PubMed Health⌕ Search

Biomedical subjects

Jorge Correale

Publications and source records attributed to Jorge Correale.

14 recordsLinked to original sources
PubMed2007

Association between parasite infection and immune responses in multiple sclerosis.

OBJECTIVE: To assess whether parasite infection is correlated with a reduced number of exacerbations and altered immune reactivity in multiple sclerosis (MS). METHODS: A prospective, double-cohort study was performed to assess the clinical course and radiological findings in 12 MS patients presenting associated eosinophilia. All patients presented parasitic infections with positive stool specimens. In all parasite-infected MS patients, the eosinophilia was not present during the 2 previous years. Eosinophil counts were monitored at 3- to 6-month intervals. When counts became elevated, patients were enrolled in the study. Interleukin (IL)-4, IL-10, IL-12, transforming growth factor (TGF)-beta, and interferon-gamma production by myelin basic protein-specific peripheral blood mononuclear cells were studied using enzyme-linked immunospot (ELISPOT). FoxP3 and Smad7 expression were studied by reverse-transcriptase polymerase chain reaction. RESULTS: During a 4.6-year follow-up period, parasite-infected MS patients showed a significantly lower number of exacerbations, minimal variation in disability scores, as well as fewer magnetic resonance imaging changes when compared with uninfected MS patients. Furthermore, myelin basic protein-specific responses in peripheral blood showed a significant increase in IL-10 and TGF-beta and a decrease in IL-12 and interferon-gamma-secreting cells in infected MS patients compared with noninfected patients. Myelin basic protein-specific T cells cloned from infected subjects were characterized by the absence of IL-2 and IL-4 production, but high IL-10 and/or TGF-beta secretion, showing a cytokine profile similar to the T-cell subsets Tr1 and Th3. Moreover, cloning frequency of CD4+CD25+ FoxP3+ T cells was substantially increased in infected patients compared with uninfected MS subjects. Finally, Smad7 messenger RNA was not detected in T cells from infected MS patients secreting TGF-beta. INTERPRETATION: Increased production of IL-10 and TGF-beta, together with induction of CD25+CD4+ FoxP3+ T cells, suggests that regulatory T cells induced during parasite infections can alter the course of MS.

Adult↗
PubMed2006

The risk of relapses in multiple sclerosis during systemic infections.

OBJECTIVES: To assess the risk of multiple sclerosis (MS) relapses, MRI activity, and T cell responses during systemic infections (SI) in patients with MS. METHODS: The authors prospectively studied 60 patients with MS. Twenty patients were evaluated with sequential MRI on initial visit, and 2 and 12 weeks later. Blood samples were collected at first infection symptom and 2, 5, 12, and 24 weeks later, and production of IL-4, IL-10, IL-12, IFN-gamma, TNFalpha, VLA-4, LFA-1, MMP-9, and MMP-2 were measured after infectious antigens (Ag) stimulation. RESULTS: Increased risk of relapse and MRI activity were observed during SI. Numbers of IFN-gamma, TNFalpha, and IL-12 secreting cells, serum concentrations of MMP-9, and expression of VLA-4 and LFA-1 after PBMC viral or bacterial Ag stimulation were higher in samples collected during exacerbations associated to SI. Transwell analysis demonstrated that soluble factors produced during viral stimulation have little effect on myelin specific T cells activity. In contrast, PBMC viral stimulation in the presence of cognate myelin Ag induces maximal effector responses at 20 to 30 times lower than the Ag alone. CONCLUSIONS: There was a significant association between systemic infections and risk of MS relapse, increased MRI activity, and T cells activation. Furthermore, infectious agents increased myelin specific T-cells sensitivity to cognate Ag.

Adult↗
PubMed2006

Myelin basic protein and myelin oligodendrocyte glycoprotein T-cell repertoire in childhood and juvenile multiple sclerosis.

Multiple sclerosis (MS) is usually a disease of young adulthood, its clinical onset occurring between 20 and 40 years of age; however, today there is general consensus that MS can also occur in children, adolescents and even in infants. In order to gain further insight into the T-cell repertoire present in this particular group of patients myelin basic protein (MBP)-, MBP exon-2- and myelin oligodendrocyte glycoprotein (MOG)Igd-specific T-cell lines (TCLs) were isolated from 18 patients whose symptoms had started before the age of 16. Epitope specificity was established by measuring proliferative responses, and interferon-y (IFN-y) secretion by using a panel of overlapping synthetic peptides. For MOGIgd, the T-cell response was focused on three main immunodominant epitopes comprising residues 1-26, 36-60 and 63-87. For MBP the predominant immune responses were directed against peptides 83-102, 139-153 and 146-162. When compared to those observed in adult-onset MS patients, anti-MOGIgd specificity and anti-MBP responses showed similar results. Moreover, the number of MBP exon-2 TCLs isolated, and the magnitude of the specific IFN-gamma secretion induced were similar, both in childhood/juvenile-onset and adult-onset MS patients. Thus, despite differences in the clinical and neuroimaging manifestations of MS, these results would seem to indicate that both the spectrum of MBP found, as well as the MOGIgd epitopes recognized by peripheral blood T cells in MS, appear to be similar for childhood/juvenile-onset and adult-onset patients.

