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At least 163 records · Page 9Linked to original sources

The diverse pathogenic potential of anti-DNA antibodies from various sources to induce experimental systemic lupus erythematosus.

It has previously been shown that immunization with pathogenic anti-DNA idiotypes (Ids; e.g. 16/6 Id) leads to the induction of experimental system lupus erythematosus (SLF) in naive mice. The disease is characterized by serological (e.g. anti-double-strand DNA), clinical (elevation of erythrocyte sedimentation rate, leukopenia and proteinuria) and histological (immune complex deposition in kidneys) parameters. To determine whether the 16/6 Id carrying anti-DNA antibodies has unique pathogenic ability, in the current study we have employed diverse sources of anti-DNA antibodies to induce experimental SLE. An IgM anti-DNA antibody lacking the 16/6 Id was able to induce the production of the serological markers of experimental SLE, but not the clinico-histological findings. Furthermore, an IgA anti-DNA (16/6 Id derived from the serum of a patient with celiac disease was very effective in inducing the whole presentation of experimental SLE. Other anti-DNA antibodies failed to induce the autoimmune condition. Combined with our previous experience, the current study points to the diverse potential of various anti-DNA antibodies to induce SLE. The 16/6 Id is only one of a list of the potent pathogenic anti-DNA Ids. These facts may explain in part the diversity of clinical presentations of SLE, including asymptomatic subjects who carry high serum titers of anti-DNA antibodies.

Animals↗

Stress tolerance and pathogenic potential of a mannitol mutant of Cryptococcus neoformans.

Cryptococcus neoformans produces large amounts of the acyclic hexitol mannitol in culture and infected animals, but the functional and pathogenic significance of mannitol production by this fungus is not known. We exposed C. neoformans H99 (Cn H99) to UV irradiation (1 x LD50) and screened survivors for mannitol production. A mutant, Cn MLP (Mannitol Low Producer), synthesized less mannitol from glucose (2.7 vs 8.2 nmol per 10(8) cells min-1 at 37 degrees C) and contained less intracellular mannitol (1 vs 11 mumol per 10(6) cells at 37 degrees C) than did Cn H99. Cn MLP and Cn H99 were similar with respect to carbon assimilation patterns, rates of glucose consumption, growth rates at 30 degrees C, urease and phenoloxidase activities, morphology, capsule formation, mating type, electrophoretic karyotype, rapid amplification of polymorphic DNA (RAPD) patterns and antifungal susceptibility. However, Cn MLP was more susceptible than was Cn H99 to growth inhibition and killing by heat and high NaCl concentrations. Also, the LD50 values in mice injected intravenously were 3.7 x 10(6) c.f.u. for Cn MLP compared to 6.9 x 10(2) c.f.u. for Cn H99. Moreover, 500 c.f.u. Cn H99 intravenously killed 12 of 12 mice by 60 d, whereas all mice given the same inoculum of Cn MLP survived. Classical genetic studies were undertaken to determine if these differences were due to a single mutation, but the basidiospores were nonviable. These results suggest that the abilities of C. neoformans to produce and accumulate mannitol may influence its tolerance to heat and osmotic stresses and its pathogenicity in mice.

Animals↗

The pathogenic potential of endogenous retroviruses: facts and fantasies.

Endogenous retroviruses are descendants of viruses that became cellular genes by integration into their host's genome. They still contribute to pathogenicity as a partner in recombination events, by de novo insertion after mobilization followed by activation of downstream proto-oncogenes, or by gene disruption. Re-expression of viral proteins accompanied by loss of immune tolerance could induce immune disturbances.

Animals↗

Inhibition of potentially pathogenic yeastlike fungi by clotrimazole in combination with 5-fluorocytosine or amphotericin B.

