Arrival of rabbit haemorrhagic disease virus 2 to northern Europe: Emergence and outbreaks in wild and domestic rabbits (Oryctolagus cuniculus) in Sweden.

Incursion of rabbit haemorrhagic disease virus (RHDV) into Sweden was documented in 1990 and it is now considered endemic in wild rabbit (Oryctolagus cuniculus) populations. Rabbit haemorrhagic disease virus 2 (RHDV2), a new, related lagovirus was first detected in France in 2010, and has spread rapidly throughout Europe and beyond. However, knowledge of RHDV2 in northern Europe is sporadic and incomplete, and in Sweden, routinely available diagnostic methods to detect rabbit haemorrhagic disease (RHD) do not distinguish between types of virus causing disease. Using RHDV2-specific RT-qPCR, sequencing of the VP60 gene and immunological virus typing of archived and prospective case material from the National Veterinary Institute's (SVA) wildlife disease surveillance programme and diagnostic pathology service, we describe the emergence of RHDV2 in Sweden in both wild and domestic rabbits. The earliest documented outbreak occurred on 22 May 2013, and from May 2013 to May 2016, 10 separate incidents of RHDV2 were documented from six different municipalities in the southern half of Sweden. Phylogenetic analysis of the VP60 gene shows clear clustering of Swedish isolates into three separate clusters within two different clades according to geographic location and time, suggesting viral evolution, multiple introduction events or both. Almost all cases of RHD examined by SVA from May 2013 to May 2016 were caused by RHDV2, suggesting that RHDV2 may be replacing RHDV as the predominant cause of RHD in Sweden.

The α2-adrenoceptor antagonist yohimbine normalizes increased islet blood flow in GK rats: a model of type 2 diabetes.

Overexpression of α2A-adrenoceptors contributes to type 2 diabetes in GK rats. We aimed to investigate if α2-adrenoceptor inhibition affected islet blood flow in these rats. Anesthetized GK and Wistar-F rats were given the α2-adrenoceptor inhibitor yohimbine (2.5 mg/kg BW) intravenously. The GK rats had higher blood glucose and serum insulin concentrations than WF rats. Yohimbine affected neither of these values in WF rats, but decreased blood glucose and increased serum insulin concentrations in GK rats. Total pancreatic and islet blood flows, measured with microspheres, were increased in GK when compared to WF rats. Yohimbine affected none of the blood flow values in WF rats, whereas islet blood flow in GK rats was reduced to values similar to those seen in WF rats. Overexpression of α2-adrenoceptors may contribute to the increased islet blood flow seen in GK rats, and may be eligible for pharmacologic intervention.

Two-week treatment with the ß3-adrenoceptor antagonist SR59230A normalizes the increased pancreatic islet blood flow in type 2 diabetic GK rats.

The Goto-Kakizaki (GK) rat, a type 2 diabetes model, has increased pancreatic islet and white adipose tissue (WAT) blood flow, and this can be normalized by acute administration of SR59230A, a ß3 -adrenoceptor antagonist. We now implanted osmotic pumps which allowed a constant release of saline or SR59230A (0.6 mg/kg × day) for 2 weeks. A decrease in islet blood flow was seen also after 2 weeks of continuous SR59230A treatment in the GK rat. However, no improvement in glucose tolerance was seen in the GK rats. Neither did SR59230A affect insulin secretion from isolated islets in vitro. WAT blood flow was not affected by the 2-week SR59230A treatment. Thus, the increased islet blood flow seen in the GK rat can be normalized for up to 2 weeks, which opens the possibilities for further studies on the long-term functional role on the islet blood flow increase in this type 2 diabetes model.

Endothelin-1 markedly decreases the blood perfusion of transplanted pancreatic islets in rats.

