Clinical correlates of the "rods and rings" antinuclear antibody pattern.

The "rods and rings" (RR) antinuclear antibody (ANA) pattern is believed to be restricted to hepatitis C virus (HCV) infection and related to the treatment. This is a 4-year retrospective study of all patients with RR pattern from the 20,000 serum samples received at the Hospital Universitari de Bellvitge for ANA testing. Two control groups with HCV patients without RR pattern: ANA-positive (n = 74) and ANA negative (n = 75) were included. Eighty-seven patients had samples with the RR pattern. Seventy-three were infected with HCV (prevalence of 15% in the HCV population). The RR pattern could not be related to ribavirin treatment, clinical status, biochemistry data, hepatic fibrosis, IL28B genotype, HCV genotype or the presence of autoantibodies related with autoimmune hepatitis. As 14 cases presented other diseases, mainly of autoimmune origin, the presence of RR antibodies may also be explained by alterations in immune regulation caused by autoimmunity or HCV in a particular genetic background.

The effect of simvastatin on inflammatory cytokines in community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial.

OBJECTIVES: It has been suggested that statins have an effect on the modulation of the cytokine cascade and on the outcome of patients with community-acquired pneumonia (CAP). The aim of this prospective, randomised, double-blind, placebo-controlled trial was to determine whether statin therapy given to hospitalised patients with CAP improves clinical outcomes and reduces the concentration of inflammatory cytokines. SETTING: A tertiary teaching hospital in Barcelona, Spain. PARTICIPANTS: Thirty-four patients were randomly assigned and included in an intention-to-treat analysis (19 to the simvastatin group and 15 to the placebo group). INTERVENTION: Patients were randomly assigned to receive 20 mg of simvastatin or placebo administered in the first 24 h of hospital admission and once daily thereafter for 4 days. OUTCOME: Primary end point was the time from hospital admission to clinical stability. The secondary end points were serum concentrations of inflammatory cytokines and partial pressure of arterial oxygen/fractional inspired oxygen (PaO2/FiO2) at 48 h after treatment administration. RESULTS: The trial was stopped because enrolment was much slower than originally anticipated. The baseline characteristics of the patients and cytokine concentrations at the time of enrolment were similar in the two groups. No significant differences in the time from hospital admission to clinical stability were found between study groups (median 3 days, IQR 2-5 vs 3 days, IQR 2-5; p=0.47). No significant differences in PaO2/FiO2 (p=0.37), C reactive protein (p=0.23), tumour necrosis factor-α (p=0.58), interleukin 6 (IL-6; p=0.64), and IL-10 (p=0.61) levels at 48 h of hospitalisation were found between simvastatin and placebo groups. Similarly, transaminase and total creatine kinase levels were similar between study groups at 48 h of hospitalisation (p=0.19, 0.08 and 0.53, respectively). CONCLUSIONS: Our results suggest that the use of simvastatin, 20 mg once daily for 4 days, since hospital admission did not reduce the time to clinical stability and the levels of inflammatory cytokines in hospitalised patients with CAP. TRIAL REGISTRATION NUMBER: ISRCTN91327214.

Pretransplant low CD3+CD25high cell counts or a low CD3+CD25high/CD3+HLA-DR+ ratio are associated with an increased risk to acute renal allograft rejection.

BACKGROUND: Detection of markers predicting allograft rejection is important for risk assessment before kidney transplantation, as well as to minimize posttransplantation immunosuppression. METHODS: We studied the expression of CD25, HLA-DR, CD134, CD62L, and CD44 by flow cytometry in CD4, CD8, and CD3 cells, from pretransplant blood samples from 91 transplanted patients accounting for 16 episodes of acute renal rejection in the first month after transplantation. RESULTS: None of the activation markers showed a significant association to acute rejection. Early rejectors showed less pretransplant CD3CD25 cells than nonrejectors (0.79%±0.50% vs. 1.51%±0.79% of CD3 cells; P=0.001) and a lower CD3CD25/CD3HLA-DR ratio (0.043±0.034 vs. 0.111±0.079; P<0.00001). When levels of CD25 cells fell below 0.7% of CD3 cells, the odds ratio of suffering an episode of acute rejection was 105 fold (95% confidence interval: 11.41-966.43, P<0.0001), with a sensitivity (true-positive results) of 0.63 and a specificity (true-negative results) of 0.98 for predicting the risk of acute rejection. Furthermore, when the CD3CD25/CD3HLA-DR ratio fell below 0.04, the odds ratio of suffering an episode of acute rejection was 7.71 fold (95% confidence interval: 2.29-25.97, P=0.001), with a sensitivity of 0.56 and a specificity of 0.86 for predicting risk of acute rejection. CONCLUSIONS: Our results suggest that low pretransplant levels of CD3CD25 cells or a low CD3CD25/CD3HLA-DR ratio could identify those patients with an increased risk of early acute allograft rejection. If these data can be independently confirmed, pretransplant CD3CD25 cells and the CD3CD25/CD3HLA-DR ratio might provide additional information for risk assessment before kidney transplantation.