Clotrimazole (CTM) has a doubtful future with respect to use in treatment of the systemic mycoses. To assess the potential of CTM in combined drug regimens, antifungal effects of CTM together with 5-fluorocytosine (5-FC) or amphotericin B (AMB) were tested in a synthetic liquid medium against Candida albicans, Candida tropicalis, and Torulopsis glabrata. Viable counts were monitored over a 48-h incubation period. Weak inhibitory concentrations of CTM were tested in combination with levels of 5-FC or AMB that alone produced transient antifungal effects followed by rapid recovery of proliferative capacity. Results were similar for each of the organisms studied. Between 24 and 48 h, when cultures containing 5-FC or AMB alone were in the recovery phase, CTM plus 5-FC and CTM plus AMB continued to markedly suppress cell multiplication. It would appear that weak inhibitory concentrations of CTM can act together with 5-FC or AMB to produce antifungal effects greater than that obtained with either of the latter two drugs alone.

Amphotericin B↗

The pathogenic potential of commensal species of Neisseria.

Although Neisseria species other than N gonorrhoeae and N meningitidis normally comprise part of the commensal bacterial flora of the oropharynx, they may occasionally act as opportunistic pathogens. Infections in which these organisms have been implicated include cases of endocarditis, meningitis, septicaemia, otitis, bronchopneumonia and possibly genital tract disease. In this paper, the clinical and pathological features of such infections are described, together with a discussion of factors that may contribute to their development.

Adolescent↗

Survey of the hemagglutinin (HA) cleavage site sequence of H5 and H7 avian influenza viruses: amino acid sequence at the HA cleavage site as a marker of pathogenicity potential.

The deduced amino acid sequence at the hemagglutinin (HA) cleavage site of 76 avian influenza (AI) viruses, subtypes H5 and H7, was determined by reverse transcription-polymerase chain reaction and cycle sequencing techniques to assess pathogenicity. Eighteen of the 76 viruses were isolated in 1993 and 1994 from various sources in the United States. In addition, 34 H5 (4 highly pathogenic [HP] and 30 non-highly pathogenic [non-HP]) and 24 H7 (3 HP and 21 non-HP) repository viruses, isolated between 1927 and 1992, were sequenced and the sequences compared to those in recent isolates. All repository HP H5 and H7 viruses studied had multiple basic amino acids adjacent to the HA cleavage site and most had basic amino acids in excess of the proposed minimum motif B-X-B-R (B = basic amino acids arginine or lysine, X = nonbasic amino acid, R = arginine) that has been associated with high pathogenicity. Of the non-HP viruses studied, 35 of 38 for H5 and 30 of 31 for H7 conformed to the motif B-X-X-R and B-X-R, respectively. Two non-HP H5 viruses had the motif X-X-X-R at the cleavage site and a third had the motif B-X-X-K (K = basic amino acid lysine). One non-HP H7 (A/Pekin robin/CA/30412-5/94) had four basic amino acids (K-R-R-R) adjacent to the cleavage site. Although the Pekin robin isolate did not produce disease in chickens under the conditions of the study it did have the amino acid sequence compatible with that in HP AI viruses and, therefore, is considered potentially HP. This is the first account of an H7 virus that is non-HP in chickens but meets the molecular criterion to be classified as HP.

Amino Acid Sequence↗

Sparse diversity of potential pathogenic soil micro-fungi in the Ukraine.

Soil from steppe and garden reserves, and urban park and wharf regions in the Ukraine, U.S.S.R., were studied for keratinophilic as well as for other predominant micro-fungal species. Most of the fungi were nonpathogens, and potential skin infecting fungi were limited to Microsporum gypseum and Trichophyton ajelloi. Species diversity identified population variation between collection sites.

Fungi↗

Surface proteins and the pathogenic potential of Listeria monocytogenes.

On the basis of the recently determined genome sequence of Listeria monocytogenes, we performed a global analysis of the surface-protein-encoding genes. Only proteins displaying a signal peptide were taken into account. Forty-one genes encoding LPXTG proteins, including the previously known internalin gene family, were detected. Several genes encoding proteins that, like InlB and Ami, possess GW modules that attach them to lipoteichoic acids were also identified. Additionally, the completed genome sequence revealed genes encoding proteins potentially anchored in the cell membrane by a hydrophobic tail as well as genes encoding P60-like proteins and lipoproteins. We describe these families and discuss their putative implications for host-pathogen interactions.

Amino Acid Motifs↗

Type I interferon modulation of cellular responses to cytokines and infectious pathogens: potential role in SLE pathogenesis.

