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PubMed2004

Monocyte apoptosis in uremia is normalized with continuous blood purification modalities.

Uremia is associated with a state of immune dysfunction. Dysregulation of homeostasis may be directly related to abnormal apoptosis regulation in uremia, which is crucial for the maintenance of the biological system. We demonstrated that plasma from three groups of uremic subjects, i.e. hemodialysis (HD) patients, peritoneal dialysis (PD) patients and patients with predialysis chronic renal failure (CRF), has different apoptotic potential on U937 monocytes. The plasma of HD and CRF subjects when incubated with U937 cells induced higher levels of apoptosis compared with that of PD and control subjects (HD 26.08 +/- 11.39, CRF 24.87 +/- 9.07, PD 12.13 +/- 4.51, controls 11.69 +/- 4.02). Furthermore, the phagocytic ability of U937 cells incubated with the various plasma demonstrated an impaired response in the HD and CRF subjects (HD 27.56 +/- 6.67, CRF 30.24 +/- 9.08, PD 36.55 +/- 9.80, controls 40.04 +/- 6.98). These results suggest that continuous blood purification, such as in PD, may have advantages over intermittent therapies in removing uremic apoptotic molecules and potentially maintaining biological function and homeostasis.

Apoptosis↗
PubMed2004

Expression of TH1/TH2-related chemokine receptors on peripheral T cells and correlation with clinical disease activity in patients with multiple sclerosis.

Th1 cells play an important role in the pathogenesis of multiple sclerosis (MS), a disease likely linked to an autoimmune process. We measured the levels of chemokines in serum or cerebrospinal fluid (CSF) samples by ELISA, and also studied the expression of Th1-related CXCR3/CCR5 chemokine receptors and Th2-related CCR4/CCR3 chemokine receptors on blood cells from MS patients using three-color flow cytometry. The Bonferroni correction was used for the statistical analysis. The levels of CXCL10, CCL3, and CCL5 in the CSF samples for the MS groups were significantly higher than those for the control group. However, the levels of CCL2 in both the CSF and serum samples for the remission group were significantly higher than those for the active group. The percentage of CXCR3-expressing CD4+ T cells in patients with MS was significantly elevated compared with the healthy controls. Moreover, MS patients in an active phase showed a more increased CD4+CXCR3+/CD4+CCR4+ ratio than patients in a remission phase. The increased percentage of CD4+CXCR3+ cells in the blood was associated with relapses in MS. This study suggested that the CD4+CXCR3+/CD4+CCR4+ ratio could be a sensitive maker of immune dysfunction in MS.

Adult↗
PubMed1996

AILD-like dysplasia transformed in AILD-type T cell lymphoma in an HTLV-1 carrier: usefulness of interferon-alpha.

A 61-year-old Japanese woman who was an HTLV-1 carrier had angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)-like dysplasia that transformed into AILD-type lymphoma after 3 years. Complete remission was achieved with interferon-alpha (IFN-alpha) treatment following a previous combination of anticancer drugs. IFN-alpha was also effective for maintenance therapy after this complete, albeit transient, remission. From clinical and pathological studies on AILD patients, it appears that AILD may in some cases be the consequence of an immune dysfunction caused by HTLV-1 infection and that AILD-type lymphoma is a malignant disorder of peripheral T cell clones different from those T cells incorporating the HTLV-1 virus.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Severe erosive stomatitis: association with immunological diseases?

We present 2 cases of severe erosive stomatitis. The first case involves the rare association of an extensive, erosive lichen planus with a Castleman's tumor. The second case involves the association of lichen planus pemphigoides with severe, obstructive lung disease (bronchiolitis obliterans). We believe that in both cases the conjunction of these conditions is not fortuitous but perhaps due to an underlying immune dysfunction. With patients presenting a severe, therapy-resistant, erosive stomatitis, one should be alerted to the possibility of immunological diseases and/or tumors.

Adult↗
PubMed1994

Testicular tumor and the acquired immunodeficiency syndrome.

