Dendritic Cells as a Nexus for the Development of Multiple Sclerosis and Models of Disease

Multiple sclerosis (MS) results from an autoimmune attack on the central nervous system (CNS). Dysregulated immune cells invade the CNS, causing demyelination, neuronal and axonal damage, and subsequent neurological disorders. Although antigen-specific T cells mediate the immunopathology of MS, innate myeloid cells have essential contributions to CNS tissue damage. Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that promote inflammation and modulate adaptive immune responses. This review focuses on DCs as critical components of CNS inflammation. Here, evidence from studies is summarized with animal models of MS and MS patients that support the critical role of DCs in orchestrating CNS inflammation.

[1]  Gregory F. Wu,et al.  A single-cell analysis framework allows for characterization of CSF leukocytes and their tissue of origin in multiple sclerosis , 2022, Science Translational Medicine.

[2]  B. Becher,et al.  Single-cell multiomics in neuroinflammation. , 2022, Current opinion in immunology.

[3]  F. Ginhoux,et al.  Twin study reveals non-heritable immune perturbations in multiple sclerosis , 2022, Nature.

[4]  F. Ginhoux,et al.  IFNγ and GM-CSF control complementary differentiation programs in the monocyte-to-phagocyte transition during neuroinflammation , 2022, Nature Immunology.

[5]  F. Ginhoux,et al.  Expanding dendritic cell nomenclature in the single-cell era , 2022, Nature Reviews Immunology.

[6]  F. Quintana,et al.  The Immune Response in Multiple Sclerosis. , 2021, Annual review of pathology.

[7]  D. Reich,et al.  A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis , 2021, Nature.

[8]  L. Bozzacco,et al.  Unboxing dendritic cells: Tales of multi‐faceted biology and function , 2021, Immunology.

[9]  W. Brück,et al.  CNS inflammation after natalizumab therapy for multiple sclerosis: A retrospective histopathological and CSF cohort study , 2021, Brain pathology.

[10]  J. Gordon,et al.  Regulatory Dendritic Cells, T Cell Tolerance, and Dendritic Cell Therapy for Immunologic Disease , 2021, Frontiers in Immunology.

[11]  C. Reis e Sousa,et al.  Dendritic Cells Revisited. , 2021, Annual review of immunology.

[12]  H. Waldner,et al.  Priming of myelin-specific T cells in the absence of dendritic cells results in accelerated development of Experimental Autoimmune Encephalomyelitis , 2020, bioRxiv.

[13]  N. Voelcker,et al.  Inducing immune tolerance with dendritic cell-targeting nanomedicines , 2020, Nature Nanotechnology.

[14]  E. Leray,et al.  Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition , 2020, Multiple sclerosis.

[15]  M. Mann,et al.  Cell-Type- and Brain-Region-Resolved Mouse Brain Lipidome. , 2020, Cell reports.

[16]  S. Nutt,et al.  Transcriptional Networks Driving Dendritic Cell Differentiation and Function. , 2020, Immunity.

[17]  I. Amit,et al.  Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation , 2020, Nature Immunology.

[18]  E. Kenigsberg,et al.  A conserved dendritic-cell regulatory program limits antitumour immunity , 2020, Nature.

[19]  F. Tang,et al.  Meningeal lymphatic vessels regulate brain tumor drainage and immunity , 2020, Cell Research.

[20]  H. D. de Vries,et al.  Inflammation of the choroid plexus in progressive multiple sclerosis: accumulation of granulocytes and T cells , 2020, Acta Neuropathologica Communications.

[21]  N. Yosef,et al.  Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis , 2018, Nature Communications.

[22]  P. Parizel,et al.  Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration , 2019, BMJ Open.

[23]  F. Ginhoux,et al.  Single-Cell Analysis of Human Mononuclear Phagocytes Reveals Subset-Defining Markers and Identifies Circulating Inflammatory Dendritic Cells. , 2019, Immunity.

[24]  B. Becher,et al.  GM-CSF and CXCR4 Define a T Helper Cell Signature in Multiple Sclerosis , 2019, Nature Medicine.

[25]  B. Becher,et al.  Fate-Mapping of GM-CSF Expression Identifies a Discrete Subset of Inflammation-Driving T Helper Cells Regulated by Cytokines IL-23 and IL-1β. , 2019, Immunity.

