Inflammatory molecules in Frontotemporal Dementia: cerebrospinal fluid signature of progranulin mutation carriers.

Mutations in progranulin gene (GRN) are one of the major causes of autosomal dominant Frontotemporal Lobar Degeneration (FTLD). Progranulin displays anti-inflammatory properties and is likely a ligand of Tumor Necrosis Factor (TNF) receptor 2, expressed on microglia. A few cytokines and chemokines are altered in cerebrospinal fluid (CSF) from patients with sporadic FTLD, whereas no information is available in familial cases. We evaluated, through BioPlex, levels of 27 inflammatory molecules, including cytokines, chemokines, and related receptors, in CSF and matched serum, from FTLD patients carrying GRN mutations as compared with sporadic FTLD with no GRN mutations and controls. Mean±SD Monocyte Chemoattractant Protein-1 (MCP-1) levels were significantly increased in CSF from sporadic FTLD patients as compared with controls (334.27±151.5 versus 159.7±49pg/ml; P⩽0.05). In GRN mutation carriers versus controls, CSF levels of MCP-1 were unchanged, whereas Interferon-γ-inducible protein-10 (IP-10) levels were increased (809.17±240.0 versus 436.61±202.5pg/ml; P=0.012). In the same group, TNFα and Interleukin (IL)-15 levels were decreased (3.18±1.41 versus 35.68±30.5pg/ml; P=0.013 and 9.34±5.54 versus 19.15±10.03pg/ml; P=0.023, respectively). Conversely, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) levels were decreased in patients, with or without mutations, as compared with controls (4.63±3.30 and 2.58±20 versus 87.57±70pg/ml, respectively; P<0.05). Moreover, IP-10, IL-15 and RANTES CSF levels were not influenced by age, whereas MCP-1 levels increased with age (ρ=0.48; P=0.007). In conclusion, inflammatory de-regulation was observed in both sporadic FTLD and GRN carriers compared to controls, with a specific inflammatory profile for the latter group.

Distinguishing the cerebrospinal fluid cytokine profile in neuropsychiatric systemic lupus erythematosus from other autoimmune neurological diseases.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious complication in SLE. Although the mechanism of NPSLE remains unclear, cytokines and chemokines are considered to be involved in their pathogenesis. Here we used Bio-Plex Pro assays to examine 27 types of cytokines and chemokines in the cerebrospinal fluid (CSF) of 32 NPSLE patients. We used the CSF of 20 patients with multiple sclerosis (MS) and 22 patients with neuromyelitis optica (NMO) as a disease control group. Fourteen of 27 cytokines/chemokines were significantly higher in the NPSLE patients compared to the MS/NMO patients. We could identify six "minimum predictive markers" by using a weighted-voting algorithm that could distinguish NPSLE from MS and NMO: interleukin (IL)-17, IL-2, interferon (IFN)-γ, IL-5, basic fibroblast growth factor (FGF)-basic and IL-15. The determination of various types of CSF cytokine profiles may contribute to the diagnosis of NPSLE and may help elucidate the mechanisms underlying this disease.

The role of IL-15 in central nervous system disorders.

IL-15 is a proinflammatory cytokine. It is produced by activated blood monocytes, macrophages, dendritic cells, and activated glial cells. It promotes T-cell proliferation, induction of cytolytic effector cells including natural killer and cytotoxic cells and stimulates B-cell to proliferate and secrete immunoglobulins. Little information is available on the exact role of IL-15 in the neurological diseases. Microglial cells are the main regulators of both innate and adaptive immune responses in the central nervous system (CNS). IL-15 may be involved in the inflammatory reactions and microglial activation of some common CNS disorders such as multiple sclerosis, Alzheimer's and Parkinson's disease, but its exact role in their pathogenesis is not clear.

