Neuroimmunology: An expanding frontier in 21st century neurology

Pakistan Journal of Neurological Sciences (PJNS), Dec 2017

The recent discovery of functional lymphatic vessels lining the dural sinuses shattered the long held view of the absence of CNS lymphatic vas culature and provided solid neuroanatomical ground for Neuroimmunology1. Moreover, it has been shown that there is the presence of what is known as the inflammatory reflex.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://ecommons.aku.edu/cgi/viewcontent.cgi?article=1193&context=pjns

Neuroimmunology: An expanding frontier in 21st century neurology

Pakistan Journal of Neurological Sciences (PJNS) Neuroimmunolog y: An expanding frontier in 21st centur y neurolog y Mohammad Saeed 0 0 Shifa International Hospital, Shifa Tameer-e-Millat University , Islamabad - Article 1 Neuroimmunology: An expanding frontier in 21st century Neurology 1Consultant Rheumatologist, Medlife Clinic, 2South City Hospital, Karachi, 3Professor of Neurology, Shifa International Hospital, Shifa Tameer-e-Millat University, Islamabad Date of submission: May 22, 2017 Date of revision: June 29, 201 7 Date of acceptance: June, 2017 The recent discovery of functional lymphatic vessels lining the dural sinuses shattered the long held view of the absence of CNS lymphatic vas culature and provided solid neuroanatomical ground for Neuroimmunology1. Moreover, it has been shown that there is the presence of what is known as the inflammatory reflex. This is mediated by sensory neurons and transmitted directly to immune cells such as the macro phages and T-cells via specialized cholinergic receptors2. These findings demonstrate a strong interaction between the nervous and immune systems. One of the major proteins that contribute to the pathogenesis of Parkinson's disease (PD) is alpha-synuclein (aSyn). Surprisingly, alpha-synuclein pathogenic inclusions were recently shown spread to the brain from the gastro intestinal tract (GIT) in a manner similar to prion diseases3. With the vagus nerve tracking through the GIT, it plays a key role in the interaction of the brain with the immune system. Inflammation in the GIT leads to over expression and aggregation of aSyn in the enteric nervous system and spreads to the vagal dorsal motor nucleus in the brainstem via the nerve4. GIT micro bio me has been shown to be a key component of this spread by release of mediators affecting inflammation3.The prion-like mechanism of spread has previously been demonstrated for ALS as well5, where mutant SOD1 converts normal mitochondrial SOD1 into an abnormal protein leading to mitochondrial aggregations and dys function5. In the brain, the astrocytes maintain the blood-brain-barried (BBB) while the micro glia directly contribute to immune defense mechanisms. Alzheimer's disease (AD) is characterized by plaques and neuro fibrillary tangles (NFT), the latter being composed predominantly of the misfolded protein Tau. In a mouse model it was shown that antibodies directed against Tau prevented the spread of NFTs. Modulation of the Fc portion of the antibodies led to absence of binding to micro glia with consequent reduction of release of inflammatory mediators and ensuing neuroinflammation6. Thus such a strategy could have immune-therapeutic effects onAD. Multiple sclerosis (MS) has seen rapid immun other apeutic advances with the advent of monoclonal antibodies. Nataluzimab (an integrin inhibitor preventing lymphocyte extra vasation) and Rituximab (B-cell inhibitor) showed remarkable success in disease management. Recently Ocrelizumab, a humanized form of Rituximab, was recently approved by FDA for treatment of Primary progressive MS7. Teriflunamide, a hepatic metabolite of an old antirheumatic drug - Leflunomide, was also approved by FDA for MS8. In resource limited countries such as Pakistan, Leflunomide has been successfully used for treatment of MS, though formal studies to assess its efficacy are currently lacking. Several neuropsychiatric syndromes and immune encephalitis are now yielding to the power of Neuroimmunology and being routinely diagnosed to be mediated by antibodies such as the anit-GABA, anti-NMDA, anti-VGKC (CASPR2& LGI1) and the more familiar dsDNA. This has opened doors to treatments which were previously impossible. Now chemical or biological immunomodulators are helping to bring such vague diseases under excellent clinical control. Furthermore the recent introduction of onco-neural antibodies is an added tool in the diagnosis of previously elusive paraneoplastic neurological syndromes. These pathobiologic advances, combined with immunotherapeutics and a broad range of available antibody tests has made Neuroimmunology a major diagnostic and therapeutic field of immense clinical significance. P A K I S T A N J O U R N A L O F N E U R O L O G I C A L S C I E N C E S 0 1 Conflict of interest: Author declares no conflict of interest. Funding disclosure: Nil Author's contribution: Mohammad Saeed; concept, data collection, data analysis, manuscript writing, manuscript review Arsalan Ahmed; data collection, data analysis, manuscript writing, manuscript review 1. Louveau A , Smirnov I , Keyes TJ , et al. Structural and functionalfeatures of central nervous system lymphatic vessels . Nature . 2015 Jul16; 523 ( 7560 ): 337 - 41 . PubMed PMID: 26030524 2. Pavlov VA , Tracey KJ . Neural circuitry and immunity . Immunol Res . 2015 Dec; 63 ( 1- 3 ): 38 - 57 . PubMed PMID: 26512000 . 3. Sampson TR , Debelius JW , Thron T , et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease . Cell. 2016 Dec 1 ; 167 ( 6 ): 1469 - 1480 e12. PubMed 27912057. 4. Houser MC , Tansey MG . The gut-brain axis: is intestinal inflammation a silent driver of Parkinson's disease pathogenesis? NPJ Parkinsons Dis . 2017 Jan 11 ; 3:3 . PubMed PMID : 28649603 . 5. Deng HX , Shi Y , Furukawa Y , et al. Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria . ProcNatlAcadSci U S A. 2006 May 2 ; 103 ( 18 ): 7142 - 7 . PubMed PMID: 16636275 . 5. Deng HX , Shi Y , Furukawa Y , et al. Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria . ProcNatlAcadSci U S A. 2006 May 2 ; 103 ( 18 ): 7142 - 7 . PubMed PMID: 16636275 . 6. Lee SH , Le Pichon CE , Adolfsson O , et al. Antibody-Mediated Targeting of Tau In Vivo Does Not Require Effector Function and Microglial Engagement . Cell Rep . 2016 Aug 9 ; 16 ( 6 ): 1690 - 1700 . PubMed PMID: 27475227 . 7. Montalban X , Hauser SL , Kappos L , et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis . N Engl J Med 2017 ; 376 : 209 - 220 . 8. O 'Connor P , Wolinsky JS , Confavreux C , et al. Randomized trial of oral teriflunomide for relapsingmultiple sclerosis . New Engl J Med 2011 ; 365 : 1293 - 1303 .


This is a preview of a remote PDF: https://ecommons.aku.edu/cgi/viewcontent.cgi?article=1193&context=pjns

Mohammad Saeed, Arsalan Ahmad. Neuroimmunology: An expanding frontier in 21st century neurology, Pakistan Journal of Neurological Sciences (PJNS), 2017,