Immunocompromised patients, particularly those suffering from the acquired immunodeficiency syndrome (AIDS), present an increased risk of tumoral pathology. From the observation of a testicular lymphoma associated with Epstein-Barr virus in a HIV + patient, we review 19 cases of testicular tumor in HIV + patients previously published in the literature. These tumors are either lymphomas (4 cases) or germ cell tumors (15 cases). Their diagnosis was not difficult, although in the first stages enlarged and painful testicles are often wrongly identified as orchiepididymitis and treated as such. Therapy management proves to be delicate as a result of the significant tumor spread seen in these patients with dysfunctional immune systems. Regarding lymphomas, a low-dose multiagent chemotherapy with intrathecal chemotherapy was recommended by Levine. Concerning germ cell tumors, Wilson prefers an instant aggressive treatment with retroperitoneal lymphadenectomy (whether or not combined with chemotherapy) to avoid the risk of recurrence. In fact, tumor relapses will be difficult to control in the progressive stages of immunodeficiency syndrome.

Adult↗
PubMed1997

Sera from chronic chagasic patients with complex cardiac arrhythmias depress electrogenesis and conduction in isolated rabbit hearts.

BACKGROUND: Immune dysfunction has long been proposed as a mechanism for the etiopathogenesis of the chronic phase of Chagas' disease. Antibodies of chagasic patients have been shown to interfere with electric and mechanical activity of embryonic myocardial cells in culture. Here, we demonstrate that antibodies derived from a group of chronic chagasic patients are able to induce disturbances in the electrogenesis and conduction in isolated adult rabbit hearts. METHODS AND RESULTS: Sera from chronic chagasic patients with complex cardiac arrhythmias (ChA+) decreased heart rate (from 131+/-26 to 98+/-37 bpm [mean+/-SD]; n=6; P<.05) in isolated rabbit hearts when perfused at a dilution of 1:100 (vol:vol) by the Langendorff method. Sera from another experimental group of four chronic chagasic patients without complex arrhythmias (ChA-) and two control groups composed of five Wolff-Parkinson-White (WPW) syndrome patients and five orthopedic surgery patients did not affect heart rate when tested under similar conditions. In addition, sera from five of six ChA+ patients and from one WPW patient induced AV conduction blockade. Effects of the sera from ChA+ patients are due to their IgG fractions. Both serum and IgG effects are blocked by atropine (10 micromol/L). CONCLUSIONS: Antibodies of ChA+ patients decrease heart rate and induce AV conduction block in isolated adult rabbit hearts through activation of muscarinic receptors.

Adult↗
PubMed1998

Left ventricular structure and function in children infected with human immunodeficiency virus: the prospective P2C2 HIV Multicenter Study. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group.

BACKGROUND: The frequency of, course of, and factors associated with cardiovascular abnormalities in pediatric HIV are incompletely understood. METHODS AND RESULTS: A baseline echocardiogram (median age, 2.1 years) and 2 years of follow-up every 4 months were obtained as part of a prospective study on 196 vertically HIV-infected children. Age- or body surface area-adjusted z scores were calculated by use of data from normal control subjects. Although 88% had symptomatic HIV infection, only 2 had CHF at enrollment, with a 2-year cumulative incidence of 4.7% (95% CI, 1.5% to 7.9%). All mean cardiac measurements were abnormal at baseline (decreased left ventricular fractional shortening [LV FS] and contractility and increased heart rate and LV dimension, mass, and wall stresses). Most of the abnormal baseline cardiac measurements correlated with depressed CD4 cell count z scores and the presence of HIV encephalopathy. Heart rate and LV mass showed significantly progressive abnormalities, whereas FS and contractility tended to decline. No association was seen between longitudinal changes in FS and CD4 cell count z score. Children who developed encephalopathy during follow-up had depressed initial FS, and FS continued to decline during follow-up. CONCLUSIONS: Subclinical cardiac abnormalities in HIV-infected children are common, persistent, and often progressive. Dilated cardiomyopathy (depressed contractility and dilatation) and inappropriate LV hypertrophy (elevated LV mass in the setting of decreased height and weight) were noted. Depressed LV function correlated with immune dysfunction at baseline but not longitudinally, suggesting that the CD4 cell count may not be a useful surrogate marker of HIV-associated LV dysfunction. However, the development of encephalopathy may signal a decline in FS.

