UMLS:C0004364 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0004364 (autoimmune disease)
24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis (MS), is a typical CD4(+) T-cell-mediated autoimmune disease of the central nervous system (CNS) characterized by perivascular inflammation culminating in focal demyelinations. Like MS, EAE induced by proteolipid protein (PLP) usually follows the form of a relapsing-remitting disease. We have previously described an immunotherapy model in which infusion of autologous B cells expressing the PLP encephalitogenic determinant induced PLP-specific unresponsiveness and protected mice from induction of EAE. Here we show that the same treatment when initiated after disease onset, which resembles the clinical situation presented in MS, completely protects all treated animals from further relapses. We also show that protected animals were unresponsive to PLP as measured by delayed-type hypersensitivity (DTH). This represents a novel immunotherapeutic approach that can be exploited to develop treatments for human MS and other T-cell-mediated autoimmune diseases.
...
PMID:Complete protection from relapsing experimental autoimmune encephalomyelitis induced by syngeneic B cells expressing the autoantigen. 1498 58

Molecular mimicry is the main postulated mechanism by which infectious agents induce autoimmune disease. A number of animal models have been utilized to establish a link between molecular mimicry and autoimmunity. However, a model of infectious disease whereby a natural pathogen expressing a known mimic epitope can induce autoimmunity to a known self-antigen leading to clinical autoimmune disease is still lacking. We have engineered a recombinant Theiler's murine encephalomyelitis virus (TMEV) to express an encephalitogenic myelin proteolipid protein PLP139-151 epitope (PLP-TMEV) and a PLP139-151 mimic peptide naturally expressed by Haemophilus influenzae (HI-TMEV). Infection of mice with either PLP-TMEV or HI-TMEV induces early-onset disease that is associated with the activation of cross-reactive PLP139-151-specific immunopathologic CD4+ Th1 cells. Based on results from this model, we hypothesize, due to the considerable degeneracy in the T cell repertoire, that induction of full-blown autoimmune disease via molecular mimicry is a tightly regulated process requiring multiple factors related to the pathogen expressing the potential mimic epitope. In this review, we will discuss how various factors related to the infectious environment control whether or not autoimmune disease is initiated. Contributing factors include the nature of the innate immune response to the pathogen which determines the immunopathologic potential of the induced cross-reactive T cells, the capacity of the mimic epitope to be processed and presented from its natural flanking sequences in the pathogen-encoded protein, the site(s) of the primary infection in the host and the ability of the pathogen to persist, and the potential requirement for multiple infections with the same or different pathogens.
...
PMID:Innate and adaptive immune requirements for induction of autoimmune demyelinating disease by molecular mimicry. 1503 15

The mouse protein Qa-1 (HLA-E in humans) is essential for immunological protection and immune regulation. Although Qa-1 has been linked to CD8 T cell-dependent suppression, the physiological relevance of this observation is unclear. We generated mice deficient in Qa-1 to develop an understanding of this process. Qa-1-deficient mice develop exaggerated secondary CD4 responses to foreign and self peptides. Enhanced responses to proteolipid protein self peptide were associated with resistance of Qa-1-deficient CD4 T cells to Qa-1-restricted CD8 T suppressor activity and increased susceptibility to experimental autoimmune encephalomyelitis. These findings delineate a Qa-1-dependent T cell-T cell inhibitory interaction that prevents the pathogenic expansion of autoreactive CD4 T cell populations and consequent autoimmune disease.
...
PMID:Analysis of regulatory CD8 T cells in Qa-1-deficient mice. 1511 10

We have previously shown that naive SJL (H-2(s)) mice, which are highly susceptible to myelin proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE), have a very high frequency (1/20,000 CD4 T cells) of PLP(139-151)-reactive T cells in the naive repertoire. In this study, we examine the function of this endogenous PLP(139-151)-reactive repertoire in vivo and find that this repertoire encompasses the precursors of pathogenic T cells. Because SJL mice do not develop spontaneous EAE, we have explored the mechanisms that keep this autopathogenic repertoire in check and prevent the development of spontaneous autoimmunity. We crossed IL-4 and IL-10 deficiency onto the SJL background and analyzed the roles of these two immunoregulatory cytokines in regulating the size and effector function of the endogenous PLP(139-151)-reactive repertoire and development of autoimmune disease. We find that IL-10 is important in the homeostatic regulation of the endogenous PLP(139-151)-reactive repertoire in that it both limits the size of the repertoire and prevents development of effector autoaggressive T cells. SJL IL-10(-/-) mice with high numbers of PLP(139-151)-specific precursors in the repertoire did not develop spontaneous EAE, but when they were injected with pertussis toxin, they showed atypical clinical signs of EAE with small numbers of typical mononuclear cell infiltrates predominantly in the meninges. EAE could be inhibited by prior tolerization of the mice with soluble PLP(139-151) peptide. These findings indicate that IL-10 may contribute to the regulation of the endogenous autoimmune repertoire.
...
PMID:IL-10 plays an important role in the homeostatic regulation of the autoreactive repertoire in naive mice. 1524 Jun 69