Type I interferons (IFNs) are pleiotropic cytokines that have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). A key aspect of type I IFN biology is that previous exposure to type I IFNs alters subsequent cellular responses to extracellular stimuli. Type I IFNs may either prime cells for stronger responses to viruses, bacterial pathogens and cytokines such as IL-6 and IFN-gamma, or may suppress cellular responses to LPS and TNFalpha. Herein, we review type I IFN signal transduction via the Jak-STAT pathway, and mechanisms by which type I IFNs prime or suppress responses to environmental factors. We develop a hypothesis that type I IFN-dependent priming/enhancement of cellular responses to pro-inflammatory cytokines such as IFNgamma and IL-6 contributes to pathogenesis of SLE. In addition, cross-regulation between type I IFNs and TNFalpha and its potential role in SLE pathogenesis is discussed.

Cytokines↗

Interaction of a hydroxyproline-rich glycoprotein from tobacco callus with potential pathogens.

A hydroxyproline-rich glycoprotein was isolated from tobacco (Nicotiana tabacum L.) callus tissue cultures by an acidic-ethanol extraction procedure and purified to about 95% homogeneity by ion exchange chromatography on carboxymethyl cellulose. This glycoprotein agglutinated cells of an avirulent strain (B-1) of the bacterial pathogen Pseudomonas solanacearum but not its parental, virulent isolate (K-60). Bacterial lipopolysaccharide (from K-60 strain) inhibited this agglutination. The tobacco glycoprotein also agglutinated zoospores of both compatible and incompatible races of Phytophthora parasitica var. nicotianae. Although 34 potential haptens were tested, no low-molecular-weight carbohydrate that inhibited bacterial or fungal agglutination was found. The agglutination activity of the tobacco glycoprotein was sensitive to pronase and sodium periodate. The apparent molecular weight of the glycoprotein was 120,000. The protein moiety was basic (12% lysine and 5% histidine) and contained 38% hydroxyproline. The carbohydrate moiety comprised 26% (by weight) of the glycoprotein, and contained 87% arabinose, 8% galactose, and 5% glucose. The glycoprotein labeled with fluorescein isothiocyanate bound significantly better to the avirulent isolate (B-1) of P. solanacearum than to the virulent strain (K-60). Binding to the avirulent cells was inhibited by incubation in a higher ionic strength medium (e.g. 0.2 m NaCl). The labeled glycoprotein also bound to cystospores and mycelia of both races of P. parasitica var. nicotianae. This fungal-glycoprotein interaction was inhibited by the lipopolysaccharide from strain K-60 and by higher ionic strength conditions.

Journal Article↗

Potential pathogenicity of deglycosylated IgG cross reactive with streptokinase and fibronectin in the serum of patients with rheumatoid arthritis.

OBJECTIVE: Fibronectin (FN) and the streptococcal plasminogen activator streptokinase (SK) share the epitope LTSRPA. This epitope is not reactive in native FN and it reacts with anti-SK antibodies only after plasmin digestion of the protein. To investigate a potential correlation between the high levels of anti-LTSRPA antibodies in sera of patients with rheumatoid arthritis (RA) and the perpetuation of the immune response characteristic of this disease, we analyzed their capacity to activate complement and the process of binding to the serum lectin mannan binding protein (MBP). METHODS: We used a radioimmunoassay to evaluate immune complexes between anti-LTSRPA IgG and FN, plasmin degraded FN, or the LTSRPA peptide for their capacity to activate complement C5 to C5a. Purified human serum lectin MBP was used to quantify the degree of exposed mannose or N-acetylglucosamine residues in the Fc region of anti-LTSRPA IgG of patients with RA and healthy controls. RESULTS: Anti-LTSRPA IgG from patients with RA have a greater capacity to activate complement C5 to C5a when bound to either the LTSRPA peptide or plasmin degraded FN in vitro. We found a very strong correlation between the complement activating capacity of the RA immune complexes and their binding to MBP. CONCLUSION: The enhanced capacity of RA anti-LTSRPA IgG immune complexes to activate complement C5 to C5a is directly correlated with their binding capacity to MBP. As MBP binding depends on exposed mannose or N-acetylglucosamine residues in the Fc region of the IgG molecule, these studies suggest that defective glycosylation of circulating anti-SK IgG may play a role in the etiology of RA.

