Reducing the phagocytic ability of monocytes in patients with multiple sclerosis (original) (raw)
Related papers
Monocytes in multiple sclerosis: phenotype and cytokine profile
Journal of Neuroimmunology, 2001
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-a 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 Fcg 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-a 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.
Peripheral blood monocytes in multiple sclerosis exacerbations
2011
Objectives: Monocytes (MO), macrophages, and microglia have a central role in the central nervous system inflammation of multiple sclerosis (MS). During clinical activity in MS, MO activation markers increase and some interleukins and tumor necrosis factor-alpha levels are elevated. Our aim was to determine levels of absolute MO count and percentage in peripheral blood of MS patients during the attacks. Methodology: We assessed the percentage of MO by examining the blood smears in 28 patients with definite MS, in 20 patients with acute cerebrovascular disease (CVD) and in 20 healthy control subjects. Results: The mean value of absolute MO count in MS patients, CVD and control groups were as 606.67± 170.52, 746.50±414.76 and 360.00±109.54 respectively. The mean values of MO percentage in MS patients, CVD and control group were 8.34±2.61%, 5.56±2.48% and 5.36±1.50% respectively. The mean percentage of MO was significantly elevated in MS patients compared with the both groups of CVD and control (P<0.001). Conclusion: Our results suggest a possible role of an increase in MO activation in the acute exacerbations of Multiple Sclerosis.
Journal of Interferon & Cytokine Research, 2005
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). In active disease, a transmigration of autoreactive T cells to myelin antigens recruited from the peripheral blood (PBMC) to the CNS occurs, and there these cells prolong their survival and contribute to the perpetuation of the inflammation. In the active local lesions of MS patients, these cells display activation and apoptosis surface markers and secrete a range of cytokines. The aim of this research is to study on PBMCs and in the serum of stable and active MS subjects (1) the behavior of the CD40/CD40L system and the consequent balance of Th1 and Th2 cytokines and (2) the apoptosis marker system CD95/CD95L and tumor necrosis factor (TNF)binding receptors, TNFRI and TNFRII. A possible excess of activation marker expression affecting and driving Th1 cytokine production or a parallel impairment of apoptosis may contribute to MS relapses. Our results may indicate that a dysregulation of early activation and apoptosis receptor systems and a profound and complex imbalance of cytokine production occurred in the peripheral blood of MS patients. This impairment could account for active phases of the disease.
Monocyte-derived cytokines in multiple sclerosis
Clinical and Experimental Immunology, 2003
MS is an inflammatory, presumably autoimmune, disease mediated by the activation of T cells, B cells and monocytes (MO). Inflammation is thought to occur early during the relapsing-remitting phase of MS (RRMS), whereas in the later phases of MS such as secondary progressive MS (SPMS), inflammation tends to diminish. Our objective was to compare the types and amounts of proinflammatory and regulatory cytokines produced by MO from relapsing-remitting patients with or without treatment with IFN-b (RRMS + therapy, RRMStherapy), respectively, from secondary progressive patients (SPMS) and from healthy controls (HC). MO were isolated by a density-gradient technique and three different techniques (RNase protection assay, ELISA and intracellular cytokine staining) were used to assess cytokine levels. An increase in IL6, IL12 and TNF-a was observed by all three methods for RRMStherapy and for SPMS patients compared to HC and RRMS + therapy patients. We conclude that proinflammatory and regulatory monokines can be derived from MO of MS patients and that these levels are modulated by IFN-b therapy. Although it is believed that inflammation tends to diminish in SPMS patients, our data show that inflammatory cytokines continue to be released at high levels, suggesting that IFN-b or IL10 treatment may be beneficial for this group.
The American Journal of Pathology, 2012
tion on their accumulation in blood during disease, the mechanisms that regulate their infiltration into the central nervous system (CNS), and whether medications affect their biology. We found a significant and prolonged elevation of CD11b ؉ CCR2 ؉ Ly6C high proinflammatory monocytes in the blood of mice by the second day of immunization for EAE. At onset of clinical signs, levels of proinflammatory monocytes plummeted to those in naive mice. At day 16, when the majority of mice were at peak disease severity, clinical scores were inversely correlated to the proportion of proinflammatory monocytes in blood, and directly correlated with that in the spinal cord. Treatment with the MS medication laquinimod prevented EAE, correspondent with retention of proinflammatory monocytes in blood. The reduced entry of proinflammatory monocytes into the CNS by laquinimod was attributed to reduction of their levels of CD62L and matrix metalloproteinase-9. Moreover, the spinal cord of laquinimod-treated mice did not have elevated levels of CCR2 and CCL2, which provide chemotactic cues for monocytes. These results shed light on the important role of the trafficking of proinflammatory monocytes into the CNS to promote disease activity, and they identify a mechanism of action of laquinimod in MS. (Am J Pathol 2012, 181:642-651; http://dx.doi. org/10.1016/j.ajpath.2012.05.011)
Microglial Phagocytosis—Rational but Challenging Therapeutic Target in Multiple Sclerosis
International Journal of Molecular Sciences, 2020
Multiple sclerosis (MS) is the most common autoimmune and demyelinating disease of the central nervous system (CNS), characterized, in the majority of cases, by initial relapses that later evolve into progressive neurodegeneration, severely impacting patients’ motor and cognitive functions. Despite the availability of immunomodulatory therapies effective to reduce relapse rate and slow disease progression, they all failed to restore CNS myelin that is necessary for MS full recovery. Microglia are the primary inflammatory cells present in MS lesions, therefore strongly contributing to demyelination and lesion extension. Thus, many microglial-based therapeutic strategies have been focused on the suppression of microglial pro-inflammatory phenotype and neurodegenerative state to reduce disease severity. On the other hand, the contribution of myelin phagocytosis advocating the neuroprotective role of microglia in MS has been less explored. Indeed, despite the presence of functional olig...
