Clonal exhaustion as a result of immune deviation

An overwhelming virus infection that spreads within a few days throughout the host can cause deletion of the specific cytotoxic T lymphocytes (CTL). This phenomenon is known as ‘clonal exhaustion’. Current explanations for this phenomenon are ‘clonal’, and consider either the terminal differentiation of the virus-specific CTL to an effector phenotype, or the lack of help and antigen presentation for a specific CTL clone. The virus remains controlled by some other form of immunity in the exhausted state. Candidates are innate immunity (especially NK cells andmacrophages) and a T helper type 2 based immune response. Surprisingly, the role of this other form of immunity in causing exhaustion has been ignored so far. Developing a mathematical model, we here investigate the possibility that this inter-clonal immunity is responsible for exhaustion by down regulating the CTL response. The model is based on previously published exhaustion data for Lymphocytic choriomeningitis virus as an in vivo model. We demonstrate that several complicated experiments on clonal exhaustion are consistentwith inter-clonal regulation. By interpreting the available data with a mathematical model, we compare this novel mechanism with the mechanisms suggested previously.     

Structuro-functional changes in the placenta as a result of exposure to atmospheric pollutants

Under the influence of atmospheric pollutions certain structural-functional changes take place in placenta: terminal villi per stipulated square unite, villi with desquamated epithelium, with dilated vessels, with deposition of fibrinoid masses, with plasmodial buds increase in number; section area occupied by epithelial layer decreases; RNA concentration and histoenzymatic activity change in the latter.     

Cardiovascular birth defects and prenatal exposure to female sex hormones: a reevaluation of data reanalysis from a large prospective study.

In data of the U.S. Collaborative Prenatal Study (CPS), the Drug Epidemiology Unit (DEU) reported a relative risk of about 2.3 between maternal female sex hormone exposure during months 1 to 4 of pregnancy and cardiovascular malformation in infants (Heinonen et al., '77a N. Engl. J. Med., 296:67-70). Wiseman and Dodds-Smith ('84) reexamined the original CPS data and found the DEU had made errors in classification of exposure and disease of some cases. Also they challenged the classification of cases as "exposed" in those born to mothers who received the compounds outside the day 19 to 50 window of cardiovascular embryogenesis. Wiseman and Dodds-Smith stated that their reanalysis "clearly showed that there was [in the data used by the DEU] no statistically significant association between exposure in the critical organogenic period of pregnancy and cardiac malformation in offspring." They did not undertake any statistical analysis, but their reanalysis resulted in a widespread nonacceptance of the association reported by the DEU. The study reported here reclassified the cases of the original DEU study in accord with the implications of the Wiseman and Dodds-Smith reanalysis of exposure and disease. After this reclassification, an effect magnitude measure of association, the relative risk rose from 2.33 to 2.48 and remained nominally significant statistically at the .05 level. Thus, if anything, the quantitative consequences of the Wiseman and Dodds-Smith review of the data, when applied in an unbiased manner, result in an increase in the measure of effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of prenatal and postnatal exposure to vitamin A on the development of the murine immune system

Vitamin A and its derivatives are known to enhance the immune system and affect embryogenesis. In this study, five daily subcutaneous injections of retinol palmitate (0.001 mg/kg body weight) were administered to eight female SW mice before mating. Six more weekly injections of retinol palmitate were given during pregnancy and lactation. Eight controls were similarly treated with saline. Four of the eight vitamin-A-treated females had litters, whereas seven of the eight saline-treated females had litters. Resultant litters did not differ in size or appearance. At 12 weeks of age, serum IgM and IgG1 levels were significantly higher in the progeny of vitamin-A-treated mothers before but not after immunization with a test antigen, sheep red blood cells (SRBC). This difference was not seen when other progeny were tested at the age of one year. Anti-SRBC titers did not differ in the two groups of progeny at the age of 12 weeks or one year. One-year-old progeny of vitamin-A-treated mothers weighed significantly more than did control progeny; significant enlargement of the heart, spleen, and kidneys was observed. However, organ-to-body-weight ratios did not differ significantly. In a separate experiment, adult female mice treated with varying doses of vitamin A (five daily doses of 0.0001, 0.0005, or 0.001 mg/kg body weight) showed a dose-dependent reduction of serum IgG1 and hematocrits, but no change in serum IgM levels or leukocyte counts. Resting untreated mice had IgM levels which were one-half those seen in saline-treated controls. These studies indicate that large doses of vitamin A can affect some aspects of the developing and mature murine immune system.     