BACKGROUND: Transplantation of insulin-producing ß-cells is the only available curative treatment for type 1 diabetes. However, graft function declines within the first years after transplantation, which may reflect inadequate vascular engraftment. Endothelin-1 (ET-1) is a potent vasoconstrictor whose production is regulated by both hypoxia and inflammation. Moreover, the plasma concentration of ET-1 is elevated in patients with type 1 diabetes. The aim of this study was to investigate the gene expression and effects of ET-1 and its 2 receptor antagonists, BQ123 and BQ788, on blood flow in syngeneic rat islet transplants. METHODS: Pancreatic islets from Wistar Furth rats were isolated and transplanted syngeneically under the kidney capsule. Transplant and kidney cortex blood flow was measured using laser Doppler flowmetry after administration of ET-1 via topical application, or after administration of BQ123 and BQ788 intravenously. The grafts and isolated islets were analyzed for mRNA expression of ET-1, ET(A) receptor, ET(B) receptor, and endothelin-converting enzyme 1 using by reverse-transcription polymerase chain reaction. RESULTS: ET-1 markedly decreased transplant blood flow (77.5 ± 4.4% 1 minute after administration; n = 6), whereas neither BQ123 nor BQ788 had vascular effects. No differences in relative gene expression between the grafts and freshly isolated control islets were seen for ET-1 (0.65 ± 0.14 [n = 8] vs 0.79 ± 0.24 [n = 5]), ET(A) receptor (0.37 ± 0.14 [n = 8] vs 0.25 ± 0.04 [n =5]), ET(B) receptor (4.78 ± 1.43 [n = 8] vs 1.94 ± 0.32 [n = 5]), or endothelin converting enzyme 1 (7.25 ± 1.88 [n = 8] vs 11.83 ± 0.95 [n = 5]) when expressed as 2(-ΔCt). CONCLUSION: Exogenous ET-1 strongly affects the blood perfusion of transplanted islets, and endogenous levels can, if up-regulated, contribute to graft failure.

Diet and hip fractures among elderly Europeans in the EPIC cohort.

BACKGROUND/OBJECTIVES: Evidence on the role of diet during adulthood and beyond on fracture occurrence is limited. We investigated diet and hip fracture incidence in a population of elderly Europeans, participants in the European Prospective Investigation into Cancer and nutrition study. SUBJECTS/METHODS: 29, 122 volunteers (10,538 men, 18,584 women) aged 60 years and above (mean age: 64.3) from five countries were followed up for a median of 8 years and 275 incident hip fractures (222 women and 53 men) were recorded. Diet was assessed at baseline through validated dietary questionnaires. Data were analyzed through Cox proportional-hazards regression with adjustment for potential confounders. RESULTS: No food group or nutrient was significantly associated with hip fracture occurrence. There were suggestive inverse associations, however, with vegetable consumption (hazard ratio (HR) per increasing sex-specific quintile: 0.93, 95% confidence interval (CI): 0.85-1.01), fish consumption (HR per increasing sex-specific quintile: 0.93, 95% CI: 0.85-1.02) and polyunsaturated lipid intake (HR per increasing sex-specific quintile: 0.92, 95% CI: 0.82-1.02), whereas saturated lipid intake was positively associated with hip fracture risk (HR per increasing sex-specific quintile: 1.13, 95% CI: 0.99-1.29). Consumption of dairy products did not appear to influence the risk (HR per increasing sex-specific quintile: 1.02, 95% CI: 0.93-1.12). CONCLUSIONS: In a prospective study of the elderly, diet, including consumption of dairy products, alcohol and vitamin D, did not appear to play a major role in hip fracture incidence. There is however, weak and statistically non-significant evidence that vegetable and fish consumption and intake of polyunsaturated lipids may have a beneficial, whereas saturated lipid intake a detrimental effect.

Physical activity in middle-aged women and hip fracture risk: the UFO study.

UNLABELLED: In a population-based case-control study, we demonstrate that middle-aged women who were active with walking or in different physical spare time activities were at lower risk of later sustaining a hip fracture compared to more sedentary women. INTRODUCTION: In middle-aged women participating in the Umeå Fracture and Osteoporosis (UFO) study, we investigated whether physical activity is associated with a subsequent decreased risk of sustaining a hip fracture. METHODS: The UFO study is a nested case-control study investigating associations between bone markers, lifestyle, and osteoporotic fractures. We identified 81 female hip fracture cases that had reported lifestyle data before they sustained their fracture. Each case was compared with two female controls who were identified from the same cohort and matched for age and week of reporting data, yielding a total cohort of 237 subjects. Mean age at baseline was 57.2 ± 5.0 years, and mean age at fracture was 65.4 ± 6.4 years. RESULTS: Conditional logistic regression analysis with adjustments for height, weight, smoking, and menopausal status showed that subjects who were regularly active with walking or had a moderate or high frequency of physical spare time activities (i.e. berry/mushroom picking and snow shovelling) were at reduced risk of sustaining a hip fracture (OR 0.14; 95% CI; 0.05-0.53 for walking and OR 0.19; 95% CI; 0.08-0.46, OR 0.17, 95% CI; 0.05-0.64 for moderate and high frequency of spare time activities, respectively) compared to more sedentary women. CONCLUSION: An active lifestyle in middle age seems to reduce the risk of future hip fracture. Possible mechanisms may include improved muscle strength, coordination, and balance resulting in a decreased risk of falling and perhaps also direct skeletal benefits.

