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Summary: Natural killer (NK) cells participate in the regulation of the immune response. However, the immunomodulatory function of NK cells in systemic lupus erythematosus (SLE) is not well understood. The aim of this study was to evaluate the regulatory function of NK cells in SLE patients and to identify the NK cells involved in the pathogenesis of this complex disease. We analysed the expression of NK receptors and co‐stimulatory molecules in peripheral NK cells (CD3–CD56+) from SLE patients, as well as the numbers of human leucocyte antigen D‐related (HLA‐DR)/CD11c+ NK cells. In addition, NK cell regulatory function was assessed by the detection of NK cell‐mediated dendritic cell (DC) lysis. We found that SLE patients showed increased numbers of immunoglobulin‐like transcript 2 (ILT2)+, CD86+ and CD134+ NK cells. Furthermore, NK cells from SLE patients induced higher levels of DC lysis. We were able to identify a new subset of NK cells co‐expressing CD11c and HLA‐DR. These atypical NK cells were increased in SLE patients when compared with controls. We have identified an expanded new subset of NK cells in SLE patients. This is the first study, to our knowledge, which demonstrates that NK cells in SLE patients have an altered phenotype with a high expression of receptors characteristic of dendritic cells. Our results suggest that the impairment in the regulatory function of NK cells, together with the increased number of DC‐like NK cells, could play an important role in the development of SLE and highlight the importance of NK cells as a future therapeutic target. [ABSTRACT FROM AUTHOR]

We analysed the proportions of different microparticles (MPs) in plasma from patients with rheumatoid arthritis (RA), and assessed their relationship with disease activity/therapy and their in-vitro effect on proinflammatory cytokine release. Blood and urine samples were obtained from 55 patients with RA (24 untreated and 31 under conventional therapy) and 20 healthy subjects. Fourteen patients with systemic lupus erythematosus (SLE) were also studied. The proportions of CD3+, CD14+, CD19+, CD41+ and CD62E+ MPs were determined by flow cytometry analysis. The in-vitro effect of plasma MPs on the release of interleukin (IL)-1, IL-6, IL-17 and tumour necrosis factor (TNF)-α was also analysed. We detected that the proportions of different types of annexin-V+ MPs were enhanced in plasma (CD3+, CD14+, CD19+, CD41+ and CD62E+ MPs) and urine (CD14+, CD3+ and CD19+ MPs) from RA patients with high disease activity (DAS28 index > 5·1). Accordingly, a significant positive correlation was observed between the levels of MPs and DAS28 score, and these levels diminished significantly at week 4 of immunosuppressive therapy. Finally, MPs isolated from patients with high disease activity induced, in vitro, an enhanced release of IL-1, IL-17 and TNF-α. In SLE, enhanced levels of different types of plasma MPs were also detected, with a tight correlation with disease activity. Our data further support that MPs have a relevant role in the pathogenesis of RA and suggest that the analysis of the proportions of these microvesicles in plasma could be useful to monitor disease activity and therapy response in patients with RA. [ABSTRACT FROM AUTHOR]

Tuberculosis remains one of the most important infectious diseases worldwide. Several studies have suggested that genetic factors may affect susceptibility to tuberculosis, but the specific genes involved have not yet been fully characterized. NRAMP1/SLC11 A1 and P2X7 genes have been linked to increased risk for tuberculosis in some African and Asiatic populations. To explore the potential role of these genes in the susceptibility to pulmonary tuberculosis in a Mexican mestizo population, we evaluated the association of D543N and 3′-UTR polymorphisms in NRAMP1/SLC11 A1 and − 762 and A1513C polymorphisms in P2X7 genes with the risk for tuberculosis. Polymerase chain reaction (PCR) amplification of genomic DNA followed by restriction fragment length polymorphism analysis, and allelic-specific PCR was employed. We found no significant differences in allelic frequency in NRAMP1/SLC11 A1 gene polymorphisms in 94 patients with tuberculosis compared to 100 healthy contacts. Similarly, no significant association of the P2X7−762 gene polymorphism with tuberculosis was detected. In contrast, the P2X7 A1513C polymorphism was associated significantly with tuberculosis ( P = 0·02, odds ratio = 5·28, 95% CI, 0·99–37·69), an association that had not been reported previously. However, when the function of P2X7 was assessed by anl-selectin loss assay, we did not find significant differences in patients compared to healthy contacts or between PPD+ and PPD– control individuals. This study further supports the complex role of P2X7 gene in host regulation of Mycobacterium tuberculosis infection, and demonstrates that different associations of gene polymorphisms and tuberculosis are found in distinct racial populations. [ABSTRACT FROM AUTHOR]

