Intrathecal delivery of IFN-gamma protects C57BL/6 mice from chronic-progressive experimental autoimmune encephalomyelitis by increasing apoptosis of central nervous system-infiltrating lymphocytes.

The exclusive detrimental role of proinflammatory cytokines in demyelinating diseases of the CNS, such as multiple sclerosis, is controversial. Here we show that the intrathecal delivery of an HSV-1-derived vector engineered with the mouse IFN-gamma gene leads to persistent (up to 4 wk) CNS production of IFN-gamma and inhibits the course of a chronic-progressive form of experimental autoimmune encephalomyelitis (EAE) induced in C57BL/6 mice by myelin oligodendrocyte glycoprotein (MOG)(35-55). Mice treated with the IFN-gamma-containing vector before EAE onset showed an earlier onset but a milder course of the disease compared with control mice treated with the empty vector. In addition, 83% of IFN-gamma-treated mice completely recovered within 25 days post immunization, whereas control mice did not recover up to 60 days post immunization. Mice treated with the IFN-gamma-containing vector within 1 wk after EAE onset partially recovered from the disease within 25 days after vector injection, whereas control mice worsened. Recovery from EAE in mice treated with IFN-gamma was associated with a significant increase of CNS-infiltrating lymphocytes undergoing apoptosis. During the recovery phase, the mRNA level of TNFR1 was also significantly increased in CNS-infiltrating cells from IFN-gamma-treated mice compared with controls. Our results further challenge the exclusive detrimental role of IFN-gamma in the CNS during EAE/multiple sclerosis, and indicate that CNS-confined inflammation may induce protective immunological countermechanisms leading to a faster clearance of encephalitogenic T cells by apoptosis, thus restoring the immune privilege of the CNS.

Tumor necrosis factor alpha and its receptors in relapsing-remitting multiple sclerosis.

In the attempt to further characterize the extent and timing of tumor necrosis factor (TNF)alpha-system activation during multiple sclerosis (MS), we performed a cross-sectional and a longitudinal study in a total of 73 relapsing-remitting MS patients. We assessed serum levels of soluble TNFalpha, soluble TNFalpha receptor 1 (R1) and soluble TNFalpha receptor 2 (R2) in 65 relapsing-remitting MS patients in different phases of disease. TNFalpha, R1 and R2 serum levels measured in MS patients did not differ from those measured in healthy individuals and did not correlate with (a) clinical relapses, (b) presence of gadolinium-enhancing brain-magnetic resonance imaging (MRI) lesions, and (c) bioactivity of TNFalpha. We also measured in 8 additional relapsing-remitting MS patients peripheral blood mononuclear cells (PBMC) mRNA levels of TNFalpha, R1 and R2 every 15 days for one year. In 4 of these patients we also measured levels of soluble TNFalpha, R1 and R2 every 15 days for 5 months across a clinical exacerbation. PBMC TNFalpha, R1 and R2 mRNA levels and serum levels of soluble R1 and R2, but not TNFalpha, fluctuated concordantly (P<0.05) and peaked a mean of 6 weeks before clinical and MRI evidence of disease activity. Moreover, we found a significant positive correlation between cumulative TNFalpha and R2 mRNA levels (measured during the follow-up period in the 8 MS patients studied serially) and the number of clinical attacks recorded in these patients during the study. Our data show that serum levels of soluble TNFalpha, R1, and R2 in MS patients do not differ from those of healthy individuals. However, although within normal values, the transcription and production rate of all these molecules fluctuate concordantly in the peripheral blood during the course of the disease (with the exception of soluble TNFalpha) and their maximal elevation significantly precedes the occurrence of clinical exacerbations. It is not clear whether soluble TNFalpha escapes recognition by commonly used assays or is simply not released in its soluble form in MS patients. In any case, measurement of TNFalpha mRNA levels and R1 and R2 mRNA and protein levels appears to be a better indicator of disease fluctuations during the course of MS than assessments of soluble TNFalpha protein.

Acute phase proteins and prognosis in multiple myeloma.

