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R Press

Publications and source records attributed to R Press.

At least 19 recordsLinked to original sources
PubMed2006

Increased soluble 4-1BB ligand (4-1BBL) levels in peripheral blood of patients with multiple sclerosis.

4-1BB ligand (4-1BBL; CD137L) is a member of the tumour necrosis factor superfamily expressed primarily on antigen presenting cells such as B cells, macrophages and dendritic cells. Its engagement with the receptor 4-1BB (CD137) has been shown to promote T-cell activation and regulate proliferation and survival of T cells. The role of the costimulatory molecule in multiple sclerosis (MS) remains unclear. In this study, the expression of 4-1BBL and soluble 4-1BBL (s4-1BBL) protein levels were analysed in peripheral blood of MS patients. Compared with healthy controls, MS patients had an increase in both plasma s4-1BBL protein levels and expression of 4-1BBL in CD14(+) monocytes. In contrast, myelin basic protein-reactive T-cell proliferation was not found to be inhibited by the use of an anti-4-1BBL antibody. The elevated s4-1BBL protein levels in the MS patients may function as a self-regulatory mechanism of 4-1BB/4-1BBL interaction and costimulation.

4-1BB Ligand↗
PubMed2005

Dendritic cells in the cerebrospinal fluid and peripheral nerves in Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.

The role of antigen-presenting cells (APC) involved in induction of T and B cell mediated autoaggressive immunity in Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is poorly understood. We studied the numbers and phenotype of dendritic cells (DC) in blood and cerebrospinal fluid (CSF) over the course of GBS and CIDP before and after immunomodulatory treatment. Four out of seven GBS patients examined prior to treatment with high-dose intravenous immunoglobulins (IvIg) had elevated numbers of CD123(+) plasmacytoid DC in the CSF, while both GBS and CIDP patients examined prior to treatment had elevated numbers of CD11c(+) myeloid DC in the CSF, as compared to patients with noninflammatory neurological diseases (OND). The percentages of blood DC expressing the cell surface marker CD1a, co-stimulatory molecules CD80 and CD86, adhesion molecule CD54, and chemokine receptors CCR1, CCR2, CCR5, and CXCR4 were not affected in GBS or CIDP. The immunohistochemistry of sural nerve biopsies revealed CD11c(+)CD83(-)CD14(-)CD16(-) immature myeloid DC at low numbers, mostly in the perineurium, without difference between CIDP patients and controls. In contrast, the numbers of CD11c(+)CD14(+)/CD16(+) macrophages were higher within the endoneurium in CIDP patients compared with the controls. The recruitment of DC to CSF in GBS and CIDP may be important in capturing antigens released from inflamed spinal nerve roots into CSF and in transferring these antigens from CSF to local lymph nodes, where naive T and B cells may be activated.

Antigens, CD↗
PubMed2003

Aberrated levels of cerebrospinal fluid chemokines in Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.

Infiltration of spinal nerve roots and peripheral nerves by macrophages and T cells are rather consistent immunopathologic findings in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Chemokines play a central role in recruitment of leukocytes to inflamed tissue. Chemokines have been implicated in the pathogenesis of the experimental autoimmune neuritis (EAN), which represents an animal model of GBS, but the role of chemokines in GBS and CIDP is not clear. Since chemokines may be released into CSF from inflamed spinal nerve roots, we studied the concentrations of the chemokines MCP-1, MIP-1beta, MIP-3beta, IP-10, SDF-1alpha, RANTES, and SLC in the CSF by sandwich ELISA in patients over the course of GBS and CIDP, before and after immunomodulatory treatment. Controls consisted of patients with noninflammatory neurological disorders. Patients examined in the acute phase of GBS prior to treatment with intravenous high dose immunoglobulins (IvIg) had elevated CSF levels of MCP-1 (a chemoattractant for blood monocytes and dendritic cells) and IP-10 (a chemoattractant for T cells). Patients with CIDP examined prior to immunomodulatory treatment had elevated CSF levels of MIP-3beta (a chemoattractant for mature dendritic cells, naïve and recently activated T cells) and IP-10. Levels of MIP-3beta tended to decreased during follow-up in those CIDP patients responding favorably to immunomodulatory treatment. CSF levels of MCP-1 and IP-10 correlated with the CSF:plasma albumin ratio in both GBS and CIDP patients. In CIDP patients, CSF levels of MIP-3beta also correlated with the CSF:plasma albumin ratio. These data implicate MCP-1 and IP-10 in the pathogenesis of GBS, and IP-10 and MIP-3beta in the pathogenesis of CIDP.

