Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The T cell response against myelin basic protein (MBP) has been extensively studied in humans because of its putative role in the pathophysiology of multiple sclerosis (MS). Higher concordance rates in monozygous twins as well as an increased risk in relatives suggest the role of genetic factors in MS susceptibility. Very little is known about the shaping of T cell repertoire towards self antigens in humans and their contribution to disease susceptibility in autoimmune disorders. Here we report the comparative T cell epitope recognition patterns towards the MBP auto-antigen in healthy identical twins. We have established MBP-specific T cell lines from eight sets of twins and characterized their fine epitope specificity. Intra-pair comparison showed the co-existence of shared as well as distinct epitopes in six of eight pairs and a complete absence of concordant epitope recognition within two other pairs. These findings indicate that important differences in T cell repertoires against a self antigen may be observed between genetically identical healthy individuals, rendering difficult the interpretation of the differences which may be observed between identical twins discordant for an autoimmune disease.
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PMID:Healthy monozygous twins do not recognize identical T cell epitopes on the myelin basic protein autoantigen. 752 33

To explore the mechanisms responsible for the development of tolerance to allografts after intrathymic (IT) injection of alloantigen, the well-defined model of experimental autoimmune encephalomyelitis (EAE), which mimics the human autoimmune disease multiple sclerosis, was used. This inflammatory neurologic syndrome is initiated by myelin basic protein (MBP)-reactive CD4+ T lymphocytes restricted to self-MHC class II molecules. Naive adult, EAE-susceptible Lewis (RT1(1) rats were treated IT, i.v., or i.p. with a single dose (100 micrograms) of guinea pig-myelin basic protein (GP-MBP 1-176) in PBS plus 1 ml rabbit anti-rat lymphocyte serum i.p. Twenty-one days later, all rats were challenged by intradermal hind footpad injections of 50 micrograms GP-MBP in PBS emulsified in CFA. Only IT, but not i.p. or i.v., administration of GP-MBP plus anti-lymphocyte serum conferred marked resistance to a subsequent systemic challenge of GP-MBP, as demonstrated by the prevention of weight loss and paralysis characteristic of EAE. The IT administration dramatically decreased the size and number of histologic perivascular infiltrates observed per visual field in spinal cord of the tolerant animals and decreased GP-MBP-specific T lymphocyte in vitro proliferation (p < 0.01), whereas proliferation to a nonspecific mitogen (Con A) was not altered. With the addition of rIL-2, the decreased Ag-specific proliferative responses of IT-treated animals increased to control levels. Adoptive transfer of 100 x 10(6) splenocytes from tolerant hosts i.v. to naive syngeneic Lewis rats challenge with 100 micrograms GP-MBP in CFA had no effect on clinical or histologic EAE. Exposure of MBP to maturing thymocytes results in functionally immunounresponsive lymphocytes and prevention of autoimmune EAE.
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PMID:Immunological tolerance to a defined myelin basic protein antigen administered intrathymically. 752 8

Immunization with the multideterminant autoantigen myelin basic protein (MBP) causes experimental allergic encephalomyelitis (EAE), a T-cell-mediated autoimmune disease that serves as a model for multiple sclerosis (MS). MBP peptides Ac1-11 and p35-47 induce potent EAE in mice of the H-2u haplotype. T cells specific for Ac1-11 predominantly utilize one T-cell receptor (TCR) V beta gene segment, V beta 8.2. All T-cell clones and hybridomas analyzed, regardless of TCR V beta usage, utilize D beta 2 and J beta 2 elements. The NZW mouse strain (H-2z), which contributes to the spontaneous 'lupus-like' illness in (NZB x NZW)F1 mice, has a genomic deletion encompassing D beta 2 and J beta 2 gene segments. The NZW strain expresses class II (I-A and I-E) genes which share identical sequences with H-2u class II. We investigated whether these strains are susceptible to EAE induced with intact MBP and known encephalitogenic MBP peptides. In vitro analysis demonstrated that NZW antigen-presenting cells (APC) can present MBP and MBP peptide Ac1-11 to an encephalitogenic T-cell clone derived from an H-2u mouse, confirming the functional identity of NZW class-II (I-A) molecules with their respective H-2u class-II gene products. In vivo results demonstrated that NZW and (NZB x NZW)F1 mice are susceptible to EAE induced with intact MBP and Ac1-11. MBP p35-47 caused EAE in (NZB x NZW)F1 mice, which express alleles for both the normal (NZB) TCR beta-gene locus, and the abnormal (NZW) TCR beta-gene locus containing the J beta 2 deletion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:'Lupus-prone' mice are susceptible to organ-specific autoimmune disease, experimental allergic encephalomyelitis. 752 28