Adolescent↗
PubMed2006

[Neuronal injury in multiple sclerosis].

The concept of multiple sclerosis (MS) as a demyelinating disease is deeply ingrained. Although the existence of a neurodegenerative component has always been apparent, it has only recently become emphasized. Thus, in recent years several studies have identified axonal degeneration as the major determinant of irreversible neurological disability in patients with MS. Axonal injury begins at disease onset and remains clinically silent for many years; irreversible neurological disability develops when a threshold of axonal loss is reached and CNS compensatory mechanisms are exhausted. The precise mechanisms of axonal loss are poorly understood, and three hypotheses have been proposed: 1) The damage is caused by an inflammatory process, 2) There is an excessive accumulation of intra-axonal Ca2+, 3) Demyelinated axons undergo degeneration due to lack of trophic support by myelin, or myelin forming cells. Although MS has traditionally been regarded as a disease of white matter, demyelination can also occur in the cerebral cortex. Cortical lesions exhibit neuronal injury represented by dendritic and axonal transection as well as neuronal apoptosis. Because conventional nuclear magnetic resonance (NMR) is limited in its ability to provide specific information about axonal pathology in MS, new techniques such as, diffusion-weighted MRI, proton magnetic resonance spectroscopy, functional MRI, as well as novel techniques designed to measure atrophy have been developed to monitor MS evolution. Recognition that MS is in part a neurodegenerative disease should trigger critical rethinking on the pathogenic mechanisms of this disease and provides new targets for a rational treatment.

Apoptosis↗
PubMed2005

Mitoxantrone as rescue therapy in worsening relapsing-remitting MS patients receiving IFN-beta.

We assessed the action of mitoxantrone (MX) when given as rescue therapy in patients with relapsing-remitting (RR) multiple sclerosis (MS), whose disease activity worsens despite IFN-beta treatment. Ten very active RR MS patients received MX 12 mg/m2 monthly, for 3 months, and then returned to the original treatment with IFN-beta. Following treatment with MX, 70% of patients were able to return to IFN-beta treatment, stabilising EDSS and relapse rate during a follow-up period of 15-18 additional months. In contrast, in 30% of the patients who were taken off MX and returned to IFN-beta treatment the EDSS score deteriorated and the number of exacerbations increased significantly. The latter patients were switched again to MX treatment at 3-month intervals, stabilising EDSS and relapse rate during 15-18 additional months. Clinical findings correlated with the number of Gd-enhancing lesions disclosed in MRI scans. Immunological data were consistent with the clinical and MRI benefits observed. We conclude that brief courses of MX may provide a safe treatment alternative for RR MS patients who experience rapid and severe worsening of their disease despite IFN-beta treatment.

Adult↗
PubMed2004

Activation of humoral immunity and eosinophils in neuromyelitis optica.

OBJECTIVE: To study immunologic alterations in patients with neuromyelitis optica (NMO). METHODS: The authors studied 8 patients with NMO together with 16 healthy subjects, 16 patients with relapsing remitting multiple sclerosis (RRMS), and 16 patients with secondary progressive MS (SPMS), matched for age and sex, as controls. Because recent histopathologic studies have demonstrated that active NMO lesions consist of perivascular immunoglobulin (Ig) deposition and eosinophil infiltration, IL-5, IL-6, IL-12, IgG, and IgM production by anti-myelin oligodendrocyte glycoprotein (MOG) mononuclear cells in peripheral blood and CSF were selected for study using ELISPOT. Eotaxin-2 (Eo-2) and eotaxin-3 (Eo-3) levels were also assessed using ELISA and eosinophil cationic protein (ECP) levels by radioimmunoassay. RESULTS: MOG-specific responses in CSF showed significant increase in IL-5, IL-6, IgG, and IgM secreting cells in NMO patients compared with patients with RRMS, SPMS and healthy subjects. Interestingly, numbers of IgM secreting cells were significantly higher than identical specificity IgG secreting ones. Moreover, CSF Eo-2, Eo-3, and ECP levels were also significantly higher in NMO patients compared to all three control populations. Anti-MOG IL-12 secreting cells were increased in CSF and peripheral blood from NMO, RRMS, and SPMS patients when compared to healthy subjects. CONCLUSIONS: These observations suggest that neuromyelitis optica is associated with a major humoral immune response (particularly anti-MOG IgM production) and eosinophil activation present exclusively in CSF.

