Cytokine profile of myelin basic protein?reactive T cells in multiple sclerosis and healthy individuals (original) (raw)
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Cytokines in multiple sclerosis: methodological aspects and pathogenic implications
Multiple Sclerosis, 2002
Multiple sclerosis (MS) is one of the leading causes of disability among young adults of Caucasian origin. One hundred and fifty years after the first description of the disease, the cause of MS remains unknown. Ironically, the few hypotheses concerning MS pathogenesis that are valid today were first proposed over a hundred years ago. However, equipped with the advanced technology of molecular biology and imaging systems, we are at present progressively uncovering clues to understanding the pathogenesis of the disease. It is clearly evident that aberrant immune responses occur in MS, and it is likely that the spectrum of cytokines produced decisively influences disease outcome. The detrimental consequences of IFN-γ and the beneficial effects of IFN-βtreatment in MS support this hypothesis. However, there are still major gaps in our knowledge of the involvement of cytokines in MS. Numerous studies have addressed the question of cytokine levels in MS, often with conflicting results; e...
Science translational medicine, 2015
Myelin-reactive T cells have been identified in patients with multiple sclerosis (MS) and healthy subjects with comparable frequencies, but the contribution of these autoreactive T cells to disease pathology remains unknown. A total of 13,324 T cell libraries generated from blood of 23 patients and 22 healthy controls were interrogated for reactivity to myelin antigens. Libraries derived from CCR6(+) myelin-reactive T cells from patients with MS exhibited significantly enhanced production of interferon-γ (IFN-γ), interleukin-17 (IL-17), and granulocyte-macrophage colony-stimulating factor (GM-CSF) compared to healthy controls. Single-cell clones isolated by major histocompatibility complex/peptide tetramers from CCR6(+) T cell libraries also secreted more proinflammatory cytokines, whereas clones isolated from controls secreted more IL-10. The transcriptomes of myelin-specific CCR6(+) T cells from patients with MS were distinct from those derived from healthy controls and, notably, ...
International Immunology, 2009
MBP-specific autoreactive T cells are considered pro-inflammatory T cells and thought to play an important role in the pathogenesis of multiple sclerosis (MS). Here, we report that MBP 83-99-specific T cells generated from MS patients (n 5 7) were comprised of pro-inflammatory and regulatory subsets of distinct phenotypes. The pro-inflammatory phenotype was characterized by high production of IFN-g, IL-6, IL-21 and IL-17 and low expression of FOXP3, whereas the regulatory subset expressed high levels of FOXP3 and exhibited potent regulatory functions. The regulatory subset of MBP-specific T cells appeared to expand from the CD4 1 CD25 2 T-cell pool. Their FOXP3 expression was stable, independent of the activation state and it correlated with suppressive function and inversely with the production of IFN-g, IL-6, IL-21 and IL-17. In contrast, the phenotype and function of FOXP3 low MBP-specific T cells were adaptive and dependent on IL-6. The higher frequency of FOXP3 high MBP-specific T cells was observed when IL-6 was neutralized in the culture of PBMC with MBP. The study provides new evidence that MBP-specific T cells are susceptible to pro-inflammatory cytokine milieu and act as either pro-inflammatory or regulatory T cells.
Update on Inflammation, Neurodegeneration, and Immunoregulation in Multiple Sclerosis
Clinical Neuropharmacology, 2009
Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system of uncertain etiology. There is consensus that a dysregulated immune system plays a critical role in the pathogenesis of MS; therefore, we aim to summarize current hypotheses concerning the complex cellular and molecular interactions involved in the immunopathology of MS. Although CD4 + T lymphocytes have long been implicated in the immunopathology of MS, the role of other T-cell subtypes has been recognized. CD4 + and CD8 + cells have been isolated from different locations within MS lesions and F/C T cells have been isolated from early MS lesions. The prevalent dogma has been that CD4 + T H 1 cells release cytokines and mediators of inflammation that may cause tissue damage, although CD4 + T H 2 cells may be involved in modulation of these effects. Recent evidence, however, suggests that additional T-cell subsets play a prominent role in MS immunopathology: T H 17 cells, CD8 + effector T cells, and CD4 + CD25 + regulatory T cells. In addition, laboratory and clinical data are accumulating on the prominent role of B lymphocytes and antigenpresenting cells in MS pathogenesis. On the basis of these observations, new therapeutic approaches for MS will need to focus on resetting multiple components of the immune system.
Journal of Neuroimmunology, 1996
Lymphotoxin-a (LT-(r) and, tumonr necrosis factor-a (TNF-a) promote inflammation in autoimmune diseases and have been detected in the multiple sclerosis (MS) brain lesions and blood, suggesting these cytokines are also present in the cerebrospinal fluid (CSF). To study this, mononuclear cells (MNC) were examined for transcripts of LT-a and TNF-a, using in situ hybridization (ISH) with synthetic oligonucleotide probes. Most patients with MS had LT-a and TNF-a mRNA-expressing MNC in their CSF at mean frequencies of about l/2800 cells for both cytokines. Numbers were dramatically higher than in the paired blood specimens. Control patients with other inflammatory neurological diseases (OIND) also had LT-a and TNF-a mRNA-expressing cells in CSF but at mean frequencies of only l/36 000 and l/ 18 000 cells, respectively. In blood, levels were similar in OIND and MS. To elucidate the influence of myelin antigen stimulation on LT-a and TNFk expression, MNC were cultivated with or without myelin basic protein. Strongly elevated levels of MBP-reactive TNF-a mRNA-expressing cells were detected in the MS patients' CSF, in particular when examined during clinical exacerbations, as well as MBP-reactive LT-a mRNA-expressing MNC. No such patterns were observed in the OIND controls. The strong accumulation of LT-a-and TNF-a-producing cells and of MBP-reactive LT-a and TNF-a mRNA-positive cells in the immediate vicinity of the demyelinating process in MS patients implicates a role of these cytokines in the development of MS.