AIDS Dementia Complex↗
PubMed2006

Deficiency of SHP-1 protein-tyrosine phosphatase in "viable motheaten" mice results in retinal degeneration.

PURPOSE: Viable motheaten mutant mice (abbreviated allele symbol me(v)) are deficient in Src-homology 2-domain phosphatase (SHP)-1, a critical negative regulator of signal transduction in hematopoietic cells. These mice exhibit immune dysfunction, hyperproliferation of myeloid cells, and regenerative anemia. This study focused on the role of SHP-1 in retinal homeostasis. METHODS: Ophthalmoscopy, histology, transmission electron microscopy (TEM), electroretinography (ERG), immunohistochemistry, Western blot, bone marrow transplantation, and genetic crosses were performed for phenotypic characterization and functional studies of retinal degeneration (RD) in me(v)/me(v) mice. RESULTS: Fundus examinations of me(v)/me(v) mice revealed numerous, small white spots. Histologic examination demonstrated photoreceptor loss beginning at 3 weeks of age, and TEM revealed disorganization and reduction in the number of outer segments, as well as the presence of phagocytic cells in the subretinal space. Rod- and cone-mediated ERGs were abnormal. SHP-1 protein was expressed in mouse and human retinal lysates and was localized to the outer nuclear layer of the retina in me(v)/me(v) and control mice. Autoantibodies are not necessary for RD, as B-cell-deficient me(v)/me(v) Igh-6(tm1Cgn) mice had no attenuation of photoreceptor cell loss compared with age-matched me(v)/me(v) mice. Histologic examination of lungs and retinas from normal recipients of me(v)/me(v) marrow revealed the classic acidophilic macrophage pneumonia of me(v)/me(v) mice, but no retinal degeneration. CONCLUSIONS: me(v)/me(v) mice exhibit normal retinal development with the onset of RD at 3 weeks of age and a rapidly progressive loss of photoreceptors. These findings support the hypothesis that SHP-1 plays a critical role in retinal homeostasis.

Animals↗
PubMed1978

Deoxyguanosine triphosphate as a possible toxic metabolite in the immunodeficiency associated with purine nucleoside phosphorylase deficiency.

Purine nucleoside phosphorylase (PNP) deficiency is associated with a severe defect in thymus-derived (T)-lymphocyte function combined with normal bone marrow-derived (B)-lymphocyte function. To investigate the role of this enzyme deficiency in the resulting immune dysfunction, we measured the levels of ribonucleoside and deoxyribonucleoside triphosphates in erythrocytes from two unrelated PNP-deficient, T-lymphocyte-deficient patients. Both PNP-deficient patients have abnormally high levels of deoxyguanosine triphosphate (deoxy-GTP) in their erythrocytes (5 and 8 nmol/ml packed erythrocytes). In contrast, normal controls and adenosine deaminase-deficient, immunodeficient patients do not have detectable amounts of deoxyGTP (<0.5 nmol/ml packed erythrocytes). We propose that deoxyguanosine, a substrate of PNP, is the potentially lymphotoxic metabolite in PNP deficiency. The mechanism of toxicity involves phosphorylation of deoxyguanosine to deoxyGTP, which acts as a potent inhibitor of mammalian ribonucleotide reductase.

Adenosine Deaminase↗
PubMed1988

Release of interleukin 1 inhibitory activity (contra-IL-1) by human monocyte-derived macrophages infected with human immunodeficiency virus in vitro and in vivo.