Serum IL-6 levels have been shown to correlate with disease severity and prognosis in patients with plasma cell dyscrasias. Among its pleiotropic actions, IL-6 is also the major regulator of the acute phase response in humans. The possible impact on survival of the major serum acute phase proteins (s.APP) [C-reactive protein (s.CRP), alpha-1-antitrypsin (s.AAT), haptoglobin, acid alpha-1-glycoprotein and alpha-2-macroglobulin (used as control)] was assessed on a population of 103 consecutive, previously untreated myeloma patients. Univariate analysis showed that among the acute phase proteins only s.AAT (P = 0.015) and s.CRP (P = 0.027) were significantly correlated with survival. The multivariate Cox proportional hazard model applied to s.APP and other common parameters showed that s.beta-2-microglobulin (s.b2M), s.calcium, s.creatinine, BM plasma cell percentage, age and s.AAT correlated significantly with survival. Combining s.b2M and s.AAT allowed stratification of myeloma patients: those with low levels of s.b2M (< or = 3 mg/l) and of s.AAT (< or = 3 g/l) presented an excellent prognosis (median survival exceeding 10 years) while those presenting higher values of the two parameters presented a median survival of 2.5 years (P = 0.002).

Acute Guillain-Barré syndrome associated with asymptomatic HIV infection.

A 25-year-old male drug addict presented with a rapidly progressive ascending tetraplegia, requiring assisted ventilation. One month earlier he had fever (40 degrees C) and asthenia. Cerebrospinal fluid (CSF) examination showed elevated albumin level and albuminocytologic dissociation. HIV testing was positive in both serum and CSF. Plasma exchange therapy only partially improved the symptomatology. After five months the patient remained with a moderate tetraparesis. Differences between this and other cases of Guillain-Barré syndrome in HIV-seropositive patients reported in the literature are discussed.

Tumor necrosis factor alpha levels in serum and cerebrospinal fluid of patients with AIDS.

We used a sensitive enzyme-linked immunosorbent assay technique to measure tumor necrosis factor alpha (TNF alpha) levels in serum and cerebrospinal fluid (CSF) samples from 30 patients infected with human immunodeficiency virus type 1 and from 10 normal controls. We found detectable levels of TNF alpha in 19 of 30 CSF and in 17 of 30 serum samples. The values of TNF alpha ranged between 20-90 pg/ml. All the patients had overt AIDS. More elevated TNF alpha levels in CSF correlate with focal damage within the central nervous system (p less than 0.01). Our results suggest that an intrathecal production of TNF alpha may occur during active inflammation in course of AIDS.

Elevated alpha-tumor necrosis factor levels in spinal fluid from HIV-1-infected patients with central nervous system involvement.

To assess the role of alpha-tumor necrosis factor in the pathogenesis of central nervous system involvement during human immunodeficiency virus type 1 infection, we recorded clinical data and measured alpha-tumor necrosis factor levels in serum and cerebrospinal fluid samples from 45 patients infected with human immunodeficiency virus type 1, classified as group II/III (10), group IV A (5), group IV B (10), and group IV C-1 (20) of the Centers for Disease Control acquired immunodeficiency syndrome classification system and 42 controls. Alpha-tumor necrosis factor was above the limit of detection in only 3 of 15 sera and 3 of 15 cerebrospinal fluid samples from patients in group II/III and group IV A, whereas it was detected in 17 of 30 sera (p less than 0.05) and 22 of 30 cerebrospinal fluid (p less than 0.0002) samples from clinically more advanced patients (group IV B and group IV C-1). Alpha-tumor necrosis factor mean values were 21.5 pg/ml in sera and 50.0 pg/ml in cerebrospinal fluid from group IV B patients and 30.4 pg/ml in sera and 24 pg/ml in cerebrospinal fluid from group IV C-1 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Isoelectric focusing herpes simplex virus-gB overlay study in brainstem encephalitis.

We report a case of herpetic brainstem encephalitis (HBE) retrospectively diagnosed in adult patient. Conventional immunovirological studies failed to disclose the etiology of this patient's affection. An isoelectric focusing-antigen overlay (IEF-O) technique showed that the target of one of the four cerebrospinal fluid oligoclonal bands was herpes simplex virus (HSV)-1 glycoprotein B, indicating a specific anti-HSV immunoresponse restricted to the CNS. IEF-O may represent a useful support for in vivo diagnosis of HBE.

Serum and cerebrospinal fluid herpes simplex virus type 1 immunoglobulin G and M titers in four cases of herpes simplex encephalitis.

Herpes simplex virus type 1 (HSV-1) IgG and IgM ELISA titers were serially determined in serum and cerebrospinal fluid (CSF) samples from 4 patients with HSV-1 encephalitis during a follow-up period of 1-26 months. In 3 out of 4 patients HSV-1 IgM titers raised in CSF during the acute phase of disease, thus allowing differentiation between primary and reactivated forms of HSV-1 encephalitis. HSV-1 IgG titers showed a sharp elevation earlier in serum than in CSF. Specific IgG index documented a large intrathecal production of HSV-1 IgG and their persistence 2 years following clinical onset. The initial trend of serum and CSF specific IgG titer represents a reliable tool for a retrospective diagnosis of HSV-1 encephalitis.