Apoptosis of peripheral blood lymphocytes in Parkinson patients.

Neuronal cell death by apoptosis is a mechanism involved in Parkinson's disease and indirect signs of apoptosis have been found in brain neurons and blood lymphocytes. The present study was aimed to directly assess the presence of enhanced apoptosis in lymphocytes from 89 idiopathic Parkinson's disease patients, 33 untreated and 56 treated, compared with 33 healthy individuals. The study of both spontaneous and activation-induced apoptosis of T-lymphocyte subsets by annexin-V binding and flow cytometry showed that Parkinson patients increased the expression of Fas in circulating CD4(+) T cells, mainly "naive," that correlated with the decrease of these cells in blood. Spontaneous and activation-induced apoptosis of CD4(+) T-cell subsets were also significantly increased. Thus, in Parkinson patients, peripheral blood CD4(+) T cells have an increased susceptibility to apoptosis with Fas involvement. This fact explains the decrease in the number of CD4(+) T-cell subsets observed in Parkinson and could be related to the neurodegenerative process.

Description of flow cytometry examinations related to human cell differentiation molecules in clinical immunology.

Human cell differentiation molecules, also known as "CD", are cell-surface molecules reacting with different monoclonal antibodies. The fraction of cells belonging to each immunophenotype is measured by flow cytometry. This brief communication proposes the application into clinical immunological laboratories, of the syntax recommended by the International Union of Pure and Applied Chemistry and the International Federation of Clinical Chemistry and Laboratory Medicine to describe biological properties. Following this syntax, all properties related to human cell differentiation molecules examined by flow cytometry, but not limited to, may be described in the same way. In addition, the application of the IUPAC-IFCC recommended syntax in clinical immunology may facilitate unequivocal written or electronic communication between healthcare professionals world-wide.

Early hematopoietic microchimerism predicts clinical outcome after kidney transplantation.

BACKGROUND: The presence of a few circulating donor cells in recipient's blood was first thought to be only an epiphenomenon of solid organ transplantation, also called microchimerism, but several authors have suggested that these circulating cells may contribute to tolerance induction. This study aims to assess the rate of microchimerism after kidney transplantation and determine its influence on acute rejection in a 4-year follow-up. METHODS: A total of 84 single-kidney recipients were included for microchimerism detection and quantification 2, 6, 12, and 18 months after transplantation by specific detection of non-shared STR, VNTR, human leukocyte antigen-A, -B, -DRB1, and SRY alleles. Kinetic establishment of microchimerism was monitored in a double kidney transplanted recipient for 150 min after declamping and after 7 days. RESULTS: Microchimerism was detected in 56.2% of kidney recipients 2 months after transplantation (M2): this fell to 30.1% at 12 months. In renal calcineurin inhibitor-based immunosuppression cohort (n=73), the microchimerism-negative group (n=32) showed 37.9% biopsy-proven acute rejection (BPAR), whereas in the microchimerism-positive group (n=41), no recipient did (P<0.001). Regardless of immunosuppression, BPAR incidence was 35.6% and 4.9%, respectively (P<0.001). Multivariate study showed microchimerism as a protective factor against BPAR (odds ratio: 8.3; 95% confidence interval: 1.8 to 37.9; P = 0.006), blinding other well-known rejection-risk variables. Microchimerism M2 presence did not correlate with a multifactorial critical outcome such as late graft loss. CONCLUSION: Microchimerism was frequent after kidney transplantation and correlated with a significantly lower incidence of rejection. We propose that early microchimerism monitoring could help early detection of low rejection-risk recipients.