[26]  M. Juan,et al.  Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide-loaded tolerogenic dendritic cells in a phase 1b trial , 2019, Proceedings of the National Academy of Sciences.

[27]  F. Quintana Myeloid cells in the central nervous system: So similar, yet so different , 2019, Science Immunology.

[28]  B. Becher,et al.  Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation , 2019, Science Immunology.

[29]  Guang-Xian Zhang,et al.  Distinct Role of IL-27 in Immature and LPS-Induced Mature Dendritic Cell-Mediated Development of CD4+ CD127+3G11+ Regulatory T Cell Subset , 2018, Front. Immunol..

[30]  M. Filippi,et al.  Multiple sclerosis , 2018, Nature Reviews Disease Primers.

[31]  S. Eisenbarth Dendritic cell subsets in T cell programming: location dictates function , 2018, Nature Reviews Immunology.

[32]  Jonathan Kipnis,et al.  The Meningeal Lymphatic System: A New Player in Neurophysiology , 2018, Neuron.

[33]  Christopher C. Overall,et al.  CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature , 2018, Nature Neuroscience.

[34]  Eyal David,et al.  Microglial MHC class II is dispensable for experimental autoimmune encephalomyelitis and cuprizone‐induced demyelination , 2018, European journal of immunology.

[35]  Clare Baecher-Allan,et al.  Multiple Sclerosis: Mechanisms and Immunotherapy , 2018, Neuron.

[36]  Z. Berneman,et al.  To the Brain and Back: Migratory Paths of Dendritic Cells in Multiple Sclerosis , 2018, Journal of neuropathology and experimental neurology.

[37]  B. Becher,et al.  High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease. , 2018, Immunity.

[38]  N. Pochet,et al.  Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis , 2017, Nature Communications.

[39]  T. Dubovik,et al.  High-dimensional, single-cell characterization of the brain's immune compartment , 2017, Nature Neuroscience.

[40]  Xia Zhang,et al.  Multiple sclerosis: Pathology, diagnosis and treatments , 2017, Experimental and therapeutic medicine.

[41]  B. Clarkson,et al.  CCR7 deficient inflammatory Dendritic Cells are retained in the Central Nervous System , 2017, Scientific Reports.

[42]  F. Quintana,et al.  Tolerogenic dendritic cells , 2016, Seminars in Immunopathology.

[43]  N. McGovern,et al.  Unsupervised High-Dimensional Analysis Aligns Dendritic Cells across Tissues and Species , 2016, Immunity.

[44]  Steffen Jung,et al.  Gatekeeper role of brain antigen‐presenting CD11c+ cells in neuroinflammation , 2016, The EMBO journal.

[45]  E. Cano,et al.  DNGR‐1+ dendritic cells are located in meningeal membrane and choroid plexus of the noninjured brain , 2015, Glia.

[46]  C. Yang,et al.  Inhibition of Interferon Regulatory Factor 4 Suppresses Th1 and Th17 Cell Differentiation and Ameliorates Experimental Autoimmune Encephalomyelitis , 2015, Scandinavian journal of immunology.

[47]  B. Becher,et al.  The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity. , 2015, Immunity.

[48]  Manuel A. Friese,et al.  Immunopathology of multiple sclerosis , 2015, Nature Reviews Immunology.

[49]  M. Colonna,et al.  The multifaceted biology of plasmacytoid dendritic cells , 2015, Nature Reviews Immunology.

[50]  B. Clarkson,et al.  CCR2-Dependent Dendritic Cell Accumulation in the Central Nervous System during Early Effector Experimental Autoimmune Encephalomyelitis Is Essential for Effector T Cell Restimulation In Situ and Disease Progression , 2015, The Journal of Immunology.

[51]  B. Clarkson,et al.  Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE , 2014, Journal of Neuroimmunology.

[52]  E. Unanue,et al.  Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model , 2014, The Journal of experimental medicine.

[53]  Y. Ao,et al.  Astrocyte CCL2 sustains immune cell infiltration in chronic experimental autoimmune encephalomyelitis , 2014, Journal of Neuroimmunology.

[54]  Florent Ginhoux,et al.  Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny , 2014, Nature Reviews Immunology.

