Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations of CD95 and CD95L, lpr and gld, respectively, are associated with spontaneous autoimmune disease and alteration of immune privilege. In lpr or gld animals these processes would be expected to exacerbate experimental allergic encephalomyelitis (EAE), an animal model of the autoimmune demyelinating disease multiple sclerosis. However, here we show that the lpr and gld mutations did not overcome the MHC-defined limits of disease and, surprisingly, did not exacerbate the pathology of EAE on a sensitive haplotype. In fact, the mutations dramatically ameliorated clinical signs of EAE without affecting the development of a Th1 response or inflammatory cell infiltration into the central nervous system. Fewer apoptotic cells were detected in inflammatory lesions of lpr mice than in wild-type lesions of similar severity. Our results indicate that CD95L is not an instrumental component of immune privilege in the central nervous system, and that functional CD95 and CD95L are important for the progression of clinical disease.
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PMID:Fas and Fas ligand enhance the pathogenesis of experimental allergic encephalomyelitis, but are not essential for immune privilege in the central nervous system. 931 3

The role and fate of B cells in the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE) are unknown. Using enzyme-linked immunospot assays we now show that B cells reactive to myelin basic protein (MBP) accumulate in the CNS of Lewis rats with acute EAE induced by immunization with MBP and adjuvants. We also report that B cells are eliminated from the CNS by apoptosis during spontaneous recovery from this disease. Apoptotic B cells were identified by flow cytometry of inflammatory cells extracted from the spinal cord and by histological sections of the spinal cord using light and electron microscopic immunocytochemistry. B cell apoptosis occurred preferentially in the CNS rather than in the peripheral lymphoid organs and was maximal just prior to the onset of spontaneous clinical recovery. Three colour flow cytometry indicated that B cells expressing CD95 (Fas) or CD95 ligand (CD95L) were highly vulnerable to apoptosis, whereas B cells expressing Bcl-2 were relatively protected from apoptosis. We propose that B cells are eliminated from the CNS by the interaction of CD95L and CD95 on the same B cell and that this contributes to the spontaneous resolution of CNS inflammation and clinical recovery in acute EAE.
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PMID:B cell apoptosis in the central nervous system in experimental autoimmune encephalomyelitis: roles of B cell CD95, CD95L and Bcl-2 expression. 1075 81

The elimination of inflammatory cells within the central nervous system (CNS) by apoptosis plays an important role in protecting the CNS from immune-mediated damage. T cells, B cells, macrophages, and microglia all undergo apoptosis in the CNS. The apoptotic elimination of CNS-reactive T cells is particularly important, as these cells can recruit and activate other inflammatory cells. T-cell apoptosis contributes to the resolution of CNS inflammation and clinical recovery from attacks of experimental autoimmune encephalomyelitis (EAE), an animal model of the demyelinating disease multiple sclerosis (MS). T-cell apoptosis in the CNS in EAE occurs in both an antigen-specific and an antigen-nonspecific manner. In antigen-specific T-cell apoptosis, it is proposed that T cells that recognize their antigen in the CNS, such as CNS-reactive T cells, are deleted by the process of activation-induced apoptosis after activation of the T-cell receptor. This may result from the ligation of T-cell death receptors (such as CD95 (Fas) or tumor necrosis factor (TNF) receptor 1) by CD95 ligand (CD95L) or TNF expressed by the same T cell or possibly by microglia, astrocytes or neurons. Inadequate costimulation of the T cell by antigen-presenting glial cells may render T cells susceptible to activation-induced apoptosis. T cells expressing CD95 may also die in an antigen-nonspecific manner after interacting with glial cells expressing CD95L. Other mechanisms for antigen-nonspecific T-cell apoptosis include the endogenous release of glucocorticosteroids, deprivation of interleukin-2, and the release of nitric oxide by macrophages or glia. Apoptosis of autoreactive T cells in the CNS is likely to be important in preventing the development of autoimmune CNS diseases such as MS.
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PMID:Apoptosis of inflammatory cells in immune control of the nervous system: role of glia. 1159 22

