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Nucleotide variation in the p53 tumor-suppressor gene of voles from Chernobyl, Ukraine.

The 1986 Chernobyl disaster contaminated vast regions of Ukraine and Belarus with a variety of radioactive isotopes and heavy metals. While over 90% of the radioactive isotopes have decayed into stable compounds, radiation levels in contaminated areas are still extraordinarily high. In fact, some rodents living near the reactor have internal 134,137Cs concentrations approaching 80 000 Bq/g. Several recent genetic analyses of vertebrates have illustrated that mutation rates of organisms exposed to radiation from Chernobyl are higher than in control groups, but none have studied DNA sequences. Nucleotide sequences of rodent mitochondrial genes were originally reported to have been hypervariable, but those results were subsequently retracted. Herein, I report the results of a pilot study to determine the extent of nucleotide variation at the p53 gene in four species of rodents (voles) from Chernobyl and from control sites. I sequenced a 788 bp region (coding and non-coding) of p53 in 30 different mice comprising four different species of Microtus. Nucleotide variation at the population level was due to deletions and substitutions; both were limited to introns. There were no significant differences between the number of haplotypes in radioactive and control populations (p=0.60). Rare or private alleles might have arisen due to unique mutational pressures at Chernobyl. Alternatively, natural selection might have favored one allele over others (i.e., a selective sweep). Neither scenario is strongly supported by these data. Thus, no apparent genetic effects of the Chernobyl disaster on the p53 gene of resident voles were revealed; more extensive surveys will be necessary to determine if mutation rates are indeed elevated in mice from Chernobyl. However, two salient points emerge; the first involves the utility of introns as markers for mutations in coding regions and the second considers the relative merits of cloning in mutation detection studies.

Animals↗

[Measures for disinfection and sterilization of poultry housing after an outbreak of S. enteritidis].

Recommendations for correct cleansing and disinfection of S. enteritidis-contaminated chicken farms are given. References are made to the legal context and to its significance in a S. enteritidis control program. Quality and quantity of the suggested sampling procedure are based on WHO recommendations and on a four years experience of the author. 26 chicken farms on which S. enteritidis or S. typhimurium had been isolated in the previous crop have been monitored after disinfection. The results of 981 samples are presented. Salmonellae could not be isolated by swabs from visible clean surfaces after disinfection. Critical control points remain in the farm biotope: These are intermediate ceiling, litter beetle, rodents, exhaust ventilation fluff, margin zone of the outer building. These critical control points cannot be effectively disinfected. In case of demonstration of S. enteritidis from surfaces of the interior of the chicken house, a redisinfection will be necessary. S. enteritidis out of the farm biotope does not justify redisinfection of the farm.

Animals↗

A two-step process for controlling the surface smoothness of polyelectrolyte-based microcapsules.

Biocompatibility is one of the crucial requirements to be fulfilled when designing devices for immunoisolation of transplanted cells. The quality of the capsule surface (smoothness/roughness) influences the nature of cell overgrowth on it by immunocytes, which eventually may lead to the transplant failure. A microcapsule has been developed based on the polyelectrolyte complexation of the polyanions sodium alginate and cellulose sulphate with the polycation poly(methylene-co-guanidine), which was successfully tested in rodent animal models. Recently, the principles for controlling the surface smoothness of these capsules has been identified. This paper reports on a two-step process used for production of stable capsules with improved surface properties. The methodology involves separating the process of drop shape recovery and precursor capsule formation from the process of membrane formation by applying a two-reactor design. The multi-loop reactors are connected in series, and the process separation is given by the different composition of cation solutions flowing in each reactor. This process enables one to prepare the microcapsule immunoisolation device, which can differ in the extent of surface roughness and, thus, is suitable for studying the effect of surface morphology of the immunoisolation device on cell overgrowth. The effect of this process on the capsule permeability has also been evaluated.

Alginates↗

Controlling the efficiency of excision repair.

