title: Mucopolysaccharide diseases: a complex interplay between neuroinflammation, microglial activation and adaptive immunity.
abstract: Mucopolysaccharide (MPS) diseases are lysosomal storage disorders (LSDs) caused by deficiencies in enzymes required for glycosaminoglycan (GAG) catabolism. Mucopolysaccharidosis I (MPS I), MPS IIIA, MPS IIIB and MPS VII are deficient in the enzymes α-L-Iduronidase, Heparan-N-Sulphatase, N-Acetylglucosaminidase and Beta-Glucuronidase, respectively. Enzyme deficiency leads to the progressive multi-systemic build-up of heparan sulphate (HS) and dermatan sulphate (DS) within cellular lysosomes, followed by cell, tissue and organ damage and in particular neurodegeneration. Clinical manifestations of MPS are well established; however as lysosomes represent vital components of immune cells, it follows that lysosomal accumulation of GAGs could affect diverse immune functions and therefore influence disease pathogenesis. Theoretically, MPS neurodegeneration and GAGs could be substantiating a threat of danger and damage to alert the immune system for cellular clearance, which due to the progressive nature of MPS storage would propagate disease pathogenesis. Innate immunity appears to have a key role in MPS; however the extent of adaptive immune involvement remains to be elucidated. The current literature suggests a complex interplay between neuroinflammation, microglial activation and adaptive immunity in MPS disease.
authors: The Transplant Centre, UHSM, University of Manchester, Manchester, England, UK.
authors: Louise D
authors: LD
authors: Archer
authors: Kia J
authors: KJ
authors: Langford-Smith
authors: Brian W
authors: BW
authors: Bigger
authors: James E
authors: JE
authors: Fildes
mesh_terms: D056704:Adaptive Immunity; D001343:Autophagy; D001402:B-Lymphocytes / Q000166:cytology; D003713:Dendritic Cells / Q000166:cytology; D004798:Enzymes / Q000172:deficiency; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism; D017628:Microglia / Q000473:pathology*; D009083:Mucopolysaccharidoses / Q000175:diagnosis* / Q000276:immunology* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000276:immunology; D009474:Neurons / Q000473:pathology*; D018384:Oxidative Stress; D010455:Peptides / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D004798:Enzymes; D010455:Peptides; D051193:Toll-Like Receptors
references: Mediators Inflamm. 2010;2010:
references: 20706656
references: J Innate Immun. 2011;3(4):411-9
references: 21178327
references: Cell Signal. 1998 Oct;10(9):619-28
references: 9794243
references: J Immunol. 1991 Jul 15;147(2):455-9
references: 1830063
references: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):345-50
references: 11756671
references: Acta Neuropathol. 2008 Feb;115(2):159-74
references: 17924126
references: Brain Res. 2000 Jul 7;870(1-2):211-21
references: 10869521
references: Biochim Biophys Acta. 2009 Apr;1793(4):664-73
references: 18706940
references: J Immunol. 2009 Dec 15;183(12):7832-41
references: 19933854
references: J Clin Invest. 2006 Apr;116(4):905-15
references: 16557302
references: J Exp Med. 1991 May 1;173(5):1099-109
references: 2022921
references: J Immunol. 2007 Mar 1;178(5):2721-9
references: 17312114
references: J Neurosci. 2006 Dec 6;26(49):12826-37
references: 17151286
references: Curr Opin Immunol. 2010 Jun;22(3):333-40
references: 20363604
references: PLoS One. 2011 Jan 27;6(1):e16269
references: 21298000
references: Nat Neurosci. 2007 Nov;10(11):1387-94
references: 17965659
references: Semin Immunol. 1993 Dec;5(6):393-400
references: 7510137
references: Arch Dis Child. 1993 Sep;69(3):403-6
references: 8215557
references: J Neurochem. 2006 Nov;99(4):1176-87
references: 17018025
references: EMBO J. 2010 Nov 3;29(21):3607-20
references: 20871593
references: Genes Brain Behav. 2011 Aug;10(6):673-82
references: 21635693
references: J Immunol. 2003 Mar 1;170(5):2540-8
references: 12594280
references: J Immunol. 2000 Aug 1;165(3):1599-604
references: 10903769
references: J Leukoc Biol. 2004 Jun;75(6):1010-5
references: 15020649
references: Pediatrics. 2009 Jan;123(1):19-29
references: 19117856
references: J Immunol. 2003 Nov 15;171(10):5140-7
references: 14607913
references: J Pediatr. 2004 May;144(5 Suppl):S27-34
references: 15126981
references: J Neurochem. 1978 May;30(5):965-73
