Regulation of immunity in Multiple Sclerosis : CD4+ T cells and the influence of natalizumab

Abstract

Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) and the most common neurological cause of disability in young adults. In most cases, the disease course is characterised by the cycling of relapses and remissions, so called relapsingremitting MS (RR-MS). Although extensively studied, the underlying mechanisms are not fully elucidated, yet CD4 + T cells have been shown to be of importance in disease pathology.A range of treatments are available; the most effective to date being natalizumab, a monoclonal antibody directed against the adhesion molecule VLA-4 on the lymphocyte surface, thereby preventing entry into the CNS.The aim of this thesis was to assess the nature of lymphocyte populations in MS. This was achieved by studying CD4 + T helper cells (TH) and regulatory T cells (TREG) in peripheral blood. In addition, the influence of natalizumab was also investigated, both regarding the effect of the drug on the composition of the peripheral lymphocyte compartment as well as its effects on CD4 + T cells in vitro.We showed an imbalance in the mRNA expression of CD4 + T helper cell lineage specific transcription factors in peripheral blood. While TH1 and TH17 associated TBX21 and RORC expression was comparable in MS and healthy individuals, the TH2 and TREG associated A sizable effect of natalizumab treatment was seen in the composition of peripheral lymphocyte populations after one year of treatment. While the number of lymphocytes increased over all, the largest increase was seen in the NK and B cell compartments. ABSTRACT Furthermore, T cells from patients with MS displayed decreased responsiveness towardsantigens and mitogens in vitro. Natalizumab treatment was able to normalise the responsiveness in blood, an effect not solely dependent on the increased number of cells.The importance of CD4 + T cells in human disease, including MS, was shown by a systems biology approach; using GWAS data, genes associated with CD4 + T cell differentiation were enriched for many, not only immune-related, diseases. Furthermore, global CD4 + T cell gene expression (by microarray) could discriminate between patients and controls. Lastly, using in vitro treated CD4 + T cells, we could show that natalizumab perturbated gene expression differently in patients responding to the drug compared to those not responding.In

Somal site of synthesis of fast transported materials in mammalian nerve fibers

“…Similar results with acetoxycycloheximide in retinal neurons on optic nerve outflow of labelled incorporated components were reported by McEwen and Grafstein (1968) and with puromycin by Sjostrand and Karlsson (1969). However, some amount of RNA is present in axons (Miani, de Girolamo, & di Girolamo, 1966;Koenig, 1965 and1967;Edstrom, Edstrom and Hokfelt, 1969) and protein synthesis was found possible in axons separated from Schwann cells (Koenig, 1967;Edstrom and Sjostrand, 1969). There is also the possibility that some materials gain access to the axon via the Schwann cells (Singer & Salpeter, 1968).…”