The early studies are recounted, that led to the discovery of the ubiquitous process of DNA excision repair, followed by a review of the pathways of transcription-coupled repair (TCR) and global genomic nucleotide excision repair (GGR). Repair replication of damaged DNA in UV-irradiated bacteria was discovered through the use of 5-bromouracil to density-label newly synthesized DNA. This assay was then used in human cells to validate the phenomenon of unscheduled DNA synthesis as a measure of excision repair and to elucidate the first example of a DNA repair disorder, xeroderma pigmentosum. Features of the TCR pathway (that is defective in Cockayne syndrome (CS)) include the possibility of "gratuitous TCR" at transcription pause sites in undamaged DNA. The GGR pathway is shown to be controlled through the SOS stress response in E. coli and through the activated product of the p53 tumor suppressor gene in human cells. These regulatory systems particularly affect the efficiency of repair of the predominant UV-induced photoproduct, the cyclobutane pyrimidine dimer, as well as that of chemical carcinogen adducts, such as benzo(a)pyrene diol-epoxide. Rodent cells (typically lacking the p53-controlled GGR pathway) and tumor virus infected human cells (in which p53 function is abrogated) are unable to carry out efficient GGR of some lesions. Therefore, caution should be exercised in the interpretation of results from such systems for risk assessment in genetic toxicology. Many problems in excision repair remain to be solved, including the mechanism of scanning the DNA for lesions and the subcellular localization of the repair factories. Also there are persisting questions regarding the multiple options of repair, recombination, and translesion synthesis when replication forks encounter lesions in the template DNA. That is where the field of DNA excision repair began four decades ago with studies on the recovery of DNA synthesis in UV-irradiated bacteria.

Animals↗

Plasma agouti-related protein levels in women with anorexia nervosa.

Agouti-related protein (AGRP) is the competitive antagonist of alpha-melanocyte stimulating hormone (alpha-MSH) located at melanocortin receptors 3 and 4 (MC3R and MC4R), and also acts as an MC4R inverse agonist. Hypothalamic AGRP controls food intake and body weight in rodents. It has also been found in human plasma. To study the possibility of disturbances in melanocortin receptor-related peptides in eating disorders, plasma AGRP, alpha-MSH, and leptin levels were measured in 18 female patients with anorexia nervosa (AN) (age, 23.5+/-7.1 yr; body mass index (BMI) 14.5+/-1.8 kg/m(2)) and 17 age-matched female controls (age, 25.8+/-3.9 yr; BMI 20.2+/-1.6 kg/m(2)). Blood samples were collected after overnight fasting, and plasma peptides levels were measured using ELISA. Plasma AGRP levels increased significantly in AN patients when compared with controls (P<0.01) while plasma alpha-MSH levels were not significantly different. Plasma leptin levels decreased significantly in AN patients when compared with controls (P<0.001). In addition, plasma AGRP levels were negatively correlated with leptin (r=-0.41, P<0.01) and BMI (r=-0.40, P<0.05) in all subjects. In conclusion, plasma AGRP elevation may be related to energy homeostasis disturbance in AN, and in addition to leptin, peripheral AGRP levels could be used as a nutritional marker in AN patients.

Adolescent↗

Cell cycle control in isoproterenol-induced murine salivary acinar cell proliferation.