Experimental autoimmune encephalomyelitis (EAE) is an animal autoimmune disease mediated by CD4+ T cells. Analysis of TCR expression revealed that limited TCR elements (V beta 8.2, V alpha 2 or 4) were utilized by myelin basic protein (MBP) specific T cells in mice with H-2u haplotype and Lewis rats. The usage of a particular beta chain complementarity determining region 3 (CDR3) motif has also been shown. However, it remains unclear to what extent these observations can be extrapolated. Here we studied the TCR sequences of MBP 89-101/I-A(s) specific T cell clones derived from SJL/J mice, using the polymerase chain reaction on reverse transcribed mRNA. Although the V beta usage was less restricted than in H-2u mice, they predominantly utilized V beta 17a and expressed LGG or related motifs in the V beta-D beta-J beta junctions. Furthermore, a single alpha chain rearrangement between V alpha 1.1 and J alpha BBM142 with no N region diversity was preferentially used. Concordantly, immunization with a peptide corresponding to the alpha chain CDR3 was found to significantly alter the clinical course of EAE. Comparison of the published TCR junctional regions demonstrates that the CDR3 motifs (LGG in beta chain, CA*R*NY motif in alpha chains) are expressed by other encephalitogenic clones. Notably, the CA*R*NY was conserved in PL/J mice clones that recognize a distinct MBP-MHC determinant. It suggests that an antigen-independent mechanism may contribute to conserving the alpha chain motif. The implications of these observations are discussed.
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PMID:Analysis of T cell antigen receptors of myelin basic protein specific T cells in SJL/J mice demonstrates an alpha chain CDR3 motif associated with encephalitogenic T cells. 752 42

The properties and outcome of an immune response are best predicted by the lymphokine phenotype of the responding T cells. Cytokines produced by CD4+ T helper type 1 (Th1) T cells mediate delayed type hypersensitivity (DTH) and inflammatory responses, whereas cytokines produced by Th2 T cells mediate helper T cell functions for antibody production. To determine whether induction of Th2-like cells would modulate an inflammatory response, interleukin 4 (IL-4) was administered to animals with experimental allergic encephalomyelitis (EAE), a prototypic autoimmune disease produced by Th1-like T cells specific for myelin basic protein (MBP). IL-4 treatment resulted in amelioration of clinical disease, the induction of MBP-specific Th2 cells, diminished demyelination, and inhibition of the synthesis of inflammatory cytokines in the central nervous system (CNS). Modulation of an immune response from one dominated by excessive activity of Th1-like T cells to one dominated by the protective cytokines produced by Th2-like T cells may have applicability to the therapy of certain human autoimmune diseases.
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PMID:Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. 752 45

Characterization of T cells responding to autoantigens is central to understanding autoimmune disease. We have used somatic mutation at the hypoxanthine guanine phosphoribosyltransferase (HPRT) gene as an index of T-cell amplification in vivo. With this strategy we previously showed that myelin basic protein-reactive T cells can be isolated only from the HPRT mutant T-cell population cultured from the peripheral blood of multiple sclerosis patients and not from normal individuals. In this study, 165 HPRT mutant and 104 wild-type clones were examined for their reactivity to myelin basic protein and overlapping peptides of myelin basic protein. Five HPRT mutant clones that recognized myelin basic protein and myelin basic protein peptides along with three clones that responded to myelin basic protein peptide alone were isolated. All but one of the eight clones recognized peptides derived from the carboxy terminus of myelin basic protein (p84-168). Sequence analysis showed heterogeneous expression of T-cell receptor V alpha and V beta genes and CDR3s. These studies showed that in vivo amplified autoimmune T cells from patients with long-standing disease use diverse T-cell receptor elements in the recognition of C-terminal myelin basic protein peptides.
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PMID:Myelin basic protein peptide specificity and T-cell receptor gene usage of HPRT mutant T-cell clones in patients with multiple sclerosis. 752 75