Interleukin-15 and interleukin-12 are elevated in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

BACKGROUND: There is evidence that immunological factors may be involved in pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). Interleukin (IL)-15 and IL-12 are proinflammatory cytokines produced by activated blood and glial cells. They promote T cell differentiation and proliferation. PATIENTS AND METHODS: We measured by ELISA serum and cerebrospinal fluid (CSF) levels of IL-15 and IL-12 in 21 patients with ALS and 19 patients with other noninflammatory neurological disorders (NIND) studied as a control group. IL-15 and IL-12 serum and CSF levels were also correlated with duration of the disease, the disability level determined using the revised ALS Functional Rating Scale and the clinical subtype of the disease onset in patients with ALS. RESULTS: IL-15 and IL-12 serum levels were higher in patients with ALS as compared with patients with NIND (p = 0.014 and p = 0.011, respectively). IL-15 and IL-12 CSF levels were also increased in patients with ALS (p = 0.011 and p = 0.005, respectively). IL-15 and IL-12 levels were not correlated with disease duration, disability scale or clinical subtype of the disease onset in ALS patients. CONCLUSIONS: Our findings suggest that these molecules may be involved in the pathogenic mechanisms acting as potential markers of immune activation in ALS.

Measurement of soluble inflammatory mediators in cerebrospinal fluid of human immunodeficiency virus-positive patients at distinct stages of infection by solid-phase protein array.

The objective of this study was to evaluate immune cytokine expression in cerebrospinal fluid (CSF) of patients with human immunodeficiency virus-1 (HIV-1)-associated dementia (HAD) using a novel cytokine array assay. HIV-1 induces a condition resembling classical subcortical dementia, known as HAD. The immune mechanisms contributing to HAD have not been elucidated. Cytokine expression in CSF was determined by solid-phase protein array in 33 neurologically asymptomatic HIV-positive male patients and were compared to levels in non-HIV controls and patients with HAD. Neurological examinations and lumbar and venous punctures were conducted in all patients and controls. Interleukin (IL)-1, IL-4, and IL-10, were up-regulated in all treated acquired immunodeficiency syndrome (AIDS) patients independent of neurological status compared to controls. In contrast, interferon gamma (IFN-gamma), IL-1alpha, IL-15, and tumor necrosis factor alpha (TNF-alpha) were highly expressed in patients with HAD compared to undemented HIV-positive patients. These results show that solid-phase protein array can detect immunological changes in patients infected with HIV. Cytokine expression levels differ in different disease stages and in patients on different treatment paradigms. Pending further validation on a larger number of patients, this method may be a useful tool in CSF diagnostics and the longitudinal evaluation of patient with HAD.

[Concentrations of pro-inflammatory cytokines IFN-gamma, IL-6, IL-12 and IL-15 in serum and cerebrospinal fluid in patients with neuroborreliosis undergoing antibiotic treatment]. / Zmiany stezenia wybranych cytokin prozapalnych IFN-gamma, IL-6, IL-12 i IL-15 w surowicy oraz plynie mózgowo-rdzeniowym pod wplywem antybiotykoterapii u chorych na neuroborelioze.

UNLABELLED: Pathogenesis of Lyme disease, including neuroborreliosis, remains unclear. However, pro-inflammatory cytokines seem to be involved and might be used to monitor the course of the disease. It has been also shown that B. burgdorferi protects itself from elimination by modulating function of the host's immune system. THE AIM OF THIS STUDY: The purpose of this study was to evaluate the serum and cerebrospinal fluid (CSF) concentrations of selected cytokines in patients with neuroborreliosis and their change during antibiotic treatment. MATERIAL AND METHODS: The group of 25 patients was examined, all undergoing antibiotic therapy due to meningitis caused by Borrelia burgdorferi infection. The group included 10 (40%) females and 15 (60%) males in the mean age x = 42,3 years. The control group for serum measurements consisted of 25 healthy individuals (mean age x =43, 1) while control group for CSF study included 10 patients (aged x = 53,5 years) from whom CSF with normal parameters was taken during diagnostic procedures neurosurgical. We examined serum and CSF before and after antibiotics for concentrations of interferon-gamma (INF-gamma), interleukin-6 (IL-6), interleukin-12 (IL-12) and interleukin-15 (IL-15). RESULTS: In the first examination the significant increase of IFN-gamma, IL-6, IL-2, IL-15 serum and CSF concentration was detected in comparison to control group. After 4-weeks antibiotic treatment the concentrations of studied cytokines decreased significantly in serum as well as in CSF but remained increased in comparison with controls. CONCLUSIONS: Although antibiotic treatment leads to withdrawal of clinical symptoms of neuroborreliosis and normalization of CSF general parameters, pro-inflammatory cytokines' concentrations in serum and CSF remain elevated. It may be explained by the persistence of inflammatory conditions, perhaps related to surviving of a fraction of Borrelia burgdorferi spirochetes within CNS tissue. This phenomenon might lead to development of chronic CNS lesions.