Adult↗
PubMed2001

Temporal profile of anti-ganglioside antibodies and their relation to clinical parameters and treatment in Guillain-Barré syndrome.

Elevated anti-ganglioside antibody levels mainly of anti-GM1 and anti-GD1a specificities have been reported in THE serum of patients with Guillain-Barré syndrome (GBS). The relevance of anti-ganglioside antibodies other than anti-GM1 and anti-GD1a IgG antibodies and the temporal profile of anti-ganglioside antibodies in GBS is less clear. We studied serum antibodies to GM1, GD1a, GD1b, GQ1b, sulfatide and cardiolipin of the IgM, IgG and IgA classes over the course of GBS in patients who were untreated or treated with high dose intravenous immunoglobulin (IvIg). Antibodies to GD1b, GQ1b, sulfatide and cardiolipin were not detected in the sera of the GBS patients examined in this study. Anti-GM1 IgG titers peaked around 40 days and anti-GD1a IgM around 90 days after GBS onset. Titers of anti-GM1 IgG antibodies decreased following IvIg treatment. Patients with antibody peaks, defined as fivefold or higher increase in antibody titer compared to the lowest antibody titer over the course of GBS, had higher disability scores during the first two weeks of GBS and a worse clinical outcome (anti-GM1 IgG and anti-GD1a IgM antibody peaks) and axonal damage (anti-GD1a IgM antibody peaks), compared to patients without peak antibody titers. Anti-GM1 IgG and anti-GD1a IgM antibodies are thus strongly associated with more severe- and predominantly axonal cases of GBS. The appearance of anti-GM1 IgG and anti-GD1a antibody peaks in the serum after the termination of the acute phase of GBS suggests that these antibodies are produced secondary to nerve damage in GBS. The data does not exclude the possibility that secondarily secreted anti-GM1 IgG and anti-GD1a IgM antibodies may themselves be biologically active and play a role in disease propagation and/or recovery from disease in some patients with GBS.

Antibodies↗
PubMed2001

IL-10 and IFN-gamma in Guillain-Barré syndrome. Network Members of the Swedish Epidemiological Study Group.

Guillain-Barré syndrome (GBS) is an acute inflammatory disease affecting myelin and axons of the peripheral nervous system (PNS). GBS is considered to be caused by breakdown of tolerance to autoantigens of the PNS. The involvement of cytokines in GBS and in relation to treatment with high dose intravenous immunoglobulin (IvIg) is incompletely known. We studied the temporal profiles of IL-10 and IFN-gamma-secreting blood mononuclear cells (MNC) over the course of GBS, using enzyme-linked immunospot (ELISPOT) assays. Pretreatment levels of blood MNC spontaneously secreting IL-10 were higher in the acute phase of GBS than in control patients with aseptic meningitis, other neurological diseases, diabetic neuropathy and healthy subjects. Levels of IFN-gamma-secreting blood MNC were not increased over the course of GBS. Patients treated with IvIg had lower numbers of IL-10-secreting MNC compared to untreated patients. High levels of IL-10-secreting MNC correlated with serum anti-ganglioside IgM antibody levels, and with neurophysiological signs of axonal damage. The present data suggests that IFN-gamma is not involved in GBS pathogenesis, and IL-10 being up-regulated in the early phase of GBS and associated with axonal damage, may have a pathogenetic role in GBS.

Adult↗
PubMed2001

Monocytes in multiple sclerosis: phenotype and cytokine profile.