Infection of monocyte-macrophages with human immunodeficiency virus may be central to the pathogenesis of the acquired immunodeficiency syndrome. The ability of infected macrophages to prime T cells through IL-1 production was investigated in vitro. Purified human monocytes maintained in suspension culture were infected with strain HIV-DV. Intracellular expression of virus p24 antigen increased from undetectable levels immediately after infection to 13-59% of cells by 10-14 d; infected macrophages remained viable for up to 60 d. Supernatants collected between 14 and 20 d after infection were examined in the murine thymocyte co-mitogenesis assay and demonstrated to contain a potent IL-1 inhibitor, designated contra-IL-1. Contra-IL-1 activity was present in all supernatants examined after 4 d of infection, and peaked coincident with peak p24 antigen expression. Inhibitory activity was not present in uninfected cells. Contra-IL-1 activity eluted after gel filtration with an approximate molecular weight of 9 kD. Inhibitory activity was removed by exposure to heat or acid pH, or by incubation with chymotrypsin or staphylococcal V8 protease. Contra-IL-1 did not inhibit IL-2- or IL-4-dependent proliferation of murine T cell lines. Despite its ability to inhibit IL-1 activity, contra-IL-1 did not interfere with the binding of recombinant IL-1 beta to a fibroblast cell line. Contra-IL-1 inhibited the proliferation of normal peripheral blood mononuclear cells to both concanavalin A and tetanus toxoid; inhibition could be attenuated by the addition of exogenous IL-1. Messenger RNA extracted from infected macrophages was examined by Northern analysis for the presence of message to IL-1 beta. No message was apparent, suggesting that the presence of contra-IL-1 was not obscuring the concomitant release of IL-1. Infected macrophages stimulated with endotoxin generated readily detectable message for IL-1 beta. Spleen macrophages purified from two patients with AIDS complicated by immune thrombocytopenia spontaneously expressed p24 antigen in vitro and released contra-IL-1 activity into the media. Contra-IL-1 may contribute to the immune dysfunction of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia.

OBJECTIVE: Abnormalities in the immune system in schizophrenia have been described. However, important findings such as high levels of activating cytokines in the CSF and signs of CNS inflammation have been controversial. The authors conducted a trial of the new selective cyclooxygenase-2 inhibitor celecoxib, an immunomodulatory drug, in schizophrenic patients to evaluate its therapeutic effects. METHOD: In a prospective, double-blind evaluation, 50 patients with an acute exacerbation of schizophrenia were randomly assigned to either risperidone plus celecoxib or risperidone plus placebo. After a washout period, 25 patients received 2-6 mg/day of risperidone plus placebo and 25 received risperidone plus 400 mg/day of celecoxib for 5 weeks. The treatment effect was calculated by analysis of covariance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or risperidone dose or plasma level. RESULTS: Over 5 weeks, both groups of patients showed significant improvement in scores on the Positive and Negative Syndrome Scale and on all subscales. However, the celecoxib group showed significantly greater improvement in the total score. CONCLUSIONS: Additional treatment with celecoxib has significant positive effects on the therapeutic action of risperidone with regard to total schizophrenia psychopathology. Moreover, the fact that treatment with an immunomodulatory drug showed beneficial effects on schizophrenia symptoms indicates that immune dysfunction in schizophrenia is not just an epiphenomenon but is related to the pathomechanism of the disorder. However, a nonimmunological therapeutic effect of celecoxib mediated by the N-methyl-D-aspartic acid receptor has to be taken into account.

Adolescent↗
PubMed1994

Nutrition support in critical illness.

Sepsis, shock, multiple trauma, and burns are often associated with altered metabolism characterized by severe catabolism, wasting of the lean body mass, immune dysfunction, and compromised wound healing. Nutrition support is one of the mainstays in the management of these critically ill patients and is aimed at minimizing these complications. The purpose of this article is to compare stress hypermetabolism and starvation metabolism, to review current recommendations for the provision of energy and substrate to the critically ill patient, and to review pertinent literature regarding enteral vs parenteral nutrition. Finally, this article will provide a brief overview of new and future therapies with emphasis on specific substrates and growth factors and the potential for their use in the critically ill patient.