Murine experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell-mediated autoimmune disorder directed against myelin proteins within the CNS. We propose that variant peptides containing amino acid substitutions at MHC anchor residues will provide a unique means to controlling the polyclonal autoimmune T cell response. In this study, we have identified an MHC variant of proteolipid protein (PLP) 139-151 (145D) that renders PLP(139-151)-specific T cell lines anergic in vitro, as defined by a significant reduction in proliferation and IL-2 production following challenge with wild-type peptide. In vivo administration of 145D before challenge with PLP(139-151) results in a significant reduction in disease severity and incidence. Importantly, we demonstrate the ability of an MHC variant peptide to ameliorate established EAE. An advantage to this treatment is that the MHC variant peptide does not induce an acute hypersensitivity reaction. This is in contrast to previous work in the PLP(139-151) model demonstrating that anaphylactic shock resulting in death occurs upon rechallenge with the encephalitogenic peptide. Taken together, these data demonstrate the effectiveness of MHC anchor-substituted peptides in the treatment of EAE and suggest their utility in the treatment of other autoimmune disorders.
...
PMID:Amelioration of established experimental autoimmune encephalomyelitis by an MHC anchor-substituted variant of proteolipid protein 139-151. 1574 67

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). It is thought that autoimmunity plays a major role in the development of the disease. Despite understanding MS as the cell-mediated autoimmune disease, recent studies suggest a role of humoral response in MS pathogenesis. The contribution of antibodies with anti-MOG specificity in the pathology of EAE (experimental allergic encephalomyelitis), an animal model of MS, in rodents and recently in primates has been demonstrated. B lymphocytes, plasma cells, and autoantibodies reacting with myelin proteins are present in the chronic and active plaques of MS patients. These antibodies, which recognize myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), myelin-oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein (OSP), 2',3' cyclic nucleotide 3'-phosphodiesterase (CNP), and transaldolase (TAL), have been identified mostly in cerebrospinal fluid and in serum. So far, the antibodies directed against MBP, MOG, and OSP have been characterized in detail. However, the role of autoantibodies in MS pathogenesis is still controversial. A direct role in the demyelination process, by the activation of complement and cytotoxic cells, has been shown only for the anti-MOG antibodies. Identification of the antigens and epitopes targeting the autoimmune response in MS is of great importance, not only for understanding of MS pathology, but also for potential therapeutic use. Recently, antigen therapy trials have been conducted in MS patients. It seems, however, that only the recognition of the individual immunological response in each MS patient, including autoantigens and the subspecificity of autoreactive T and B lymphocytes, can allow for an effective fight against this destructive disease.
...
PMID:[Epitopes on myelin proteins recognized by autoantibodies present in multiple sclerosis patients]. 1576 8

Multiple sclerosis (MS) is thought to be an autoimmune disease in which an unknown trigger initiates an immune response against brain proteins. This autoaggressive response causes the breakdown of the myelin sheaths that protect nerve axons, leading to impaired nerve conduction and subsequent neurodegeneration that are characteristic of MS. Many studies have attempted to determine the exact target within the brain. However, there appear to be multiple targets, which may change over time. No single study has examined all targets nor looked at how they can change over the course of the disease and whether these changes are related to the course of disease. We have approached this by using the single-cell resolution capability of the enzyme-linked immunospot assay to examine cytokine reactivity in MS patients in response to a very large set of overlapping peptides that span the two major proteins of myelin: myelin basic protein and proteolipid protein. Our goal was to use the enzyme-linked immunospot assay to perform comprehensive epitope mapping in relapsing-remitting MS patients in a longitudinal study to help define the role of myelin responses in disease progression.
...
PMID:Epitope mapping in multiple sclerosis using the ELISPOT assay. 1593 55