Multiple sclerosis (MS) is an inflammatory demyelinating disease characterised by immune abnormalities in the central nervous system (CNS) as well as systemically. Activated, blood-borne monocytes are abundant in MS lesions, the properties of circulating monocytes are incompletely known. To delineate phenotype and levels of cytokine secreting monocytes in MS patients' blood, ELISPOT assays were used for detection and enumeration of monocytes secreting the cytokines IL-6, IL-12, TNF-alpha and IL-10. In parallel, the expression by monocytes of co-stimulatory molecules (CD40, CD80, CD86), major histocompatibility complex molecules (HLA-ABC, HLA-DR) and Fcgamma receptors (CD16, CD64) was examined by flow cytometry. Levels of blood monocytes secreting IL-6 and IL-12 were higher in patients with untreated MS and other neurological diseases (OND) compared to healthy controls, while levels of monocytes secreting TNF-alpha and IL-10 did not differ between groups. MS patients' blood monocytes also displayed elevated mean fluorescence intensity for the co-stimulatory molecule CD86, and MS patients with longer disease duration (>10 years) and higher disease severity (EDSS >3) had higher percentages of CD80 expressing monocytes compared to patients with short duration or lower severity. In conclusion, monocyte aberrations occur in MS and may change over the disease course.

Adult↗
PubMed2001

Multiple sclerosis: elevated expression of matrix metalloproteinases in blood monocytes.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by blood-brain barrier (BBB) breakdown. Disruptions of BBB continuity result in an influx of activated T cells and monocytes, and could contribute to lesion formation in the CNS. Matrix metalloproteinases (MMP) are enzymes implicated in BBB disruption, and in degradation of extracellular matrix proteins and myelin components. An imbalance in levels of MMP and tissue inhibitors of MMP (TIMP) has been implicated in the pathogenesis of MS. Since monocytes form a major cell population in acute MS lesions and may facilitate their entrance into the CNS by secretion of MMP, knowledge on MMP expression by blood monocytes could be useful to improve our understanding of the pathogenesis of MS. In the present study, we examined the expression of MMP-1, -3, -7, -9, -14 and TIMP-1 mRNA by blood monocytes in patients with MS using in situ hybridization. Levels of MMP-1, -3, -7, -9 and of TIMP-1 mRNA expressing monocytes were elevated in MS compared to controls, while those of MMP-14 did not differ. We therefore conclude that MS is associated with elevated levels of MMP and TIMP expressing blood monocytes that may contribute to MS pathogenesis.

Female↗
PubMed2001

Dendritic cells derived from patients with multiple sclerosis show high CD1a and low CD86 expression.

Dendritic cells (DC) are important antigen presenting cells (APC) and play a major role in initiating and orchestrating immune responses by priming T cells. Little is known about involvement of DC in multiple sclerosis (MS), where auto-aggressive T cells against myelin autoantigens are considered to contribute to inflammation and demyelination in the central nervous system. In this study, we compared phenotype and cytokine secretion of DC from patients with MS, other neurological diseases (OND) and healthy subjects. DC were generated from blood adherent mononuclear cells (MNC) by culture for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The yield and morphology of DC were similar in MS patients and controls. In both, the DC phenotype was that of immature myeloid lineage, comprising CD1a+ and CD11c+. The proportion of CD1a+ DC, being important for presentation of lipid antigens to T cells, was higher in MS patients compared to controls. The proportion of CD86+ DC, a co-stimulatory molecule that is assumed to promote Th2 differentiation, was low in MS. Low proportions of CD86+ DC were only observed in untreated MS patients but not in patients treated with IFN-beta. Production of IL-10 and IL-12 p40 by DC did not differ in MS patients and controls. These findings indicate that alterations of functionally important surface molecules on DC are associated with MS.

Adult↗
PubMed2000

IL-12 elispot assays to detect and enumerate IL-12 secreting cells.