Physical activity is the strongest predictor of calcaneal peak bone mass in young Swedish men.

SUMMARY: In a highly representative sample of young adult Swedish men (n = 2,384), we demonstrate that physical activity during childhood and adolescence was the strongest predictor of calcaneal bone mineral density (BMD), and that peak bone mass was reached at this site at the age of 18 years. INTRODUCTION: The purpose of the present study was to determine if physical activity during growth is associated with peak calcaneal BMD in a large, highly representative cohort of young Swedish men. METHODS: In this study, 2,384 men, 18.3 +/- 0.3 (mean +/- SD) years old, were included from a population attending the mandatory tests for selection to compulsory military service in Sweden. BMD (g/cm(2)) of the calcaneus was measured using dual-energy X-ray absorptiometry. Training habits were investigated using a standardized questionnaire. RESULTS: Regression analysis (with age, height, weight, smoking, and calcium intake as covariates) demonstrated that history of regular physical activity was the strongest predictor and could explain 10.1% of the variation in BMD (standardized beta = 0.31, p < 0.001). A regression model with quadratic age effect revealed maximum BMD at 18.4 years. CONCLUSIONS: We found that history of physical activity during growth was the strongest predictor of peak calcaneal BMD in young men.

Reversal of high pancreatic islet and white adipose tissue blood flow in type 2 diabetic GK rats by administration of the beta3-adrenoceptor inhibitor SR-59230A.

Previous studies have shown that the Goto-Kakizaki (GK) rat, a nonobese type 2 diabetes model, has an increased white adipose tissue (WAT) and islet blood flow when compared with control rats. The aim of the study was to examine if these increased blood flow values in GK rats could be affected by the beta(3)-adrenoceptor antagonist SR-59230A. We measured organ blood flow with a microsphere technique 10 min after administration of SR-59230A (1 mg/kg body wt), or the corresponding volume of 0.9% NaCl solution (1 ml/kg body wt) in rats anaesthetized with thiobutabarbital. The GK rat had an increased blood flow in all intra-abdominal adipose tissue depots except for the sternal fat pad compared with Wistar-Furth (WF) rats. However, no differences were seen in the blood perfusion of subcutaneous white or brown adipose tissue. The blood flow was also increased in both the pancreas and in the islets in the GK rat compared with WF rats. SR-59230A treatment affected neither WAT nor pancreatic blood flow in WF rats. In GK rats, on the other hand, SR-59230A decreased both WAT and islet blood flow values to values similar to those seen in control WF rats. The whole pancreatic blood flow was not affected by SR-59230A administration in GK rats. Interestingly, the brown adipose tissue blood flow in GK rats increased after SR-59230A administration. These results suggest that beta(3)-adrenoceptors are involved in regulation of blood flow both in islet and in adipose tissue.

The beneficial effects of exercise on BMD are lost after cessation: a 5-year follow-up in older post-menopausal women.

This study investigates whether the positive effects on bone mineral density (BMD, g/cm(2)) and neuromuscular function following a combined weight-bearing program are sustained in older women, a longer period after cessation of training. Thirty-four women (18 exercisers and 16 controls) aged 73-88 years, who completed a 12-month randomized-controlled trial, were invited to a 5-year follow-up assessment of BMD and neuromuscular function. Both groups sustained significant losses in BMD of the femoral neck, trochanter, and Ward's triangle during the follow-up period. Significant losses were also seen in all neuromuscular function tests. The inter-group change was, however, significant only for maximal walking speed where the exercise group had a significantly greater loss. In conclusion, this study suggests that gains in bone density and neuromuscular functions achieved by training are lost after cessation of training. Continuous high-intensity weight-loading physical activity is probably necessary to preserve bone density and neuromuscular function in older women.

Relationships between physical activity and physical capacity in adolescent females and bone mass in adulthood.

