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Studies in experimental animal models of human autoimmune diseases have revealed that CD4+CD25+ T regulatory (Tr) cells are of thymic origin and have potentials in preventing auto-aggressive immunity. Myasthenia gravis (MG) is the best-characterized autoimmune disease. Changes in the thymus are found in a majority of patients with MG. Thymectomy has beneficial effects on the disease severity and course in a substantial proportion of MG patients. But the occurrence and characteristics of Tr cells have not yet been defined in MG. We determined the frequencies and properties of circulating CD4+CD25+ versus CD4+CD25– cells in MG patients and healthy controls (HCs), with special focus on the effect of thymectomy on CD4+CD25+ cells. CD4+CD25high cells comprise only about 2% of blood lymphocytes in both MG patients and HCs. Frequencies of CD4+CD25high cells were similar in MG patients irrespective of treatment with thymectomy. CD4+CD25+ cells in both MG patients and HCs are mainly memory T cells and are activated to a greater extent than CD4+CD25– cells, as reflected by high levels of CD45RO and human leucocyte antigen (HLA)-DR-positive cells. In both MG patients and HCs, CD4+CD25+ cells also contained a high proportion of CD95-expressing cells as possible evidence of apoptosis-proneness. Upon stimulation with anti-CD3/CD28 monoclonal antibodies, CD4+CD25+ cells responded more vigorously than CD4+CD25– cells in MG, irrespective of treatment with thymectomy, as well as in HCs. Although CD4+CD25– cells are mainly naïve T cells, in non-thymectomized MG patients, they are activated to a greater extent as reflected by higher expression of HLA-DR and CD95 on the surface compared to HCs. The data thus show that there is no deficiency of CD4+CD25+ cells in MG, nor is the proportion of CD4+CD25+ cells influenced by thymectomy. [ABSTRACT FROM AUTHOR]

CD8+ T cells can perform both Th 1 - and Th2-like functions by producing cytokines such as interferon- γ (IFN-γ) and interleukin-4 (IL-4), as well as the immune response down-regulating transforming growth factor-β (TGF-β), which are all involved in the development of experimental autoimmune myasthenia gravis (EAMG), a model for human MG. We have reported that depletion of CD8+ T cells results in the suppression of EAMG accompanied by the down-regulation of AChR-specific B cell responses and AChR-reactive IFN-γ secreting Th1-like cells. To identify the involvement of IFN-7, IL-4 and TGF-β in the development of EAMG after CD8+ T cell depletion, the expression of mRNA for these cytokines was studied in mononuclear cells from popliteal, inguinal and mesenteric lymph nodes, spleen and thymus by adopting in situ hybridization with complementary DNA oligonucleotide probes. Depletion of CD8+ T cells resulted in decreased levels of IFN-γ and IL-4 mRNA expressing cells in different lymphoid organs except thymus, but no change in the numbers of TGF-γ mRNA expressing cells. The results imply that the suppression of EAMG after depletion of CD8γ T cells is caused by decreasing the effector factors but not by increasing the suppressor factor(s). [ABSTRACT FROM AUTHOR]

The antibody response to Borrelia (B.) burgdorferi, and to measles virus as control antigen, was analysed by agarose isoelecirie focusing (AIF) and immunoblot of joint fluid and serum from 10 patients with Lyme arthritis and 10 controls with rheumatoid arthritis. Among the Lyme arthritis patients, six had oligoclonal anti-B, burgdorferi IgG antibody bands in joint fluid and corresponding serum, one patient had oligoclonal antibody bands in joint fluid only and also an elevated B. burndorleri-specific joint fluid to serum antibody ratio as evidence of intra-joint production of specific antibodies, and the remaining three patients were negative for oligoclonal specific antibody bands. Absorption with B. burgdorferi antigen confirmed the specificity of the oligoclonal antibody bands. They comigrated only partially on AIF with oligoclonal bands of tolal IgG, and the specificity of most oligoclonal IgG in joint fluid and serum in Lyme arthritis remains undefined. Among the controls, no anti-B. burgdorferi IgG antibodies were detected by AIF and immunoblot. Instead, 9 of the 10 rheumatoid arthritis patients had oligoclonal antimeasles IgG antibody hands which were restricted to the joint fluid in three of them, indicating local production. We conclude that Lyme arthritis is often accompanied by an oligoclonal specific antibody response in joint fluid and serum simultaneously, and occasionally by intrasynovial synthesis of oligoclonal-specific antibodies. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) lymphocytes from two patients with tuberculous meningitis proliferated stronger than the corresponding peripheral blood lymphocytes (PBL) when stimulated with tuberculin purified protein derivative (PPD) in the lymphocyte transformation test after 3 days of culture. This might indicate an accumulation of specifically primed lymphocytes within the central nervous system. CSF lymphocytes and PBL from nine of ten patients with acute aseptic meningitis investigated as controls showed no or low responses when stimulated with. PPD, whereas the remaining patient displayed a significant proliferation of CSF lymphocytes, which was more pronounced than that of PBL. Stimulation with the mitogens phytohaemagglutinin, concanavalin A, and pokeweed mitogen gave lower proliferation of CSF lymphocytes compared with PBL in tuberculous and aseptic meningitis. Evaluation of the proliferative response of CSF lymphocytes compared with PBL on stimulation with PPD might be a useful complement in the diagnosis of tuberculous meningitis. [ABSTRACT FROM AUTHOR]

