T helper-17 activation dominates the immunologic milieu of both amyotrophic lateral sclerosis and progressive multiple sclerosis.

MS (multiple sclerosis) and ALS (amyotrophic lateral sclerosis) differ in important respects, but common pathogenic features seem to be shared in these two diseases. To shed light on such features, immunophenotypic and functional analysis were performed in peripheral monocytes and T lymphocytes of ALS and primary progressive (PP) MS patients and healthy controls (HC). Results showed that TH1-, TH17-, and IL-6-driven inflammation characterize both diseases; this is unsuccessfully hampered by TH2 activation and, possibly, BDNF secretion. Results herein clarify the pathogenic similarities between ALS and PP-MS and could be helpful for the design of novel diagnostic and therapeutic approaches to ALS.

[1]  M. Clerici,et al.  Cytokine production and surface marker expression in acute and stable multiple sclerosis: altered IL-12 production and augmented signaling lymphocytic activation molecule (SLAM)-expressing lymphocytes in acute multiple sclerosis. , 1998, Journal of immunology.

[2]  F. Annunziato,et al.  The transient nature of the Th17 phenotype , 2010, European journal of immunology.

[3]  M. Schwartz,et al.  Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: A dialogue with microglia , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Newcombe,et al.  Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration , 2012, The Journal of experimental medicine.

[5]  Andreas Radbruch,et al.  Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions. , 2010, Immunity.

[6]  M. Michalopoulou,et al.  Interleukin‐17 and interleukin‐23 are elevated in serum and cerebrospinal fluid of patients with ALS: a reflection of Th17 cells activation? , 2010, Acta neurologica Scandinavica.

[7]  L. Glimcher,et al.  T-bet in disease , 2011, Nature Immunology.

[8]  M. Filippi,et al.  Single-cell analysis of cytokine production shows different immune profiles in multiple sclerosis patients with active or quiescent disease , 2001, Journal of Neuroimmunology.

[9]  M. Clerici,et al.  Multiple sclerosis-associated retroviral agent (MSRV)-stimulated cytokine production in patients with relapsing-remitting multiple sclerosis , 2009, Multiple sclerosis.

[10]  S. Dhib-jalbut,et al.  Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis , 2002, Neurology.

[11]  W. Brück,et al.  BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? , 2002, Brain : a journal of neurology.

[12]  W. Leonard,et al.  Cytokine mediators of Th17 function , 2009, European Journal of Immunology.

[13]  Massimo Filippi,et al.  Towards a neuroimaging biomarker for amyotrophic lateral sclerosis , 2011, The Lancet Neurology.

[14]  D. Littman,et al.  Plasticity of CD4+ T cell lineage differentiation. , 2009, Immunity.

[15]  R. Flavell,et al.  Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. , 2009, Current opinion in pharmacology.

[16]  H. Neumann,et al.  Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis. , 2010, Brain : a journal of neurology.

[17]  B. Trapp,et al.  Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis , 2011, Progress in Neurobiology.

[18]  Hans Lassmann,et al.  Cortical demyelination and diffuse white matter injury in multiple sclerosis. , 2005, Brain : a journal of neurology.

[19]  Hans Lassmann,et al.  The relation between inflammation and neurodegeneration in multiple sclerosis brains , 2009, Brain : a journal of neurology.

[20]  P. Sørensen,et al.  Demyelination versus remyelination in progressive multiple sclerosis. , 2010, Brain : a journal of neurology.

[21]  R. Gold,et al.  Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination , 2011, Acta Neuropathologica.

[22]  M. Strong,et al.  The Pathobiology of Amyotrophic Lateral Sclerosis: A Proteinopathy? , 2005, Journal of neuropathology and experimental neurology.

[23]  P. Mcgeer,et al.  Inflammatory processes in amyotrophic lateral sclerosis , 2002, Muscle & nerve.

[24]  S. Sawcer,et al.  Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of C9ORF72 , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[25]  Nathalie Arbour,et al.  Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation , 2007, Nature Medicine.

[26]  F. Sallusto,et al.  Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17–producing human T helper cells , 2007, Nature Immunology.

[27]  K. Kawabe,et al.  Interleukin‐17 and ‐23 levels in amyotrophic lateral sclerosis , 2011, Acta neurologica Scandinavica.

[28]  J. Niland,et al.  Cerebrospinal fluid interleukin 6 in amyotrophic lateral sclerosis: immunological parameter and comparison with inflammatory and non-inflammatory central nervous system diseases , 1998, Journal of the Neurological Sciences.

[29]  T. Holmøy,et al.  T cells in amyotrophic lateral sclerosis , 2008, European journal of neurology.

[30]  F. Jadidi-Niaragh,et al.  Th17 Cell, the New Player of Neuroinflammatory Process in Multiple Sclerosis , 2011, Scandinavian journal of immunology.

[31]  M. Tuszynski,et al.  Potential therapeutic uses of BDNF in neurological and psychiatric disorders , 2011, Nature Reviews Drug Discovery.

[32]  M. Rovaris,et al.  Costimulatory Pathways in Multiple Sclerosis: Distinctive Expression of PD-1 and PD-L1 in Patients with Different Patterns of Disease1 , 2009, The Journal of Immunology.

[33]  Shimon Sakaguchi,et al.  Natural regulatory T cells: mechanisms of suppression. , 2007, Trends in molecular medicine.

[34]  James Sayre,et al.  IL-17A is increased in the serum and in spinal cord CD8 and mast cells of ALS patients , 2010, Journal of Neuroinflammation.

[35]  G. Guazzi,et al.  IL-6 detection in multiple sclerosis brain , 1997, Journal of the Neurological Sciences.

[36]  M. Filippi,et al.  Programmed cell death of myelin basic protein-specific T lymphocytes is reduced in patients with acute multiple sclerosis , 2005, Journal of Neuroimmunology.

[37]  Tony Wyss-Coray,et al.  Inflammation in Neurodegenerative Disease—A Double-Edged Sword , 2002, Neuron.

[38]  M. Clerici,et al.  CD4+CD25+FoxP3+PD1— regulatory T cells in acute and stable relapsing‐remitting multiple sclerosis and their modulation by therapy , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  F. Shi,et al.  Differential Effects of IL-21 during Initiation and Progression of Autoimmunity against Neuroantigen1 , 2005, The Journal of Immunology.

[40]  F. Barkhof,et al.  Use of ultrasmall superparamagnetic particles of iron oxide (USPIO)‐enhanced MRI to demonstrate diffuse inflammation in the normal‐appearing white matter (NAWM) of multiple sclerosis (MS) patients: An exploratory study , 2009, Journal of magnetic resonance imaging : JMRI.

[41]  M. Etemadifar,et al.  Multiple sclerosis and amyotrophic lateral sclerosis: is there a link? , 2012, Multiple sclerosis.