Alterations in Both the Activatory and Inhibitory Potential of Peripheral Blood CD4+ T Cells in Rheumatoid Arthritis Patients Correlate with Disease Progression

The chronic nature of rheumatoid arthritis (RA) suggests immune dysfunction, including persistent systemic activation. Therefore, we evaluated the activatory and inhibitory potential as well as proliferative activity of peripheral blood (PB) CD4+ T cells from RA patients in different stages of the disease and after different therapeutic interventions. We found that CD4+ T cells from RA patients were activated in vivo concerning decreased CD28 expression and increase of CD40L, CD69, and CTLA-4 expression; however, the extent of stimulation was suboptimal when compared to healthy controls. Consequently, impaired proliferative activities of these cells were found in all patients irrespective of the active disease duration. Treatment with methotrexate (MTX) and/or inhibitors of TNF-alpha (iTNF) did not significantly influence systemic activation in RA patients, which corresponded with the maintenance of inflammation markers; however, partial restoration of CD28 and CTLA-4 expression as well as clinical improvement were observed. In patients with early disease (the MTX group), we noted higher capacity of CD4+ T cells for restoration of T cell function, whereas cells from the iTNF group with progressive disease remained with a proliferative defect after the treatment. In conclusion, our study demonstrates that the dysregulated expression of molecules interfering with CD4+ T cell signaling may result in functional impairment of the effector T cells and correlates with disease progression.     

Study of differentiation of fresh human leukemic cells by low dose cytosine arabinoside (LD Ara-C) and 12-O-tetradecanoylphorbol-13-acetate (TPA)

The effect of LD Ara-C (10(-8) mol/l) (Ara-C), TPA (1.6 x 10(-7) mol/l) and 13-cis-retinoic acid (RA) (10(-6) mol/l) on the differentiation in liquid culture of bone marrow cells from 5 patients with acute lymphoblastic, 17 patients with acute myelogenous leukemia, 1 patient in myeloid and 1 in lymphoid crisis of chronic granulocytic leukemia was studied. Ara-C induced morphological and cytochemical differentiation into monocytic cells in 2 cases (M1, M5 type). TPA induced convincing morphological and cytochemical features of maturation into monocytic cells in 4 cases (two M1, one M2, and one M5 type) and into differentiated myeloid cells in 2 cases (M1, M4 type). RA in one case (M2 type) out of three AML studied induced cytochemical and immunocytochemical features of maturation. The results of the study indicate that although TPA is a better inducer of blast cell differentiation than Ara-C, however, neither is a potent differentiation agent of leukemic blasts in liquid culture. The heterogeneity of leukemic blasts within the same type of leukemia was confirmed by their different response to differentiating agents.     

KIR/HLA gene combinations influence susceptibility to B-cell chronic lymphocytic leukemia and the clinical course of disease

The aim of this study was to analyze the association between gene polymorphisms of killer-cell immunoglobulin-like receptors (KIRs) and their human leukocyte antigen (HLA) ligands and susceptibility to B-cell chronic lymphocytic leukemia (B-CLL) and the clinical course of disease. The distribution of individual KIR genes in 197 B-CLL patients and 200 controls was similar, except for a tendency for lower frequencies of the KIR2DS3 and KIR2DL5 genes among B-CLL patients (26.9% vs 35.5%, P = 0.06, 46.2% vs 55.5%, P = 0.06). The associations between KIR2DS3 and B-CLL reached statistical significance in women (P = 0.05). Moreover, we found a trend toward a lower frequency of genotypes with the presence of five or six activating KIR genes in B-CLL patients compared to controls (20.8% vs 29.0%, P = 0.06), and a significantly higher frequency of individuals possessing genotypes with a prevalence of inhibitory over activating KIR genes (ratio < 0.71) among B-CLL patients (P = 0.04). The HLA-Bw4 specificity was significantly reduced among B-CLL patients (48.7% vs 63.0%, P = 0.005), which resulted from a decreased frequency of HLA-Bw4(Thr80) (21.6% vs 32.0%, P = 0.02). Moreover, among HLA-Bw4-positive individuals, progression-free survival (PFS) tended to be higher in the presence of KIR3DS1 (77% ± 9% vs 39% ± 13%, P = 0.07). However, in B-CLL patients, the presence of HLA-C2 was associated with decreased PFS (49% ± 9% vs 75% ± 7%, P = 0.02), and among HLA-C2-positive patients, the probability of PFS was significantly reduced in the absence of KIR2DS1 (34% ± 11% vs 77% ± 7%, P = 0.007). Our results indicate that the pattern of inhibitory/activating KIR genes, together with their HLA ligands, is associated with susceptibility to B-CLL and affects the clinical course of this disease.     

CD40L, CD28, and CTLA-4 expression on CD4+ T cells in kidney graft recipients: a relationship with post-transplantation clinical course

