high doses of an environmental mycobacterial saprophyte before infection.

Mycobacteria are ubiquitous in the environment, but they are not part of the normal human microbial flora. It has been suggested that variable contact with mycobacteria can influence susceptibility to mycobacterial pathogens and the efficacy of subsequent Mycobacterium bovis BCG vaccination. To test this, mice were immunized with high or low doses of an environmental saprophyte, M. vaccae, that is intensely immunogenic as an autoclaved preparation. Two months later, they received an intratracheal challenge with M. tuberculosis H37Rv. Recipients of a low Th1-inducing dose (10(7) organisms) were partially protected and maintained a high ratio of interleukin 2 (IL-2)-positive to IL-4-positive cells in the perivascular, peribronchial, and granulomatous areas of the lung, whereas in unimmunized controls the IL-4-positive cells increased markedly between days 21 and 28. In contrast, recipients of the high dose (10(9) organisms), which primes Th2 as well as Th1 cytokine production, died more rapidly than unimmunized controls and showed massive pneumonia from day 7. The ratio of IL-2-positive to IL-4-positive cells in all compartments of the lung rapidly fell to 1 by day 14 for these animals. These events correlated with cytokine mRNA profiles and with increases in the local toxicity of tumor necrosis factor alpha (TNF-alpha), demonstrable only when a major Th2 component was present. These data indicate that cross-reactive epitopes present in an environmental saprophyte can evoke either protective responses or responses that increase susceptibility to M. tuberculosis. The latter are associated with the presence of a Th2 component and increased sensitivity to TNF-alpha.

Animals↗
PubMed1996

On the interaction between agalactosyl IgG and Fc gamma receptors.

One of the serum abnormalities observed in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is the occurrence of IgG that lacks the terminal galactose on asparagine-linked biantennary complex type oligosaccharides [Gal(0)-IgG] located in the CH2 domain. Additionally, IgG without glycosylation is known to be defective in several effector functions due to a reduced ability to bind to its specific receptors (Fc gamma R). It has thus been speculated that, by analogy with unglycosylated IgG, Gal(0)-IgG may also be functionally impaired or exert altered effector mechanisms. If this were true, Gal(0)-IgG could contribute to the phenotype of above-mentioned autoimmune diseases, like impaired immune complex clearance and defective down-regulation of activated B cells. Here, we show by three different methods that the interaction of Gal(0)-IgG and normally glycosylated IgG with the low-affinity Fc gamma RII (CD32) is indistinguishable with respect both to binding and receptor-mediated signalling. These data argue against a prominent role for Fc gamma R-dependent Gal(0)-IgG interactions in the etiology or pathogenesis of autoimmune diseases.

Animals↗
PubMed1995

Presence of hsp65 in bacterial extracts (OM-89): a possible mediator of orally-induced tolerance?

Heat shock proteins (HSP) have been implicated in rodent models of autoimmunity, particularly arthritis, and there is suggestive though inconclusive evidence that they may also play a role in human autoimmune disease. The simplest hypothesis is based on molecular mimicry due to the amino-acid sequence homology between mammalian and microbial HSP. Recently OM-89, an extract of several strains of Escherichia coli, has shown some efficacy in the treatment of rheumatoid arthritis (RA) when taken orally. Using species-specific antibodies, we show here that OM-89 contains the 65 kDa HSP (hsp65), while hsp65 was not detected in another bacterial extract containing other microorganisms, including Staphylococcus aureus (OM-85). We suggest that if the human homologue of hsp65 is a relevant target antigen in the human disease, the efficacy of the preparation could be due to induction of oral tolerance or to switching the Th1 response towards Th2. Alternatively, even if the human hsp65 is not a target molecule in RA joints, OM-89 may evoke bystander suppression of joint inflammation via induction of TGF beta-secreting effector cells. These hypotheses should be tested in further studies.

Humans↗
PubMed1995

Tuberculosis in children.

Tuberculosis in children is a growing problem, both globally and in many industrialized countries. With a rising incidence, clinicians will again face the challenge of the myriad presentations of tuberculous disease. Multidrug resistance and HIV coinfection present additional complications. Renewed interest in tuberculosis among scientists has led to progress in our understanding of antimycobacterial effector mechanisms, the regulation of Th1 and Th2 immune responses, virulence factors, and the potential for immunotherapeutic agents to reduce the duration of antituberculous therapy.