The cytokine IL-12 promotes Th(1)type immune responses and plays a key role in immune regulation. The complex nature of IL-12 hampered its detection without use of stimulants that might give less relevant information. To detect circulating IL-12 p40, we developed enzyme-linked immunospot (ELISPOT) assays that allow enumeration of IL-12 p40 secreting cells without prior in vitro stimulation of the cells. In parallel, intracellular staining of IL-12 p40 by flow cytometry was performed to compare the two methods. IL-12 p40 secreting cells were detected in healthy subjects at a mean number of 103+/-155 per 10(5)blood mononuclear cells (MNC). Numbers of IL-12 p40 secreting blood MNC correlated with IL-12 p40 positive blood MNC detected by flow cytometry. Bacterial endotoxins and the inflammatory cytokines TNF-alpha and IFN-gamma control IL-12 production by antigen presenting cells. Utilizing IL-12 p40 ELISPOT assays, we could confirm occurrence of elevated numbers of IL-12 p40 secreting blood MNC after stimulation with TNF-alpha, IFN-gamma, LPS, LPS+TNF-alpha or LPS+IFN-gamma, compared to cultures without stimulant. Due to its central role in inflammation and autoimmunity, IL-12 is an attractive target for immunotherapy. IL-12 p40 ELISPOT assays represent a sensitive, specific and reliable tool for investigating the role of IL-12 in both health and disease.

Adult↗
PubMed2000

Clinical epidemiology of Guillain-Barré syndrome in adults in Sweden 1996-97: a prospective study.

We described clinical manifestations, outcomes, prognostic indicators and clinico-epidemiological subgroups for 53 adult patients with Guillain-Barré syndrome (GBS) in Sweden during the period 1996-97. These patients were identified from a population of 2.8 million inhabitants and prospectively followed up for one year by a network of neurologists. An additional 10 cases, of whom five were adults who had not been prospectively followed up, were not included in the analyses. At 6 months after onset 80% of the patients could walk without aid, while at 1 year 46% were fully recovered, 42% had mild residual signs or symptoms, 4% had moderate and 6% severe disabilities, and 2% had died. Intravenous human immunoglobulin or plasmapheresis were used in 72% of the patients. The sum of the Medical Research Council (MRC) score at nadir was found as the only significant predictor for residual signs at 1 year in a multivariate model. Three subgroups, with different clinico-epidemiological characteristics, were identified by using cluster analysis. In conclusion, GBS in Sweden is frequently preceded by a respiratory infection, is often treated with immunomodulatory therapies, and exhibits a high recovery rate and a low fatality rate.

Adult↗
PubMed2000

Pathogen analysis and genetic predisposition testing using microelectronic arrays and isothermal amplification.

BACKGROUND: A simple yet powerful tool for providing for rapid gene identification in the clinic would be the combination of isothermal gene amplification with electronic microchip analysis. This is a first report of such a union of these technologies. METHODS: The first assay demonstrates discrimination between four bacterial pathogens. For this, one portion of the bacterial 16S rRNA gene encompassing a microheterogeneous region was isothermally amplified using Strand Displacement Amplification (SDA). Type identification was then made by "sandwich" assay format either using selective electronic hybridization of amplicons to sequence-specific capture oligonucleotides and a universal, fluorescently labeled reporter oligonucleotide, or, alternatively, sequence-specific reporters and a universal capture oligonucleotide. The second assay tested for the presence or absence of the Factor V Leiden point mutation using DNA obtained from 18 patients in a blind assay. For this, allele-specific SDA was developed. Following amplification using a sense-biotinylated primer and either the corresponding antisense wild type or mutant primer, multiple patient amplicons were targeted to specified locations on the microarray and visualized using a fluorescently labeled reporter oligonucleotide. Positive signals were scored as greater than or equal to two times the background. RESULTS: Bacterial type-specific signals were between 3- to 10-fold greater than nonspecific in both assay formats. Using allele-specific SDA, 100% agreement was observed between PAGE analysis, microarray results, and clinical diagnosis in Factor V mutation analysis. CONCLUSIONS: We demonstrated two model clinical assays combining amplified materials and microelectronic arrays, one potentially suitable for pathogen screening and the other for a deleterious genetic mutation.

Bacteria↗
PubMed1998

Recovery from Guillain-Barré syndrome is associated with increased levels of neutralizing autoantibodies to interferon-gamma.