The eukaryotic cell cycle is a summary of a complex network of signal transduction pathways resulting in both DNA replication and cell division. Cyclin-dependent kinases (CDKs) control the cell cycle in all eukaryotes, whereas other proteins, known as cyclins, act as their regulatory subunits. Chronic injection with isoproterenol (ISO) can induce acinar cell proliferation in rodent salivary glands. Cyclins and CDK proteins from control and ISO-treated murine parotid acinar cells were detected by using Western blotting techniques. By comparing the expression of these cell cycle regulatory kinases in the parotid acinar cell transition from a quiescent state to a hypertrophic state, we found rapid increases in the protein levels of all CDKs, cyclin D and proliferating cell nuclear antigen (PCNA). The highest protein levels for CDKs and cyclins appeared at about 72 hr of ISO stimulation and were coincident with the highest rate of increase in gland wet weight. After 72 hr, the increase of both cell cycle protein and gland wet weight began to subside. By using a co-immunoprecipitation method, the following cell cycle regulators (CDK-cyclin complexes) were detected, CDK4-cyclin D, CDK2-cyclin E, CDK2-cyclin A, and cdc2-cyclin B, along with an increase in kinase activity over control untreated animals. Additionally, we detected significant decreases in the newly isolated CDK inhibitor (CKI) p27kip but not Wee 1 kinase. The increased levels of CKI correlated with a decrease in kinase activity of CDK/cyclin complexes by 144 hr of chronic isoproterenol treatment. Our data suggest that the holoenzymes for cell cycle control (cyclin-CDK complexes) function as a final regulatory mechanism leading to salivary gland acinar cell proliferation. The gradual decline in protein levels of the CDKs and cyclins after 3 days of chronic treatment further indicates that ISO-induced proliferation of parotid acinar cells is self-limiting and non-tumorigenic.

Animals↗

Adaptive changes in Plasmodium transmission strategies following chloroquine chemotherapy.

Both theory and data suggest that malaria parasites divert resources from within-host replication to the production of transmission stages (gametocytes) when conditions deteriorate. Increased investment into transmission stages should therefore follow subcurative treatment with antimalarial drugs, but relevant clinical studies necessarily lack adequate control groups. We therefore carried out controlled experiments to test this hypothesis, using a rodent malaria (Plasmodium chabaudi) model. Infections treated with a subcurative dose of the antimalarial chloroquine showed an earlier peak and a greater rate of gametocyte production relative to untreated controls. These alterations led to correlated changes in infectivity to mosquitoes, with the consequence that chloroquine treatment had no effect on the proportion of mosquitoes infected. Treatment of human malaria commonly does not result in complete parasite clearance. If surviving parasites produce compensatory increases in their rate of gametocyte production similar to those reported here, such treatment may have minimal effect on decreasing, and may actually increase, transmission. Importantly, if increased investment in transmission is a generalized stress response, the effect might be observed following a variety of antimalarial treatments, including other drugs and potential vaccines. Similar parasite life history counter-adaptations to intervention strategies are likely to occur in many disease-causing organisms.

Adaptation, Biological↗

Human and rat beta cells differ in glucose transporter but not in glucokinase gene expression.

Glucose homeostasis is controlled by a glucose sensor in pancreatic beta-cells. Studies on rodent beta-cells have suggested a role for GLUT2 and glucokinase in this control function and in mechanisms leading to diabetes. Little direct evidence exists so far to implicate these two proteins in glucose recognition by human beta-cells. The present in vitro study investigates the role of glucose transport and phosphorylation in beta-cell preparations from nondiabetic human pancreata. Human beta-cells differ from rodent beta-cells in glucose transporter gene expression (predominantly GLUT1 instead of GLUT2), explaining their low Km (3 mmol/liter) and low VMAX (3 mmol/min per liter) for 3-O-methyl glucose transport. The 100-fold lower GLUT2 abundance in human versus rat beta-cells is associated with a 10-fold slower uptake of alloxan, explaining their resistance to this rodent diabetogenic agent. Human and rat beta-cells exhibit comparable glucokinase expression with similar flux-generating influence on total glucose utilization. These data underline the importance of glucokinase but not of GLUT2 in the glucose sensor of human beta-cells.

Animals↗

A decade of plague epidemiology and control in the western Usambara mountains, north-east Tanzania.

