Vitamin D and polymorphisms of VDR gene in patients with systemic lupus erythematosus

The susceptibility for the development of systemic lupus erythematosus (SLE) is related to environmental, hormonal, genetic, and immunological factors. Numerous genes have been linked to the emergence of SLE, including vitamin D receptor (VDR) gene that synthesizes the receptor of vitamin D. Several polymorphisms have been described since the discovery of this gene, and their effects on VDR activity are still poorly understood. Vitamin D’s biological functions are mediated by VDR. Vitamin D exerts many actions on the immune system, and several studies have suggested its role in the pathogenesis of autoimmune diseases. SLE patients have low blood levels of vitamin D, which raises the possibility of association between the deficiency of this vitamin and the onset of the disease. BsmI and FokI polymorphic variants seem to be related to the onset of the disease in Asian patients. In this article, we review the aspects related to the metabolism and immunoregulatory effects of vitamin D, VDR, and main polymorphisms involving the VDR gene and the relationship between vitamin D levels and its receptor with SLE.     

Matrix metalloproteinase gene polymorphisms in patients with rheumatoid arthritis

Several genetic factors seem to be involved in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to analyze whether functional polymorphisms in the promoter region of the MMP-1, -3 and -9 genes were associated with RA. The study population comprises 110 RA patients and 100 healthy controls. The –1607 1G/2G MMP-1, –1171 5A/6A MMP-3, and –1562 C/T MMP-9 polymorphisms were analyzed. The frequency of the 5A allele of MMP-3 gene was significantly higher in the controls when compared with the RA patients (0.45 vs. 0.32, P < 0.01). No significant differences were observed in the allele frequencies for the MMP-1 and -9 polymorphisms between RA patients and controls. Individuals carrying MMP-3 5A allele have significant higher frequency of extra-articular manifestations and rheumatoid nodules than individuals homozygous for 6A allele (P < 0.05). The results presented in this study provide evidence of an association between the MMP-3 gene polymorphism and RA.     

The chemokine receptor CCR5 genetic polymorphism and expression in rheumatoid arthritis patients

OBJECTIVES: To identify the genetic polymorphism of the chemokine receptor CCR5 (the Delta32 allelic variant) in patients with rheumatoid arthritis (RA) and compare the findings with healthy controls. To compare the CCR5 phenotypic expression in T cells and monocytes isolated from the peripheral blood and synovial fluid in a subgroup of RA patients. METHODS: CCR5 genes of 92 RA patients and 160 healthy controls were genotyped using specific primers flanking the region of deletion. The ethnic distribution was similar between the groups. Flow cytometric analysis was used for immunophenotyping the T cells and monocytes isolated from the peripheral blood and synovial fluid of eight RA patients. The isolated cells were triple stained with CD4 or CD8, CD25 and CCR5 monoclonal antibodies. RESULTS: There was no difference in the CCR5Delta32 genotypic frequency between the RA patients and the control group (0.055 and 0.063, respectively, p = 0.989). No homozygote for the CCR5Delta32 allele was seen in either group. Five heterozygotes were identified in the RA patient group, whose disease was shown to be aggressive. A significant enrichment of activated CCR5+ monocytes was seen in the synovial fluid of the RA patients subjected to arthrocentesis, who were all homozygotes for the CCR5 wild-type genotype. CONCLUSION: A protective role for the CCR5 allelic variant in RA development was not observed. Disease severity in the heterozygotes suggests that other proinflammatory mechanisms might overcome this mutation in vivo. The activated CCR5+ monocyte enrichment in the rheumatoid synovial fluid might indicate that this cell population has an important role in the pathogenesis of the disease.     

Oesophageal dysmotility in systemic sclerosis: comparison of HRCT and scintigraphy

The aim of this study was to compare oesophageal abnormalities observed in high-resolution CT with radionuclide transit in patients with systemic sclerosis. 76 patients with systemic sclerosis were evaluated by high-resolution CT and oesophageal transit scintigraphy. Residual activity > or =20% (in relation to peak activity) at 15 s after the beginning of the swallow of the labelled liquid (in supine position) was considered indicative of oesophageal dysfunction. Supra-aortic and infra-aortic oesophageal coronal diameters were measured in high-resolution CT. Oesophageal dilatation was deemed present when the diameters exceeded 10 mm. 19 patients (25%) had supra-aortic oesophageal dilatation and 48 patients (63.1%) had infra-aortic dilatation. The prevalence of radionuclide transit delay was 77.6%. All patients (19/19) with supra-aortic dilatation had oesophageal dysfunction, compared with 70.2% (40/57) of the patients with no supra-aortic dilatation (p = 0.004). Oesophageal dysfunction was present in 97.9% (47/48) of patients with infra-aortic dilatation, compared with 42.9% (12/28) in patients without it (p < 0.001). Receiver operating characteristic (ROC) curves have demonstrated that the supra-aortic and infra-aortic diameters had good discriminatory capacity for oesophageal dysfunction in systemic sclerosis (area under the curve, 95% confidence interval: 0.80, 0.70-0.89 and 0.92, 0.86-0.98, respectively). There is a clinically significant association between oesophageal dysmotility and high-resolution CT findings of oesophageal coronal dilatation. The evaluation of infra-aortic oesophageal coronal diameter can provide additional useful information about the functional and anatomic conditions of the oesophagus in systemic sclerosis.     

Protective effect of RC‐3095, an antagonist of the gastrin‐releasing peptide receptor,in experimental arthritis

Objective

To evaluate the antiinflammatory effects of RC‐3095 in 2 experimental models of arthritis, collagen‐induced arthritis (CIA) and antigen‐induced arthritis (AIA), and to determine the mechanisms of action involved.

Methods

RC‐3095 was administered daily to mice with CIA and mice with AIA, after induction of disease with methylated bovine serum albumin. Disease incidence and severity were assessed using a clinical index and evaluation of histologic features, respectively. In mice with CIA, gastrin‐releasing peptide receptor (GRPR) was detected by immunohistochemical analysis, while in mice with AIA, migration of neutrophils, presence of glycosaminoglycans, and lymphocyte proliferation, determined using the MTT assay, were assessed. Expression of cytokines interleukin‐17 (IL‐17), IL‐1β, and tumor necrosis factor α (TNFα) was evaluated in all mouse knees using enzyme‐linked immunosorbent assay. Treg cell production was assessed by flow cytometry in the joints of mice with AIA.

Results

In mice with AIA, administration of RC‐3095 reduced neutrophil migration, mechanical hypernociception, and proteoglycan loss. These findings were associated with inhibition of the levels of all 3 proinflammatory cytokines, decreased lymphocyte proliferation, and increased Treg cell numbers. In the CIA model, treatment with RC‐3095 led to a significant reduction in arthritis clinical scores and the severity of disease determined histologically. Synovial inflammation, synovial hyperplasia, pannus formation, and extensive erosive changes were all dramatically reduced in the arthritic mice treated with RC‐3095. Furthermore, arthritic mice treated with RC‐3095 showed a significant reduction in the concentrations of IL‐17, IL‐1β, and TNFα, and showed a diminished expression of GRPR.

Conclusion

These findings suggest that the GRP pathway has a significant role in chronic arthritis, and its inhibition can be explored as a possible therapeutic strategy in rheumatoid arthritis.