Fas(t) track to apoptosis in MS: TNF receptors may suppress or potentiate CNS demyelination.
Explore the source record for details and available documents.
Apoptosis↗
Biomedical subjects
B M Segal
Publications and source records attributed to B M Segal.
CpG oligonucleotides are potent adjuvants for the activation of autoreactive encephalitogenic T cells in vivo.
The mechanism of action of microbial adjuvants in promoting the differentiation of autoimmune effector cells remains to be elucidated. We demonstrate that CpG-containing oligodeoxynucleotides (ODN) can completely substitute for heat-killed mycobacteria in the priming of encephalitogenic myelin-reactive T cells in vivo. The adjuvanticity of the CpG ODN was secondary to their direct ability to induce IL-12 or to act synergistically with endogenous IL-12 to promote Th1 differentiation and encephalitogenicity. T cells primed in the absence of CpG with Ag and IFA alone appeared to be in a transitional state and had not undergone differentiation along a conventional Th pathway. Unlike Th2 cells, they expressed low levels of the IL-12R beta 2 subunit and retained the ability to differentiate into encephalitogenic effectors when reactivated in vitro under Th1-polarizing conditions. These results support the use of CpG ODN as adjuvants but also suggest that they could potentially trigger autoimmune disease in a susceptible individual.
Adjuvants, Immunologic↗
Metallocyclopeptide complexes with MII(S.Cys)4 chromophores.
The tetracysteinyl peptide cyclo[Lys1,12](Gln-Cys-Gly-Val-Cys-Gly-Lys-Cys-Ile-Ala-Cys-Lys) ([symbol: see text] L(Cys.SH)4) was synthesized by solid-phase methods using an Fmoc/t-Bu/allyl strategy on a PAL-PEG-PS support. The formation of the 1:1 complexes with M = Fe2+, Co2+, and Ni2+ was observed by spectrophotometric monitoring of reactions in aqueous solution at pH 7.5. Size exclusion chromatography indicated that the peptide is a monomer and the complexes are dimers [M2([symbol: see text]L(Cys.S)4)2] in aqueous buffer at pH 7.5. Cobalt and nickel K-edge X-ray absorption data and EXAFS analysis of [Co2([symbol: see text] L(Cys.S)4)2] and [Ni2([symbol: see text] L(Cys.S)4)2] as lyophilized solids are reported. Derived bond distances are Co-S = 2.30 A and Ni-S = 2.21 A. From the collective results provided by absorption spectra, K-edges, EXAFS, and bond length comparisons with known structures, it is shown that [Fe2([symbol: see text] L(Cys.S)4)2] and [Co2([symbol: see text] L(Cys.S)4)2] possess distorted tetrahedral structures and [Ni2([symbol: see text] L(Cys.S)4)2] has distorted square planar stereochemistry. The Co(II) chromophore is particularly distinctive of the assigned structure, displaying three components of the parent tetrahedral ligand field transition 4A2-->4T1(P) (610, 685, 740 nm). The observed structures conform to the intrinsic stereochemical preferences of the metal ions. Structures for the binuclear complexes are suggested. These are the first characterized metal complexes of a cysteinyl cyclopeptide and among the few well-documented complexes of synthetic cyclopeptides. This study is a desirable first step in the design of cyclic peptides for the binding of mononuclear and polynuclear metal centers.
Absorptiometry, Photon↗
Reduced mono-, di-, and tetracubane-type clusters containing the [MoFe3S4]2+ core stabilized by tertiary phosphine ligation.