Specific activation of B-cell clones within the central nervous system in course of herpes simplex encephalitis.

Total and virus-specific immunoglobulin (Ig) G oligoclonal bands were studied in paired serum and cerebrospinal fluid (CSF) of four patients with herpes simplex virus type 1 (HSV-1) encephalitis. We used the isoelectric focusing in agarose gel, a sensitive technique for protein separation, followed by passive transfer of proteins on nitrocellulose paper and specific immunostaining. Oligoclonal bands were observed in serum and CSF of all patients. HSV-1-specific oligoclonal IgG bands were present in the CSF only during a limited period of the disease, having their counterpart in serum during the remaining periods. Our findings contribute to tackle the issue of B-cell activation within central nervous system and peripheral blood compartments in course of HSV-1 encephalitis.

Devic's neuromyelitis optica: long-term follow-up and serial CSF findings in two cases.

Sixteen cerebrospinal fluid (CSF) specimens serially obtained during long-term follow-up of two patients with Devic's neuromyelitis optica (DNO) were compared with 65 CSF samples from patients with multiple sclerosis (MS). By statistical analysis, the CSF profile in DNO was found to differ from that observed in MS, mainly showing pleocytosis, blood-brain barrier damage, and absence of persistent immunoglobulin G synthesis within the central nervous system. Oligoclonal bands, detected with isoelectric focusing, were present in CSF of 92% of the patients with MS, and in three CSF specimens from one patient with DNO during the first 6 months after disease onset. The bands disappeared in two subsequent samples. This finding has never been described in MS. One patient with DNO had an apparent chronic-relapsing course probably due to steroid dependence. The clinical and CSF features of our cases favour the nosographic independence of DNO and MS.

Tumor necrosis factor in serum and cerebrospinal fluid of patients with multiple sclerosis.

We measured levels of alpha-tumor necrosis factor (alpha-TNF) in cerebrospinal fluid and serum samples from 50 drug-free patients with multiple sclerosis, 25 patients with other neurological diseases, 27 patients with non-neurological diseases, and 10 normal subjects. The most elevated levels of alpha-TNF were found in patients with inflammatory or autoimmune diseases. Comparable serum levels of alpha-TNF were detected in normal control subjects, patients with multiple sclerosis, and patients with degenerative neurological diseases. In patients with multiple sclerosis, alpha-TNF levels were also unrelated to time elapsed between the occurrence of clinical exacerbation and the time of sample collection. Only 3 patients with chronic progressive multiple sclerosis had detectable alpha-TNF in the cerebrospinal fluid. Our data do not support a role for elevated levels of circulating alpha-TNF in the maintenance of the disease. However, we cannot rule out the possibility that a transient elevation of alpha-TNF triggers the cellular events leading to demyelination in multiple sclerosis.

Sicca syndrome and anti-SSA/Ro antibodies in patients with suspected or definite multiple sclerosis.

Thirty-eight consecutive patients with primary Sjögren's syndrome (SS) and 36 with suspected (15 cases) or probable to definite (21 cases) multiple sclerosis (MS) underwent thorough neuropsychiatric and rheumatological examinations in order to detect either the presence of central neurologic involvement in SS or the presence of clinical and immunologic abnormalities typical of SS in MS. The only neuropsychiatric abnormality we found in patients first recorded for primary SS was major depression in 5 cases. On the other hand, one patient with suspected MS because of mild gait ataxia and right hemiparesis fulfilled the diagnostic criteria for SS. As for serologic tests, 6 out of 21 patients with probable to definite MS and 1 out of 15 with suspected MS had low-titre antinuclear antibodies. One patient with definite MS had also circulating anti-SSA/Ro antibodies, detected by gel double diffusion, but did not develop sicca symptoms after a 2-year follow-up. In the present study, the association between SS and MS was considerably weaker than that recently reported in other studies, and might be regarded as a chance finding.

Acute experimental allergic encephalitis. Treatment with fungal polysaccharides.

This report describes the effects of a fungal polysaccharide mixture on the Experimental Allergic Encephalitis (EAE) in guinea pigs. The clinical, histopathological and IgG intrathecal synthesis related studies in the EAE sensitized group was compared with that observed in EAE sensitized groups treated with fungal polysaccharides. The results indicate that the fungal polysaccharide mixture is capable of inducing a more localized and milder inflammatory reaction in the guinea pig with EAE. We hypothesize that the fungal polysaccharides can activate complement by the alternative pathway, subtracting it to the specific immune response to EAE.