Adult↗
PubMed2004

Staufen recruitment into stress granules does not affect early mRNA transport in oligodendrocytes.

Staufen is a conserved double-stranded RNA-binding protein required for mRNA localization in Drosophila oocytes and embryos. The mammalian homologues Staufen 1 and Staufen 2 have been implicated in dendritic RNA targeting in neurons. Here we show that in rodent oligodendrocytes, these two proteins are present in two independent sets of RNA granules located at the distal myelinating processes. A third kind of RNA granules lacks Staufen and contains major myelin mRNAs. Myelin Staufen granules associate with microfilaments and microtubules, and their subcellular distribution is affected by polysome-disrupting drugs. Under oxidative stress, both Staufen 1 and Staufen 2 are recruited into stress granules (SGs), which are stress-induced organelles containing transiently silenced messengers. Staufen SGs contain the poly(A)-binding protein (PABP), the RNA-binding proteins HuR and TIAR, and small but not large ribosomal subunits. Staufen recruitment into perinuclear SGs is paralleled by a similar change in the overall localization of polyadenylated RNA. Under the same conditions, the distribution of recently transcribed and exported mRNAs is not affected. Our results indicate that Staufen 1 and Staufen 2 are novel and ubiquitous SG components and suggest that Staufen RNPs are involved in repositioning of most polysomal mRNAs, but not of recently synthesized transcripts, during the stress response.

Actin Cytoskeleton↗
PubMed2004

Preliminary studies of cytokine secretion patterns associated with pregnancy in MS patients.

Multiple sclerosis has a tendency to remit during pregnancy, followed by an increase in the risk for disease relapses in the postpartum period. In this communication, preliminary data are presented to indicate that activated peripheral blood mononuclear cells (PBMC) from the postpartum period secrete elevated levels of gamma-interferon (IFN-gamma) relative to those collected during the third trimester. In addition, myelin antigen-specific T cell lines established from the third trimester of pregnancy secrete elevated levels of interleukin-10. The data suggest that the study of the mechanisms underlying natural fluctuations in disease activity during pregnancy and the postpartum period holds promise for a better understanding of factors capable of initiating and regulating remission and exacerbation in MS.

Adult↗
PubMed2004

The neuroprotective role of inflammation in nervous system injuries.

The contribution of inflammation to the pathogenesis of several nervous system disorders has long been established. Other observations, however, indicate that both inflammatory cells and mediators may also have beneficial functions, assisting in repair and recovery processes. There is compelling evidence to indicate that in the injured nervous system, as in other tissues, macrophages are needed at an early stage after injury in order for healing to take place. Likewise, activated T cells of a particular specificity can reduce the spread of damage. This neuroprotective effect of T cells may be caused, at least in part, by the production of neurotrophic factors such as neurotrophin-3 or brain-derived neurotrophic factor. Interestingly, recent findings indicate that immune cells are able to produce a variety of neurotrophic factors which promote neuronal survival and may also mediate anti-inflammatory effects. Numerous cytokines are induced after nervous system injuries. Some cytokines, such as TNF-alpha, IL-1 and IFN-gamma, are well known for their promotion of inflammatory responses. However, these cytokines also have immunosuppressive functions and their subsequent expression also assists in repair or recovery processes, suggesting a dual role for some pro-inflammatory cytokines. This should be clarified, as it may be crucial in the design of therapeutic strategies to target specific cytokine(s). Finally, there is a growing body of evidence to show that autoreactive IgM antibodies may constitute an endogenous system of tissue repair, and therefore prove of value as a therapeutic strategy. Available evidence would appear to indicate that the inflammatory response observed in several neurological conditions is more complex than previously thought. Therefore, the design of more effective therapies depends on a clear delineation of the beneficial and detrimental effects of inflammation.

Animals↗
PubMed2003

Time course of T-cell responses to MOG and MBP in patients with clinically isolated syndromes.