[55]  K. Kristensson,et al.  Tryps and trips: cell trafficking across the 100-year-old blood–brain barrier , 2014, Trends in Neurosciences.

[56]  Steffen Jung,et al.  Development and function of dendritic cell subsets. , 2014, Immunity.

[57]  Aly A. Khan,et al.  Transcriptional programming of dendritic cells for enhanced MHC class II antigen presentation , 2013, Nature Immunology.

[58]  V. Kuchroo,et al.  IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39 , 2013, Nature Immunology.

[59]  Miriam Merad,et al.  The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. , 2013, Annual review of immunology.

[60]  B. Becher,et al.  Communication between pathogenic T cells and myeloid cells in neuroinflammatory disease. , 2013, Trends in immunology.

[61]  H. Hammad,et al.  Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. , 2013, Immunity.

[62]  C. Constantinescu,et al.  Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS) , 2011, British journal of pharmacology.

[63]  R. Steinman,et al.  Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain , 2011, The Journal of experimental medicine.

[64]  J. Libbey,et al.  Experimental autoimmune encephalomyelitis as a testing paradigm for adjuvants and vaccines. , 2011, Vaccine.

[65]  B. Engelhardt,et al.  Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle , 2011, Fluids and Barriers of the CNS.

[66]  A. Damasceno,et al.  Plasmacytoid dendritic cells are increased in cerebrospinal fluid of untreated patients during multiple sclerosis relapse , 2011, Journal of Neuroinflammation.

[67]  R. Steinman,et al.  Microbial Stimulation Fully Differentiates Monocytes to DC-SIGN/CD209+ Dendritic Cells for Immune T Cell Areas , 2010, Cell.

[68]  B. Engelhardt,et al.  α4β1 Integrin Mediates the Recruitment of Immature Dendritic Cells across the Blood-Brain Barrier during Experimental Autoimmune Encephalomyelitis , 2010, The Journal of Immunology.

[69]  A. Mildner,et al.  CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. , 2009, Brain : a journal of neurology.

[70]  L. Fugger,et al.  Pathogenic CD8+ T cells in multiple sclerosis , 2009, Annals of neurology.

[71]  A. Lüth,et al.  Topical application of sphingosine-1-phosphate and FTY720 attenuate allergic contact dermatitis reaction through inhibition of dendritic cell migration. , 2009, The Journal of investigative dermatology.

[72]  B. Engelhardt,et al.  Cutting Edge: Natalizumab Blocks Adhesion but Not Initial Contact of Human T Cells to the Blood-Brain Barrier In Vivo in an Animal Model of Multiple Sclerosis1 , 2009, The Journal of Immunology.

[73]  Irah L. King,et al.  Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. , 2009, Blood.

[74]  D. Voehringer,et al.  Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity , 2009, The Journal of experimental medicine.

[75]  B. Hemmer,et al.  Decrease in the numbers of dendritic cells and CD4+ T cells in cerebral perivascular spaces due to natalizumab. , 2008, Archives of neurology.

[76]  W. Karpus,et al.  Production of CCL2 by Central Nervous System Cells Regulates Development of Murine Experimental Autoimmune Encephalomyelitis through the Recruitment of TNF- and iNOS-Expressing Macrophages and Myeloid Dendritic Cells1 , 2008, The Journal of Immunology.

[77]  S. Miller,et al.  Cutting Edge: Central Nervous System Plasmacytoid Dendritic Cells Regulate the Severity of Relapsing Experimental Autoimmune Encephalomyelitis1 , 2008, The Journal of Immunology.

[78]  J. Newcombe,et al.  CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions , 2007, Journal of Neuroimmunology.

[79]  P. Calabresi,et al.  Dendritic cells are abundant in non-lesional gray matter in multiple sclerosis. , 2007, Experimental and molecular pathology.

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

[81]  D. Gray,et al.  IL-10 permits transient activation of dendritic cells to tolerize T cells and protect from central nervous system autoimmune disease. , 2007, International immunology.

[82]  T. Ziemssen,et al.  Glatiramer acetate: mechanisms of action in multiple sclerosis. , 2007, Autoimmunity reviews.