P2X7 is a channel receptor gated by adenosine triphosphate (ATP) that is involved in the killing of intracellular mycobacteria. To explore further the role of P2X7 in immunity against Mycobacterium tuberculosis, we studied its expression and function in 19 patients with pulmonary tuberculosis (TB) and 19 healthy contacts. Flow cytometry analysis showed a similar and variable expression of P2X7 in TB patients and healthy subjects. In contrast, P2X7 mARN levels were significantly higher in TB patients. When the function of the P2X7 receptor in peripheral blood mononuclear cells (PBMC) was assessed by the effect of exogenous ATP on apoptosis, the uptake of the fluorescent marker Lucifer yellow or extracellular signal regulated kinase (ERK) phosphorylation, no significant differences were detected in patients and controls. However, mRNA macroarray analysis showed that upon stimulation with ATP, the PBMC from TB patients showed a significant induction of a higher number of cytokine genes (27 of 96), and a lower number of apoptosis genes (20 of 96) compared to healthy controls (17 and 76 genes, respectively). These results suggest that although the PBMC from TB patients do not show apparent abnormalities in the expression of P2X7, and the intracellular signals generated through it, the pattern of gene expression induced by ATP in these cells is different from that found in healthy contacts. This phenomenon suggests a defective function of P2X7 in the immune cells from TB patients, a condition that may contribute to the inability of these patients to eliminate the mycobacteria. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the effect of Adalimumab on different immune parameters in patients with RA. Adalimumab was administered (40 mg every other week for 26 weeks) to eight patients with RA that were refractory to conventional drug therapy. Peripheral blood samples were obtained at days 0, 15 and 180 of Adalimumab therapy, and the following immune parameters were assessed: Number, phenotype, and function of regulatory T lymphocytes. The induction of apoptosis of immune cells and the in vitro and in vivo reactivity towards M. tuberculosis were also analysed. All patients responded to Adalimumab (ACR response 50–70), and a modest but significant increase in the number and function of regulatory T cells was observed at day 15 of anti-TNF-α therapy. In addition, an increased percent of apoptotic cells was detected in the peripheral blood at day 15 of Adalimumab therapy. Unexpectedly, most of these effects were not further observed at day 180. However, two patients showed a persistent and marked reduction in the reactivity to M. tuberculosis. Although we have found that Adalimumab affects the number and function of regulatory T lymphocytes, and the apoptosis of immune cells, these effects are transient and its possible causal relationship with the therapeutic activity of this biological agent remains to be determined. Nevertheless, the down-regulatory effect of Adalimumab on the reactivity to M. tuberculosis could be related to an enhanced risk of tuberculosis reactivation. [ABSTRACT FROM AUTHOR]

SUMMARY The aim of this work was to investigate the effect of cadmium, lead and arsenic on the apoptosis of human immune cells. Peripheral blood mononuclear cells (MNC) were incubated with increasing concentrations of these metals and then cellular apoptosis was determined by flow cytometry and by DNA electrophoresis. We found that arsenic induced a significant level of apoptosis at 15 μM after 48h of incubation. Cadmium had a similar effect, but at higher concentrations (65 μM). In addition, cadmium exerted a cytotoxic effect on MNC that seemed to be independent of the induction of apoptosis. In contrast, concentrations of lead as high as 500 μM were nontoxic and did not induce a significant degree of apoptosis. Additional experiments showed that arsenic at concentrations as low as 1·0 μM had a significant pro-apoptotic effect when cells were cultured in the presence of this pollutant for more than 72 . Non-T cells were more susceptible than T lymphocytes to the effect of arsenic and cadmium. Interestingly, MNC from children chronically exposed to arsenic showed a high basal rate of apoptosis and a diminished in vitro sensibility to this metalloid. Our results indicate that both arsenic and cadmium are able to induce apoptosis of lymphoid cells, and suggest that this phenomenon may contribute to their immunotoxic effect in vivo . [ABSTRACT FROM AUTHOR]

Examines the effect of co-stimulatory signals on the reactivity of gamma delta T cells to mycobacterial antigens. Enhancement of gamma delta T cells reactivity; Association of tuberculosis with HIV infection; Role of interleukin-10 in gamma delta T cell proliferation.