Outbreaks of human plague have been occurring in the Western Usambara mountains since 1980, involving many cases and deaths. Epidemiological surveys and control activities were carried out from June 1980 to May 1990. Rodents were trapped live, identified and serologically tested for plague, using the passive haemagglutination and passive haemagglutination inhibition tests. Rodent fleas were collected, processed, identified and counted. House fleas were caught with light traps and similarly treated. People and domestic carnivores were serologically tested for the disease. Various plague control measures were undertaken. A total of 2433 animals, 2254 rodent fleas and 1366 house fleas were collected. Average indices of rodent and house fleas were 0.93 and 5.38 respectively. Rattus rattus and Mastomys natalensis were the most abundant rodent species. Xenopsylla brasiliensis and Dinopsyllus lypusus were their commonest flea ectoparasites while Pulex irritans was the major house flea. Of 2044 rodent, 1880 human and 176 dog sera tested, 5.5%, 0.5% and 6.3% respectively were positive. It was concluded that plague was active in the focus despite the control measures and that common reservoirs and efficient vectors were present. It was suggested that dogs were probably involved in the epidemiology of the disease, that P. irritans was not susceptible to the insecticide used and that the flea was probably involved in murine plague transmission. Bacteriological research on the causative agent to establish the nature of its long persistence in the area and maintenance of a surveillance service are recommended.

Animals↗

Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial.

CONTEXT: Prolonged calorie restriction increases life span in rodents. Whether prolonged calorie restriction affects biomarkers of longevity or markers of oxidative stress, or reduces metabolic rate beyond that expected from reduced metabolic mass, has not been investigated in humans. OBJECTIVE: To examine the effects of 6 months of calorie restriction, with or without exercise, in overweight, nonobese (body mass index, 25 to <30) men and women. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of healthy, sedentary men and women (N = 48) conducted between March 2002 and August 2004 at a research center in Baton Rouge, La. INTERVENTION: Participants were randomized to 1 of 4 groups for 6 months: control (weight maintenance diet); calorie restriction (25% calorie restriction of baseline energy requirements); calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); very low-calorie diet (890 kcal/d until 15% weight reduction, followed by a weight maintenance diet). MAIN OUTCOME MEASURES: Body composition; dehydroepiandrosterone sulfate (DHEAS), glucose, and insulin levels; protein carbonyls; DNA damage; 24-hour energy expenditure; and core body temperature. RESULTS: Mean (SEM) weight change at 6 months in the 4 groups was as follows: controls, -1.0% (1.1%); calorie restriction, -10.4% (0.9%); calorie restriction with exercise, -10.0% (0.8%); and very low-calorie diet, -13.9% (0.7%). At 6 months, fasting insulin levels were significantly reduced from baseline in the intervention groups (all P<.01), whereas DHEAS and glucose levels were unchanged. Core body temperature was reduced in the calorie restriction and calorie restriction with exercise groups (both P<.05). After adjustment for changes in body composition, sedentary 24-hour energy expenditure was unchanged in controls, but decreased in the calorie restriction (-135 kcal/d [42 kcal/d]), calorie restriction with exercise (-117 kcal/d [52 kcal/d]), and very low-calorie diet (-125 kcal/d [35 kcal/d]) groups (all P<.008). These "metabolic adaptations" (~ 6% more than expected based on loss of metabolic mass) were statistically different from controls (P<.05). Protein carbonyl concentrations were not changed from baseline to month 6 in any group, whereas DNA damage was also reduced from baseline in all intervention groups (P <.005). CONCLUSIONS: Our findings suggest that 2 biomarkers of longevity (fasting insulin level and body temperature) are decreased by prolonged calorie restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass. Studies of longer duration are required to determine if calorie restriction attenuates the aging process in humans. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00099151.

Adult↗

Seasonal adaptations of Siberian hamsters. II. Pattern of change in daylength controls annual testicular and body weight rhythms.