Treatment of oxidized clusters [(Cl4cat)(MeCN)MoFe3S4Cl3]2- (1) and [(Meida)MoFe3S4Cl3]2- (2) with tertiary phosphines in the presence of NaBPh4 in acetonitrile results in chloride substitution at the iron sites and the formation of clusters with the reduced [MoFe3S4]2+ core. Thus, 1 is a precursor to [(Cl4cat)(MeCN)MoFe3S4(PR3)3] (R = But (3), Pri (4)) and [(Cl4cat)2(Et3P)2Mo2Fe6S8(PEt3)4] (5). Cluster 2 affords [[(Meida)MoFe3S4(PCy3)3]4Fe2(mu-Cl)L2]3+ (L = THF (6), MeCN (7)). The structures of 3-7 were established by X-ray analysis. Clusters 3 and 4 are single cubanes, centrosymmetric 5 (previously reported in a different space group: Demadis, K. D.; Campana, C. F.; Coucouvanis, D. J. Am. Chem. Soc. 1995, 117, 7832) is a double cubane with a rhomboidal Fe2S2 bridge, and 6 and 7 are tetracubanes. In the latter, four Meida oxygen atoms from different cubanes bind each of two central high-spin Fe(II) atoms in trans-Fe(mu-Cl)LO4 coordination. The topology of these clusters is not precedented. Zero-field Mössbauer parameters for all clusters are reported. Isomer shift considerations suggest the formulation [Mo3+Fe2+2Fe3+S4] for reduced clusters. Voltammetry of 3 and 4 reveals four-member electron transfer series encompassing the oxidation levels [MoFe3S4]4+,3+,2+,+ in the potential interval + 1.0 to -1.3 V vs SCE in dichloromethane. Compared to the clusters with monoanionic ligands at the iron sites, phosphine ligation shifts redox potentials to more positive values. This effect arises from reduction of cluster negative charge and the tendency of phosphines to stabilize lower oxidation states. The synthesis of reduced clusters 4 from 1 and of [Fe4S4(PPri3)4]+ from [Fe4S4Cl4]2- is accompanied by the formation of Pri3PS, detected by 31P NMR, indicating that the phosphine is the reductant. This result implies a similar function of tertiary phosphines in the synthesis of 3 and 5-7. (Cl4cat = tetrachlorocatecholate(2-); Meida = N-methyliminodiacetate(2-).)
Crystallography, X-Ray↗
Role of costimulation in the induction of the IL-12/IL-12 receptor pathway and the development of autoimmunity.
Costimulation mediated by the interactions of the B7 Ags (CD80/CD86) on APC with CD28 on the responding T cell regulates the magnitude of the immune response and may influence Th1/Th2 development. The IL-12Rbeta2 subunit plays a critical role in maintaining IL-12 responsiveness and controlling Th1 lineage commitment. We demonstrate that IL-2 and IL-12 resulting from CD28/B7 interactions both play a critical role in the induction of expression of the IL-12Rbeta2 subunit and as a result the differentiation of pathogenic autoreactive effector cells. These findings suggest that targeting IL-2 and IL-12 simultaneously may be effective in the treatment of Th1-mediated autoimmunity.
Abatacept↗
The costimulatory effect of IL-18 on the induction of antigen-specific IFN-gamma production by resting T cells is IL-12 dependent and is mediated by up-regulation of the IL-12 receptor beta2 subunit.
IL-18 was originally described as a cytokine which induced IFN-gamma production by established Th1 cells in an IL-12-independent manner. However, subsequent studies demonstrated that exogenous IL-18 in the absence of IL-12 failed to drive Th1 differentiation of naive cells and induced IFN-gamma from established Th1 cells only in combination with IL-12. We have examined the role of endogenous IL-18 in controlling Th1 lineage commitment. When naive TCR-transgenic T cells were stimulated with antigen, anti-IL-18 antibodies resulted in partial inhibition of IFN-gamma production, but did not inhibit Th1 differentiation. To distinguish whether the inhibitory effect of anti-IL-18 antibodies was mediated directly by blocking IFN-gamma production or indirectly by blocking IL-12Rbeta2 up-regulation, naive T cells from IL-12 - / - mice were stimulated with anti-CD3 and IL-18. These cells failed to produce IFN-gamma, but markedly up-regulated IL-12Rbeta2 expression. We propose that the major effect of IL-18 on Th1 development is mediated by up-regulation of IL-12Rbeta2 expression, thereby enhancing IL-12-mediated signaling. The enhancement of IL-12Rbeta2 expression by IL-18 may be particularly important for the differentiation of foreign antigen- or autoantigen-specific Th1 cells when the stimulatory concentration of IL-12 in the microenvironment is just below the threshold required for Th1 development.
Amino Acid Sequence↗
Regulation of interleukin (IL)-12 receptor beta2 subunit expression by endogenous IL-12: a critical step in the differentiation of pathogenic autoreactive T cells.
The interleukin (IL)-12 receptor (R)beta2 subunit is the critical molecule involved in maintaining IL-12 responsiveness and controlling T helper cell type 1 lineage commitment. We demonstrate that IL-12 and interferon (IFN)-gamma play separate, but complementary, roles in regulating IL-12Rbeta2 expression on antigen-specific CD4(+) T cells. These results are consistent with our previous observation that IL-12 can promote autoimmune disease through IFN-gamma-independent as well as -dependent pathways. Therefore, we compared the induction of IL-12 by, and the expression of the IL-12Rbeta2 subunit on, myelin basic protein (MBP)-specific T cells from experimental allergic encephalomyelitis (EAE)-susceptible SJL (H-2(s)) mice and from EAE- resistant B10.S mice (H-2(s)). B10.S mice had an antigen-specific defect in their capacity to upregulate the IL-12Rbeta2 subunit. Defective expression was not secondary to the production of suppressive cytokines, but to a failure of B10.S MBP-specific T cells to upregulate CD40 ligand expression and to induce the production of IL-12. IL-12Rbeta2 expression as well as encephalitogenicity of these cells could be restored by the addition of IL-12. These results suggest that the development of immunotherapies that target the IL-12Rbeta2 subunit may be useful for the treatment of autoimmune diseases.