1988
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system of unknown etiology, but a disease in which immunopathologic events are likely important [1]. It is a chronic disease, frequently with an clinically relapsing course [2], but the pathologic processes may actually be continuous, although accentuated at times [3]. It also has a restricted age distribution, with the peak onset between 20 and 40 years of age. In addition to the inflammation, which is predominantly made up of monocyte-macrophage-microglia and lymphocytes and/ or their progeny, and demyelination, the other characteristic pathologic feature is gliosis [4]. This gliosis relates to the astrocytes, although there is some controversy as to whether these cells become more prominent, increase in number, or both. There has been considerable interest in the possibility that MS is an autoimmune immunopathologic disease with a component of myelin/oligodendrocyte, the target for an antibody and/or cellular response. To date, the evidence is indirect [5, 6] and the antigen has certainly not been unambiguously identified [7]. More recently, there has been increasing interest in other interactions between the immune and nervous systems. This has been made possible by several scientific advances, including the ability to identify, purify, and study the function of subsets of cells of both the immune and nervous system as well as to purify and characterize secretory products of cells of both systems. In addition, genetic engineering has allowed the production of single products of inflammatory cells, and the use of monoclonal antibodies allows the unequivocal identification of epitopes of important surface and cytoplasmic components of cells of the nervous system on the immune system. Much of this recent activity has centered on interactions between products of activated inflammatory cells (cytokines=lymphokines+monokines) and glial cells [oligodendrocytes, astrocytes, macrophages, microglia (brain phagocytic cells)] and brain vascular endothelial cells [8, 9]. These cytokines are clearly present in the nervous system and CSF of patients with MS [10]. An extension of this line of investigation is the study of glial cells serving functions traditionally associated with celIs of the immune system such as presentation of antigen [11], production of monokines [12, 13], phagocytosis [14], and production of enzymes such as proteases which could contribute to myelin breakdown and even act as stimulators of B-cell proliferation and differentiation [15]. Although much has been learned, there are many unanswered questions of considerable neurobiologic, immunologic, and pathologic importance.
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.
Autoreactive lymphocytes in multiple sclerosis: Pathogenesis and treatment target
Frontiers in Immunology
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by destruction of the myelin sheath structure. The loss of myelin leads to damage of a neuron’s axon and cell body, which is identified as brain lesions on magnetic resonance image (MRI). The pathogenesis of MS remains largely unknown. However, immune mechanisms, especially those linked to the aberrant lymphocyte activity, are mainly responsible for neuronal damage. Th1 and Th17 populations of lymphocytes were primarily associated with MS pathogenesis. These lymphocytes are essential for differentiation of encephalitogenic CD8+ T cell and Th17 lymphocyte crossing the blood brain barrier and targeting myelin sheath in the CNS. B-lymphocytes could also contribute to MS pathogenesis by producing anti-myelin basic protein antibodies. In later studies, aberrant function of Treg and Th9 cells was identified as contributing to MS. This review summarizes the aberrant function and coun...
Frontiers in Immunology, 2021
Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS). Besides the vital role of T cells, other immune cells, including B cells, innate immune cells, and macrophages (MФs), also play a critical role in MS pathogenesis. Tissue-resident MФs in the brain's parenchyma, known as microglia and monocytederived MФs, enter into the CNS following alterations in CNS homeostasis that induce inflammatory responses in MS. Although the neuroprotective and anti-inflammatory actions of monocyte-derived MФs and resident MФs are required to maintain CNS tolerance, they can release inflammatory cytokines and reactivate primed T cells during neuroinflammation. In the CNS of MS patients, elevated myeloid cells and activated MФs have been found and associated with demyelination and axonal loss. Thus, according to the role of MФs in neuroinflammation, they have attracted attention as a therapeutic target. Also, due to their different origin, location, and turnover, other strategies may require to target the various myeloid cell populations. Here we review the role of distinct subsets of MФs in the pathogenesis of MS and different therapeutic agents that target these cells.