Levels of IL-15 in serum and cerebrospinal fluid of patients with Behçet's disease.

Interleukin-15 (IL-15) is a novel proinflammatory cytokine, involved in the pathogenesis of inflammatory/autoimmune disease. The objective of our study was to measure serum and cerebrospinal fluid (CSF) IL-15 levels in patients with Behçet's disease (BD). CSF/serum IL-15 ratio was introduced to assess the origin of elevated IL-15 levels. We measured serum and CSF-IL-15 levels in 40 patients with BD (20 patients in active stage). Inflammatory and non-inflammatory neurological disease patients acted as controls. Active BD patients have significantly higher serum IL-15 levels (median 10.4 pg/ml; range 5.3-17.4) compared with BD in remission (6.05 pg/ml; 4-10.4) and healthy controls (4.65 pg/ml; 3.9-6.2). Similar serum IL-15 levels were found in active neuro-BD and inflammatory neurological disease (9.5 pg/ml; 5-13). Elevated levels of IL-15 were observed in CSF samples from neuro-BD patients (11 pg/ml; 8.5-15) and inflammatory neurological disease patients (10 pg/ml; 6.5-14) compared with patients with non-inflammatory neurological disease (4 pg/ml; 4-5.5; P < 0.001). Vascular cerebral BD lesions were associated with high CSF/serum IL-15 ratio. Our findings suggest that IL-15 is involved in BD inflammatory process, particularly in vasculitis foci, as an elevated CSF/serum IL-15 ratio characterizes vascular cerebral lesions.

IL-15 is elevated in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia.

Interleukin-15 is a novel proinflammatory cytokine. It is produced by activated blood monocytes, macrophages, and glial cells. The objective of our study was to assess the role of interleukin-15 as a marker of increased proinflammatory activity in patients with Alzheimer's disease and frontotemporal dementia. We measured cerebrospinal fluid interleukin-15 levels in 17 patients with Alzheimer's disease and 7 patients with frontotemporal dementia in comparison with 17 patients with amyotrophic lateral sclerosis and 15 patients with Parkinson's disease. Patients with Alzheimer's disease and frontotemporal dementia had significantly higher cerebrospinal fluid interleukin-15 levels compared with patients with noninflammatory neurological diseases (P < .05 and P < .01, respectively). In Alzheimer's disease, a significant positive correlation was noted between interleukin-15 levels and age of onset (R = .48, P = .05). Our findings suggest that interleukin-15 may be implicated in the pathophysiology of Alzheimer's disease and frontotemporal dementia.

IL-15 is elevated in sera of patients with relapsing-remitting multiple sclerosis.

Interleukin-15 is a novel cytokine produced by monocytes/macrophages and sharing several biological activities with IL-2. IL-15 induces T cell proliferation, enhances natural killer (NK) cell cytotoxicity and also stimulates B cells to proliferate and secrete immunoglobulins. The purpose of our study was to measure IL-15 levels in the serum and CSF of 21 patients with relapsing-remitting form of MS, 9 with active gadolinium enhancing lesions in MRI, 12 without enhancing MRI lesions and to compare the results with the control group. IL-15 levels were measured by ELISA. We found a significant increase of IL-15 in the sera of patients with MS in comparison with the control group consisting of 8 patients with tension headache. IL-15 serum levels were highest in patients with active, gadolinium enhancing lesions. IL-15 CSF levels were low and there was no difference between studied groups. The results may suggest the contribution of IL-15 in the immunopathogenesis of multiple sclerosis.

Levels of interleukin-15-expressing blood mononuclear cells are elevated in multiple sclerosis.