Amino Acid Sequence↗
The critical role of IL-12 and the IL-12R beta 2 subunit in the generation of pathogenic autoreactive Th1 cells.
Experimental Allergic Encephalomyelitis (EAE) is a demyelinating disease of the central nervous system which is an animal model for the human autoimmune disease, multiple sclerosis. EAE is mediated by CD4+ T cells and the T cells responsible for disease induction produce Th1 cytokines. IL-12 produced by monocytes and dendritic cells is the most critical factor which influences the development and differentiation of pathogenic autoreactive Th1 cells. Here, we review our recent studies on the critical contributions of IL-12 and the IL-12R beta 2 subunit to the generation of autoreactive effector cells which mediate EAE. In addition, we discuss the potential contribution of IL-18 to the upregulation of the IL-12/IL-12R beta 2 pathway and the contribution of the suppressor cytokines, IL-4 and IL-10, in downregulating this pathway. Collectively, our studies demonstrate that the IL-12/IL-12R beta 2 pathway is a critical intermediary in the process of Th1 differentiation which can be both positively or negatively regulated. This pathway remains an attractive immunotherapeutic target for blockade of function with inhibitory reagents or downregulation by Th2 cytokines.
Animals↗
An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease.
Cells of the innate immune system secrete cytokines early in immune responses that guide maturing T helper (Th) cells along appropriate lineages. This study investigates the role of cytokine networks, bridging the innate and acquired immune systems, in the pathogenesis of an organ specific autoimmune disease. Experimental allergic encephalomyelitis (EAE), a demyelinating disease of the central nervous system, is widely used as an animal model for multiple sclerosis. We demonstrate that interleukin (IL)-12 is essential for the generation of the autoreactive Th1 cells that induce EAE, both in the presence and absence of interferon gamma. The disease-promoting effects of IL-12 are antagonized by IL-10 produced by an antigen nonspecific CD4+ T cell which, in turn, is regulated by the endogenous production of IL-12. This unique immunoregulatory circuit appears to play a critical role in controlling Th cell differentiation and provides a mechanism by which microbial triggers of the innate immune system can modulate autoimmune disease.
Adoptive Transfer↗
The straight talk on immune deviation.
Explore the source record for details and available documents.
Animals↗
Microbial products induce autoimmune disease by an IL-12-dependent pathway.
The development and exacerbation of autoimmune diseases are associated with antecedent infectious illness. Microbial products such as LPS, bacterial DNA, or oligonucleotides containing an unmethylated cytosine-guanine dinucleotide have cytokine modulating properties. These products converted quiescent myelin basic protein-specific T cells into effector cells capable of transferring experimental allergic encephalomyelitis. The disease-promoting properties of the microbial products were solely dependent on their capacity to induce the production of IL-12.
Animals↗
IL-12 unmasks latent autoimmune disease in resistant mice.
Inbred mice exhibit a spectrum of susceptibility to induction of experimental allergic encephalomyelitis (EAE). We have compared the immune responses of the susceptible SJL (H-2s) and resistant B10.S (H-2s) strains to determine factors other than the MHC background which control resistance/susceptibility to EAE. The resistance of the B10.S strain was found to be secondary to an antigen-specific defect in the generation of Th 1 cells that produce IFN gamma. This defect in IFN gamma production could be restored by exposure of the myelin basic protein (MBP)-reactive T cells to IL-12 with the subsequent induction of the ability to transfer EAE to naive recipients. These findings have important implications for the therapeutic use of IL-12 and IL-12 antagonists and may explain the association between relapses/exacerbation of autoimmune disease and infectious diseases.
Amino Acid Sequence↗
Substance use and abuse in adolescence: an overview.
Substances are widely used by youth as a means of excitement, consolation, belonging to a referent group, rebellion, a symbol of social and sexual maturity and independence. The destabilization of the family, permissiveness, indifference of the adult world, ethical confusion, peer pressure and the decline of self-discipline among the young are the essential causes of adolescent substance use and abuse. Preventive and treatment efforts are flawed by disagreements in the area of diagnosis and strategy, lack of cohesiveness, insufficient funds and deficiencies in follow-up procedures.