Studies of rodent photoperiodism almost without exception have employed fixed day lengths (DLs) and abrupt transitions from long to short DLs. Because the natural progression of changes in DL carries predictive information and may have physiological consequences, we determined seasonal fluctuations in testis size and body weight in Siberian hamsters maintained in a year-long pattern of increasing and decreasing DLs. A cycle of gonadal development, regression, and recrudescence, and corresponding changes in body weight, were observed in hamsters maintained in separate simulated natural photoperiods (SNPs) in which DLs neither fell below nor exceeded the putative critical DL of 13 h. Gradually decreasing DLs as long as 15.3 h induced gonadal regression, and DLs as short as 12.3 h supported ponderal growth, depending on the hamster's prior photoperiodic history. DLs experienced by hamsters during development influenced the adult incidence of responsiveness to short DLs. Photorefractoriness to short DLs occurred earlier in hamsters kept in static 10-h than in 12-h DLs. Increasing DLs in winter had little impact on the rate of gonadal recrudescence and weight gain. These data extend earlier investigations in showing the photoperiodic history determines gonadal responses over a broad range of DLs and influences gonadal responsiveness to short DLs and the triggering of the interval timer underlying recrudescence.

Adaptation, Physiological↗

Characterization of kallikrein cDNAs from the African rodent Mastomys.

Kallikreins comprise a family of serine proteases that are required for the processing of hormone precursors, thereby controlling many physiological processes including blood flow, ion transport, and inflammation. In rodents such as mouse, rat, and Mastomys, many kallikreins are expressed in the submandibular gland (SMG), but only a limited number, notably true tissue (glandular) kallikrein, are expressed in the kidney. We report here the cloning and characterization of kallikrein cDNAs from the Mastomys SMG. Two of these are expressed in the kidney as well as in the SMG, and one may code for the true tissue kallikrein of Mastomys. A third kallikrein is expressed only in the SMG and bears some resemblance to a murine nerve growth factor-associated protein. The existence of a family of Mastomys SMG kallikreins suggests that these enzymes act as prohormone-processing enzymes in Mastomys. DNA sequence analysis and hybridization studies demonstrate that, although Mastomys kallikreins are very similar in structure to both mouse and rat kallikreins, their expression patterns differ. The expression of more than one Mastomys glandular kallikrein in the kidney is similar to that in the rat, but the sequence and nonsexually dimorphic expression of the putative tissue kallikrein most closely resembles mouse. Mastomys represents an interesting hybrid between mouse and rat, providing an important animal model for studies of kallikrein expression and regulation.

Amino Acid Sequence↗

Harnessing the therapeutic potential of glucagon-like peptide-1: a critical review.

Glucagon-like peptide-1 (GLP-1) is synthesized from proglucagon in enteroendocrine cells and regulates glucose homeostasis via multiple complementary actions on appetite, gastrointestinal motility and islet hormone secretion. GLP-1 is secreted from the distal gut in response to food ingestion, and levels of circulating GLP-1 may be diminished in patients with type 2 diabetes mellitus. GLP-1 administration stimulates glucose-dependent insulin secretion, inhibits glucagon secretion, and lowers blood glucose in normal and diabetic rodents and in humans. GLP-1 exerts additional glucose-lowering actions in patients with diabetes mellitus already treated with metformin or sulfonylurea therapy. GLP-1 inhibits gastric emptying in healthy individuals and those with diabetes mellitus, and excess GLP-1 administration may cause nausea or vomiting in susceptible individuals. Chronic GLP-1 treatment of normal or diabetic rodents is associated with bodyweight loss and GLP-1 agonists transiently inhibit food intake and may prevent bodyweight gain in humans. The potential for GLP-1 therapy to prevent deterioration of beta-cell function is exemplified by studies demonstrating that GLP-1 analogs stimulate proliferation and neogenesis of beta-cells, leading to expansion of beta-cell mass in diabetic rodents. The rapid N-terminal inactivation of bioactive GLP-1 by dipeptidyl peptidase-IV (DPP-IV) limits the utility of the native peptide for the treatment of patients with diabetes mellitus, and has fostered the development of more potent and stable protease-resistant GLP-1 analogs which exhibit longer durations of action. The importance of DPP-IV for glucose control is illustrated by the phenotype of rodents with genetic inactivation of DPP-IV which exhibit reduced glycemic excursion and increased levels of circulating GLP-1 in vivo. Inhibitors of DPP-IV potentiate incretin action by preventing degradation of GLP-1 and glucose-dependent insulinotropic peptide, and lower blood glucose in normal rodents and in experimental models of diabetes mellitus. Hence, orally available DPP-IV inhibitors also represent a new class of therapeutic agents that enhance incretin action for the treatment of patients with type 2 diabetes mellitus.