references: 96217
references: Curr Opin Immunol. 2007 Feb;19(1):87-92
references: 17129719
references: Annu Rev Immunol. 1994;12:991-1045
references: 8011301
references: J Biol Chem. 2005 Jun 24;280(25):23820-8
references: 15805102
references: Ann N Y Acad Sci. 2002 May;962:318-31
references: 12076984
references: Genet Mol Biol. 2010 Oct;33(4):589-604
references: 21637564
references: J Clin Invest. 2004 Jan;113(2):200-8
references: 14722612
references: Semin Immunopathol. 2010 Dec;32(4):397-413
references: 20740284
references: J Biol Chem. 2004 Jan 9;279(2):1415-21
references: 14578353
references: Mol Cell Neurosci. 2005 Jul;29(3):381-93
references: 15890528
references: Nat Med. 1999 Nov;5(11):1249-55
references: 10545990
references: J Immunol. 2000 Apr 1;164(7):3573-80
references: 10725712
references: Eur J Immunol. 1994 Jan;24(1):239-46
references: 8020562
references: Cold Spring Harb Perspect Biol. 2010 Oct;2(10):a005579
references: 20826549
references: Immunity. 2001 Feb;14(2):145-55
references: 11239447
references: Paediatr Respir Rev. 2011 Jun;12(2):133-8
references: 21458742
references: J Exp Med. 2006 Oct 2;203(10):2293-303
references: 16982810
references: Cell Death Differ. 2005 Nov;12 Suppl 2:1509-18
references: 16247498
references: Transplantation. 1994 Apr 15;57(7):1087-94
references: 8165708
references: Rheumatology (Oxford). 2011 Dec;50 Suppl 5:v41-8
references: 22210670
references: Curr Mol Med. 2009 Feb;9(1):4-14
references: 19199937
references: J Exp Med. 1992 Jul 1;176(1):287-92
references: 1613462
references: J Comp Neurol. 2004 Dec 20;480(4):415-26
references: 15558784
references: J Neuroinflammation. 2008 Oct 09;5:43
references: 18844999
references: J Immunol. 1999 Nov 15;163(10):5353-7
references: 10553059
references: J Leukoc Biol. 1999 Sep;66(3):391-400
references: 10496308
references: J Immunol. 2002 May 15;168(10):5233-9
references: 11994480
references: J Immunol. 2000 Oct 1;165(7):3804-10
references: 11034386
references: FEBS Lett. 1987 Nov 2;223(2):284-8
references: 2822487
references: J Leukoc Biol. 2008 Apr;83(4):853-63
references: 18162511
references: Brain Res. 2009 Jul 7;1279:99-108
references: 19409882
references: Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13766-71
references: 11095740
references: J Immunol. 2001 Mar 15;166(6):3789-96
references: 11238621
references: Neurochem Res. 2003 Oct;28(10):1563-74
references: 14570402
references: Biochem Biophys Res Commun. 2004 Jan 9;313(2):453-8
references: 14684184
references: J Immunol. 2002 Jun 1;168(11):5521-9
references: 12023347
references: Nat Rev Mol Cell Biol. 2005 Jun;6(6):439-48
references: 15928708
references: J Immunol. 2010 Jul 15;185(2):1238-47
references: 20554956
references: Science. 2002 Apr 12;296(5566):301-5
references: 11951032
references: J Exp Med. 1996 Jun 1;183(6):2669-74
references: 8676088
references: Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10954-9
references: 11005868
references: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2580-5
references: 18250339
references: Immunity. 1996 Jun;4(6):565-71
references: 8673703
references: Nat Med. 1999 Jan;5(1):90-6
references: 9883845
references: Glia. 2004 Nov 15;48(3):197-206
references: 15390122
references: Nat Rev Neurosci. 2007 Jan;8(1):57-69
references: 17180163
references: Nat Immunol. 2011 Jun 19;12(8):770-7
references: 21685908
references: J Neurol Neurosurg Psychiatry. 1987 Jun;50(6):699-703
references: 3112309
references: Brain. 2006 Jan;129(Pt 1):212-23
references: 16230319
references: J Immunol. 1993 Apr 1;150(7):2659-67
references: 8454848
references: Immunol Rev. 2009 Jan;227(1):234-47
references: 19120488
references: Am J Transplant. 2006 Sep;6(9):2023-34
references: 16827791
references: Cell Tissue Res. 2011 Jan;343(1):43-55
references: 20734065
references: Brain Res. 1992 Aug 7;587(2):250-6
references: 1381982
references: Immunobiology. 2004;209(1-2):79-87
references: 15481143
references: Immunology. 2008 Mar;123(3):314-25
references: 18067554
references: Semin Immunopathol. 2009 Nov;31(4):513-25
references: 19763574
references: Semin Immunol. 2003 Feb;15(1):23-32
references: 12495638
references: J Inherit Metab Dis. 2013 Mar;36(2):257-62
references: 22773246
references: J Immunol. 2005 Feb 1;174(3):1566-73
references: 15661917
references: Adv Exp Med Biol. 2005;560:11-8
