Intrathecal expression of IL-5 and humoral response in patients with tick-borne encephalitis.

AIM: The aim of the study was to assess the role of an early specific humoral response in human infection with a tick-borne encephalitis virus (TBEV) and the role of IL-5 as its potential mediator and marker. MATERIALS AND METHODS: The retrospective study involved a cohort of 199 patients diagnosed with TBE, in whom anti-TBEV IgM and IgG antibody titers were analyzed on admission and compared with clinical presentation and basic laboratory parameters. The prospective study included 50 TBE patients in whom IL-5 serum and CSF concentration was measured with ELISA on admission in the TBE neurologic phase and in selected patients before discharge, at follow-up or in samples obtained before the neurologic phase onset. RESULTS: The serum anti-TBEV IgM correlated with good clinical outcome and the CSF anti-TBEV IgM with more pronounced CSF inflammation on admission, but also with its more complete resolution on follow-up. The serum anti-TBEV IgG correlated with milder presentation and better outcome. Concentration of IL-5 was increased in CSF but not in the serum of TBE patients. IL-5 concentration index on admission favored its intrathecal synthesis. IL-5 did not correlate significantly with clinical presentation and specific IgM and IgG titers. CONCLUSIONS: Specific anti-TBEV IgM systemic and intrathecal response and IgG systemic response are protective, together favoring milder presentation, better outcome and resolution of central nervous system (CNS) inflammation. IL-5 is expressed intrathecally in TBE, but its pathogenetic role remains unclear.

Plasma But Not Cerebrospinal Fluid Interleukin 7 and Interleukin 5 Levels Pre-Antiretroviral Therapy Commencement Predict Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome.

BACKGROUND: Patients with human immunodeficiency virus/AIDS-associated cryptococcal meningitis (CM) frequently experience clinical deterioration, known as cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), upon initiation of antiretroviral therapy (ART). The immunological mechanisms underlying C-IRIS are incompletely defined and no reliable predictive biomarkers exist. We investigated whether plasma or cerebrospinal fluid (CSF) levels of cytokines and chemokines predicted C-IRIS and are potential predictive biomarkers. METHODS: Patients with CM who experienced C-IRIS (N = 27) upon ART initiation were compared to CD4+ T-cell count-matched patients without C-IRIS (N = 27). Plasma and CSF collected pre-ART were assayed for cytokines and chemokines using a 17-plex Luminex kit or enzyme-linked immunosorbent assay. Cox proportional hazards regression and principal component analyses were also performed. RESULTS: Plasma interleukin (IL) 2, IL-4, IL-5, IL-7, IL-17, interferon-γ, and tumor necrosis factor-α levels were higher in C-IRIS patients compared to controls (all P < .05), with IL-5 and IL-7 significant after Bonferroni-Holm correction. In multivariate Cox proportional hazards regression, high IL-5 (hazard ratio [HR], 5.76 [95% confidence interval {CI}, .77-43.0]; P = .088) and IL-7 (HR, 9.30 [95% CI, 1.96-44.0]; P = .005) were predictive of C-IRIS. Plasma IL-5 (P = .0008) and IL-10 (P = .0089) were lower in those who achieved CSF cryptococcal culture negativity compared to those with positive cultures pre-ART. There were no significant differences in CSF cytokine or chemokine levels between cases and controls. CONCLUSIONS: High plasma IL-5 and IL-7 levels pre-ART were associated with increased risk of developing C-IRIS. High IL-5 levels may reflect a Th2 environment associated with impaired clearance of cryptococci while high IL-7 levels may reflect IL-7/IL-7R pathway dysfunction in T cells, both of which could be associated with C-IRIS immunopathogenesis.

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.

Pathogenetic factors for excessive IgA production: Th2-dominated immune response in canine steroid-responsive meningitis-arteritis.