In this study, we assessed the expression of activation markers on gammadelta T cells in central nervous system (CNS) lesions of SJL mice adoptively sensitized to develop experimental autoimmune encephalomyelitis (EAE) using myelin basic protein-reactive T cells. Although disease expression is known to be dependent upon T cells that express the alphabeta T cell receptor (TCR), a role for gammadelta T cells has been implicated in some studies but not in others. Using three-color flow cytometric analysis of both total and gammadelta T cells in spleen and CNS, the data showed that expression of CD69 (early activation marker), CD62L (lymphocyte homing receptor), CD25 (IL-2Ralpha), CD122 (IL-2Rbeta) and CD95/CD95L (Fas/FasL), fluctuated on gammadelta T cells in EAE lesions in a disease-related fashion. Furthermore, the pattern of expression for these markers on gammadelta T cells was distinct from that found on the total lymphocyte population. Cytokine analysis of gammadelta T cells in the CNS demonstrated a bias towards a Th1-like cytokine profile. From these data, we conclude that gammadelta T cells in EAE lesions display an activated phenotype and form a dynamic component of the total lymphocyte population in the CNS, supporting a contributory role for these cells.
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PMID:gammadelta T cells express activation markers in the central nervous system of mice with chronic-relapsing experimental autoimmune encephalomyelitis. 1177 50

Upon peripheral immunization with myelin epitopes, susceptible rats and mice develop T cell-mediated demyelination similar to that observed in the human autoimmune disease multiple sclerosis (MS). In the same animals, brain injury does not induce autoimmune encephalomyelitis despite massive release of myelin antigens and early expansion of myelin specific T cells in local lymph nodes, indicating that the self-specific T cell clones are kept under control. Using entorhinal cortex lesion (ECL) to induce axonal degeneration in the hippocampus, we identified possible mechanisms of immune tolerance after brain trauma. Following ECL, astrocytes upregulate the death ligand CD95L, allowing apoptotic elimination of infiltrating activated T cells. Myelin-phagocytosing microglia express MHC-II and the costimulatory molecule CD86, but lack CD80, which is found only on activated antigen presenting cells (APCs). Restimulation of invading T cells by such immature APCs (e.g. CD80 negative microglia) may lead to T cell anergy and/or differentiation of regulatory/Th3-like cells due to insufficient costimulation and presence of high levels of TGF-beta and IL-10 in the CNS. Thus, T cell -apoptosis, -anergy, and -suppression apparently maintain immune tolerance after initial expansion of myelin-specific T lymphocytes following brain injury. This view is supported by a previous metastatistical analysis which rejected the hypothesis that brain trauma is causative of MS (Goddin et al., 1999). However, concomitant trauma-independent proinflammatory signals, e.g., those evoked by clinically quiescent infections, may trigger maturation of APCs, thus shifting a delicate balance from immune tolerance and protective immune responses to destructive autoimmunity.
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PMID:Self-tolerance in the immune privileged CNS: lessons from the entorhinal cortex lesion model. 1294 47

Death ligands induce apoptosis, which is a cell suicide program leading mainly to selective elimination of an organism's useless cells. Importantly, the dying cell is an active participant in its own demise ("cellular suicide"). Under physiological conditions, apoptosis is most often found during normal cell turnover and tissue homeostasis, embryogenesis, induction and maintenance of immune tolerance, development of the nervous system, and endocrine-dependent tissue atrophy. However, apoptotic processes have also been suggested to contribute to the pathology of the autoimmune demyelinating disease multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis. Here, apoptosis plays a double role. On one hand, impaired apoptosis may result in increased numbers or persistence of activated myelinspecific T cells. On the other hand, local tissue damage involves apoptosis of oligodendrocytes and neurons, leading to the clinical symptoms. In this article, an overview is given of the current knowledge of the roles of apoptosis-mediating and immune regulatory death ligands of the tumor necrosis factor (TNF) family (TNF, lymphotoxin-beta, OX40L [CD134L], CD154 [CD40L], CD95L, CD70 [CD27L], CD153 [CD30L], 4-1BBL [CD137L], TRAIL, TWEAK, BAFF, GITRL) in the pathogenesis of MS and of their implications for related therapeutic strategies.
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PMID:Death ligands and autoimmune demyelination. 1684 Jul 7