This study investigates whether physical activity and physical performance in adolescence are positively related to adult bone mineral density (BMD). In 1974, physical activity, endurance, and muscular strength were measured in 204 randomly selected female students, age 16.1 +/- 0.3 year (range 15-17 years). Twenty years later, 36 of the women volunteered to undergo a measurement of their BMD. Women who were members in a sports club in adolescence had significantly higher adult BMD (mean differences of 5% to 17% depending on site) compared with subjects who were not engaged in a sports club. Furthermore, women with persistent weight-bearing activity in adulthood had significantly higher BMD compared with women who had stopped being active or had never been active. The differences ranged between 5% and 19% with the highest difference found in trochanter BMD. Stepwise regression analyses showed that membership in a sports club at baseline was a significant independent predictor of BMD in the total body, lumbar spine, legs, trochanter, and femoral neck, explaining 17-26% of the variation in BMD. Change in body weight was a strong independent predictor of BMD of the total body and arms, explaining 8% of the variation in both sites. In addition, running performance at baseline was an independent predictor of total body BMD, whereas the two-hand lift performance significantly predicted BMD of the total body, legs and trochanter. The hanging leg-lift and handgrip were both significant predictors of arm BMD. In conclusion, membership in a sports club and site-specific physical performance in adolescence together with the change in body weight were significantly associated with adult BMD in premenopausal women.

The genetic contribution to canine personality.

The domestic dog may be exceptionally well suited for behavioral genetic studies owing to its population history and the striking behavior differences among breeds. To explore to what extent and how behavioral traits are transmitted between generations, heritabilities and genetic correlations for behavioral traits were estimated in a cohort containing over 10,000 behaviorally tested German shepherd and Rottweiler dogs. In both breeds, the pattern of co-inheritance was found to be similar for the 16 examined behavioral traits. Furthermore, over 50% of the additive genetic variation of the behavioral traits could be explained by one underlying principal component, indicating a shared genetic component behind most of the examined behavioral traits. Only aggression appears to be inherited independently of the other traits. The results support a genetic basis for a broad personality trait previously named shyness-boldness dimension, and heritability was estimated to be 0.25 in the two breeds. Therefore, breeds of dogs appear to constitute a valuable resource for behavioral genetic research on the normal behavioral differences in broad personality traits.

Association of oestrogen receptor alpha gene polymorphisms with postmenopausal bone loss, bone mass, and quantitative ultrasound properties of bone.

BACKGROUND: The gene encoding oestrogen receptor alpha (ESR1) appears to regulate bone mineral density (BMD) and other determinants of osteoporotic fracture risk. OBJECTIVE: To investigate the relation between common polymorphisms and haplotypes of the ESR1 gene and osteoporosis related phenotypes in a population based cohort of 3054 Scottish women. RESULTS: There was a significant association between a common haplotype "px", defined by the PvuII and XbaI restriction fragment length polymorphisms within intron 1 of the ESR1 gene, and femoral neck bone loss in postmenopausal women who had not received hormone replacement therapy (n = 945; p = 0.009). Annual rates of femoral neck bone loss were approximately 14% higher in subjects who carried one copy of px and 22% higher in those who carried two copies, compared with those who did not carry the px haplotype. The px haplotype was associated with lower femoral neck BMD in the postmenopausal women (p = 0.02), and with reduced calcaneal broadband ultrasound attenuation (BUA) values in the whole study population (p = 0.005). There was no association between a TA repeat polymorphism in the ESR1 promoter and any phenotype studied, though on long range haplotype analysis subjects with a smaller number of TA repeats who also carried the px haplotype had reduced BUA values. CONCLUSIONS: The ESR1px haplotype is associated with reduced hip BMD values and increased rates of femoral neck bone loss in postmenopausal women. An association with BUA may explain the fact that ESR1 intron 1 alleles predict osteoporotic fractures by a mechanism partly independent of differences in BMD.

Chromosomal size variation in Trypanosoma cruzi is mainly progressive and is evolutionarily informative.

