accepted lecture

Abstract:
Multiple sclerosis (MS) is a chronic disorder characterized by multifocal inflammatory infiltrates (T cells, B cells, macrophages) within the central nervous system (CNS) and concomitant degradation of myelin, oligodendrocytes and axons, along with reactive microgliosis. Disease background is thought to include two overlapping processes: polyphasic myelin destruction (inflammatory demyelination) and progressive axonopathy (neurodegeneration) with little capacity for repair. The pathology is generally believed to reflect autoimmune attack upon myelin auto-antigens but the mechanisms resulting in the escalation of the autoimmune response and leading to the damage of white and gray matter in the CNS have not been so far fully clarified.
Lipid antigens are substantial myelin components and they also may constitute potential candidates for autoimmune attack in MS. We have recently explored the seem to be role of bioactive lipids, particularly ceramide, in the pathomechanism of autoimmune demyelination in MS. Specifically, we examined TNF- and IFN- effect, the two Th1 pro-inflammatory cytokines known to be accumulated in MS brain, upon a human oligodendroglioma (HOG) cell line. Our results suggested an exosome-mediated new mechanism of synergistic cytotoxicity of TNF- and IFN-. Ceramide-laden exosomes, when released from stressed or cytokine-targeted oligodendrocytes in vivo, may “broadcast” the cell death signal and promote the immune response that occurs under demyelinating conditions in the CNS. For this reason exosomes offer new molecular insights into MS pathology and perhaps could be used in the future as bioactive markers for the disease activity. On the other hand, it is well known that ceramide play a central role in sphingolipids metabolism which intricate scenario with numerous potential therapeutic targets, e.g. “engineered” exosomes can be used as an efficient vehicles for delivery of therapeutic agents across the blood-brain barrier.
A complex and heterogeneous picture of MS immunopathology may suggest the presence of various immunoregulatory abnormalities in this disease. These may result from disturbed functional interactions of many cellular components of the immune system, especially regulatory T cells. Natural killer T (NKT) cells may perform major regulatory functions in immunity, however their function in MS is not yet fully understood. In our studies, we identified glycosphingolipid (GSL)-reactive CD1-restricted lymphocytes especially those of the NKT and NKR+ phenotype and with T cell regulatory functions. GSL-driven anergy of circulating lymphocytes in MS suggests that the altered immune response in MS is via robust invariant NKT (iNKT) activation with potent cellular and cytokine activities. Diverse GSLs including the endogenous myelin acetylated-galactosylceramides (FMCs) can drive activation critical to controlling CNS inflammation and fostering myelin repair. Rendering iNKT-cells hyporesponsiveness to an endogenous GSL is a novel insight into diseases manifesting aberrant iNKT-cell activation. Furthermore, the state of anergy following stimulation with the auto-antigen FMC-7 may have significant clinical implications, according to the theory of antigen-specific therapy of autoimmune diseases.
An equally important factor in the pathology of MS, apart from (sub)acute demyelination, is progressive axonal and neuronal damage, resulting in accumulating neurological deficit and disability. Earlier reports indicate that calpain has been implicated in MS autoimmune mechanism, including demyelination, axonal damage, loss of neurons and oligodendrocytes and modulation of proteins involved in apoptotic pathways. We hypothesized that this Ca2+ dependent cysteine protease plays a key regulatory role in immune activation of MS pathology and its deactivation (inhibition) causes remission with control of autoimmune inflammation and neurodegeneration. Our studies yielded new findings regarding the mechanism of progressive MS that have implications for potential treatment. Based on two primary culture models  rat and human  we identified calpain as a key neuron injury signal driving the toxic component of reactive microgliosis. Specifically, we determined that calpain, released upon neuron damage, activates microglia to produce reactive oxygen species and nitric oxide that are selectively toxic to neurons. Our findings indicate that damaged neurons themselves are culpable in propagating further neurotoxicity with pro-inflammatory signals to microglia. These studies provide much needed insight into the nature of progressive phase of MS, with emerging putative preventive and therapeutic options. These novel findings (e.g., targeting calpain inhibition) may provide valuable insight into the mechanisms by which Th1 cells elicit neurodegeneration and appear promising in the treatment of progressive types of MS but also other neurodegenerative disorders.
Biography:
Dr. Maria Podbielska had done her Habilitation from Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland in 2019,Ph.D from Institute of Immunology & Experimental Therapy Polish Academy of Sciences, Wroclaw, Poland in 2003,Master of Science & Engineer: Wroclaw University of Technology, Department of Chemistry, Wroclaw, Poland in 1997 and Professional Experience is from Ludwik Hirszfled Institute of
Immunology & Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland and Postdocs are 2012 and 2014-2016 Medical University of South Carolina, Charleston, SC, USA ,2010-2011 Heinrich Heine University, Düsseldorf, Germany,2004-2010 Georgia Regents University, Augusta, GA, USA.