Humoral immunity in experimental syphilis: the demonstration of IgG as a treponemicidal factor in immune rabbit serum

The neutralizing activity present in immune rabbit serum (IRS) against virulent Treponema pallidum was shown to be mediated by IgG and complement. IgG was isolated and purified from both IRS and nonimmune rabbit serum (NRS) by the use of an affinity system in which staphylococcal protein A was conjugated to Sepharose 4B. The purity of the isolated IgG fractions was demonstrated by both immunoelectrophoresis and SDS-polyacrylamide gel electrophoresis. Fractions of IgG were tested for specific neutralizing activity as measured by an in vitro-in vivo neutralization test. Lesions failed to develop at 80% of the sites inoculated with treponemal suspensions containing IgG from IRS in the presence of unheated NRS as a source of complement; delayed atypical lesions were observed at the remaining sites. In contrast, typical lesions developed at all sites inoculated with suspensions containing IgG from IRS in the presence of heated NRS. They were significantly delayed, however, as compared with lesion development at control sites inoculated with suspensions containing IgG from NRS. These results provide the first direct evidence for an IgG complement-mediated treponemicidal mechanism operative in immune serum from rabbits with latent syphilis.     

Humoral immune responses of amphioxus Branchiostoma belcheri to challenge with Escherichia coli

Humoral parameters of amphioxus Branchiostoma belcheri, including lysozyme, antimicrobial activity, microbial agglutinin and haemagglutinins were measured before and after challenge with Escherichia coli. Humoral fluids from unchallenged B. belcheri had lysozyme, antimicrobial, microbial agglutinating and haemagglutinating activities, which may represent part of the baseline level of innate immunity in this organism. After challenge with E. coli, the lysozyme activity, growth-inhibiting activities against E. coli and Vibrio alginolyticus, microbial agglutinating activities against Micrococcus lysodeikticus, Bacillus subtilis and Staphylococus aureus, and haemagglutinating activities against rabbit and human A and O erythrocytes in the humoral fluids were all increased significantly. In contrast, the agglutinating activities against Vibrio harveyi and E. coli and the haemagglutinating activity against human B erythrocytes in the humoral fluids were reduced in response to E. coli challenge. It appears that the humoral fluids of B. belcheri contain components that are able to differentiate different microbes and different human blood cell types.     

Enhancement of the immune response to surface antigens of the influenza B virus as a result of their covalent binding with a synthetic polymer carrier

The primary immune response (the number of antibody-forming cells, AFC) and the delayed type hypersensitivity (DTHS) were studied in mice immunized either with isolated glycoproteins of influenza virus (hemagglutinin, HA and HA plus neuraminidase, HA plus NA) or with their conjugates with an acrylic acid copolymer (CP) and N-vinylpyrrolidone of equimolar composition. Immunization of mice with conjugates containing virus proteins (virogates-HA-CP or HA plus NA-CP--entailed a 50-100 increment of the number of IgM- and IgG-AFC, anti-HA as compared with analogous parameters during immunization of animals with isolated virus proteins. Immunization of mice with the virogate HA-CP gives rise to the development of a more pronounced DTHS to HA. The authors discuss the possibility of the use of this basically new approach to the design of highly immunogenous vaccine preparations, effective in the control of influenza and other virus diseases.     

Unfolding of the bacterial nucleoid both in vivo and in vitro as a result of exposure to camphor.

Both prokaryotic and eukaryotic cells are sensitive to killing by camphor; however, the mechanism by which camphor kills has not been elucidated. We report here that camphor unfolds the nucleoid of Escherichia coli and that unfolding does not require DNA replication, translation, or cell division. We show that exposure of isolated nucleoids to camphor results in unfolding of the chromosome.     