Interleukin-15 (IL-15) is a novel IL-2-like cytokine expressed by cells of the monocyte/macrophage and epithelial lineages. Cytokines might be involved in the pathogenesis of multiple sclerosis (MS). Using immunocytochemistry, we analysed spontaneous expression of IL-15 by peripheral blood (PB) and cerebrospinal fluid (CSF) mononuclear cells (MNC) from patients with MS, other neurological diseases (OND) and healthy controls. IL-15- positive peripheral blood mononuclear cells (PBMNC) were elevated in patients with MS compared to healthy controls (P < 0.05). The elevation of IL-15- positive PBMNC was restricted to patients with chronic progressive MS and not observed in patients studied during the relapsing-remitting phase of MS. The numbers of IL-15- expressing PBMNC correlated with the duration and disability of MS (r = 0.45, P < 0.001, and r = 0.39, P < 0.01, respectively). IL-15 was undetectable in CSF MNC, and ELISA showed low CSF levels of IL-15 in occasional patients with MS and OND. IL-15 is a potent growth factor for gammadelta T cells, but there was no correlation between IL-15 expression by PBMNC and percentage of gammadelta T cells in blood from the MS patients. Together, these data demonstrate that IL-15 expression by PBMNC is upregulated in the chronic stage of MS.

IL-15 mRNA expression is up-regulated in blood and cerebrospinal fluid mononuclear cells in multiple sclerosis (MS).

IL-15, produced by monocytes and epithelial cells, is a novel cytokine with actions similar to IL-2. IL-15 induces T cell proliferation, B cell maturation and natural killer (NK) cell cytotoxicity, and is a chemoattractant for T cells. We investigated the expression of IL-15 mRNA in blood and cerebrospinal fluid (CSF) mononuclear cells (MNC) in MS, an inflammatory disease of the central nervous system where cytokines are involved. MS patients had higher numbers of IL-15 mRNA-expressing blood MNC than patients with aseptic meningo-encephalitis (AM) and healthy controls. In CSF, MS patients had even higher numbers of IL-15 mRNA-expressing cells than in blood. This discrepancy between IL-15 mRNA expression between blood and CSF MNC was not seen in AM patients. Patients examined during the secondary chronic-progressive phase of MS had higher numbers of IL-15 mRNA-expressing blood MNC compared with patients examined during the relapsing-remitting phase. Levels of IL-15 mRNA-positive blood MNC were similar in patients with AM, myasthenia gravis, non-inflammatory neurological diseases and healthy controls. Taken together these data indicate that IL-15 mRNA expression is up-regulated in MS, further suggesting a role for proinflammatory cytokines in the pathogenesis of MS.

Chemotactic activity on mononuclear cells in the cerebrospinal fluid of patients with viral meningitis is mediated by interferon-gamma inducible protein-10 and monocyte chemotactic protein-1.

In viral meningitis the inflammatory response involves activated T cells and monocytes which are recruited into the subarachnoid space. To identify the chemotactic signals attracting the cells to the site of infection in the meninges, we measured the levels of two CXC chemokines, interferon-gamma (IFN-gamma) inducible protein (IP)-10 and monokine induced by IFN-gamma, four CC chemokines, monocyte chemotactic protein (MCP)-1, RANTES, macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta, as well as the cytokines interleukin (IL)-15 and IL-16 in the cerebrospinal fluid (CSF) of patients suffering from viral meningitis. The results point to an involvement of two chemokines, MCP-1 and IP-10, since (1) unlike the other cytokines, MCP-1 and IP-10 were present in 97% and 79% of the CSF, respectively, at concentrations sufficient to induce chemotaxis of mononuclear cells; (2) more than 90% of the CSF of viral meningitis induced chemotaxis of peripheral blood mononuclear cells (PBMC) and all of them induced chemotaxis of activated T cells, and (3) the CSF-mediated chemotaxis of PBMC was inhibited by anti-MCP-1 antibodies and chemotaxis of activated T cells was abolished by the combination of anti-MCP-1 and anti-IP-10 antibodies. Our data provide evidence that MCP-1 and IP-10 lead to accumulation of activated T cells and monocytes in the CSF compartment in viral meningitis.