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterized by central nervous system inflammation and demyelination. Retinoids regulate cell differentiation and growth by binding to and activating retinoic acid receptors, which seem to be nuclear transcription factors. The effect of retinoids on chronic relapsing EAE produced by the transfer of myelin basic protein (MBP)-specific lymph node cells (LNC) was studied. All-trans-retinoic acid (tRA) inhibited the proliferation of MBP-specific LNC in vitro. However, the capacity of these cells to transfer EAE was markedly reduced by concentrations of tRA that only mildly inhibited T cell proliferation. The presence of tRA during in vitro MBP-specific LNC activation resulted in a considerable increase in IL-4 mRNA, whereas mRNA for IL-2, TNF-alpha, and IFN-gamma was decreased. Increased IL-4 also was detected in culture supernatants. However, the presence of a neutralizing Ab to IL-4 (11B11) during MBP-specific LNC activation in vitro did not reverse the inhibition of encephalitogenicity caused by tRA. The administration of retinoids in vivo resulted in an improved clinical course, even when given after disease onset. These findings suggest that T cell activation in the presence of tRA results in the development of T cells of the Th2 phenotype, which, in turn, might be responsible for the decrease in the encephalitogenicity of MBP-specific T cells. The modulation by retinoids of an immune response dominated by Th1-like T cells to one in which the protective cytokines of Th2-like cells predominate may have potential relevance for human demyelinating diseases such as multiple sclerosis.
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PMID:Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. 752 21

Multiple sclerosis is assumed to be an autoimmune disease mediated by T cells specific for myelin protein, such as, myelin basic protein (MBP) and PLP. Several groups reported that PLP-specific T cells are activated in the cerebrospinal fluid and, to a lesser extent, in the peripheral blood of the patients. We identified seven T cell epitopes within PLP residue 85-159. The T cell responses to these epitopes were higher in MS than in healthy subjects. PLP 95-116 and 105-124 specific T cells were more frequently established from DR2 MS than from non-DR2 MS, indicating that the DR2 restricted T cells recognizing these determinants are involved in the pathogenesis of MS. It is found PLP-specific T cells preferentially use V beta 5 and V beta 2 families though the usage is not exclusive. TCR beta chain complementary determining region 3 (CDR3) amino acid motifs of some PLP-specific T cells were homologous to those of MS lesion T cells, so it is likely that PLP-specific T cells infiltrate MS lesions. To our surprise, the CDR3 motifs of PLP-specific clones resemble those of MBP-specific clones. According to these facts, some antigen-independent pressure might give a common structure to T cells involved in MS.
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PMID:[T cell immunity to proteolipid protein (PLP) in multiple sclerosis (MS): identification of DR2-associated PLP determinants and conserved TCR CDR3 motifs]. 752 67

T cell activation requires both Ag/MHC recognition and costimulatory signals. The present studies were designed to test whether the loss of tolerance to myelin basic protein (MBP) requires costimulation by members of the B7 receptor family. CTLA-4Ig, a fusion protein ligand for B7-1 and B7-2, was used to assess the role of B7-mediated costimulation in chronic relapsing experimental allergic encephalomyelitis (EAE) induced by the transfer of MBP specific T cell lines. In adoptively transferred EAE, administering CTLA-4Ig to donor mice or during in vitro activation of MBP specific-T cells resulted in diminution of clinical disease. The presence of CTLA-4Ig during both the immunization and in vitro activation stages was most effective in preventing clinical signs of disease. This diminution in clinical disease was paralleled by a decreased proliferative response and reduced production of IL-2 and IL-4, but not IFN-gamma, after antigenic stimulation of encephalitogenic T cells in vitro. In contrast, CTLA-4Ig treatment of recipient animals after the transfer of MBP-activated T cells affected neither disease course nor severity. These results indicate that additional costimulatory pathways may be involved in established EAE, or that some cells are independent of costimulation or, alternatively, that CTLA-4Ig does not enter brain parenchyma in therapeutic concentrations. Thus, we conclude that costimulation provided by B7 molecules plays a major role in the development of encephalitogenic T cells and in the establishment of chronic relapsing EAE, a prototypic CD4+ T cell-mediated autoimmune disease.
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PMID:Role of B7:CD28/CTLA-4 in the induction of chronic relapsing experimental allergic encephalomyelitis. 752 5

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that serves as a model for the human disease multiple sclerosis. We evaluated rolipram, a type IV phosphodiesterase inhibitor, for its efficacy in preventing EAE in the common marmoset Callithrix jacchus. In a blinded experimental design, clinical signs of EAE developed within 17 days of immunization with human white matter in two placebo-treated animals but in none of three monkeys that received rolipram (10 mg/kg s.c. every other day) beginning 1 week after immunization. In controls, signs of EAE were associated with development of cerebrospinal fluid pleocytosis and cerebral MRI abnormalities. In the treatment group, there was sustained protection from clinical EAE, transient cerebrospinal fluid pleocytosis in only one of three animals, no MRI abnormality, and marked reduction in histopathologic findings. Rolipram-treated and control animals equally developed circulating antibodies to myelin basic protein. Thus, inhibition of type IV phosphodiesterase, initiated after sensitization to central nervous system antigens, protected against autoimmune demyelinating disease.
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PMID:Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterase inhibitor. 753 38


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