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The cause of multiple sclerosis (MS) is unknown. Recently reported abnormal T-cell responses to several myelin proteins and myelin basic protein (MBP) peptides in peripheral blood constitute one line of evidence that autoimmune mechanisms could be involved in the pathogenesis of the disease. Monosymptomatic unilateral optic neuritis (ON) is a common first manifestation of MS and important to examine for a possible restriction of the T-cell repertoire early in the disease. T-cell activities to MBP and the MBP amino acid sequences 63-68, 110-128 and 148-165 were examined by short-term cultures of mononuclear cells from cerebrospinal fluid (CSF) and blood in the presence of these antigens, and subsequent detection and counting of antigen-specific T cells that responded by interferon-gamma (IFN-γ) secretion. Most patients with MS and ON had MBP and MBP peptide-reactive T cells in CSF, amounting to mean values of between about 1 per 2000 and 1 per 7000 CSF cells and without immunodominance for any of the peptides. Numbers were 10-fold to 100-fold lower in the patients' blood. Values were similar in ON and MS, and no evidence was obtained for a more restricted T-cell repertoire in ON. The MBP peptide-recognizing T-cell repertoire was different in CSF than in blood in individual patients with ON and MS, thereby giving further evidence for an autonomy of the autoimmune T-cell response in the CSF compartment. No relations were observed between numbers of autoreactive T cells and presence of oligoclonal IgG bands in CSF or abnormalities on magnetic resonance imaging of the brain in ON or clinical variables of MS. The high numbers of MBP and MBP peptide-reactive T cells could play a role in the pathogenesis of ON via secretion of effector molecules, one of them being IFN-γ, as well as in the transfer of ON to MS. [ABSTRACT FROM AUTHOR]

A protein factor that stimulates CD8+ lymphocytes to produce and secrete IFN-γ has been purified from Trypanosoma brucei brucei (T.b. brucei). This was accomplished by raising monoclonal antibodies (MoAbs) against a fraction of T.b. brucei obtained by gel filtration, which contained high levels of material inducing rat mononuclear cells (MNC) to IEN-γ production. MoAbs from four hybridomas strongly inhibited trypanosome-induced IFN-γ production. One of them (MO1) was used for purification of the trypanosome-derived lymphocyte triggering factor (TLTF) by affinity chromatography. SDS electrophoresis of the purified TLTF displayed a band of 42-45 kDa MW. Gel filtration of homogenates of whole parasites yielded several peaks of IFN-γ-inducing activity with a lowest MW of 41 -46 kDa. Bioactivity of all peaks was blocked by MO1, suggesting that a single molecule, or a single epitope of additional molecules, is responsible for the different peaks with IFN-γ-inducing activity. IFN-γ released from MNC stimulates T.b. brucei growth. Blocking of TLTF in vitro with MOI inhibited MNC supported growth of the parasites. To study the in vivo relevance of TLTF in the course of experimental African trypanosomiasis, MOI was used to treat rats and mice at different times after infection. Treatments instituted at different time-points after infection suppressed parasite growth, abrogated the IFN-γ production by splenocytes induced by the infection and prolonged survival of the animals. The data support the hypothesis that TLTF and IFN-y have a crucial regulatory function in the parasite host interactions and that these molecules influence the disease course during experimental African trypanosomiasis. [ABSTRACT FROM AUTHOR]

We evaluated the B-cell response in cerebrospinal fluid (CSF) and blood by enumerating cells secreting antibodies to myelin-associated glycoprotein (MAG) and, for reference, to myelin basic protein (MBP), two myelin components which may constitute targets for autoimmune attack in multiple sclerosis (MS). Among 25 untreated MS patients, 12 had cells in CSF secreting anti- MAO IgG antibodies (mean value 1 per 1429 CSF cells) and three also had cells secreting anti- MAO antibodies of the IgM isotype but at lower levels. In CSF from 2 out of 10 MS patients examined, anti-MAO and anti-MBP IgO antibody-secreting cells were present concurrently. Antibody-secreting cells were less frequent in blood and bone marrow, reflecting compartmentalization to CSF. Anti-MAG antibody-secreting cells were found in CSF from only 1 out of 27 control patients. The intrathecal production of anti-MAG and anti-MBP antibodies may be important in the pathogenesis of MS. [ABSTRACT FROM AUTHOR]

