Rheumatoid arthritis (RA) is closely associated with HLA-DRB1 alleles that code a five-amino acid sequence motif in positions 70–74 of the HLA-DRβ chain, called the shared epitope (SE). The mechanistic basis of SE-RA association is unknown. We have recently found that the SE functions as an allele-specific signal transducing ligand that activates a nitric oxide (NO)-mediated pathway in other cells. To better understand the role of the SE in the immune system, here we have examined its effect on T cell polarization in mice. In CD11c+CD8+ dendritic cells (DCs) the SE inhibited the enzymatic activity of indoleamine 2,3 dioxygenase (IDO), a key enzyme in immune tolerance and T cell regulation, while in CD11c+CD8− DCs the ligand activated robust production of IL-6. When SE-activated DCs were co-cultured with CD4+ T cells, the differentiation of Foxp3+ T regulatory (Treg) cells was suppressed, while Th17 cells were expanded. The polarizing effects could be seen with SE-positive synthetic peptides, but even more so, when the SE was in its natural tri-dimensional conformation as part of HLA-DR tetrameric proteins. In vivo administration of the SE ligand resulted in higher abundance of Th17 cells in the draining lymph nodes and increased IL-17 production by splenocytes. Thus, we conclude that the SE acts as a potent immune-stimulatory ligand that can polarize T cell differentiation toward Th17 cells, a T cell subset that has been recently implicated in the pathogenesis of autoimmune diseases, including RA.

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The shared epitope (SE) - an HLA-DRB1-encoded 5-amino acid sequence motif carried by the vast majority of rheumatoid arthritis (RA) patients - is a risk factor for severe disease. The mechanistic basis of RA-SE association is unknown. This group has previously demonstrated that the SE acts as a signal transduction ligand that activates nitric oxide and reactive oxygen species production. SE-activated signaling depends on cell surface calreticulin, a known innate immunity receptor previously implicated in immune regulation, autoimmunity and angiogenesis. Recent evidence that the SE enhances the polarization of Th17 cells, which is a key mechanism in autoimmunity, is discussed highlighting one of several potential functional effects of the SE in RA.

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The aims of the study were (1) to quantify the influence of selected imaging parameters on the image quality (slice thickness, mAs, and beam orientation) defining optimal conditions for scan protocols and (2) to evaluate the benefits of the 3D reconstruction techniques for visualization of NDS structures in dogs. CT-DCG was performed bilaterally in 32 heads of dogs. CT transverse images were obtained using a combination of two slice thickness values (0.8 mm and 2 mm) and two mAs values (50 mAs and 300 mAs). Two beam projection orientations were also tested: transverse plane (perpendicular to the hard palate) and oblique to the hard palate. Three-dimensional images were obtained using Volume Rendering (VR). Transverse beam projection proved to be superior for the assessment of the inferior and superior lacrimal canaliculi and lacrimal sac. In this study, there was no statistical difference regarding mAs values (50 mAs and 300 mAs) and slice thickness values (0.8 mm and 2 mm). Three-dimensional images were helpful for the assessment of topographic relationship between nasolacrimal structures and cranial landmarks.

The objective of this study was to determine intraocular pressure (IOP) and cardiac changes in normocapnic dogs maintained under controlled ventilation and anesthetized using sevoflurane or desflurane. Sixteen healthy adult mixed-breed dogs, seven males and nine females, weighing 10-15 kg were used. The dogs were randomly assigned to one of two groups composed of eight animals anesthetized with sevoflurane (SEVO) or desflurane (DESF). In both groups, anesthesia was induced with propofol (10 mg/kg), and neuromuscular blockade was achieved with rocuronium (0.6 mg/kg/h i.v.). No premedication was given. Ventilation was adjusted to maintain end-tidal carbon dioxide partial pressure at 35 mmHg. Anesthesia was maintained with 1.5 minimum alveolar concentration (MAC) of sevoflurane or desflurane. In both groups IOP was measured by applanation tonometry (Tono-Pen) before induction of anesthesia. IOP, mean arterial pressure (MAP), heart rate (HR), cardiac index (CI) and central venous pressure (CVP) were also measured 45 min after the beginning of inhalant anesthesia and then every 20 min for 60 min. A one-way repeated measures anova was used to compare data within the same group and Student's t-test was used to assess differences between groups. P < 0.05 was considered statistically significant. Measurements showed normal IOP values in both groups, even though IOP increased significantly from baseline during the use of desflurane. IOP did not differ between groups. CI in the desflurane group was significantly greater than in the sevoflurane group. Sevoflurane and desflurane have no clinically significant effects on IOP, MAP, HR, CI or VCP in the dog.

Calreticulin (CRT) plays a role in the clearance of dying cells and has been implicated in autoimmunity. Recent evidence indicates that cell surface CRT (csCRT) acts as a signal transducing receptor for the rheumatoid arthritis (RA) shared epitope (SE). The SE binding site on CRT has been mapped to amino acid residues 217-223 in the P-domain. Upon interaction with dendritic cells (DCs), the SE activates potent immune regulatory events. In CD8α + DCs, which express higher abundance of csCRT, the SE inhibits the tolerogenic enzyme indoleamine 2,3 dioxygenase with resultant inhibition of regulatory T (Treg) cell differentiation. In CD8α -DCs, the SE ligand increases secretion of IL-6 and IL-23 and facilitates generation of Th17 cells, a T cell subset known to play a role in autoimmunity. Based on these recent findings, here we discuss the possibility that the csCRT may play a pathogenic role in RA by transducing SE-activated Th17-polarizing signals.