Achieving donor-specific hyporesponsiveness is associated with FOXP3+ regulatory T cell recruitment in human renal allograft infiltrates.

Exploring new immunosuppressive strategies inducing donor-specific hyporesponsiveness is an important challenge in transplantation. For this purpose, a careful immune monitoring and graft histology assessment is mandatory. Here, we report the results of a pilot study conducted in twenty renal transplant recipients, analyzing the immunomodulatory effects of a protocol based on induction therapy with rabbit anti-thymocyte globulin low doses, sirolimus, and mofetil mycophenolate. Evolution of donor-specific cellular and humoral alloimmune response, peripheral blood lymphocyte subsets and apoptosis was evaluated. Six-month protocol biopsies were performed to assess histological lesions and presence of FOXP3+ regulatory T cells (Tregs) in interstitial infiltrates. After transplantation, there was an early and transient apoptotic effect, mainly within the CD8+ HLADR+ T cells, combined with a sustained enhancement of CD4+ CD25(+high) lymphocytes in peripheral blood. The incidence of acute rejection was 35%, all steroid sensitive. Importantly, only pretransplant donor-specific cellular alloreactivity could discriminate patients at risk to develop acute rejection. Two thirds of the patients became donor-specific hyporesponders at 6 and 24 mo, and the achievement of this immunologic state was not abrogated by prior acute rejection episodes. Remarkably, donor-specific hyporesponders had the better renal function and less chronic renal damage. Donor-specific hyporesponsiveness was inhibited by depleting CD4+ CD25(+high) T cells, which showed donor-Ag specificity. FOXP3+ CD4+ CD25(+high) Tregs both in peripheral blood and in renal infiltrates were higher in donor-specific hyporesponders than in nonhyporesponders, suggesting that the recruitment of Tregs in the allograft plays an important role for renal acceptance. In conclusion, reaching donor-specific hyporesponsiveness is feasible after renal transplantation and associated with Treg recruitment in the graft.

Modulation of the pathology of late xenograft rejection by PAF-antagonist UR-12670 in the hamster-to-rat liver xenotransplant model.

PAF antagonists have been used in xenotransplantation to alleviate the pathogenesis of hyperacute rejection. This study evaluated the ability of the PAF antagonist UR-12670 to improve graft function in late xenograft rejection (LXR) in an orthotopic liver xenotransplantation model, and the involvement of PAF (platelet activating factor) in this type of rejection. The recipients of a hamster xenograft received standard immunosuppression (tacrolimus 0.2 mg/kg/30 days, MMF 25 mg/kg/8 days). Study groups: group A, without UR-12670, group B, UR-12670 (20 mg/kg/8 d) and group C, continuous administration of UR-12670 (20 mg/kg/d). Serum levels of xenoantibodies were evaluated by flow cytometry and tissue deposits by immunofluorescence. Immunoblot and indirect immunofluorescence assessed specificity of xenoantibodies. Conventional histology was performed. Continuous administration of UR-12670 improved the histological pattern of liver xenografts, especially necrosis, loss of hepatocytes, hemorrhage, sinusoidal congestion and lymphocyte infiltration. There was not a shift in specificity of xenoantibodies at different times posttransplantation, as demonstrated by immunoblotting and indirect immunofluorescence. UR-12670 administration had a beneficial effect on graft function and considerably improved the histopathological pattern, but it failed to induce tolerance after withdrawal of immunosuppression. UR-12670 had an immunomodulatory effect on cellular response but not on antibody production. There was not a change in the specificity of xenoantibodies produced at LXR compared with pretransplant antibodies.

Goodpasture syndrome during the course of a Schönlein-Henoch purpura.

Two months after surgical resection of a bronchogenic carcinoma, a 69-year-old patient presented with Schönlein-Henoch purpura with kidney involvement followed by pulmonary hemorrhage. The presence of an IgA linear pattern on the kidney biopsy specimen and circulating anti-glomerular basement membrane (GBM) IgA antibodies led to the diagnosis of Goodpasture syndrome, which implies the possibility that the well-known pulmonary involvement during the course of Schönlein-Henoch purpura could be caused by Goodpasture syndrome in certain cases. In cases of glomerulonephropathy with lung involvement, clinicians should not limit their investigations to anti-GBM IgG.