The evolutionary significance of chromosome size polymorphism was explored in a representative panel of 26 Trypanosoma cruzi stocks. We tested a progressive model (aCSDI) assuming that the larger the size difference between homologous chromosomes, the more divergent the parasites are. This was contrasted with a non-progressive model (Jaccard's distance), in which any chromosome size difference has the same weight. ACSDI-based dendrograms were very similar to those built-up from multilocus enzyme electrophoresis (MLEE) and random amplified polymorphic DNA (RAPD) data: structuring in 2 major lineages (T. cruzi I and T. cruz II) and 5 small subdivisions within T. cruzi II was identical, and branching was very similar. Furthermore, a significant correlation (P < 0.001) was observed between aCSDI and phenetic distances calculated from MLEE and RAPD data. In contrast, analysis of chromosome size polymorphism with Jaccard's distance generated dendrograms with relatively long branches, causing most branching points to cluster close together, which generates statistically uncertain branching points. Our results thus support a model of progressive chromosome size-variation and show that despite an extensive polymorphism, chromosomal sizes constitute valuable characters for evolutionary analyses. Furthermore, our data are consistent with the clonal evolution model previously proposed for T. cruzi.

Investigation of the functional effect of monoamine oxidase polymorphisms in human brain.

Monoamine oxidase A and monoamine oxidase B ( MAOA and MAOB) have been suggested to play a role in psychiatric disorders and/or behavioral traits. We have investigated whether different polymorphisms can account for variations in enzyme activity and/or mRNA levels in human brain. Whereas several association studies have been reported previously, this is the first study of the functional effect of MAO DNA variants in human brain. Four polymorphic changes were analyzed: a VNTR located in the MAOA promoter, a VNTR located in the first intron of the MAOA gene, and two single nucleotide polymorphisms located in exon 8 of MAOA and in intron 13 of MAOB. We studied the association of the variants and the resulting haplotypes, with expression levels and enzyme activities of both monoamine oxidases in human cortical brain autopsies. We did not find a significant association of any single MAOA polymorphism with expression levels or enzyme activity in human brain. We did, however, find an association of a particular haplotype with MAOA enzyme levels ( P=0.03). Our results suggest that a novel functional polymorphism that affects enzyme activity in human brain may exist in MAOA. For MAOB, we found a significant association ( P=0.02) between the MAOB intron 13 alleles and different levels of MAOB enzyme activity in human brain. We postulate that there may be a cis-regulatory element in linkage disequilibrium with the B-SNP13 polymorphisms that alters MAOB enzyme activity in human brain.

Interference with CD28, CD80, CD86 or CD152 in collagen-induced arthritis. Limited role of IFN-gamma in anti-B7-mediated suppression of disease.

We have investigated interference with co-stimulation by administering mAbs towards CD28, CD80, CD86, and CD152 in mice immunized for the development of collagen-induced arthritis (CIA). Anti-CD80 and anti-CD86 treatment inhibited disease score and incidence, whereas anti-CD28 treatment led only to a delayed disease onset. Administration of anti-CD152 had no effect. The CII-specific Ab-response was suppressed by the co-stimulatory blockade, with a stronger effect on IgG1 than on IgG2a. The CII-driven T cell proliferation, on the other hand, was not affected. Furthermore, T cells primed in the presence of either anti-B7 or anti-CD28 produced markedly increased amounts of IFN-gamma in response to CII. To investigate whether this increase in IFN-gamma was related to disease suppression, IFN-gamma-deficient mice were immunized with CII, treated with anti-B7 and followed for the development of arthritis. As in the wild-type mice, administration of anti-B7 to IFN-gamma-deficient mice led to a reduced disease incidence and severity as well as reduced anti-CII IgG titers. Collectively, these data stress the importance of co-stimulation for the delivery of B cell help rather than for production of Th1 cytokines. We also demonstrate that the enhanced production of IFN-gamma observed after B7-blockade is not accountable for the anti-B7 mediated inhibition of CIA.

Genetic linkage analysis of the antibody responses to myelin basic protein and myelin oligodendrocyte glycoprotein in rats immunized with rat spinal cord homogenate.

The genetic control of the antibody response to myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) was analysed in F1 and F2 crosses of DA and E3 rats, immunized with rat spinal chord homogenate. The DA rats were highly susceptible to encephalomyelitis and made antibody responses to both MBP and MOG, whereas the E3 rats were disease-resistant and responded only to MOG. The anti-MBP response was mainly controlled by the disease-promoting MHC region of the DA strain together with several disease loci outside MHC. In contrast, the anti-MOG response was associated with loci not related to or actually conferring resistance to disease.

A schizophrenia-susceptibility locus at 6q25, in one of the world's largest reported pedigrees.

