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

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

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

Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling

The primary biological function of the endogenous cellular prion protein has remained unclear. We investigated its biological function in the generation of cellular immune responses using cellular prion protein gene-specific small interfering ribonucleic acid in vivo and in vitro. Our results were confirmed by blocking cellular prion protein with monovalent antibodies and by using cellular prion protein-deficient and -transgenic mice. In vivo prion protein gene-small interfering ribonucleic acid treatment effects were of limited duration, restricted to secondary lymphoid organs and resulted in a 70% reduction of cellular prion protein expression in leukocytes. Disruption of cellular prion protein signalling augmented antigen-specific activation and proliferation, and enhanced T cell receptor signalling, resulting in zeta-chain-associated protein-70 phosphorylation and nuclear factor of activated T cells/activator protein 1 transcriptional activity. In vivo prion protein gene-small interfering ribonucleic acid treatment promoted T cell differentiation towards pro-inflammatory phenotypes and increased survival of antigen-specific T cells. Cellular prion protein silencing with small interfering ribonucleic acid also resulted in the worsening of actively induced and adoptively transferred experimental autoimmune encephalomyelitis. Finally, treatment of myelin basic protein1–11 T cell receptor transgenic mice with prion protein gene-small interfering ribonucleic acid resulted in spontaneous experimental autoimmune encephalomyelitis. Thus, central nervous system autoimmune disease was modulated at all stages of disease: the generation of the T cell effector response, the elicitation of T effector function and the perpetuation of cellular immune responses. Our findings indicate that cellular prion protein regulates T cell receptor-mediated T cell activation, differentiation and survival. Defects in autoimmunity are restricted to the immune system and not the central nervous system. Our data identify cellular prion protein as a regulator of cellular immunological homoeostasis and suggest cellular prion protein as a novel potential target for therapeutic immunomodulation

Comparison of Standard 1.5 T vs. 3 T Optimized Protocols in Patients Treated with Glatiramer Acetate. A Serial MRI Pilot Study

This study explored the effect of glatiramer acetate (GA, 20 mg) on lesion activity using the 1.5 T standard MRI protocol (single dose gadolinium [Gd] and 5-min delay) or optimized 3 T protocol (triple dose of Gd, 20-min delay and application of an off-resonance saturated magnetization transfer pulse). A 15-month, phase IV, open-label, single-blinded, prospective, observational study included 12 patients with relapsing-remitting multiple sclerosis who underwent serial MRI scans (Days −45, −20, 0; the minus ign indicates the number of days before GA treatment; and on Days 30, 60, 90, 120, 150, 180, 270 and 360 during GA treatment) on 1.5 T and 3 T protocols. Cumulative number and volume of Gd enhancing (Gd-E) and T2 lesions were calculated. At Days −45 and 0, there were higher number (p < 0.01) and volume (p < 0.05) of Gd-E lesions on 3 T optimized compared to 1.5 T standard protocol. However, at 180 and 360 days of the study, no significant differences in total and cumulative number of new Gd-E and T 2 lesions were found between the two protocols. Compared to pre-treatment period, at Days 180 and 360 a significantly greater decrease in the cumulative number of Gd-E lesions (p = 0.03 and 0.021, respectively) was found using the 3 T vs. the 1.5 T protocol (p = NS for both time points). This MRI mechanistic study suggests that GA may exert a greater effect on decreasing lesion activity as measured on 3 T optimized compared to 1.5 T standard protocol

Inhibition of SLPI ameliorates disease activity in experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>The secretory leukocyte protease inhibitor (SLPI) exerts wide ranging effects on inflammatory pathways and is upregulated in EAE but the biological role of SLPI in EAE, an animal model of multiple sclerosis is unknown</p> <p>Methods</p> <p>To investigate the pathophysiological effects of SLPI within EAE, we induced SLPI-neutralizing antibodies in mice and rats to determine the clinical severity of the disease. In addition we studied the effects of SLPI on the anti-inflammatory cytokine TGF-β.</p> <p>Results</p> <p>The induction of SLPI neutralizing antibodies resulted in a milder disease course in mouse and rat EAE. SLPI neutralization was associated with increased serum levels of TGF-β and increased numbers of FoxP3+ CD4+ T cells in lymph nodes. <it>In vitro</it>, the addition of SLPI significantly decreased the number of functional FoxP3+ CD25^hiCD4+ regulatory T cells in cultures of naive human CD4+ T cells. Adding recombinant TGF-β to SLPI-treated human T cell cultures neutralized SLPI's inhibitory effect on regulatory T cell differentiation.</p> <p>Conclusion</p> <p>In EAE, SLPI exerts potent pro-inflammatory actions by modulation of T-cell activity and its neutralization may be beneficial for the disease.</p

Effect Of Gender On T-Cell Proliferative Responses To Myelin Proteolipid Protein Antigens In Patients With Multiple Sclerosis And Controls

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. Gender influences both susceptibility to MS, with the disease being more common in women, and the clinical course of disease, with an increased proportion of males developing the primary progressive form of the disease. The basis for these differences may include genetic and immunological factors, and the immunological differences between men and women may be influenced by the effects of the sex hormones. Over several years we have collected blood from MS patients and controls, and measured T-cell responses to myelin proteolipid protein (PLP) and myelin basic protein (MBP) and have shown increased responses to PLP in MS patients compared to healthy controls and patients with other neurological diseases. In the present study we analyzed data from over 500 individuals, to determine whether there are differences between males and females in their responses to PLP and MBP. We found that there was higher frequency of increased T-cell reactivity to immunodominant PLP peptides in women than in men, particularly in non-MS individuals. We suggest that this may be relevant to the higher prevalence of MS in women