Adult↗

Genetic characterization of Listeria monocytogenes food isolates and pathogenic potential within serovars 1/2a and 1/2b.

A total of 39 Listeria monocytogenes strains isolated from raw milk, smoked meat, chicken carcass and reference strains, belonging to serovars 1/2a, 4a, 1/2b, 3b and 4b, were analysed by RAPD and by polymorphisms of the virulent genes inlAB and iap. Ten isolates, belonging to serovars 1/2a and 1/2b and, collected from raw milk and smoked meat, were further tested for pathogenicity by IP injection into mice. The clustering of the 39 L. monocytogenes strains in 3 groups at 0.45 similarity level, based on molecular typing, was observed. Distribution of serovars in these clusters was in agreement with the proposed three Listeria monocytogenes lineages. Within serovar 1/2b, the 50% lethal dose (LD50) ranged from 8.4 x 10(4) to 1.7 x 10(6) cfu.ml(-1). One of the serovar 1/2b strains, isolated from smoked meat, exhibited the lowest virulence potential evaluated by LD50 and by mean time to death (MTD) and, from this point of view, was completely different from the other strains. Our results suggest the existence of heterogeneity in virulence levels within serovars 1/2a and 1/2b. However, when comparing the isolates based on genotyping, virulence indicators and food origin, no relation could be assessed.

Animals↗

Asymptomatic intestinal colonization by pathogenic Entamoeba histolytica in amebic liver abscess: prevalence, response to therapy, and pathogenic potential.

Since the application of isoenzyme electrophoresis to the study of Entamoeba histolytica, the prevalence and natural history of asymptomatic intestinal colonization in patients with amebic liver abscess (ALA) has not been addressed. We prospectively evaluated this enteric phase in 50 patients with ALA, using two dosage regimens of metronidazole. The overall prevalence of asymptomatic colonization was 72% (36/50). All these isolates, without exception, proved to express pathogenic zymodemes. Despite a 100% clinical response of the hepatic lesions, failure to eradicate the organism from the bowel occurred in 20 of these 36 subjects. During longitudinal posttreatment surveillance, three carriers returned with second bouts of invasive disease: one with dysentery and two with liver abscesses. Thus, in patients with ALA, there is a high prevalence of intestinal colonization with exclusively pathogenic strains, and treatment with metronidazole frequently results in a continued carrier state. These carriers have a propensity for developing recurrent invasive disease and constitute a public health hazard.

Adult↗

Pathogenic potential of North American H7N2 avian influenza virus: a mutagenesis study using reverse genetics.

An H7N2 subtype avian influenza virus (AIV) first appeared in the live bird marketing system (LBMS) in the Northeastern United States in 1994. Since then this lineage of virus has become the predominant subtype of AIV isolated from the LBMS and has been linked to several costly commercial poultry outbreaks. Concern for this low pathogenicity isolate mutating to the highly pathogenic form has remained high because of the increasing number of basic amino acids at the hemagglutinin (HA) cleavage site, which is known to be associated with increased pathogenicity of AIV. To address the risk of low pathogenic LBMS-lineage H7N2 virus mutating to the highly pathogenic form of the virus, we generated a series of mutant viruses that have changes in the sequence at the HA cleavage site by using plasmid-based reverse genetics. We confirmed that a conserved proline at -5 position from the HA cleavage site could be changed to a basic amino acid, producing a virus with five basic amino acids in a row at the cleavage site, but with no increase in virulence. Increased virulence was only observed when additional basic amino acids were inserted. We also observed that the virus preferred the arginine instead of lysine at the -4 position from the cleavage site to manifest increased virulence both in vitro and in vivo. Using helper virus-based reverse genetics, where only one transcription plasmid expressing a mutated HA vRNA is used, we identified specific HA cleavage site sequences that were preferentially incorporated into the low pathogenic wild-type virus. The resultant reassortant viruses were highly pathogenic in chickens. This study provides additional evidence that H7 avian influenza viruses require an insertional event to become highly pathogenic, as compared to H5 viruses that can become highly pathogenic strictly by mutation or by insertions.

