Effector T-cells are expanded in systemic lupus erythematosus patients with high disease activity and damage indexes.

Background and objectives T-cell activation may be one of the pathogenic mechanisms of systemic lupus erythematosus (SLE). After repeated antigenic stimulation, T-cells undergo different modifications, leading to the differentiation into effector memory T-cells (CCR7-CD45RA-) and terminally differentiated effector memory (TDEM) T-cells (CCR7-CD45RA+). Similarly, down-modulation of CD28 may lead to the expansion of the CD28- T-cells, a subpopulation with peculiar effector activities. The aim of this study was the characterization of T-cell phenotype in a cohort of patients with SLE according to disease activity and damage index. Materials and methods Phenotypic analysis of peripheral blood T lymphocytes of 51 SLE patients and 21 healthy controls was done by flow-cytometry. SLE disease activity was evaluated by SLE Disease Activity Index-2000 (SLEDAI-2K) and damage by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). The variations between different groups were evaluated by Mann-Whitney test. Bonferroni correction was applied to adjust for multiple comparisons ( padj). Spearman rank test was used to evaluate the correlations between quantitative variables. Results CD4+ lymphopenia was found among SLE patients. Patients showed a trend for a higher percentage of TDEM among the CD4+ T-cell subpopulation in comparison with healthy controls ( p = .04). SLE patients were divided into two groups according to disease activity: patients with SLEDAI-2K ≥ 6 ( n = 13) had a higher percentage of circulating CD4+ T-cells with CD28- phenotype ( padj = .005) as well as those with an effector memory ( padj = .004) and TDEM ( padj = .002) phenotype and a trend of decrease of regulatory T-cells (TREGs) ( p = .02), in comparison with patients with low disease activity ( n = 38). Patients with damage (SDI ≥ 1) tended to show an expansion of TDEM among CD4+ T-cells as compared with patients with no damage ( p = .01). In SLE patients an inverse correlation was found between the percentages of TREGs and those of TDEM ( p < .01) or CD4 + CD28- ( p < .01) T-cells. Conclusions CD4+ T-cell subpopulations displaying phenotype characteristics of effector lymphocytes are proportionally expanded in patients with active SLE and a higher damage index. These findings may suggest a role of effector T-cells in the pathogenesis of the disease and in the mechanisms of damage in SLE.

Phenotype modifications of T-cells and their shift toward a Th2 response in patients with systemic lupus erythematosus supplemented with different monthly regimens of vitamin D.

BACKGROUND: Vitamin D receptor is constitutively expressed on the lymphocyte surface. Recent studies highlight that vitamin D may exert actions on T-cells, inhibiting Th1 and Th17 response and enhancing Th2 and T-regulatory (T-reg) function. METHODS: Thirty-four patients with systemic lupus erythematosus (SLE) were randomly enrolled in a two-year prospective study. In the first year, 16 patients were supplemented with an intensive regimen of cholecalciferol (IR) (300.000 UI of cholecalciferol at baseline and 50.000 UI/monthly as maintenance, 850.000 UI annually), whereas 18 with a standard regimen (SR) (25.000 UI of cholecalciferol monthly, 300.000 UI annually). During the second year, patients were switched to the other arm of treatment. Phenotypic analysis of peripheral T lymphocyte and the quantification of cytokine production from peripheral blood mononuclear cells (PBMCs) were evaluated by flow cytometry. RESULTS: At baseline, no significant difference between the two groups emerged among main T-cell subtypes. Over two years of treatment, we saw an increase in the number of T-reg cells, in the total amount of CD4+CD45RA+CCR7- T-cells, whereas a significant reduction of CD8+CD28- T-cells was observed. In addition, the analysis of PBMCs from eight patients following the IR showed the reduction of the IFN-γ/IL-4 ratio (p = 0.01) among CD8+ T-cells after 12 months. CONCLUSIONS: After a long-term of monthly treatment with vitamin D in SLE patients, an enhancement of T-reg cells and the production of Th2 cytokines should be expected.

A 24-month prospective study on the efficacy and safety of two different monthly regimens of vitamin D supplementation in pre-menopausal women with systemic lupus erythematosus.

BACKGROUND: Low vitamin D (vit.D) serum levels are common in patients with systemic lupus erythematosus (SLE) and seem to correlate with higher disease activity. We investigated the effects of different regimens of vit.D supplementation in SLE patients with inactive disease. METHODS: This 24-month prospective study included 34 SLE women who were randomized to receive, together with their ongoing treatment, a standard regimen (SR) of cholecalcipherol (25,000 UI monthly) or an intensive regimen (IR) (300,000 UI initial bolus followed by 50,000 UI monthly) for one year and then were switched to the other regimen in the second year. Patients were seen quarterly for assessment of 25-OH vit.D levels, disease activity, SLE serology and bone metabolism markers. RESULTS: By intra-patient comparison, only the IR was found able to significantly raise vit.D serum levels. After 12 months, values above 30 ng/ml were found in 75% of patients in IR while in only 28% in SR. No significant differences in disease activity and SLE serology were found at any time point between SR and IR. No changes in the mineral metabolism were observed. CONCLUSIONS: The IR was safe and effective in obtaining sufficient levels of vit.D in most SLE patients. However, both regimens of supplementation did not differently affect disease activity nor SLE serology.

Mutation analysis by a non-radioactive single-strand conformation polymorphism assay in nine families with X-linked severe combined immunodeficiency (SCIDX1).

X-linked severe combined immunodeficiency (SCIDX1) is an inherited disease characterized by profound abnormalities of cell-mediated and humoral immunity. Patients with SCIDX1 have defects in the common cytokine receptor gamma chain gene (IL2RG) that encodes a shared, essential component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9 and IL-15. We have characterized nine SCIDX1 families by using a DNA-based, non-radioactive screening method and DNA sequencing. Nine different mutations were found, scattered from exon 1 to exon 5 of the IL2RG gene. Two of these mutations have been previously identified in other unrelated patients; the other seven are novel mutations that differ from all of the 95 already reported in the IL2RG mutation data base. In addition to describing novel mutations in the IL2RG gene, this study shows that the knowledge of the genetic defect and the use of an efficient, non-radioactive, and rapid screening approach have important implications for prenatal and postnatal diagnosis, carrier female identification, and possibly prenatal therapy.