Clinical and Experimental Immunology, 2000
The up-regulated B cell responses detectable in cerebrospinal fluid (CSF) and the augmented myelin antigen-specific T cell responses observed in the CSF as well as systematically in patients with multiple sclerosis (MS) suggest the involvement of cytokines in disease development and perpetuation. Here we report on the parallel involvement of TNF-a , IL-6, IFN-g and IL-10 in MS and controls, using enzymelinked immunospot (ELISPOT) assays to detect and enumerate cytokine-secreting mononuclear cells (MNC) prepared from blood and, for IL-6 and IL-10, from CSF without in vitro stimulation. MS is associated with elevated levels of TNF-a-secreting blood MNC when compared with levels in groups of control patients with myasthenia gravis (MG) and other neurological diseases (OND) or healthy subjects. This elevation was confined to patients with untreated MS and not present in those examined during ongoing treatment with IFN-b. Untreated patients with MS had lower numbers of IL-10-secreting blood MNC compared with the three control groups. In patients undergoing treatment with IFN-b , numbers of IL-10-secreting cells were in the same range as in controls. Normalization of TNF-a from elevated, and of IL-10 from decreased levels could be one reason for the beneficial effects of IFN-b in MS, although it remains to be shown whether these changes reflect phenomena primarily involved in MS pathogenesis or secondary changes. In CSF, levels of IL-10-secreting cells were higher than in blood in both MS and OND, with no difference between these groups. Systemic aberrations of IL-6 and IFN-g and of IL-6 in CSF in MS versus controls were only minor, irrespective of treatment with IFN-b .
Clinical and Experimental Immunology, 2000
SUMMARY The up-regulated B cell responses detectable in cerebrospinal fluid (CSF) and the augmented myelin antigen-specific T cell responses observed in the CSF as well as systematically in patients with multiple sclerosis (MS) suggest the involvement of cytokines in disease development and perpetuation. Here we report on the parallel involvement of TNF-α, IL-6, IFN-γ and IL-10 in MS and controls, using enzyme-linked immunospot (ELISPOT) assays to detect and enumerate cytokine-secreting mononuclear cells (MNC) prepared from blood and, for IL-6 and IL-10, from CSF without in vitro stimulation. MS is associated with elevated levels of TNF-α-secreting blood MNC when compared with levels in groups of control patients with myasthenia gravis (MG) and other neurological diseases (OND) or healthy subjects. This elevation was confined to patients with untreated MS and not present in those examined during ongoing treatment with IFN-β. Untreated patients with MS had lower numbers of IL-10-secr...
T cells, cytokines, and autoantigens in multiple sclerosis
Current neurology and neuroscience reports, 2001
In multiple sclerosis (MS), inflammatory demyelination in the central nervous system is thought to be initiated by T cells that recognize myelin antigens. T cells are the main regulators of acquired immunity and are involved in the pathogenesis of several organ-specific autoimmune diseases. This review provides an overview of recent studies on the role of T cells in autoimmune demyelination. Because autoreactive T cells are normally present in the mature repertoire of T cells in the blood and lymphoid organs of MS patients, but also in normal controls, particular attention is devoted to the mechanisms of activation and the functional phenotype of such T cells in patients with MS. The role of cytokines as effector molecules and the main candidate antigens are also discussed.
Immunology, 2008
Autoreactive T cells are thought to play an essential role in the pathogenesis of multiple sclerosis (MS). We examined the stimulatory effect of human myelin basic protein (MBP) on mononuclear cell (MNC) cultures from 22 patients with MS and 22 sex-matched and age-matched healthy individuals, and related the patient responses to disease activity, as indicated by magnetic resonance imaging. The MBP induced a dose-dependent release of interferon-c (IFN-c), tumour necrosis factor-a (TNF-a) and interleukin-10 (IL-10) by patient-derived MNCs. The patients' cells produced higher amounts of IFN-c and TNF-a, and lower amounts of IL-10, than cells from healthy controls (P < 0Á03 to P < 0Á04). Five patients with MS and no controls, displayed MBP-induced CD4 + T-cell proliferation. These high-responders exhibited enhanced production of IL-17, IFN-c, IL-5 and IL-4 upon challenge with MBP, as compared with the remaining patients and the healthy controls (P < 0Á002 to P < 0Á01). A strong correlation was found between the MBP-induced CD4 + T-cell proliferation and production of IL-17, IFN-c, IL-5 and IL-4 (P < 0Á0001 to P < 0Á01) within the patient group, and the production of IL-17 and IL-5 correlated with the number of active plaques on magnetic resonance images (P = 0Á04 and P = 0Á007). These data suggest that autoantigendriven CD4 + T-cell proliferation and release of IL-17 and IL-5 may be associated with disease activity. Larger studies are needed to confirm this.