Changes in cyclic AMP concentration of the rat preoptic region as a result of long term exposure to cold

The cAMP concentration in the preoptic region was studied in rats during exposure to low ambient temperature (Ta: -10 degrees C) and after return to control Ta (22 degrees C). With respect to control cAMP concentration, changes were observed consisting of a decrease (delta cAMP: 4.19 /+- 0.15 pM/mg Pr; p < 0.001) at low Ta and an increase (delta cAMP: 1.40 /+- 0.13 pM/mg Pr; P < 0.05) after return to control Ta. In contrast, cortical cAMP concentration decreased both at low Ta (delta cAMP: 2.94 /+- 0.09 pM/mg Pr; P < 0.005) and after return to control Ta (delta cAMP: 3.21 /+- 0.09 pM/mg Pr; P < 0.001). such cAMP changes in the preoptic region may be related to different activation levels of thermoregulatory and sleep mechanisms.     

Humoral response to the Anopheles gambiae salivary protein gSG6: a serological indicator of exposure to Afrotropical malaria vectors

Salivary proteins injected by blood feeding arthropods into their hosts evoke a saliva-specific humoral response which can be useful to evaluate exposure to bites of disease vectors. However, saliva of hematophagous arthropods is a complex cocktail of bioactive factors and its use in immunoassays can be misleading because of potential cross-reactivity to other antigens. Toward the development of a serological marker of exposure to Afrotropical malaria vectors we expressed the Anopheles gambiae gSG6, a small anopheline-specific salivary protein, and we measured the anti-gSG6 IgG response in individuals from a malaria hyperendemic area of Burkina Faso, West Africa. The gSG6 protein was immunogenic and anti-gSG6 IgG levels and/or prevalence increased in exposed individuals during the malaria transmission/rainy season. Moreover, this response dropped during the intervening low transmission/dry season, suggesting it is sensitive enough to detect variation in vector density. Members of the Fulani ethnic group showed higher anti-gSG6 IgG response as compared to Mossi, a result consistent with the stronger immune reactivity reported in this group. Remarkably, anti-gSG6 IgG levels among responders were high in children and gradually declined with age. This unusual pattern, opposite to the one observed with Plasmodium antigens, is compatible with a progressive desensitization to mosquito saliva and may be linked to the continued exposure to bites of anopheline mosquitoes. Overall, the humoral anti-gSG6 IgG response appears a reliable serological indicator of exposure to bites of the main African malaria vectors (An. gambiae, Anopheles arabiensis and, possibly, Anopheles funestus) and it may be exploited for malaria epidemiological studies, development of risk maps and evaluation of anti-vector measures. In addition, the gSG6 protein may represent a powerful model system to get a deeper understanding of molecular and cellular mechanisms underlying the immune tolerance and progressive desensitization to insect salivary allergens.     

Chronic prenatal nicotine exposure sensitizes rat brain to acute postnatal nicotine challenge as assessed with ornithine decarboxylase

Prenatal exposure to nicotine has been shown to produce postnatal up-regulation of central nervous system nicotinic receptors and to alter subsequent differentiation of neural tissues. In the current study, pregnant rats received nicotine infusions of 6 mg/kg/day throughout gestation, administered by osmotic minipump implants; the postnatal development of cholinergic receptor reactivity was examined through measurements of the ability of acute nicotine administration to stimulate midbrain + brainstem ornithine decarboxylase (ODC) activity, a key regulatory enzyme in neural cell differentiation and growth. In control rats, the ODC response to nicotine was absent at birth and developed during the second postnatal week in parallel with the known ontogenetic rise of nicotinic receptors. Offspring of the nicotine-infused dams exhibited hyper-reactivity of ODC to postnatal acute nicotine challenge: the response developed earlier than in controls and subsequently the magnitude of the effect was 2-3 times greater. Since the development of cholinergic transmission influences differentiation of target cells, alterations in cholinergic nicotinic receptor mediated responses likely explain the delayed appearance of abnormal cell differentiation associated with prenatal nicotine.     

Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene initiate a majority of colorectal cancers. Acquisition of chromosomal instability is an early event in these tumors. We provide evidence that the loss of APC leads to a partial loss of interkinetochore tension at metaphase and alters mitotic progression. Furthermore, we show that inhibition of APC in U2OS cells compromises the mitotic spindle checkpoint. This is accompanied by a decrease in the association of the checkpoint proteins Bub1 and BubR1 with kinetochores. Additionally, APC depletion reduced apoptosis. As expected from this combination of defects, tetraploidy and polyploidy are consequences of APC inhibition in vitro and in vivo. The removal of APC produced the same defects in HCT116 cells that have constitutively active beta-catenin. These data show that the loss of APC immediately induces chromosomal instability as a result of a combination of mitotic and apoptotic defects. We suggest that these defects amplify each other to increase the incidence of tetra- and polyploidy in early stages of tumorigenesis.     