[83]  S. Miller,et al.  CNS myeloid DCs presenting endogenous myelin peptides 'preferentially' polarize CD4+ TH-17 cells in relapsing EAE , 2007, Nature Immunology.

[84]  J. Goverman,et al.  Active induction of experimental allergic encephalomyelitis , 2006, Nature Protocols.

[85]  J. Goverman,et al.  Passive induction of experimental allergic encephalomyelitis , 2006, Nature Protocols.

[86]  G. Mancardi,et al.  Dendritic Cells in Multiple Sclerosis Lesions: Maturation Stage, Myelin Uptake, and Interaction With Proliferating T Cells , 2006, Journal of neuropathology and experimental neurology.

[87]  K. Chiba FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. , 2005, Pharmacology & therapeutics.

[88]  B. Becher,et al.  Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis , 2005, Nature Medicine.

[89]  T. Mcclanahan,et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation , 2005, The Journal of experimental medicine.

[90]  Kazuo Suzuki,et al.  Critical roles of interferon regulatory factor 4 in CD11bhighCD8α– dendritic cell development , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[91]  R. Ravid,et al.  Expression of CCR7 in multiple sclerosis: Implications for CNS immunity , 2004, Annals of neurology.

[92]  M. Kapsenberg Dendritic-cell control of pathogen-driven T-cell polarization , 2003, Nature Reviews Immunology.

[93]  H. Link,et al.  Inflammation in the Central Nervous System: the Role for Dendritic Cells , 2003, Brain pathology.

[94]  P. Lipsky,et al.  Dendritic cells, chemokine receptors and autoimmune inflammatory diseases , 2002, Immunology and cell biology.

[95]  V. Kostulas,et al.  Elevated expression of CCR5 by myeloid (CD11c+) blood dendritic cells in multiple sclerosis and acute optic neuritis , 2002, Clinical and experimental immunology.

[96]  Laurence Zitvogel,et al.  Antigen presentation and T cell stimulation by dendritic cells. , 2002, Annual review of immunology.

[97]  Michel C. Nussenzweig,et al.  Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo , 2001, The Journal of experimental medicine.

[98]  B. Rollins,et al.  Absence of Monocyte Chemoattractant Protein 1 in Mice Leads to Decreased Local Macrophage Recruitment and Antigen-Specific T Helper Cell Type 1 Immune Response in Experimental Autoimmune Encephalomyelitis , 2001, The Journal of experimental medicine.

[99]  V. Kostulas,et al.  Two subsets of dendritic cells are present in human cerebrospinal fluid. , 2001, Brain : a journal of neurology.

[100]  R. Coffman,et al.  Interleukin-10 and the interleukin-10 receptor. , 2001, Annual review of immunology.

[101]  C. D. DE GROOT,et al.  Macrophage inflammatory protein‐1α (MIP‐1α), MIP‐1β, and RANTES mRNA semiquantification and protein expression in active demyelinating multiple sclerosis (MS) lesions , 2000 .

[102]  H. Weiner,et al.  Resistance to Experimental Autoimmune Encephalomyelitis in Mice Lacking the Cc Chemokine Receptor (Ccr2) , 2000, The Journal of experimental medicine.

[103]  W. Kuziel,et al.  Cc Chemokine Receptor 2 Is Critical for Induction of Experimental Autoimmune Encephalomyelitis , 2000, The Journal of experimental medicine.

[104]  L. Steinman,et al.  Perivascular T Cells Express the Pro‐Inflammatory Chemokine RANTES mRNA in Multiple Sclerosis Lesions , 1997, Scandinavian journal of immunology.

[105]  M. Béné,et al.  Ultrastructural and immunohistological evidence for dendritic‐like cells within human choroid plexus epithelium , 1997, Neuroreport.

[106]  V. Perry,et al.  Stromal macrophages of the choroid plexus situated at an interface between the brain and peripheral immune system constitutively express major histocompatibility class II antigens , 1992, Journal of Neuroimmunology.

[107]  D. Linthicum,et al.  Acute experimental autoimmune encephalomyelitis in mice. I. Adjuvant action of Bordetella pertussis is due to vasoactive amine sensitization and increased vascular permeability of the central nervous system. , 1982, Cellular immunology.

[108]  A. Meshorer,et al.  Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide , 1971, European journal of immunology.