Despite transient, myelin-directed adaptive immune responses in regions of fiber tract degeneration, none of the current models of fiber tract injuries evokes disseminated demyelination, implying effective mechanisms maintaining or re-establishing immune tolerance. In fact, we have recently detected CD95L upregulation accompanied by apoptosis of leukocytes in zones of axonal degeneration induced by entorhinal cortex lesion (ECL), a model of layer-specific axonal degeneration. Moreover, infiltrating monocytes readily transformed into ramified microglia exhibiting a phenotype of immature (CD86+/CD80-) antigen-presenting cells. We now report the appearance of the axonal antigen neurofilament-light along with increased T cell apoptosis and enhanced expression of the pro-apoptotic gene Bad in cervical lymph nodes after ECL. In order to test the functional significance of such local and systemic depletory/regulatory mechanisms on subsequent immunity to central nervous system antigens, experimental autoimmune encephalomyelitis was induced by proteolipid protein immunization 30 days after ECL. In three independent experiments, we found significantly diminished disease scores and infiltrates in lesioned compared to sham-operated SJL mice. This is consistent with a previous meta-statistical analysis (Goodin et al. in Neurology 52:1737-1745, 1999) rejecting the O-hypothesis that brain trauma causes or exacerbates multiple sclerosis. Conversely, brain injuries may involve long-term tolerogenic effects towards brain antigens.
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PMID:Tolerogenic effect of fiber tract injury: reduced EAE severity following entorhinal cortex lesion. 1709 Dec 91

The central nervous system (CNS) innate immune response includes an arsenal of molecules and receptors expressed by professional phagocytes, glial cells and neurons that is involved in host defence and clearance of toxic and dangerous cell debris. However, any uncontrolled innate immune responses within the CNS are widely recognized as playing a major role in the development of autoimmune disorders and neurodegeneration, with multiple sclerosis (MS) Alzheimer's disease (AD) being primary examples. Hence, it is important to identify the key regulatory mechanisms involved in the control of CNS innate immunity and which could be harnessed to explore novel therapeutic avenues. Neuroimmune regulatory proteins (NIReg) such as CD95L, CD200, CD47, sialic acid, complement regulatory proteins (CD55, CD46, fH, C3a), HMGB1, may control the adverse immune responses in health and diseases. In the absence of these regulators, when neurons die by apoptosis, become infected or damaged, microglia and infiltrating immune cells are free to cause injury as well as an adverse inflammatory response in acute and chronic settings. We will herein provide new emphasis on the role of the pair CD200-CD200R in MS and its experimental models: experimental autoimmune encephalomyelitis (EAE) and Theiler's virus induced demyelinating disease (TMEV-IDD). The interest of the cannabinoid system as inhibitor of inflammation prompt us to introduce our findings about the role of endocannabinoids (eCBs) in promoting CD200-CD200 receptor (CD200R) interaction and the benefits caused in TMEV-IDD. Finally, we also review the current data on CD200-CD200R interaction in AD, as well as, in the aging brain.
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PMID:Brain innate immunity in the regulation of neuroinflammation: therapeutic strategies by modulating CD200-CD200R interaction involve the cannabinoid system. 2458 29

Activated B-cells increase T-cell behaviour during autoimmune disease and other infections by means of cytokine production and antigen-presentation. Functional studies in experimental autoimmune encephalomyelitis (EAE) indicate that B-cell deficiencies, and a lack of IL10 and IL35 leads to a poor prognosis. We hypothesised that B-cells play a role during tuberculosis. We evaluated B-cell mRNA expression using real-time PCR from healthy community controls, individuals with other lung diseases and newly diagnosed untreated pulmonary TB patients at three different time points (diagnosis, month 2 and 6 of treatment).We show that FASLG, IL5RA, CD38 and IL4 expression was lower in B-cells from TB cases compared to healthy controls. The changes in expression levels of CD38 may be due to a reduced activation of B-cells from TB cases at diagnosis. By month 2 of treatment, there was a significant increase in the expression of APRIL and IL5RA in TB cases. Furthermore, after 6 months of treatment, APRIL, FASLG, IL5RA and CD19 were upregulated in B-cells from TB cases. The increase in the expression of APRIL and CD19 suggests that there may be restored activation of B-cells following anti-TB treatment. The upregulation of FASLG and IL5RA indicates that B-cells expressing regulatory genes may play an important role in the protective immunity against M.tb infection. Our results show that increased activation of B-cells is present following successful TB treatment, and that the expression of FASLG and IL5RA could potentially be utilised as a signature to monitor treatment response.
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PMID:Successful TB treatment induces B-cells expressing FASL and IL5RA mRNA. 2768 72