Epidemiological studies indicate that infectious agents are important in the pathogenesis of multiple sclerosis (MS). Our previous reports showed that the infection of SJL mice with a nonpathogenic variant of Theiler's murine encephalomyelitis virus (TMEV) engineered to express a naturally occurring Haemophilus influenzae-encoded molecular mimic (HI574-586) of an immunodominant self-myelin proteolipid protein epitope (PLP139-151) induced a rapid-onset demyelinating disease associated with the activation of PLP139-151-specific Th1 responses. The current results extend our previous findings in four critical respects. We show that disease initiation by the H. influenzae mimic is prevented by tolerance to the self PLP139-151 epitope, definitively proving the occurrence of infection-induced molecular mimicry. We demonstrate that the H. influenzae mimic epitope can be processed from the flanking sequences within the native mimic protein. We show that the H. influenzae mimic epitope only induces an immunopathologic self-reactive Th1 response and subsequent clinical disease in the context of the TMEV infection and not when administered in complete Freund's adjuvant, indicating that molecular mimicry-induced disease initiation requires virus-activated innate immune signals. Lastly, we show that the infection of SJL mice with TMEV expressing the H. influenzae mimic can exacerbate a previously established nonprogressive autoimmune disease of the central nervous system. Collectively, these findings illustrate the evolving mechanisms by which virus infections may contribute to both the initiation and exacerbation of autoimmune diseases, and they have important implications for MS pathogenesis.
...
PMID:Initiation and exacerbation of autoimmune demyelination of the central nervous system via virus-induced molecular mimicry: implications for the pathogenesis of multiple sclerosis. 1595 99

Multiple Sclerosis (MS) is a chronic inflammatory degenerative disease of the central nervous system (CNS), first described over 100 years ago. MS is a clinically heterogeneous disease with an increasing incidence over time, and a population prevalence that increases with distance from the equator. It is postulated that environmental factors such as diet and population-specific genetics, influence the distribution of MS. Diagnosis is based on established clinical criteria, aided by magnetic resonance imaging, evoked potential recordings and cerebrospinal fluid examination. Whichever the type of clinical manifestation, MS is considered an organ-specific autoimmune disease, characterized by T-cell and macrophage infiltrates, triggered by CNS-specific CD4 T-cells. The prominent autoimmune etiology of MS is considered to be the aberrant activation of IFN-gamma-producing Th1 cells that recognize self-peptides of the myelin sheath, such as myelin basic protein (MBP) and proteolipid protein (PLP). Current treatments for MS aim primarily to suppress T-cell-mediated immune responses, albeit non-specifically. Experimental approaches towards the therapeutic management of MS involve the use of peptide analogs of disease-associated myelin epitopes or vaccines, to help shift T helper cell responses from Type-1 (secreting pro-inflammatory cytokines) to Type-2 (secreting anti-inflammatory cytokines) or induce peripheral T-cell tolerance. Animal models of MS have been useful to dissect disease mechanisms and evaluate new therapies. Experimental clinical trials, although few, are valuable to assess new treatment regimens and clarify possible conceptual mistakes about the disease. This review attempts to link the current knowledge of MS pathogenesis with clinical and experimental protocols of immunotherapy for MS.
...
PMID:Immunotherapy for multiple sclerosis: basic insights for new clinical strategies. 1618 Oct 82

FTY720, a sphingosine 1-phosphate receptor modulator, induces a marked decrease in the number of peripheral blood lymphocytes and exerts immunomodulating activity in various experimental allograft and autoimmune disease models. In this study, we evaluated the effect of FTY720 and its active metabolite, (S)-enantiomer of FTY720-phosphate [(S)-FTY720-P] on experimental autoimmune encephalomyelitis (EAE) in rats and mice. Prophylactic administration of FTY720 at 0.1 to 1 mg/kg almost completely prevented the development of EAE, and therapeutic treatment with FTY720 significantly inhibited the progression of EAE and EAE-associated histological change in the spinal cords of LEW rats induced by immunization with myelin basic protein. Consistent with rat EAE, the development of proteolipid protein-induced EAE in SJL/J mice was almost completely prevented and infiltration of CD4(+) T cells into spinal cord was decreased by prophylactic treatment with FTY720 and (S)-FTY720-P. When FTY720 or (S)-FTY720-P was given after establishment of EAE in SJL/J mice, the relapse of EAE was markedly inhibited as compared with interferon-beta, and the area of demyelination and the infiltration of CD4(+) T cells were decreased in spinal cords of EAE mice. Similar therapeutic effect by FTY720 was obtained in myelin oligodendrocyte glycoprotein-induced EAE in C57BL/6 mice. These results indicate that FTY720 exhibits not only a prophylactic but also a therapeutic effect on EAE in rats and mice, and that the effect of FTY720 on EAE appears to be due to a reduction of the infiltration of myelin antigen-specific CD4(+) T cells into the inflammation site.
...
PMID:FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. 1642 94

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>