By means of a microculture technique and calculation of incorporation of 14-thymidine, cerebrospinal fluid (CSF) lymphocytes from multiple sclerosis (MS) patients showed low or absent proliferation when stimulated with phytohaemagglutinin, concanavalin A, or pokeweed mitogen, in contrast to peripheral blood lymphocytes (PBL) obtained simultaneously and investigated in parallel. A lower proliferation of CSF lymphocytes compared with PBL was also found in acute aseptic meningitis, although it has been reported that CSF lymphocytes show greater proliferation than PBL when specifically stimulated. The low proliferation of MS CSF lymphocytes on mitogen stimulation may be a consequence of prolonged sensitization to an as yet unidentified antigen. The proliferation of MS CSF lymphocytes was not improved by adding irradiated PBL, making helper cell insufficiency less likely. MS CSF had no inhibitory effect on proliferation of PBL, arguing against an inhibitory effect of soluble factors in the CSF as an explanation for the depressed response of CSF lymphocytes. [ABSTRACT FROM AUTHOR]

The cytokine interleukin (IL)-10 has immune response down-regulatory properties, which include suppression of the synthesis of pro-inflammatory cytokines such as interferon (IFN)-gamma and of major histocompatibility complex (MHC) class II expression on monocytes. To further elucidate the involvement of IL-10 in multiple sclerosis (MS), an enzyme-linked immunospot assay was adopted to enumerate IL-10-secreting mononuclear cells (MNC) in peripheral blood. IFN-gamma secreting MNC were detected in parallel. Levels of IL-10-secreting cells were lower in patients with MS compared with other neurological diseases (OND) and healthy subjects. This difference was seen only in patients with untreated MS, and not in those undergoing treatment with IFN-beta-1b. No differences were observed when subgrouping the patients with MS regarding clinical phase (exacerbation, remission, secondary progression), duration of MS or disability status. Levels of IFN-gamma-secreting blood MNC did not differ in patients with MS, irrespective of treatment with IFN-beta-1b, compared with OND and healthy subjects. Patients with MS, but not the two groups of controls, had elevated numbers of IL-10- and IFN-gamma-secreting cells upon stimulation with MBP compared with culture in the absence of antigen. The data suggest that IL-10 is decreased in MS and that treatment resulting in its up-regulation beneficially influence the disease.

Mononuclear cell (MNC) infiltration of the salivary and lacrimal glands is a major feature in Sjogren's syndrome (SS) and its animal model, murine autoimmune sialoadenitis (MAS). To investigate factors that influence selective infiltration by MNC of submandibular glands in young and adult MRL/lpr mice with MAS, expression of mRNA encoding the beta-chemokines monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and regulated upon activation, normal T-cell expressed and secreted (RANTES) was investigated by in situ hybridization. MCP-1 protein production was also evaluated by immunohistochemistry. Young mice with MAS showed an early up-regulation of mRNA expression for MCP-1, MIP-1beta and RANTES, while MIP-1alpha mRNA expression was not affected. Adult mice with MAS showed a further up-regulation of mRNA expression for MCP-1, MIP-1beta and RANTES, and a remarkably strong up-regulation for MIP-1alpha. Immunohistochemistry revealed that MCP-1 protein production paralleled MCP-1 mRNA expression in both young and adult mice. These observations implicate MCP-1, MIP-1beta and RANTES as potential chemokines in induction of MAS, and MCP-1, MIP-1beta, RANTES and prominently MIP-1alpha in progression and perturbation of MAS.

Astrocytes constitute a part of the blood-brain barrier. Chemokine expression by astrocytes may contribute to leucocyte infiltration within the central nervous system (CNS) during inflammation. To investigate factor(s) regulating chemokine expression by astrocytes, we studied the induction of beta-chemokine mRNA expression in adult rat astrocytes. Astrocyte-derived monocyte chemoattractant protein- (MCP-1), RANTES, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta mRNA were induced by interferon-gamma (IFN-gamma). Tumour necrosis factor-alpha (TNF-alpha) induced MCP-1, RANTES and MIP-1beta mRNA expression, and lipopolysaccharide (LPS) induced MCP-1, MIP-1alpha and MIP-1beta mRNA expression in astrocytes. LPS-induced MCP-1, MIP-1alpha and MIP-1beta mRNA expression by astrocytes was antagonized by transforming growth factor (TGF)-beta1 and interleukin (IL)-10. TGF-beta1 and IL-10 also down-regulated MCP-1 and RANTES mRNA expression induced by TNF-alpha. IL-10, but not TGF-beta1, inhibited MIP-1beta mRNA expression induced by TNF-alpha. The results of this in vitro study suggest that beta-chemokine mRNA expression by adult rat astrocytes can be induced by LPS or proinflammatory cytokines, while regulatory cytokines, such as TGF-beta1 and IL-10, down-regulate astrocyte-derived beta-family chemokine mRNA expression induced by LPS, IFN-gamma and TNF-alpha. Further study of CNS chemokines will enhance our understanding of leucocyte recruitment to the CNS and suggest therapeutic strategies for neurological disorders.

The T-cell response to the aetiologic pathogen Borrelia (B.) burgdorferi in patients with Lyme neuroborreliosis (LN) and in control patients with other neurological diseases was examined by enumerating B. burgdorferi-reactive T cells secreting interferon-gamma (IFN-gamma) with an ELIspot assay. LN patients had elevated numbers of B. burgdorferi-reactive IFN-gamma secreting cells in blood and approximately 20-fold enriched in the cerebrospinal fluid (CSF). A positive correlation existed in CSF between B. burgdorferi-reactive IFN-gamma secreting cells and B cells secreting anti-B. burgdorferi IgG antibodies. The up-regulation of antigen-specific IFN-gamma secreting cells persisted in peripheral blood up to at least 9 months and in the CSF for at least 4 months after termination of treatment with antibiotics, when the patients were mostly free from clinical signs and symptoms due to LN. How IFN-gamma interplays with other cytokines and influences the pathogenesis of LN remains to be studied.