Diabetes Mellitus, Type 2↗

Bottom-up regulation of plant community structure in an aridland ecosystem.

We conducted a long-term rodent exclosure experiment in native grass- and shrub-dominated vegetation to evaluate the importance of top-down and bottom-up controls on plant community structure in a low-productivity aridland ecosystem. Using multiple regressions and analysis of covariance, we assessed how bottom-up precipitation pulses cascade through vegetation to affect rodent populations, how rodent populations affect plant community structure, and how rodents alter rates of plant community change over time. Our findings showed that bottom-up pulses cascade through the system, increasing the abundances of plants and rodents, and that rodents exerted no control on plant community structure and rate of change in grass-dominated vegetation, and only limited control in shrub-dominated vegetation. These results were discussed in the context of top-down effects on plant communities across broad gradients of primary productivity. We conclude that bottom-up regulation maintains this ecosystem in a state of low primary productivity that constrains the abundance of consumers such that they exert limited influence on plant community structure and dynamics.

Animals↗

Immunization of rodents against Hymenolepis infections using non-viable homologous oncospheres.

Immunity to Taiwan Taenia infection in pigs can be stimulated using homologous or heterologous non-viable Taenia oncospheres. This study was designed to determine whether homologous non-viable oncospheres could stimulate immunity to Hymenolepis infection in rodents. Hatched oncospheres were prepared from eggs of Hymenolepis diminuta, Hymenolepis nana, and Hymenolepis microstoma and kept at -70 degrees C for more than 1 month. A mixture of 500 non-viable oncospheres of each tapeworm and complete Freund's adjuvant was injected subcutaneously in four groups of Sprague-Dawley rats or ICR mice one to four times at an interval of 1 week; controls were not immunized. After immunization, each rodent was orally inoculated with three fresh active cysticercoids of H. diminuta or H. microstoma or 500 fresh eggs of H. nana. The animals were then necropsied for adult tapeworms. No rats or mice immunized with non-viable oncospheres of H. diminuta or H. nana were infected by the challenge inoculation. However, 28 of 34 mice immunized with non-viable H. microstoma oncospheres were infected after inoculation with cysticercoids. This study demonstrated complete protection against infection by homologous parasites in rats or mice immunized with non-viable oncospheres of H. diminuta and H. nana, respectively. Repeated immunization may not be required if resistance is stimulated in rodent hosts.

Animals↗

Effects of predation and dispersal on Mastomys natalensis population dynamics in Tanzanian maize fields.

1. We investigate the effects of different levels of predation pressure and rodent dispersal on the population dynamics of the African pest rodent Mastomys natalensis in maize fields in Tanzania. 2. Three levels of predation risk were used in an experimental set-up: natural level (control), excluding predators by nets and attracting avian predators by nest boxes and perch poles. Because dispersal of the rodents could mask the predation pressure treatment effects, control and predator exclusion treatments were repeated with enclosed rodent populations. 3. Population growth during the annual population rise period was faster in the absence of predators and peak population size was higher, but otherwise dynamics patterns were similar for populations where predators had access or were attracted, indicating that compensatory mechanisms operate when rodents are exposed to high levels of predation risk. Reducing dispersal of rodents removed the effect of predation on population growth and peak size, suggesting that local predators may play a role in driving rodent dispersal, but have otherwise little direct effect on population dynamics.