CD4(+) T-cell lines (TCLs) from patients with clinically isolated syndromes (CIS) were selected with purified human myelin basic protein (MBP) and recombinant human myelin oligodendrocyte glycoprotein (rhMOG), at onset of neurological symptoms and when patients developed clinically definite multiple sclerosis (CDMS). The epitope specificity of each TCL was mapped with overlapping synthetic peptides. TCLs were assessed for their ability to secrete IFN-gamma, IL-4, and IL-6. Diverse patterns of epitope recognition were observed: (a) recognition of a broad spectrum of MBP peptide epitopes with evidence of shifts over time; (b) an initial T-cell response focused to a restricted segment of the MBP molecule (83-102) that broadened over the course of disease; and (c) persistence of a focused anti-MOG T-cell response. CIS patients who failed to develop CDMS maintained a focused epitope response against two to six MBP epitopes. Most MBP peptide-specific TCLs secreted considerable amounts of IFN-gamma and low amounts of IL-4 and IL-6, whereas anti rhMOG(Igd) peptide-specific TCLs secreted preferentially IL-4 and IL-6. These data raise important issues for the pathogenesis and treatment of multiple sclerosis (MS).

Adolescent↗
PubMed2003

Temporal variations of adhesion molecules and matrix metalloproteinases in the course of MS.

Thirty patients with clinically isolated syndromes (CIS) were evaluated at the onset of neurological symptoms and when they developed clinically definite MS (CDMS). Surface expression of LFA-1alpha, VLA-4 and intercellular adhesion molecule-1 (ICAM-1) on PBMC and CSF cells was evaluated using flow cytometry. Serum and CSF concentrations of soluble vascular cell adhesion molecules-1 (VCAM-1), ICAM-1 and E-Selectin, as well as MMP-9 and MMP-2 serum concentrations were assayed using ELISA. Surface expression of LFA-1alpha and VLA-4 molecules on peripheral blood and CSF T cells and monocytes from CIS and CDMS was significantly increased compared with control subjects. Moreover, LFA-1alpha and VLA-4 expression was significantly higher in patients who developed CDMS compared with those with CIS. Similar changes were observed in the serum levels of MMP-9. Furthermore, patients with CIS and CDMS had significantly higher levels of CSF sVCAM and s-E-Selectin than control subjects. These data suggest that VLA-4, LFA-1alpha and MMP-9 play a leading role in the evolution of inflammatory demyelinating lesions in patients with CIS who develop CDMS.

Adult↗
PubMed2002

Oligoclonal bands and antibody responses in multiple sclerosis.

Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System with multifocal areas of demyelination. Although its etiology and pathogenesis remain controversial, several lines of evidence indicate that MS is mediated by a misdirected immune response against one or several myelin proteins. The involvement of diverse leukocyte subsets and their products in MS is still the subject of considerable debate. The emphasis on T cells has derived mainly from the detection of activated T cells in MS plaques and analogies with animal models of MS. Because of these observations cell-mediated immunity has dominated the research field of MS to this day. However, in recent years the role of B cells, plasma cells and immunoglobulins in MS have been re-examined, and current findings indicate that humoral immunity also plays a major role in disease pathogenesis. B cells and their products could exert several potential effects during the course of MS. Firstly, autoantibodies against specific myelin antigens could mediate damage to myelin membranes. Secondly, some studies suggest that natural autoantibodies could enhance remyelination. Thirdly, antibodies directed against myelin components can participate in anti-idiotypic networks, which may regulate the course of MS. Increased intrathecal immunoglobulin synthesis reflected by raised IgG indices and an oligoclonal pattern is the most common abnormality detected in MS patients. The introduction of more sensitive procedures for protein detection has allowed demonstrating oligoclonal bands (OCBs) in up to 95 % of patients with clinically definite MS. Although the presence of OCBs in CSF of MS patients is now well established as a sensitive laboratory test to support the clinical diagnosis, OCBs may be present in other disorders, including those not directly related to infection or abnormal immune response. Nevertheless, the pathogenesis of OCBs in MS is still obscure, and despite extensive research their antigenic target(s) have yet to be established. Therefore, a critical task is to identify the specificity of such target(s), thus providing significant clues about MS etiology. For this purpose, novel molecular immunologic strategies have been recently developed to offer alternative approaches to identify putative antigens recognized by antibodies present in MS patients. The elucidation of the mechanisms and target(s) responsible for the onset of MS has obvious implications for the further development of specific therapies.

Animals↗
PubMed2002

Myosin light chain kinase inhibitors induce retraction of mature oligodendrocyte processes.

Mature oligodendrocytes emit numerous myelinating processes. Force generating molecules are required for process outgrowth and spreading. We have analyzed the effect of the myosin II light chain kinase inhibitors ML-7 and ML-9 in cultured oligodendrocytes. Both drugs affect oligodendrocyte cell shape, provoking a retraction of high order processes. Our results suggest that the adhesion of the myelinating processes to the substrate depends on MLC phosphorylation, thus likely implicating myosin IIA.

Animals↗