BACKGROUND: Experimental studies have demonstrated that the intensity of alloreactivity against a transplanted organ results from an interaction of positive (CD40/CD40L and B.7/CD28) and inhibitory (B.7/CTLA-4) signals between antigen-presenting cells (APCs) and T lymphocytes. METHODS: We examined the CD40L, CD28, and both surface (s) and intracellular (i) CTLA-4 expressions on freshly drawn and anti-CD3+rIL-2-stimulated peripheral blood CD4+ T cells in groups of kidney transplant recipients in relation to distinct clinical course using the tri-color immunofluorescence method. RESULTS: The median proportions of freshly isolated CD3+/CD4+/CTLA-4+ and CD3+/CD4+/CD40L+ cells in all groups of graft recipients were higher than in control subjects. In patients with stable graft function (SGF), non-significantly higher sCTLA-4, significantly higher iCTLA-4 expression, and significantly lower CD40L expression on freshly drawn CD4+ T cells compared with recipients with chronic allograft nephropathy (CAN) were found. Moreover, CD4+ T cells from SGF patients showed a higher potential to express sCTLA-4 and CD40L molecules and to down-regulate the CD28 molecule in response to ex vivo stimulation than those from patients with CAN. In patients without acute graft rejection (NAGR), a markedly higher proportion of freshly drawn CD3+/CD4+/iCTLA-4+ cells compared with patients with acute graft rejection (AGR) and an up-regulation of the median percentage of CD3+/CD4+/CD40L+ cells after ex vivo stimulation was found. CONCLUSIONS: In patients with SGF, peripheral blood CD4+ T cells exhibited a higher potential to express surface CTLA-4 and CD40L and to down-regulate CD28 costimulatory molecules in response to ex vivo stimulation, indicating a relationship between the expression patterns of both costimulatory and inhibitory molecules in CD4+ T cells and clinical course after renal transplantation.     

Fas expression on T cells and sFas in relapsing-remitting multiple sclerosis

OBJECTIVES: To investigate the proportions of peripheral blood CD4+/Fas+ and CD8+/Fas+ cells and serum sFas levels in relapsing-remitting multiple sclerosis (RRMS) patients with relapses (active RRMS), those without relapses (stable RRMS), and controls over 1 year. MATERIAL AND METHODS: Sixteen RRMS patients and 10 controls were tested monthly. Cells were analyzed by dual immunofluorescence and the sFas levels by ELISA. There were 14 relapses which occurred 1223 days after the last control visits. The measurements performed at these visits in the active RRMS patients were considered as relapse-related, while the rest were regarded as relapse-unrelated. RESULTS: In active RRMS patients the median of CD4+ Fas+ to total CD4+ and CD8+ Fas+ to total CD8+ from relapse-related measurements were higher than the median from relapse-unrelated measurements (P=0.003, 0.004, respectively). The median of CD4+ Fas+ to total CD4+ from relapse-unrelated measurements in active RRMS was higher compared with stable RRMS (P = 0.005) and controls (P = 0.004). The sFas level from relapse-unrelated measurements was also higher in active RRMS than in stable RRMS (P = 0.04) and in controls (P = 0.004). CONCLUSIONS: We suggest that increased expression of Fas antigen on CD4+ subset and increased serum sFas level are valuable markers of clinical activity in MS.     

Money matters: does the reimbursement policy for second-generation antipsychotics influence the number of recorded schizophrenia patients and the burden of stigmatization?

Purpose

In Poland, non-compliance with the reimbursement policy for second-generation antipsychotics (SGA) manifested in prescribing SGA for patients with psychotic disorders other than schizophrenia may result in serious financial penalties. In this study, we aimed at investigating whether the implementation of the reimbursement policy for SGA contributed to increasing the number of patients with a diagnosis of schizophrenia relatively to the number of patients with a diagnosis of other psychotic disorders in outpatient clinics.

Methods

We analyzed data from Yearbooks of Mental Health that were published by the Institute of Psychiatry and Neurology, Warsaw, Poland in the years 1989–2009 registering the number of patients treated for various mental disorders in public facilities in Poland. Temporal trend analysis of the annual number of patients with a diagnosis of psychotic disorders, who were treated at outpatient clinics, was performed.

Results

We found a statistically significant increase in the total number of recorded schizophrenia patients treated at outpatient clinics, as well as in the number of patients treated for the first time at outpatient clinics for schizophrenia. These changes overlap with the implementation of the reimbursement policy for SGA.

Conclusion

Our results suggest that the restricted reimbursement policy for SGA altered the diagnosing process in Poland. It seems that these alterations may have serious social consequences. Given that a diagnosis of schizophrenia is more stigmatizing than a diagnosis of other psychotic disorders, it might be assumed that schizophrenia over-diagnosing, possibly due to reimbursement reasons, add to the enormous burden associated with stigmatization.     

A pro-inflammatory phenotype is associated with behavioural traits in children with Prader–Willi syndrome

European Child & Adolescent Psychiatry - Several lines of evidence indicate that immune-inflammatory alterations are widely observed in various mental disorders. Genetic syndromes with high...     

Decreased production of interferon gamma by anti-CD3 monoclonal antibody and interleukin-2 -stimulated peripheral blood mononuclear cells in Hodgkin's disease

Summary. We have examined the production of interferon (IFN) gamma by peripheral blood mononuclear cells (PBMC) in 22 patients with Hodgkin's disease (HD) in active phase of the disease, 12 patients in clinical remission and 16 healthy subjects. The level of IFN gamma in supernatants of PBMC stimulated for 72 h with anti-CD3 monoclonal antibody (mAb), measured by sandwich enzyme immunoassay (ELISA) was 50.4 ± 2.3 U/ml in active phase; 137.0 ±7.4 U/ml in clinical remission patients; and 520.0 ± 10.0 U/ml in the controls; the difference between the groups was statistically significant. Co-stimulation with interleukin-2 (rIL-2) markedly amplified production of IFN gamma. The mean levels were 220.8 ±7.0U/ml, 590-7 ±3-6U/ml and 2111.1 ± 17.3 U/ml in active phase HD, clinical remission and controls, respectively, the difference between groups was statistically significant. The patients showed the same kinetic pattern as healthy individuals. Our results indicate that patients with HD have severely impaired TCR/CD3 activation pathway resulting in significantly depressed IFN gamma response to anti-CD3 mAb and anti-CD3 + rIL-2 in vitro stimulation and provide support for the possible clinical use of IFN gamma as an immunopotentiating agent in patients with HD.