Honors and Awards:
2016 Certificate of the Polish-American Fulbright Commission received at the Ministry of Science and Higher Education in recognition of merits to promote Polish science and culture and to strengthen friendships between the peoples of the Republic of Poland and the United States of America through participation in the program of Fulbright Senior Award 2015-2016.
2015 Fulbright Senior Award nomination by the Polish-U.S. Fulbright Commission approved by J. William Fulbright Foreign Scholarship Board, Washington, DC, USA.
2014 Fellowship award approved by the Kosciuszko Foundation, New York, NY, USA.
2011 Du Pré Grant award approved by the Multiple Sclerosis International Federation, London, United Kingdom.
2007 Wroclaw Medical University Rector’s award for scientific publication, conducted in collaboration between Medical University and IIET, published in 2006 in the journal of the highest IF value (Galactosylation of IgG from rheumatoid arthritis [RA] patients-changes during therapy; Glycoconj. J. 23, 463-471, 2006).
2003 Award for Ph.D. dissertation, Institute of Immunology & Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
Professional Memberships:
since 2016 Member of the Fulbright Scholar Alumni Program administered by the Council for International Exchange of Scholars, a division of the Institute of International Education, Washington, DC, USA
since 2015 Member of the Kosciuszko Foundation Research Alumni Program, Warsaw, Poland
since 2012 Member of the Multiple Sclerosis International Federation Research Alumni Program, London, United Kingdom
since 2008 Member, The International Society of Neuroimmunology
Selected Publications:
M. Podbielska, J. O’Keeffe, E. L. Hogan Autoimmunity in multiple sclerosis: role of sphingolipids, invariant NKT cells and other immune elements in control of inflammation and neurodegeneration J. Neurol. Sci. 385, 198-214, 2018.
N. M. Trager, J. T. Butler, J. Harmon, J. Mount, M. Podbielska, A. Haque, N.L. Banik and C.C. Beeson. A Novel Aza-MBP Altered Peptide Ligand for the Treatment of Experimental Autoimmune Encephalomyelitis. Mol. Neurobiol. 55(1), 267-275, 2018.
M. Podbielska, Z.M. Szulc, E. Kurowska, E.L. Hogan, J. Bielawski, A. Bielawska, N.R. Bhat. Cytokine-induced release of ceramide-enriched exosomes as a mediator of cell death signaling in an oligodendroglial cell line. J. Lipid Res. 57(11), 2028-2039, 2016.
M. Podbielska, A. Das, A. W. Smith, A. Chauhan, S. K. Ray, J. Inoue, M. Azuma, K. Nozaki, E.L. Hogan and N.L. Banik. Neuron-Microglia Interaction Induced Bi- directional Cytotoxicity Associated with Calpain Activation. J. Neurochem. 139(3), 440-455, 2016.
J. O’Keeffe, M. Podbielska, E.L. Hogan. Invariant natural killer cells and their ligands: focus on multiple sclerosis. Immunology 145, 468-475, 2015.
M. Podbielska, N.L. Banik, E. Kurowska, E.L. Hogan. Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination. Brain Sci. 3, 1282-1324, 2013.
E.L. Hogan, M. Podbielska, J. O’Keeffe. Implications of lymphocyte anergy to glycolipids in multiple sclerosis (MS): iNKT cells may mediate the MS infectious trigger. J. Clin. Cell. Immunol. 4, 144, 2013.
C. Gately, M. Podbielska, T. Counihan, M. Hennessy, T. Leahy, A.P. Moran, E. L. Hogan, J. O’Keeffe. Invariant natural killer T-cell anergy of circulating lymphocytes to myelin polyacetylated-β-galactosyl-ceramides in multiple sclerosis. J. Neuroimmunol. 259 (1-2), 1-7, 2013.
M. Podbielska, H. Krotkiewski and E.L. Hogan. Signaling and regulatory functions of bioactive sphingolipids as therapeutic targets in multiple sclerosis. Neurochem. Res. 37, 1154-1169, 2012.
M. Podbielska, S.B. Levery and E.L. Hogan. The structural and functional role of myelin fast-migrating cerebrosides: pathological importance in multiple sclerosis. Clin. Lipidol. 6(2), 159-179, 2011.
M. Podbielska, S. Dasgupta, S.B. Levery, W.W. Tourtellotte, H. Annuk, A.P. Moran, E.L. Hogan. Novel myelin penta- and hexa-acetyl-galactosyl-ceramides: structural characterization and immunoreactivity in cerebrospinal fluid. J. Lipid Res. 51(6), 1394-1406, 2010.
M. Podbielska and E.L. Hogan. Molecular and immunogenic features of myelin lipids: incitants or modulators of multiple sclerosis? Mult. Scler. 15(9), 1011-1029, 2009.