Animals↗

Abrogation of MRL/lpr lupus nephritis by dietary flaxseed.

A diet supplemented with flaxseed, rich in alpha-linolenic acid and plant lignans (the latter, potent platelet-activating factor receptor antagonists), was tested in a murine model of lupus nephritis. MRL/lpr female mice (n = 25) were fed 15% flaxseed diet for 14 weeks commencing at 10 weeks of age. As controls, 30 MRL/lpr mice received a standard rodent diet without flaxseed. Isotope-glomerular filtration rate (14C-inulin clearance) was measured at 9, 16, and 24 weeks of age. Proteinuria was assessed at 2-week intervals. Spleen lymphocyte proliferation, quantitated by DNA analysis, was evaluated using flow cytometry at 9, 13, 19, and 21 weeks of age. Mortality was recorded throughout the study. Glomerular filtration rate at 16 weeks was greater in flaxseed-fed mice (0.15 +/- 0.03 mL/min) compared with controls (0.06 +/- 0.04 mL/min; P = 0.01). The onset of proteinuria (Albustix, Ames Division, Miles Laboratories, Rexdale, Ontario, Canada; > or = 2+) was delayed by 4 weeks in the flax-treated mice. The percentage of flaxseed-fed mice with proteinuria was lower than the control mice up to 21 weeks of age (39% v 58%; P = 0.01). Spleen lymphocyte proliferation (percentage of cells in S-phase) at 13 weeks of age was significantly higher in the control group (22.9 +/- 5.0, P = 0.01) but not in the flaxseed group (17.2 +/- 4.9) compared with baseline (9 weeks of age) values (13.0 +/- 3.5). Mortality was lower in the flaxseed-fed mice versus the control mice (assessed by Mantel-Haenszel (log-rank) test; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Collagen autoimmune arthritis.

The evidence is now fairly conclusive that collagen-induced arthritis in rodents is mediated by antitype II collagen autoimmunity. Arthritis is probably initiated by binding of antibodies to the surface of intact articular cartilage. Many of the major manifestations of arthritis, including synovial proliferation, pannus formation, marginal erosion of bone, and destruction of cartilage, can be duplicated by injection of isolated antitype II collagen antibodies. It is not known whether delayed hypersensitivity reactions to collagen can provoke similar lesions in the absence of antibody, but circumstantial evidence suggests they do not. Also clear is that not all anticollagen antibodies are capable of inducing arthritis. The minimal requirements for arthritogenic potential are currently under investigation but probably include the ability to bind native autologous type II collagen. Also IgM antibodies alone are either ineffective or are required in relatively higher concentrations than IgG for induction of arthritis. Autoimmunity to collagen is found in many spontaneous and induced rheumatic diseases other than collagen-induced arthritis. There is at present, however, no direct evidence that this autoimmunity actually contributes to the arthritic process. Nevertheless, the human disease most often associated with collagen autoimmunity is rheumatoid arthritis. In many respects the immune reactions detected in humans with rheumatoid arthritis parallel those of arthritis in rodents. That is, responsiveness is under the control of genes within or linked to the major histocompatibility locus. High responders are limited to only a few haplotypes. Cell-mediated reactions are most vigorous in response to denatured collagen and probably have limited specificity for the type of collagen recognized. Antibodies may be separated into at least two groups, one with broad specificity for denatured collagen and a second highly specific for conformation-dependent determinants on native type II collagen. The latter antibodies are of most interest to researchers because they may be like those that induce arthritis in rodents. There is also ample evidence that antibodies are deposited in the joints of rheumatoid arthritis patients, although the specificity of these antibodies is unknown. Generally, collagen-induced arthritis is a model of antibody-initiated autoimmunity arthritis. Specifically, it is a model of type II collagen autoimmune arthritis. In consideration of its extraarticular manifestations, it may justifiably be referred to as type II collagen autoimmune disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