The development of cervical and vaginal adenosis as a result of diethylstilbestrol exposure in utero

Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow-up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenoses are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Müllerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces adenosis lesions in the cervix and vagina. This review describes mouse models that can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses their molecular pathogenesis.     

Mortality of geese as a result of collision with the ground

Two incidents are reported in which groups of migrating wild geese were found dead in agricultural fields in southern Manitoba during spring. In each case, the birds died overnight and poisoning was suspected; however, the birds had lesions of severe traumatic injury. The first incident, in 1985, involved about 150 lesser snow geese (Anser caerulescens caerulescens); the second, in 2003, involved 62 Canada geese (Branta canadensis). Both incidents occurred on dark, moonless nights. One possible explanation is that the birds became disoriented in a manner analogous to spatial disorientation described in aircraft pilots and flew as a flock directly into the earth. In the first incident, geese might have been frightened by sonic booms from aircraft; in the second, there was a thunderstorm with strong gusty winds in the area.     

Identification of the steroid fatty acid ester conjugates formed in vivo in Mytilus edulis as a result of exposure to estrogens

Vertebrate-type sex steroids have been detected in a number of mollusk species and may play a role in the reproductive physiology of the animal. Mollusks are also exposed to exogenous estrogenic steroids that are present in sewage effluents, and these may add to the estrogenic burden of exposed animals. We investigated the uptake of estrogens in the blue mussel, Mytlius edulis and report for the first time the identity of estrogen fatty acid ester metabolites formed in vivo in an invertebrate. We exposed mussels to waterborne radiolabeled [(14)C]-17beta-estradiol (E2) or estrone (E1) and determined the nature of their metabolites using radio-HPLC and mass spectrometry (MS). After 13 days of exposure to 10ng/L E2, concentrations of radiolabeled residues were 2428-fold higher in M. edulis soft tissues compared with the ambient water concentration of E2. All the E2 residues in the mussel were present as a lipophilic ester which, in depuration studies, had a half-life of 8.3 days. Exposure of mussels to [(14)C]-E1 (70ng/L) resulted in formation of a similar lipophilic metabolite that after hydrolysis released [(14)C]-E2. Tandem MSMS analyses of the purified steroid ester fraction isolated from mussels exposed to either E2 or E1 revealed that they had the same composition and comprised C16:0, C16:1 and C16:2 esters of E2. This work reveals that in vivo E1 is rapidly metabolized to E2 in mussels prior to conjugation to C16 fatty acid esters, proving that C17-ketoreductase and C16 fatty acid acyl-CoA:E2 acyltransferase are important enzymes for the metabolism of estrogens in M. edulis.     

Assessment of pathological changes in fish muscle tissue, forming as a result of exposure to toxic factors in the environment

Our investigation of muscle tissue of fishes, inhabiting the regions with unfavorable ecological conditions (the river Volga), permitted to select four types of degenerative changes in muscle tissue. These alterations are associated with both the phylogenetic status of fish species and ecological dispositions of species. Using different methods of investigation several types of muscle destruction were shown. I. Destruction of myofibrillar apparatus (lysis of protofibrils), with sarcolemma remaining intact. II. Destruction of the myofibrillar apparatus, with sarcolemma, T-system, and sarcoplasmic reticulum being disrupted. III. Invasion of muscle fibers by lymphoid cells and macrophages; with sarcolemma being intact. IV. Lysis of sarcolemma by proteolytic enzymes of lymphoid elements; with muscle fibers being disintegrated. The objects of this study were muscle tissues of 8 fish species (Acipenser gueldenstadti, A. stellatus, A. ruthenus, Lucioprerca lucioperca, Esox lucius, Perca fluviatilis, Tinca tinca, Caprinus carpio). The white muscle degeneration followed the patterns of types I and II, while that of red muscles corresponded to types III and IV. White and red muscles of the Chondrostei fishes (sturgeon, stellate, sterlet) undergo destruction more frequently, than muscles of the Holostei fishes (pike, perch, zander, sazan, tench). Degenerative processes of white and red muscles of fish-eating fishes were more obvious than those of herbivorous fishes.