We have completed a genome scan of a 12-generation, 3,400-member pedigree with schizophrenia. Samples from 210 individuals were collected from the pedigree. We performed an "affecteds-only" genome-scan analysis using 43 members of the pedigree. The affected individuals included 29 patients with schizophrenia, 10 with schizoaffective disorders, and 4 with psychosis not otherwise specified. Two sets of white-European allele frequencies were used-one from a Swedish control population (46 unrelated individuals) and one from the pedigree (210 individuals). All analyses pointed to the same region: D6S264, located at 6q25.2, showed a maximum LOD score of 3.45 when allele frequencies in the Swedish control population were used, compared with a maximum LOD score of 2.59 when the pedigree's allele frequencies were used. We analyzed additional markers in the 6q25 region and found a maximum LOD score of 6.6 with marker D6S253, as well as a 6-cM haplotype (markers D6S253-D6S264) that segregated, after 12 generations, with the majority of the affected individuals. Multipoint analysis was performed with the markers in the 6q25 region, and a maximum LOD score of 7.7 was obtained. To evaluate the significance of the genome scan, we simulated the complete analysis under the assumption of no linkage. The results showed that a LOD score >2.2 should be considered as suggestive of linkage, whereas a LOD score >3.7 should be considered as significant. These results suggest that a common ancestral region was inherited by the affected individuals in this large pedigree.

The geographic distribution of monoamine oxidase haplotypes supports a bottleneck during the dispersion of modern humans from Africa.

Every genetic locus mingles the information about the evolutionary history of the human species with the history of its own evolution. Therefore, to address the question of the origin of humans from a genetic point of view, evolutionary histories from many genetic loci have to be gathered and compared. We have studied two genes residing on the X chromosome encoding monoamine oxidases A and B (MAOA and MAOB). Both genes have been suggested to play a role in psychiatric and/or behavioral traits. To search for DNA variants of the MAO genes, the sequences of exonic and flanking intronic regions of these two genes were determined in a group of Swedish males. The sequence analysis revealed several novel polymorphisms in the MAO genes. Haplotypes containing high-frequency MAOA polymorphisms were constructed, and their frequencies were determined in additional samples from Caucasian, Asian, and African populations. We found two common haplotypes with similar frequencies in Caucasian and Asian populations. However, only one of them was also the most frequent haplotype in Africans, while the other haplotype was present in only one Kenyan male. This profound change in haplotype frequencies from Africans to non-Africans supports a possible bottleneck during the dispersion of modern humans from Africa.

Histone genes expression during the cell cycle in Trypanosoma cruzi.

Histones, the basic proteins which compact DNA into the nucleosomal and solenoidal fibers are synthesized in correlation with DNA replication during the S-phase of the cell cycle. This behavior is controlled both at transcriptional and postranscriptional levels in higher eukaryotes and yeasts. We have found that histone synthesis in synchronized trypanosomes is controlled by fluctuations on the levels of their mRNAs. Though we cannot preclude the existence of a transcriptional regulatory mechanism, our results point to the participation of changes in the stability of histone mRNAs as a regulatory mechanism of their levels during the cell cycle in Trypanosoma. We have also found a postranscriptional regulatory mechanism which could be acting at the translational level. These results show both similarities and differences between Trypanosoma and higher eukaryotes regarding the expression of their histone genes.

Arthritis induced in rats with nonimmunogenic adjuvants as models for rheumatoid arthritis.

Rat models are useful for studies of the pathogenesis of rheumatoid arthritis (RA) since rats are extraordinarily sensitive to induction of arthritis with adjuvants. Injection of not only the classical complete Freund's adjuvant but also mineral oil without mycobacteria and pure adjuvants such as pristane and squalene, induce severe arthritis in many rat strains. Models like pristane-induced arthritis in rats are optimal models for RA since they fulfill the RA criteria including a chronic relapsing disease course. Arthritogenic adjuvants like pristane, avridine, squalene and mineral oil are not immunogenic since they do not contain major histocompatibility complex (MHC) binding peptides. Nevertheless, the diseases are MHC-associated and dependent on the activation of alphabetaTCR (T-cell receptor)-expressing T cells. However, it has not been possible to link the immune response to joint antigens or other endogenous components although immunization with various cartilage proteins induce arthritis but with different pathogeneses. To unravel the mechanisms behind adjuvant-induced arthritis, a disease-oriented genetic approach is optimal. Several loci that control onset of arthritis, severity and chronicity of the disease have been identified in genetic crosses and most of these have been confirmed in congenic strains. In addition, many of these loci are found in other autoimmune models in the rat as well as associated with arthritis in mice and humans.