Canine steroid-responsive meningitis-arteritis (SRMA) is a systemic inflammatory disease with a predominant manifestation within the cervical meninges, increased immunoglobulin A (IgA) levels in serum and cerebrospinal fluid (CSF), and a shift of the B:T cell ratio towards a higher percentage of B cells. A Th2-dominated immune response associated with SRMA was therefore hypothesised. Pellets of peripheral blood mononuclear cells (PBMNCs) and CSF white blood cells (CSF WBCs) from dogs in the acute phase of SRMA (n=16) and under glucocorticoid treatment for SRMA (n=16) were investigated for interleukin (IL)-2, interferon (IFN)-γ, IL-4, IL-5 and IL-10 mRNA expression by means of reverse-transcriptase real-time polymerase chain reaction. Results were compared with those of dogs with other inflammatory (n=9) and neoplastic disorders (n=10) of the central nervous system. A tendency towards low levels of Th1 response related cytokines (IL-2, IFN-γ) and high IL-4 expression was observed indicating a Th2-skewed immune response. The pronounced IL-4 production may be an important pathogenetic factor for excessive IgA production in the acute phase of SRMA and for those cases under glucocorticoid treatment.

Immunological mechanisms that associate with oligoclonal IgM band synthesis in multiple sclerosis.

We described previously that multiple sclerosis (MS) patients with oligoclonal IgM against myelin lipids (M+) develop an aggressive disease. Our aim was to assess possible mechanisms regulating the production of these antibodies. We studied B cell subsets in 180 patients with MS, and 69 with other neurological diseases. M+ MS patients showed a moderate increase of CD5(+) B-cell percentage in peripheral blood and a considerable augment of these cells in cerebrospinal fluid (CSF) that correlated with intrathecal IgM production. The appearance of CD5(+) B cells into the central nervous system (CNS) was related to increased CXCL13 and TNF-alpha levels in CSF. Moreover, the presence of oligoclonal IgM associated with a SNP at position -376 of the TNF-alpha promoter. These results help to elucidate the B lymphocytes responsible for intrathecal IgM secretion in MS and the origin of this abnormal B-cell response in patients with aggressive MS.

Cerebrospinal fluid cytokine responses in human eosinophilic meningitis associated with angiostrongyliasis.

The levels of interleukin 5 (IL5), IL10, and IL13 in the cerebrospinal fluid (CSF) were markedly higher in 30 patients with eosinophilic meningitis associated with angiostrongyliasis (EOMA) than in the controls (P<0.001). IL2, IL4, interferon gamma (IFNgamma), and tumor necrosis factor alpha (TNFalpha) levels were not significantly different (P>0.05). IL5, IL10, and TNFalpha levels correlated with eosinophil levels (P=0.023, P=0.018, and P=0.005, respectively) while IL2, IL4, IL13, and IFNgamma did not (P>0.05). Our data suggest that local T-helper-2 (TH2) cytokine responses are predominant in the CSF of patients with EOMA. Data on T lymphocyte-parasite interactions are important for the design of effective vaccines and immunotherapies. The measurement of T-helper-1 (TH1)/TH2 cytokines in the CSF may also have some potential for the diagnosis of parasite associated meningitis.

IL-15 is elevated in serum and cerebrospinal fluid of patients with multiple sclerosis.

