Study of CCR5 Gene polymorphism in rheumatoid arthritis

Chemokines are critical for the inflammatory process in autoimmune diseases such as rheumatoid arthritis [RA]. The chemokine receptor-5 [CCR5] mediates chemotaxis by CC chemokines and is expressed by lymphocytes with the phenotype and monocyte/macrophages. A 32bp deletion in the CCR5 [CCR5-delta 32 allele] abolishes receptor expression in homozygotes, while CCR5-delta 32 carriers express less receptor level than wild type homozygotes. This polymorphism is related to resistance to HIV-1 infection and progression to AIDS. It is hypothesized that CCR5-delta 32 allele may modulate the inflammatory response involved in rheumatoid arthritis and therefore may affect disease severity, susceptibility or both. In the present study 70 rheumatoid arthritis patients and 40 healthy individuals were genotyped. The frequency of CCR5-delta 32 allele was significantly higher in healthy individuals compared to rheumatoid arthritis patients [45% Vs 17%] respectively [p.value 0.033]. Homozygous delta 32 mutation was not detected in patients or controls No significant difference was found between CCR5-delta 32 carriers and wild type homozygotes regarding clinical or laboratory findings except for the tender joint count and rheumatoid factor positivity which was higher in wild type homozygotes [p.value 0.046 and 0.007 respectively]. Our data suggest that CCR5-dlta 32 carriers may partially protected against rheumatoid arthritis, and suggest CCR5 receptor as a candidate for targeted therapy in rheumatoid arthritis

Functional regulation of CD94 and CD56 NK cells in patients with autoimmune rheumatoid arthritis

Rheumatoid Arthritis [RA] is an autoimmune disease characterized by chronic inflammation of the joints, in which T-helper type 1 cytokines play an important role. Established autoimmune diseases, with similar mechanistic characteristics to RA, include systemic lupus erythematosus [SLE], psoriasis, type 1 diabetes mellitus and multiple sclerosis. Natural killer [NK] and natural killer-T [NK-T] cells are considered key to the pathogenesis of these conditions. The role of NK cells in autoimmune diseases is somehow unclear. They are a subpopulation of cytotoxic lymphocytes that express the activation markers CD16, CD56 and CD57 and the inhibitory markers CD158a and CD94, which can be either inhibitory or activatory depending on the ligand. Unlike T cells, they are able to act without prior sensitization and their role appears to be dictated mainly by the opposing forces of activatory and inhibitory receptors. The main function of NK cells is to recognize and lyse virally infected cells and malignant cells which do not express major histocompatibilty complex [MHC] class I alleles. Is to determine the rote of these molecules in the behavior of NK cells in autoimmune diseases with chronic intlammation as in patients with RA and SLE. The study included 20 RA patients, 6 SLE and 10 age matched healthy controls. MNC were isolated from peripheral blood samples of these patients to analyze NK cells using a triple color BD flowcytometer with CD56 FITC, CD91 PE and CD3 APC. Gated NK cells were characterized by being CD56 and CD94 bright while CD3 negative. Results were expressed as MFI of the included dye. RA patients had a significantly higher CD56 and CD94 MFI [14.1 +/- 4.1 and 0.5 +/- 2.5 respectively] than both SLE patients [4.1 +/- 1.3 and 1.6 +/- 0.5 respectively] and the control group [4.4 +/- 1.1 and 4.5 +/- 1.3 respectively] with a [p<0.001]. On the other hand, MFI of CD56 in SLE patients were not significantly different from controls, while the MFI of CD94 were significantly lower than controls [p<0.001]. These results suggest that CD94 had a stimulatory effect on the NK cells of RA patients and most probably an inhibitory effect on the NK cells of SLE patients. CD94 has a promoting effect on the pathology of RA patients rather than SLE patients. We recommend more studies to target the stimulatory signal of the CD94 receptors and to investigate the functional role of these cells

Role of mRNA and serum soluble cytotoxic T-lymphocyte-associated antigen-4 molecule [sCTLA-4] in systemic lupus erythematosus

SLE is a chronic inflammatory systemic autoimmune disease characterised by sustained abnormal immune activation and autoantibody production. A defect in the inhibitory molecules including CTLA-4 is one possibility of the many different mechanisms that may contribute to the pathogenesis. A soluble CTLA-4 protein was found to be present in human serum. The presence of this soluble costimulatory molecule in human serum may provide a means for T-lymphocytes to either enhance or inhibit their biologic effects through additional crossing-linking or competitive blocking to their cell-bound counterparts, thereby influencing the T cell-mediated immune responses. Is to investigate the expression of sCTLA-4 molecule in patients with systemic lupus erythema-tosus [SLE], and correlate its level with disease activity. Thirty-four SLE patients and twelve age- and sex-matched healthy individuals were enrolled in the study. Blood samples from patients and controls were subjected to the following: Quantitative detection of sCTLA-4 levels in sera measured by enzyme-linked immunosorbent assay, detection of sCTLA-4 mRNA expression in selected patients and controls detected in their peripheral blood mononuclear cells [PBMCs] by reverse transcriptase-polymerase chain reaction [RT-PCR] method, and detection of CTLA-4 gene polymorphism in promoter region detected by PCR-restriction fragment length polymorphism [RFLP] method. The serum level of sCTLA-4 in the patients with active SLE was statistically much higher than that in the healthy controls and patients not in activity [p<0.001]. The mean intensity of sCTLA-4 mRNA expression was significantly higher in SLE patients when compared to the control group [p<0.001]. There was no statistically significant difference between patients and controls regarding the mean intensity of in CTLA-4 mRNA expression. CTLA-4 gene polymorphism in promoter region at position -318 did not affect levels of sCTLA-4. We couldn't establish a statistically significant difference between patients and controls regarding the frequency of CTLA-4 polymorphism. To exclude the possible effect of corticosteroids on the expression of sCTLA-4, a comparison of sCTLA-4 mRNA as well as serum sCTLA-4 level was done between patients with and without steroid treatment, which revealed no statistically significant difference. Patients with SLE have increased sCTLA-4 expression. However the mechanism and role of increased sCTLA-4 in the pathogenesis of SLE remains tube elucidated