Critical Illness↗
PubMedDate not supplied

Serum leptin levels in acute protein deprivation.

BACKGROUND: Protein energy malnutrition (PEM) induces a host neuroendocrine response, reflected by significant elevations in circulating glucocorticoid levels and associated with metabolic and immune dysfunction. Leptin regulates food intake and body mass and has a significant impact on the hypothalamic-pituitary-adrenal axis (HPA). We hypothesized that leptin may be altered by and may play an important role in regulating the effects of PEM. METHODS: Female Balb/c mice were used. In experiment 1, mice were pair-fed either a protein-free (0% casein) or control (24% casein) diet for 7 days. In experiment 2, mice were implanted with either a placebo or corticosterone-releasing pellet and fed the control diet for 7 days. In experiment 3, adrenalectomized mice were pair-fed either the protein-free or control diet for 7 days. Serum corticosterone and leptin levels were measured in all experiments. RESULTS: PEM caused significant reductions in food intake, body weight, and total body fat, but not lean body mass. Serum corticosterone and leptin levels were significantly greater in mice fed the protein-free diet. Subcutaneous implantation of a corticosterone pellet in mice fed the control diet resulted in a significantly elevated serum leptin level compared with placebo-implanted controls. Bilateral adrenalectomy partially blunted the increased serum leptin in PEM. CONCLUSIONS: Leptin may be an important mediator of weight loss and decreased food intake in PEM. Elevated serum leptin in PEM may be secondary to elevated serum corticosterone, with other factors inherent in the host response to protein restriction also contributing to elevated serum leptin.

Acute Disease↗
PubMed1986

Beta endorphin enhances in vitro lymphokine production in patients with squamous carcinoma of the head and neck.

Recent studies of the effects of endorphins and other neuropeptides on immune mechanisms suggest that immune reactive cells have specific opioid-like and nonopioid endorphin receptors, and indicate that neuropeptides may participate in regulating in vivo immune functions. Earlier demonstrations of impaired cellular immunity and impaired lymphokine production in patients with cancer of the head and neck prompted an investigation of the in vitro effects of beta-endorphin on the production of leukocyte migration inhibitory factor (LIF) in 29 patients with head and neck cancer and in 45 normal subjects. LIF production in response to phytohemagglutinin was significantly less in the cancer patients compared to normal subjects (p less than .001). beta-endorphin significantly enhanced LIF production in the cancer patients (p = .01) to levels that did not differ significantly from normal levels. A correlation of levels of lymphocyte subpopulations in the cancer patients suggested that enhancement of lymphokine production by beta-endorphin was related to levels of T8 (suppressor/cytotoxic) cells. The results confirm earlier demonstrations of impaired lymphokine production in patients with head and neck cancer and indicate that beta-endorphin can modulate in vitro lymphokine responses in such patients. These findings suggest that neuroendocrine peptides may play an important role in regulating immune function. Further study of the role of neuropeptides in the immune response should provide additional insight into the characterization of cellular immune dysfunction associated with head and neck cancer and should lead to the development of innovative immunotherapeutic treatment strategies.

Adult↗
PubMed2006

Endotoxin stimulated interleukin-10 production is enhanced by adenosine. Possible key to septic shock associated immune deficiency?

The aim of this bench study was to investigate whether adenosine influences secretion of interleukin-10 (IL-O) in human whole blood culture stimulated with lipopolysaccharide. Whole blood from healthy human volunteers was mixed ex vivo in 1:1 ratio with RPMI 1640 culture medium and subsequently cultured at 37 degrees C with or without adenosine (total of 120 microM added in four aliquots over two hours) in the presence or absence of 100 ng/ml lipopolysaccharide for four and eight hours, respectively. There was only a minimal IL-10 production after four hours of culture regardless of the experimental conditions. However, lipopolysaccharide stimulated whole blood cultures with added adenosine released large amounts of IL-lO after eight hours. The response was similar whether adenosine was added before (5.99 pg/ml/10(6) leucocytes) or after (10.35 microg/ml/10(6) leucocytes) stimulation with lipopolysaccharide and interindividual variation was present. In conclusion adenosine enhances lipopolysaccharide stimulated IL-10 production in whole human blood and may contribute to the IL-10 mediated immune dysfunction in sepsis.