The role of CD8+ T 'cytotoxic/suppressor' T cells in induced immunospecific tolerance and during recovery after actively induced disease was examined by means of elimination of CD8+ cells from Lewis rats using in vivo treatment by Ox8 monoclonal antibodies, in experimental allergic neuritis (EAN). Animals depleted of CD8+ T cells after recovery from EAN did not show any clinical signs of relapse. Other animals were pretreated with the peripheral nerve basic protein P2 and thereby rendered resistant to disease induction with a potentially neuritogenic emulsion. The elimination of CD8+ T cells did not result in EAN here either. Thus, the CD8+ T-cell population does not seem to participate in the suppression of this autoimmune disease under these experimental conditions. [ABSTRACT FROM AUTHOR]

Antibodies against peripheral nerve myelin have previously been demonstrated in serum from patients with peripheral neuropathy and IgM paraproteinaemia, and a causal relationship has been suggested. Using enzyme-linked immunosorbent assay (ELISA), anti-myelin antibodies were found in sera from eight of 16 patients with polyneuropathy and paraproteinaemia, but also in 17% of 109 patients with peripheral neuropathy lacking monoclonal immunoglobulin, including five of 10 patients with Charcot-Marie-Tooth disease, and in 16% of 142 blood donors. The antibodies were mostly of IgM class in the two neuropathy groups, while blood donors had mostly IgA antibodies, and a few subjects of each group had antimyelin antibodies of two different isotypes. Western blot confirmed the ELISA results in a majority of antibody positive sera and revealed a 25-30 kD myelin target antigen for sera from the three groups, and for some of the non-paraproteinaemic sera also a 100 kD myelin target antigen. Our results demonstrate that the presence of serum autoantibodies against peripheral nerve myelin does not necessarily indicate a pathological event. [ABSTRACT FROM AUTHOR]

The study was undertaken to analyze intracerebral expression of pro- and anti-inflammatory cytokines after traumatic brain injury (TBI) in man in order to compare the findings with previous experimental data regarding the pathogenesis of secondary brain injury. Contused brain tissue biopsies were obtained from 12 consecutive patients undergoing surgery for brain contusions 3 h to 5 days after trauma. Cytokine expression was analyzed by in situ hybridization and immunohistochemistry. In patients undergoing surgery less than 24 h after trauma, strong expression of both the pro-inflammatory cytokines interleukin (IL)-1-beta, IL-6 and interferon (IFN)-gamma and the anti-inflammatory cytokine IL-4 was detected. In patients undergoing surgery between 3 and 5 days after trauma, IL-4 expression was significantly lower (P < 0.05) compared to the patients operated early. IL-1-beta and IFN-gamma expression remained strong in comparison to IL-6 and IL-4 expression (P < 0.05). Immunohistochemistry for IL-1-beta confirmed that the protein was produced with a temporal and regional pattern that corresponded to in situ hybridization results. The study provides in situ data on intracerebral cytokine expression after contusion in the clinical setting. Strong intracerebral cytokine expression occurs in the perilesional zone both in the early and the delayed phase after traumatic brain injury in humans. The temporal regulation of pro- and anti-inflammatory cytokines differs which reveals different therapeutic windows for pharmacological intervention.

Evidence from epidemiological, clinical and experimental studies favour the hypothesis that inflammatory events are part of the neuropathology in Alzheimer's disease. Proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) have been found in activated microglia in the vicinity of amyloid plaques in Alzheimer's disease brain. In the present study, the levels of soluble IL-1 receptor type II (sIL-1R type II), IL-1 receptor antagonist (IL-1ra), IL-1beta, IL-6 and TNF-alpha were analyzed in cerebrospinal fluid (CSF) samples from Alzheimer's disease patients and control subjects. The levels of sIL-1R type II were significantly higher in CSF from Alzheimer's disease patients than in CSF samples from control subjects (38.5+/-8 pg/ml (mean+/-S.E.M.) vs. 7.9+/-4 pg/ml, p<0.05). Measurements of the proinflammatory cytokines IL-6 and TNF-alpha showed no significant difference between the two groups, and the levels of IL-1beta and IL-1ra in the present material were too low to permit detection. The increased levels of sIL-1R type II may reflect a compensatory mechanism to balance an increased release of IL-1 receptor agonists in the Alzheimer's disease brain., (Copyright 1999 Elsevier Science B.V.)