Amino Acid Sequence↗

Pathogenic potential of Eubacterium yurii subspecies.

Several mechanisms that could contribute to the periodontopathogenic potential of Eubacterium yurii were investigated. All 18 strains examined produced RNAase and the metabolites H2S, indole and butyrate. Some strains produced phosphatase and DNAase. Methanol extracts of whole cells of E. yurii subspp. yurii and margaretiae stimulated bone resorption in vitro comparable to that produced by recognised periodontal pathogens. These results suggest that further studies should be performed to elucidate the role of E. yurii in periodontal disease.

Bone Resorption↗

Laboratory evaluation on pathogenic potentialities of Vibrio furnissii.

Sixteen strains of Vibrio furnissii recovered from 16 Brazilian patients with diarrhea were screened for virulence-associated factors. All strains were non-invasive, non-fimbriated, and did not produce either enterotoxins or cholera-like toxin. In contrast, most were hemolytic on blood agar and their broth-culture supernatants damaged HeLa cell monolayers. These cytolysins, as accepted for other enteropathogenic members of the family Vibrionaceae, might be determinants of pathogenicity in V. furnissii-mediated enteritis.

Bacterial Proteins↗

Studies on the structure, regulation, and pathogenic potential of anti-dsDNA antibodies.

Studies of anti-double-stranded (anti-ds)DNA antibodies have provided insights into how and why these antibodies arise in systemic lupus erythematosus. In this review we discuss the experimental approaches that have been used by our laboratory to study these autoantibodies. Structure/function analyses including site-directed mutagenesis have helped characterize the molecular genetics of anti-dsDNA antibodies, and more recently peptide libraries have been used to define molecular motifs that these antibodies bind. Most of the pathogenic anti-dsDNA antibodies observed in lupus are somatically mutated. We demonstrated in vitro and in vivo that anti-bacterial antibodies can mutate to acquire specificity for dsDNA. Furthermore, using a fusion partner constitutively expressing bcl-2, NSO(bcl-2), we have shown the existence of anergic or preapoptotic B cells making antibodies that cross-react with both bacterial antigen and dsDNA. Whether defects in the regulation of these antibodies might contribute to serum expression of anti-dsDNA antibodies in some individuals remains unknown. A major emphasis of this review is the regulation of anti-dsDNA antibodies in a transgenic mouse model harboring the gene for the heavy chain of a pathogenic anti-dsDNA antibody. Nonautoimmune transgenic mice effectively regulate autoreactive B cells by anergy and deletion, while their autoimmune counterparts do not. The vast majority of anergic B cells expressing high-affinity transgenic anti-dsDNA antibody fail to display allelic exclusion of the heavy chain. We postulate that this may be one mechanism that allows them to escape deletion. Comparative studies on light chain usage in both the autoimmune and the nonautoimmune transgenic mouse strains have demonstrated that within the autoreactive B-cell population, there are subsets that are differentially regulated. Ultimately transgenic animals making pathogenic autoantibodies may provide us with a system for testing novel therapies for autoimmune disease.

Animals↗

Cross-reactive antibodies have both protective and pathogenic potential.

We report the characteristics of five IgM anti-phosphorylcholine (PC) Abs derived from nonautoimmune BALB/c mice. These Abs were chosen on the basis of their unique ability to cross-react with dsDNA. Three Abs protect mice from a lethal pneumococcal infection, and all five Abs deposit in glomeruli and cause renal dysfunction. Analysis of V region gene usage shows that none of the Abs is encoded by the V1 gene segment used to encode the dominant T15+ anti-PC response typically expressed in serum of PC-immunized BALB/c mice. The demonstration of the existence of noncanonical protective anti-PC Abs that also display pathogenic autoreactivity suggests that idiotypically restricted responses may serve to prevent the expression of Abs that react with both foreign and self Ags and so help maintain self-tolerance.

Amino Acid Sequence↗