UNLABELLED: Interleukin-15 (IL-15) is a novel proinflammatory cytokine having similar biological activities to IL-2 which is implicated in the pathogenesis of multiple sclerosis. It is produced by activated blood monocytes, macrophages and glial cells. There is little information about the involvement of IL-15 in the development of multiple sclerosis (MS). The objective of our study was to measure IL-15 serum and cerebrospinal fluid (CSF) levels in MS patients and to correlate serum and CSF IL-15 concentrations with clinical parameters of the disease. CSF IL-15/Serum IL-15 ratio (c/s IL-15 ratio) was introduced to assess the origin of elevated IL-15 levels. MATERIALS AND METHODS: We measured serum and CSF IL-15 levels in 52 patients with MS and 36 age and gender matched patients with inflammatory (IND) and non-inflammatory neurological diseases (NIND) studied as control groups. IL-15 levels were correlated with clinical parameters as duration, disability, MRI activity and clinical subtypes of the disease. RESULTS: MS patients were found to have significantly higher serum IL-15 levels compared with IND (p=0.00016) and NIND patients (p=0.00045). Elevated levels of IL-15 were also found in CSF samples from MS patients compared with patients with IND (p=0.00034) and NIND (p=0.0003). Among MS subgroups there were no statistically different IL-15 serum and CSF concentrations. No significant correlation of serum and CSF IL-15 concentrations with MRI activity, disability assessed by EDSS score and duration of the disease were also found. C/S IL-15 ratio was found lower in MS patients compared with IND (p=0.01) and not significantly different compared with NIND patients (p=0.14) suggesting that systemic activation might be the source of high CSF IL-15 levels in MS patients. CONCLUSIONS: Our findings suggest a possible role of IL-15 in the immunopathogenetic mechanisms of MS.

Relationship between the clinical heterogeneity of neurocysticercosis and the immune-inflammatory profiles.

Human neurocysticercosis is caused by the establishment of Taenia solium cysticerci in the central nervous system. Neurocysticercosis may be asymptomatic or manifested by non-specific mild to severe neurological symptoms. Host factors may be involved in this heterogeneous clinical picture. An immune-inflammatory profile that underlies neurocysticercosis presentation was determined in 45 cerebral spinal fluid (CSF), from clinical and radiologically characterized neurocysticercosis patients, measuring specific IgG subclasses and cytokines. Severity related with increased cellularity in the CSF which was characterized by increased levels of IgG subclasses, IL6/IL5/IL10, proteins, and eosinophils. Multiple neurocysticercosis showed higher levels of IL5/IL6 than single neurocysticercosis. Women presented increased IL6/IL5/IL10 levels pointing out immunological differences due to gender. Severe symptomatology was found when cysticerci were located intraventricular or in the subarachnoid space of the base, inducing an exacerbated response in the CSF. These results constitute an integrative insight to understand the immune-inflammatory response that underlies symptomatic neurocysticercosis.

Eosinophils in the cerebrospinal fluid of mice infected with Angiostrongylus cantonensis are resistant to apoptosis.

Interleukin-5 (IL-5) transgenic mice were used to assess the immunological features of CSF eosinophils from mice infected with Angiostrongylus cantonensis. CSF eosinophils were hypodense by day 14 post infection (p.i.). CSF eosinophils survived longer in vitro than peritoneal eosinophils collected from cadmium sulphate (CdSO(4)) -treated normal IL-5 transgenic mice. Apoptosis was measured by Annexin V binding and the presence of a distinct laddering pattern of DNA fragmentation on agarose electrophoresis. Regardless of the presence or absence of Actinomycin D, CSF eosinophils collected from IL-5 transgenic mice from days 15-36 p.i. exhibited less apoptosis than peritoneal eosinophils collected from uninfected IL-5 transgenic mice. CSF eosinophils collected from A. cantonensis infected C57BL/6 mice at days 15-34 p.i. showed elongation of survival time and less apoptosis during in vitro cultivation. Reduced apoptosis was noted only in CSF eosinophils, but not in peritoneal eosinophils recovered from the same infected IL-5 transgenic mice. CPP32/Caspase 3 activity of cultured peritoneal eosinophils from both infected and uninfected IL-5 transgenic mice was higher than that of cultured CSF eosinophils. Stimulation with A23187 readily induced apoptosis of peritoneal eosinophils, but not CSF eosinophils or peritoneal eosinophils cultured with mouse recombinant IL-5. The latter cells were morphologically identical to hypodense eosinophils. RT-PCR analysis indicated that bcl-2 and bcl-x(L) mRNA expression was higher in CSF eosinophils compared with peritoneal eosinophils and this expression in the latter cells was upregulated after culture with mouse recombinant IL-5. These results suggest that CSF eosinophils, shifting to hypodense status through an accumulation from peripheral blood, are resistant to apoptosis. These changes may explain the long-lasting, helminthotoxic and neurotoxic actions of CSF eosinophils in A. cantonensis infection.

