Th1 versus Th17: Are T cell cytokines relevant in multiple sclerosis?

AbstractOur understanding of the pathophysiology of multiple sclerosis (MS) has evolved significantly over the past two decades as the fields of immunology and neurobiology provide new avenues of exploration into the cause and mechanism of the disease. It has been known for decades that T cells have different cytokine phenotypes, yet the cytokine phenotype of pathogenic T cells in MS is still an area of debate. In EAE, it appears that IFNγ and IL-17, produced by Th1 and Th17 cells respectively, are not the critical factor that determines T cell encephalitogenicity. However, there are molecules such as IL-23, T-bet and STAT4, that appear to be critical, yet it is unclear whether all these molecules contribute to a common, yet undefined pathway, or act in a synergistic manner which culminates in encephalitogenicity has still to be determined. Therefore, the focus of research on effector T cells in MS should focus on pathways upstream of the cytokines that define Th1 and Th17 cells, since downstream products, such as IFNγ and IL-17, probably are not critical determinants of whether an effector T cells is capable of trafficking to the CNS and inducing inflammatory demyelination

Isotropic cosmological singularities 2: The Einstein-Vlasov system

We consider the conformal Einstein equations for massless collisionless gas cosmologies which admit an isotropic singularity. After developing the general theory, we restrict to spatially-homogeneous cosmologies. We show that the Cauchy problem for these equations is well-posed with data consisting of the limiting particle distribution function at the singularity.Comment: LaTeX, 37 pages, no figures, submitted to Ann. Phy

PPAR Alpha Regulation of the Immune Response and Autoimmune Encephalomyelitis

PPARs are members of the steroid hormone nuclear receptor superfamily and play an important role in the regulation of lipid metabolism, energy balance, artherosclerosis and glucose control. Recent studies suggest that they play an important role in regulating inflammation. This review will focus on PPAR-α regulation of the immune response. We describe how PPAR-α regulates differentiation of T cells by transactivation and/or interaction with other transcription factors. Moreover, PPAR-α agonists have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) in mice, suggesting that they could provide a therapy for human autoimmune diseases such as multiple sclerosis

Regulation of Immune Responses and Autoimmune Encephalomyelitis by PPARs

PPARs are members of the steroid hormone nuclear receptor superfamily and play an important role in regulating inflammation as well as lipid metabolism. The PPAR subfamily has been defined as PPARα, PPARβ/δ, and PPARγ, each with different ligands, target genes, and biological roles. PPARs regulate the expression of target inflammatory genes through mechanisms involving both transactivation and transrepression. The anti-inflammatory properties of PPAR agonists have led to the investigation of PPAR functions in regulating autoimmune encephalomyelitis. This paper will summarize some of the general mechanisms by which PPARs regulate inflammatory gene expression and focus on the recent advances of PPAR regulation of autoimmune encephalomyelitis

Isotropic cosmological singularities 1: Polytropic perfect fluid spacetimes

We consider the conformal Einstein equations for polytropic perfect fluid cosmologies which admit an isotropic singularity. For the polytropic index gamma strictly greater than 1 and less than or equal to 2 it is shown that the Cauchy problem for these equations is well-posed, that is to say that solutions exist, are unique and depend smoothly on the data, with data consisting of simply the 3-metric of the singularity. The analogous result for gamma=1 (dust) is obtained when Bianchi type symmetry is assumed.Comment: LaTeX, 43 pages, no figures, submitted to Ann. Phy

Multiple Sclerosis Followed by Neuromyelitis Optica Spectrum Disorder: From the National Multiple Sclerosis Society Case Conference Proceedings

A woman presented at age 18 years with partial myelitis and diplopia and experienced multiple subsequent relapses. Her MRI demonstrated T2 abnormalities characteristic of multiple sclerosis (MS) (white matter ovoid lesions and Dawson fingers), and CSF demonstrated an elevated IgG index and oligoclonal bands restricted to the CSF. Diagnosed with clinically definite relapsing-remitting MS, she was treated with various MS disease-modifying therapies and eventually began experiencing secondary progression. At age 57 years, she developed an acute longitudinally extensive transverse myelitis and was found to have AQP4 antibodies by cell-based assay. Our analysis of the clinical course, radiographic findings, molecular diagnostic methods, and treatment response characteristics support the hypothesis that our patient most likely had 2 CNS inflammatory disorders: MS, which manifested as a teenager, and neuromyelitis optica spectrum disorder, which evolved in her sixth decade of life. This case emphasizes a key principle in neurology practice, which is to reconsider whether the original working diagnosis remains tenable, especially when confronted with evidence (clinical and/or paraclinical) that raises the possibility of a distinctively different disorder

Degradation of isazofos in the soil environment

Field and laboratory studies were conducted to investigate the degradation of the organophosphorus insecticide isazofos (0-5-chloro-l-isopropyl-1H-l,2,4-triazol-3-ylO,O-diethyl phosphorothioate) in soil. In a 6-year field study, soil pH was an important factor influencing the degradation of isazofos inasmuch as an increased rate of degradation was observed in soils with previous isazofos applications and pH of 6.9 or more. A laboratory study of [14Clisazofos confirmed the rapid degradation of this insecticide in high pH soils. No increased degradation rate, however, was observed in sterilized high-pH soils. The availability of isazofos to microorganisms, based on sorption of isazofos to soil, seems to be an important factor influencing the degradation of isazofos in soil. Sorption coefficients were negatively correlated with isazofos degradation rate

A class of plane symmetric perfect-fluid cosmologies with a Kasner-like singularity

We prove the existence of a class of plane symmetric perfect-fluid cosmologies with a (-1/3, 2/3, 2/3) Kasner-like singularity. These solutions of the Einstein equations depend on two smooth functions of one space coordinate. They are constructed by solving a symmetric hyperbolic system of Fuchsian equations.Comment: LaTeX, 15 pages, no figures, to appear in CQG, correction to existence proo

On the Nature of Singularities in Plane Symmetric Scalar Field Cosmologies

The nature of the initial singularity in spatially compact plane symmetric scalar field cosmologies is investigated. It is shown that this singularity is crushing and velocity dominated and that the Kretschmann scalar diverges uniformly as it is approached. The last fact means in particular that a maximal globally hyperbolic spacetime in this class cannot be extended towards the past through a Cauchy horizon. A subclass of these spacetimes is identified for which the singularity is isotropic.Comment: 7 pages, MPA-AR-94-