Adenosine↗
PubMed2005

Do we have reliable biochemical markers to predict the outcome of critical illness?

Current outcome prediction in critically ill patients relies on the art of clinical judgement and/or the science of prognostication using illness severity scores. The biochemical processes underlying critical illness have increasingly been unravelled. Several biochemical markers reflecting the process of inflammation, immune dysfunction, impaired tissue oxygenation and endocrine alterations have been evaluated for their predictive power in small subpopulations of critically ill patients. However, none of these parameters has been validated in large populations of unselected ICU patients as has been done for the illness severity and organ failure scores. A simple biochemical predictor of ICU mortality will probably remain elusive because the processes underlying critical illness are very complex and heterogeneous. Future prognostic models will need to be far more sophisticated.

Biomarkers↗
PubMed1999

Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism.

Autism is an age-dependent neurologic disorder that is often associated with autoimmune disorders in the patients' relatives. To evaluate the frequency of autoimmune disorders, as well as various prenatal and postnatal events in autism, we surveyed the families of 61 autistic patients and 46 healthy controls using questionnaires. The mean number of autoimmune disorders was greater in families with autism; 46% had two or more members with autoimmune disorders. As the number of family members with autoimmune disorders increased from one to three, the risk of autism was greater, with an odds ratio that increased from 1.9 to 5.5, respectively. In mothers and first-degree relatives of autistic children, there were more autoimmune disorders (16% and 21%) as compared to controls (2% and 4%), with odds ratios of 8.8 and 6.0, respectively. The most common autoimmune disorders in both groups were type 1 diabetes, adult rheumatoid arthritis, hypothyroidism, and systemic lupus erythematosus. Forty-six percent of the autism group reported having relatives with rheumatoid diseases, as compared to 26% of the controls. Prenatal maternal urinary tract, upper respiratory, and vaginal infections; asphyxia; prematurity, and seizures were more common in the autistic group, although the differences were not significant. Thirty-nine percent of the controls, but only 11% of the autistic, group, reported allergies. An increased number of autoimmune disorders suggests that in some families with autism, immune dysfunction could interact with various environmental factors to play a role in autism pathogenesis.

Adolescent↗
PubMed2006

Transforming growth factor beta 1 in children with systemic lupus erythematosus: a possible relation with clinical presentation of lupus nephritis.

Plasma and urinary (latent and active) TGF-beta1 levels were assessed in 32 children with active lupus and compared to 15 healthy controls of matched age and sex. Plasma latent and active TGF-beta1 levels in children with active disease were significantly lower than controls (P = 0.004 and P < 0.001 respectively). Plasma active TGF-beta1 correlated negatively with Systemic Lupus Erythematosus Disease Activity Index (r = -0.38, P = 0.03). On the contrary, urinary latent and active TGF-beta1 levels in children with active disease were significantly higher than controls (P < 0.001 and P = 0.003 respectively). Urinary active TGF-beta1 levels correlated positively with Anti-ds DNA titre (r = 0.42, P = 0.015) and negatively with serum C3 levels (r = -0.48, P = 0.005). Patients with symptomatic nephritis had significantly elevated urinary active TGF-beta1 levels in comparison to those with silent nephritis (P = 0.008). From this data we conclude that lowered plasma TGF-beta1 levels may be a feature of systemic immune dysfunction in children with active lupus while increased renal production of active TGF-beta1 seems to have a role in the clinical presentation of lupus nephritis.

Adolescent↗