Animals↗
PubMed1994

Raised agalactosyl IgG and antimycobacterial humoral immunity in Takayasu's arteritis.

OBJECTIVE: Takayasu's arteritis is an inflammatory occlusive disease of the aorta and its main branches of unknown etiology. Some suggested causes include inapparent infection with Mycobacterium tuberculosis, or autoimmunity evoked by this organism. We have therefore sought links with mycobacterial disease. METHODS: We assayed the % agalactosyl IgG, antibody to a tuberculosis-specific 38 kDa protein, and antibody to the mycobacterial 65 kDa heat shock protein (HSP), in patients with active or inactive Takayasu's arteritis, in whom the diagnosis of tuberculosis was excluded. The results were compared with findings in tuberculosis (positive controls), normal donors and patients with Wegener's granulomatosis. RESULTS: The % agalactosyl IgG in patients with active arteritis was in the range previously seen only in rheumatoid arthritis, Crohn's disease, and the mycobacterioses. Similarly, significantly raised antibody to the purified 38-kDa protein of M. tuberculosis, and to the 65-kDa HSP of M. leprae, was found in 78% of patients with Takayasu's arteritis, and the levels were higher in those with active disease. CONCLUSION: These results suggest that Takayasu's arteritis particularly clearly illustrates the occasional relationship between mycobacteria and diseases of superficially autoimmune pathogenesis.

Adolescent↗
PubMed1991

The role of oil and agalactosyl IgG in the induction of arthritis in rodent models.

The proportion of agalactosyl IgG [Gal(O)] is raised in human rheumatoid arthritis and tuberculosis. We report here that injection of pristane into the peritoneal cavities of mice on days 0 and 50, which is known to induce plasmacytomas and arthritis, also induced a rise in the proportion of Gal(O), correlating with a simultaneous rise in the level of IgG antibody binding to the 65-kDa heat-shock protein of Mycobacterium bovis (hsp65). Arthritis developed in a proportion of those CBA/Igb mice with the highest percentage of Gal(O). Pretreatment with 50 micrograms of recombinant mycobacterial hsp65 intraperitoneal (i.p.) on day -10, or with 500 rad irradiation on day -2 before the first of the two injections of pristane reduced the incidence of arthritis from 24% in control animals, to 5.3% and 0.4%, respectively. The reduced incidence of disease correlated with smaller rises in the % Gal(O) at 50-75 days, although levels at 150-200 days were not affected. The arthritogenic effect of oil was not confined to the pristane model, since a single i.p. injection of oil 21 days before immunizing DBA/1 mice with type II collagen reduced the mean day of onset of this arthritis, [which we have previously shown to correlate with raised % Gal(O)], from 38 to 15 days (p less than 0.001). One interpretation is that an autoimmunogenic stimulus, given when % Gal(O) is raised, is more likely to evoke disease. Since oil granulomata are known to secrete interleukin 6, which has B cell-regulatory properties and is secreted by rheumatoid synovial cells, we tested sera from interleukin 6-transgenic mice, and found a strikingly raised percentage of Gal(O). We suggest, therefore, that the role of oil in the induction of arthritis is the dysregulation of cytokine release of which a raised percentage of Gal(O) may be a direct or indirect consequence, associated with an increased susceptibility to autoimmunogenic stimuli.

Animals↗
PubMed1990

Terminal N-acetylglucosamine in chronic synovitis.

The distribution of terminal GlcNAc residues in normal and diseased synovial tissue has been studied using a mouse monoclonal antibody (mAb) which binds to terminal N-acetylglucosamine (GlcNAc). Normal human connective tissue, including synovium, showed no staining for terminal GlcNAc. Normal epithelial tissues, including tonsillar epithelium, skin, small intestinal epithelium and salivary epithelium showed cellular staining. Synovium from patients with definite rheumatoid arthritis showed dense granular staining of macrophages. In addition, synovium from 9 of 12 patients with definite rheumatoid arthritis showed reticular extracellular staining indicating deposition of material bearing terminal GlcNAc in the connective tissue stroma. The extracellular staining was not seen in synovium from patients with osteoarthritis. Extracellular material bearing terminal GlcNAc may act as an inflammatory stimulus in rheumatoid arthritis, either by acting as antigen or by interaction with receptors on macrophage membranes which also recognize GlcNAc on bacterial material, thus triggering biochemical pathways normally occurring in response to the presence of micro-organisms.

Acetylglucosamine↗