references: 15932016
references: Brain Res Mol Brain Res. 2002 Jun 30;103(1-2):12-27
references: 12106688
references: Mol Biol Cell. 2006 Feb;17(2):623-33
references: 16280358
references: Eur J Immunol. 2009 Oct;39(10):2748-54
references: 19637231
references: J Immunol. 2004 Sep 15;173(6):3916-24
references: 15356140
references: Nature. 1986 Nov 20-26;324(6094):266-8
references: 2946959
references: Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8425-30
references: 15155903
references: Mol Med. 2010 Mar;16(3-4):116-21
references: 20200619
references: Nature. 1997 Oct 16;389(6652):737-42
references: 9338786
references: J Neuroimmunol. 2008 Oct 15;203(1):50-7
references: 18657867
references: J Clin Invest. 2008 Aug;118(8):2686-9
references: 18654672
references: Nat Rev Immunol. 2002 Oct;2(10):735-47
references: 12360212
references: Science. 2004 Dec 3;306(5702):1786-9
references: 15539565
references: Mol Cell Biol. 2005 Feb;25(3):1025-40
references: 15657430
references: Neuroscience. 2009 Feb 6;158(3):1021-9
references: 18662748
references: Front Biosci. 1998 Mar 15;3:d313-24
references: 9488657
references: Int Immunol. 2006 Feb;18(2):291-300
references: 16361310
references: Cell Mol Neurobiol. 2009 Jun;29(4):443-8
references: 19109767
references: Pediatr Res. 2000 Jun;47(6):757-62
references: 10832733
references: PLoS One. 2012;7(4):e35787
references: 22558223
references: Neuroreport. 1999 Mar 17;10(4):703-6
references: 10208534
references: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1902-7
references: 12576554
references: Nat Rev Immunol. 2001 Dec;1(3):220-8
references: 11905831
references: J Immunol. 1995 Jan 15;154(2):871-80
references: 7814890
references: Ann Neurol. 2004 Nov;56(5):642-9
references: 15505823
references: Autophagy. 2007 May-Jun;3(3):259-62
references: 17329960
references: J Neuroinflammation. 2010 Jul 16;7:39
references: 20637096
references: J Exp Med. 2003 May 5;197(9):1141-51
references: 12732656
references: J Cell Sci. 2004 Aug 15;117(Pt 18):4219-30
references: 15316082
references: Annu Rev Immunol. 1998;16:323-58
references: 9597133
references: FASEB J. 2010 Nov;24(11):4459-66
references: 20624927
references: J Neurosci Res. 2009 Mar;87(4):978-90
references: 18951493
references: J Neurosci Res. 2007 Feb 15;85(3):612-22
references: 17139681
references: Mol Genet Metab. 2011 May;103(1):18-25
references: 21353610
references: Nat Immunol. 2004 May;5(5):524-30
references: 15048111
references: Endocrinology. 2009 Apr;150(4):2000-7
references: 19008314
references: J Neuroimmune Pharmacol. 2009 Dec;4(4):399-418
references: 19655259
references: Blood. 2009 Mar 5;113(10):2256-64
references: 18948575
references: J Immunol. 2007 May 15;178(10):6476-81
references: 17475877
references: J Biol Chem. 1997 Sep 12;272(37):23111-6
references: 9287312
references: Annu Rev Immunol. 1996;14:369-96
references: 8717519
references: Annu Rev Neurosci. 2001;24:677-736
references: 11520916
references: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3029-34
references: 14981245
references: J Biol Chem. 2011 Oct 28;286(43):37515-24
references: 21873421
references: Annu Rev Immunol. 1993;11:331-60
references: 8476565
references: Glia. 2000 Apr;30(2):134-42
references: 10719355
references: Arch Dis Child. 1995 Mar;72(3):263-7
references: 7741581
references: Brain. 2009 Feb;132(Pt 2):288-95
references: 18567623
references: Nat Rev Immunol. 2004 Jun;4(6):469-78
references: 15173835
references: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13632-7
references: 14581618
references: J Leukoc Biol. 2007 Jan;81(1):1-5
references: 17032697
references: Hum Immunol. 2005 Dec;66(12):1193-202
references: 16690406
references: J Neuroimmunol. 2000 Oct 2;110(1-2):177-85
references: 11024548
references: PLoS One. 2008 May 28;3(5):e2296
references: 18509511
references: Mol Cell Neurosci. 2006 Jan;31(1):149-60
references: 16297637
references: PLoS One. 2011;6(10):e25717
references: 22028789
references: J Neuroimmunol. 2010 Jul 27;224(1-2):93-100
references: 20681057
references: Curr Top Microbiol Immunol. 2009;335:71-84
references: 19802560
references: Hum Mol Genet. 2008 Jan 1;17(1):119-29
references: 17913701
references: J Cell Biol. 2004 Jan 5;164(1):111-22
references: 14709544
references: J Clin Invest. 2008 Aug;118(8):2868-76
references: 18654665