Multiple sclerosis: immunopathogenesis and controversies in defining the cause

PURPOSE OF REVIEW: Multiple sclerosis is a major cause of neurological disability in Western societies. The most important reason for the limited success obtained in the treatment and prevention so far is most likely related to the limited knowledge about its cause and pathogenesis. This paper discusses recent progress and controversies in the understanding of the pathogenesis and cause of multiple sclerosis. RECENT FINDINGS: Both T helper cells type 1 (Th1 cells), Th17 cells, cytotoxic T cells, B cells and regulatory T cells are involved in the inflammatory process. Axonal loss seems to be driven by inflammation during the early stages of disease but may become independent of inflammation at later stages. The target antigen of the immune response has not been identified. Weak genetic association has been established in two cytokine receptors, whereas increasing female: male ratio support the importance of environmental risk factors. A substantial proportion of intrathecal B cells are infected with Epstein-Barr virus. SUMMARY: Multiple sclerosis is a complex disease and calls for integrated efforts from immunology, epidemiology, neuroscience and genetics. In particular, the immunological implications of environmental risk factors such as vitamin D desufficiency, smoking and Epstein-Barr virus infection need to be explored.     

CYP3A4 Mediates Oxidative Metabolism of the Synthetic Cannabinoid AKB-48

Synthetic cannabinoid designer drugs have emerged as drugs of abuse during the last decade, and acute intoxication cases are documented in the scientific literature. Synthetic cannabinoids are extensively metabolized, but our knowledge of the involved enzymes is limited. Here, we investigated the metabolism of N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB-48), a compound identified in herbal blends from 2012 and onwards. We screened for metabolite formation using a panel of nine recombinant cytochrome P450 (CYP) enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4) and compared the formed metabolites to human liver microsomal (HLM) incubations with specific inhibitors against CYP2D6, 2C19, and 3A4, respectively. The data reported here demonstrate CYP3A4 to be the major CYP enzyme responsible for the oxidative metabolism of AKB-48, preferentially performing the oxidation on the adamantyl moiety. Genetic polymorphisms are likely not important with regard to toxicity given the major involvement of CYP3A4. Adverse drug-drug interactions (DDIs) could potentially occur in cases with co-intake of strong CYP3A4 inhibitors, e.g., HIV antivirals and azole antifungal agents.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9788-7) contains supplementary material, which is available to authorized users.KEY WORDS: adamantyl, cytochrome P450, metabolism, metabolites, synthetic cannabinoids     

Fucoidin, but not yeast polyphosphomannan PPME, inhibits leukocyte rolling in venules of the rat mesentery

Leukocyte rolling in venules is inhibited by several sulfated polysaccharides, by antibodies to the leukocyte adhesion receptor L- selectin (LECAM-1), and by recombinant soluble L-selectin. The sulfated fucose polymer fucoidin and the polyphosphomannan PPME bind to L- selectin and inhibit L-selectin-mediated lymphocyte adhesion to lymph node high endothelial venules (LN-HEV). We investigated whether fucoidin and PPME also inhibit leukocyte rolling. Rolling leukocyte flux was determined by intravital microscopy in 47 venules (diameter 21 to 50 microns) of the rat mesentery with and without micro-infusion of each reagent through 8-microns glass micropipettes. Micro-infusion (1 mg/mL) or intravenous (IV) injection (25 mg/kg) of fucoidin, but not vehicle, reduced leukocyte rolling by greater than 90%. The half- effective concentration was approximately 2.5 micrograms/mL. Stroboscopic fluorescence video microscopy showed that fucoidin decreased the fraction of rolling leukocytes from 44% of all leukocytes passing the venules in control to less than 1%. PPME micro-infusion (1 mg/mL) or IV injection (14 mg/kg) did not reduce leukocyte rolling. Hence, leukocyte rolling differs from lymphocyte homing with respect to the effect of PPME. This may be related to fucoidin binding to L- selectin with greater affinity than PPME. Alternatively, inflamed venular endothelium may express a ligand for L-selectin different from that constitutively expressed on LN-HEV.     

CXCL13 antibody for the treatment of autoimmune disorders

Background

Homeostatic B Cell-Attracting chemokine 1 (BCA-1) otherwise known as CXCL13 is constitutively expressed in secondary lymphoid organs by follicular dendritic cells (FDC) and macrophages. It is the only known ligand for the CXCR5 receptor, which is expressed on mature B cells, follicular helper T cells (Tfh), Th17 cells and regulatory T (Treg) cells. Aberrant expression of CXCL13 within ectopic germinal centers has been linked to the development of autoimmune disorders (e.g. Rheumatoid Arthritis, Multiple Sclerosis, Systemic Lupus Erythematosis). We, therefore, hypothesized that antibody-mediated disruption of the CXCL13 signaling pathway would interfere with the formation of ectopic lymphoid follicles in the target organs and inhibit autoimmune disease progression. This work describes pre-clinical development of human anti-CXCL13 antibody MAb 5261 and includes therapeutic efficacy data of its mouse counterpart in murine models of autoimmunity.

Results

We developed a human IgG1 monoclonal antibody, MAb 5261 that specifically binds to human, rodent and primate CXCL13 with an affinity of approximately 5 nM and is capable of neutralizing the activity of CXCL13 from these various species in in vitro functional assays. For in vivo studies we have engineered a chimeric antibody to contain the same human heavy and light chain variable genes along with mouse constant regions. Treatment with this antibody led to a reduction in the number of germinal centers in mice immunized with 4-Hydroxy-3-nitrophenylacetyl hapten conjugated to Keyhole Limpet Hemocyanin (NP-KLH) and, in adoptive transfer studies, interfered with the trafficking of B cells to the B cell areas of mouse spleen. Furthermore, this mouse anti-CXCL13 antibody demonstrated efficacy in a mouse model of Rheumatoid arthritis (Collagen-Induced Arthritis (CIA)) and Th17-mediated murine model of Multiple Sclerosis (passively-induced Experimental Autoimmune Encephalomyelitis (EAE)).

Conclusions

We developed a novel therapeutic antibody targeting CXCL13-mediated signaling pathway for the treatment of autoimmune disorders.     

Physiological role of taurine – from organism to organelle

Taurine is often referred to as a semi‐essential amino acid as newborn mammals have a limited ability to synthesize taurine and have to rely on dietary supply. Taurine is not thought to be incorporated into proteins as no aminoacyl tRNA synthetase has yet been identified and is not oxidized in mammalian cells. However, taurine contributes significantly to the cellular pool of organic osmolytes and has accordingly been acknowledged for its role in cell volume restoration following osmotic perturbation. This review describes taurine homeostasis in cells and organelles with emphasis on taurine biophysics/membrane dynamics, regulation of transport proteins involved in active taurine uptake and passive taurine release as well as physiological processes, for example, development, lung function, mitochondrial function, antioxidative defence and apoptosis which seem to be affected by a shift in the expression of the taurine transporters and/or the cellular taurine content.