Interleukin-5 and interleukin-10 are major cytokines in cerebrospinal fluid from patients with active neurocysticercosis.

Neurocysticercosis (NCC) is a common neurological disorder especially in developing countries, caused by infection of the brain with encysted larvae of the tapeworm Taenia solium. Seizures are a common finding associated with this disease. The objective of the present study was to evaluate the correlation between the levels of various cytokines present in the cerebrospinal fluid (CSF) of patients with NCC and the severity of the disease. The levels of the cytokines IL-1ss, TNF-alpha, IL-5, IL-10 and IFN-gamma were determined in the CSF of 22 patients with active NCC, 13 patients with inactive NCC and 15 control subjects. CSF from patients with active NCC presented significantly higher IL-5 levels compared to control subjects. IL-5 and IL-10 levels in CSF from NCC patients with inflammatory CSF were significantly higher than those detected in non-inflammatory CSF. These results show a predominant Th2 lymphocyte activation in human NCC and also indicate the possible use of cytokines in the CSF as a marker for the differential diagnosis between inactive disease and the active form of NCC.

Interleukin-5 and interleukin-10 are major cytokines in cerebrospinal fluid from patients with active neurocysticercosis

Neurocysticercosis (NCC) is a common neurological disorder especially in developing countries, caused by infection of the brain with encysted larvae of the tapeworm Taenia solium. Seizures are a common finding associated with this disease. The objective of the present study was to evaluate the correlation between the levels of various cytokines present in the cerebrospinal fluid (CSF) of patients with NCC and the severity of the disease. The levels of the cytokines IL-1î, TNF-alpha, IL-5, IL-10 and IFN-gamma were determined in the CSF of 22 patients with active NCC, 13 patients with inactive NCC and 15 control subjects. CSF from patients with active NCC presented significantly higher IL-5 levels compared to control subjects. IL-5 and IL-10 levels in CSF from NCC patients with inflammatory CSF were significantly higher than those detected in non-inflammatory CSF. These results show a predominant Th2 lymphocyte activation in human NCC and also indicate the possible use of cytokines in the CSF as a marker for the differential diagnosis between inactive disease and the active form of NCC

Cytokine responses in mice infected with Angiostrongylus cantonensis.

For determination of the kinetics of cytokine production and its possible role in host resistance to Angiostrongylus cantonensis in the mouse, Th1 [interleukin 2 (IL-2) and interferon gamma (IFN-gamma] and Th2 (IL-5 and IL-4) cytokine production in the cerebrospinal fluid (CSF), sera, and culture supernatants of spleen cells (SC) or cervical lymph-node cells (CLNC) of infected BALB/c and C57BL/6 mice was assessed by a sandwich enzyme-linked immunosorbent assay (ELISA). IL-5 and IL-4 were detected in CSF of both strains, with a peak response occurring at around days 12-15 and 20 postinfection (p.i.), respectively. A reverse transcriptase-polymerase chain reaction (RT-PCR) assay also revealed prominent IL-5 and IL-4 mRNA expression in T-cells but not in eosinophils in CSF. SC and CLNC stimulated with A. cantonensis young adult-worm antigen released IL-5 in vitro at and after day 20 p.i. Contrarily, IFN-gamma production in CSF and SC or CLNC culture supernatants was almost negligible before day 30 p.i. IL-5, IL-4, and IL-2 production in culture supernatants was rather prominent in resistant C57BL/6 mice as opposed to susceptible BALB/c mice as assessed by the magnitude of increase over preinfection levels. Antigen-specific IgG1 (but not IgG2a) responses were more prominent in C57BL/6 mice than in BALB/c mice. These data suggest that systemic and local Th2 cytokine responses, especially those involving IL-5, are predominant in A. cantonensis-infected mice and that IL-5 is an important cytokine underlying the innate resistance of the mouse against A. cantonensis.