Adolescent↗
The role of pathological selfobjects in the development of a form of defensive self.
This paper focuses on the kind of patient whose self functioning is based on meeting the needs of others. I suggest that the childhood history of such patients is characterized by a specific form of pathological interaction. In this interaction the parents support and facilitate only those aspects of the child that meet the parents' own narcissistic needs. In the psychotherapy of these patients this aspect of the parent-child relationship is expressed as a specific form of transference.
Adult↗
HLA restriction and TCR usage of T lymphocytes specific for a novel candidate autoantigen, X2 MBP, in multiple sclerosis.
Previous investigations of the major 18.5-kDa isoform of myelin basic protein (MBP) as a target autoantigen in multiple sclerosis (MS) have failed to identify an epitope uniformly recognized with higher frequency in MS patients compared with controls. Because remyelination has been observed in MS plaques, we were prompted to investigate T cells specific for myelin protein isoforms with up-regulated expression during remyelination. We have recently described such T cells that recognize the exon 2-encoded region of MBP (X2 MBP), a sequence included in the 21.5- and 20.2-kDa isoforms of MBP. These cells were shown to be CD4+, HLA class II restricted, and cytolytic. In members of one multiplex MS family, X2 MBP-specific T lymphocytes were as prevalent as T cells specific for immunodominant regions within the major 18.5-kDa isoform of MBP. The present study characterizes X2 MBP-specific T cell responses in additional multiplex MS family members as well as in heterogeneous (non-familial) MS patients and in healthy controls. The frequencies of X2 MBP-specific T cells in each of the affected family members from two of three MS families were significantly increased as compared with both the heterogeneous MS group and the healthy control group. Also, X2 MBP-specific T cell lines from affected family members were primarily restricted to molecules encoded by the DR2/DQw1 allele. Although TCR usage was generally heterogeneous, there was evidence of intraindividual sequence identity. These data suggest that: 1) Myelin proteins with up-regulated expression during the course of disease should be considered as candidate autoantigens in MS. 2) The functional basis for the association of DR2/DQw1 inheritance with MS susceptibility may be related to presentation of autoantigens by this allele. 3) TCR therapy will need to be individually tailored to target the most prevalent autoantigen-specific response.
Adult↗
Experimental allergic encephalomyelitis induced by the peptide encoded by exon 2 of the MBP gene, a peptide implicated in remyelination.
The discovery of T lymphocytes reactive to the peptide encoded by exon 2 of the myelin basic protein (MBP) gene in multiple sclerosis (MS) patients has drawn attention to MBP isoforms harboring that peptide as candidate autoantigens. Previously, immunological studies in MS had almost exclusively used the more abundant 18.5 kDa isoform of MBP, which does not contain the exon 2 peptide. Investigations of experimental allergic encephalomyelitis (EAE) have also focussed on the 18.5 kDa MBP isoform and its peptides. Since EAE is an animal model widely used to study MS, we examined the encephalitogenic potential of exon 2 peptide in the SJL/J mouse. Evidence for increased expression of exon 2-containing isoforms during remyelination in mouse CNS suggested that exon 2-sensitized T cells, with encephalitogenic capacity, might be important in the perpetuation of relapsing EAE (rEAE). Our experiments have demonstrated that exon 2 peptide is inherently immunogenic in SJL mice and that EAE could be induced by the adoptive transfer of exon 2-sensitized lymphocytes. Furthermore, the disease could be accentuated by the transfer of short-term exon 2-reactive lines or by a combination of adoptive transfer and antigenic challenge with exon 2 peptide. The immunodominant epitope(s) appeared to localize to the segment bordered by amino acids 59-85.
Amino Acid Sequence↗
Steroid-responsive electromyographic abnormalities in polymyalgia rheumatica.
Prior to definitive diagnosis, electrodiagnostic studies are often requested in patients with polymyalgia rheumatica to evaluate complaints of muscle aching, tenderness, and weakness. These studies are generally normal, although rare reports of electromyographic abnormalities in polymyalgia rheumatica exist. Two patients with polymyalgia rheumatica and electrodiagnostic findings consistent with diffuse denervation are described. Following steroid treatment, both patients experienced impressive clinical and electromyographic improvement. To explain this improvement, we hypothesize a steroid-responsive microvascular arteritis resulting in ischemic damage to axons of motor nerve terminal branches.
Aged↗
A borderline style of functioning--the role of family, society and heredity: an overview.
Explore the source record for details and available documents.
Adolescent↗