Guillain-Barré syndrome (GBS) is an immune-mediated demyelinating disease of peripheral nerves that is often preceded by an infection and is usually self-restricted. The Th1 cytokine interferon-gamma (IFN-gamma) is thought to be disease-promoting in organ-specific autoimmune diseases. We report the spontaneous induction of IFN-gamma and a mechanism involving the generation of neutralizing autoantibodies (Aabs) to IFN-gamma that may regulate the disease. Numbers of cells spontaneously secreting IFN-gamma in peripheral blood were augmented in GBS, in particular at the peak of clinical disease, and decreased during recovery. This decrease was associated with elevated serum concentrations of IgG Aabs to IFN-gamma. These Aabs specifically bound to IFN-gamma and neutralized its effects in a biological assay. Aabs to IFN-gamma are proposed to be another important regulatory mechanism in IFN-gamma-driven GBS.

Adult↗
PubMed1996

An outbreak of acute hepatitis C among recipients of intravenous immunoglobulin.

BACKGROUND: An association between therapy with intravenous immunoglobulin (IVIG, Gammagard, Baxter Healthcare Corp) and acute hepatitis C (HCV) was reported by the manufacturer in 1994. OBJECTIVE: We sought to describe those patients at risk at our institution who developed HCV infection after IVIG (Gammagard) treatment(s). MATERIALS: An inception cohort study of patients with exposure to contaminated IVIG in a university tertiary care institution. Twenty-three patients received suspect IVIG and presented to be screened for HCV via ELISA II and polymerase chain reaction techniques. We describe the demographics and clinical characteristics of patients diagnosed with hepatitis C infection from IVIG. RESULTS: Ten of 23 (44%) patients who had received immunoglobulin (2 g/kg) for neurologic or immunologic disorders and were tested for anti-HCV were positive. All were also HCV-RNA positive by polymerase chain reaction. None had other HCV risk factors; all but two had normal aminotransferases documented prior to therapy. The patients had received monthly therapy for periods ranging from 2 to 60 months. Four patients were asymptomatic and the others had mild symptoms. One patient spontaneously became PCR negative within 12 months after exposure. CONCLUSION: Patients who received intravenous immunoglobulin (Gammagard, Baxter Healthcare Corp) between March, 1993, and February, 1994, are at risk for acute hepatitis C. The initial sequellae appear to be mild and spontaneous remission is possible.

Acute Disease↗
PubMed1985

A survey of 77 major infectious complications of median sternotomy: a review of 7,949 consecutive operative procedures.

Sternal wound infections developed following 77 (0.97%) of 7,949 operative procedures involving median sternotomy at New York University Medical Center from 1976 to 1984. Risk factors associated with the development of a sternal wound infection included combined revascularization and valve replacement, early reexploration for bleeding, prolonged low cardiac output syndrome, and prolonged ventilatory support (greater than 24 hours). Concomitant infection at other sites with the same organism as cultured from the sternum was present in 42% of the patients. Thirty-seven patients (48%) were treated with radical debridement followed by closed antibiotic irrigation. In 31 other patients (40%), the wounds were debrided and left to heal by open granulation. Both initial treatments had equally high success rates (78.4% and 74.2%, respectively). However, the open granulation method resulted in a hospital stay that was an average of 10 days longer than the closed antibiotic irrigation method. Muscle flaps were used to expedite healing of open granulation in 9 patients. Analysis of the results of different treatment strategies revealed that if debridement was accomplished within 20 days of the initial cardiac procedure, 76% of the patients could be successfully treated with closed antibiotic irrigation. Conversely, if treatment was delayed for longer than 20 days, 81% of the patients were treated with open granulation (p less than 0.001). Also noted was an inverse relationship between the serum blood urea nitrogen (BUN) level and the success rate of initial treatment with closed antibiotic irrigation. Patients with a serum BUN level of less than 40 mg/dl at the time of debridement had a 90% success rate as opposed to a success rate of 38% when the BUN level was 40 mg/dl or greater. The data presented suggest the following conclusions. Early diagnosis is crucial to successful treatment of sternal wound infection. When diagnosis can be established within 20 days, 80% of infections can be eradicated by the simple approach of debridement and closed antibiotic irrigation. When diagnosis is delayed, however, prompt debridement followed by muscle flaps is the procedure of choice. Open granulation alone, while successful, unnecessarily prolongs the hospital course.

Adult↗