734071
research-article2017
MSJ0010.1177/1352458517734071Multiple Sclerosis JournalJI Spencer, RL Yates et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Letter
Cortical lesions and HLA genotype: Still a grey area? Date received: 26 July 2017; accepted: 23 August 2017 Substantial evidence suggests that cortical tissue injury plays a key role in the progression of permanent disability in multiple sclerosis (MS). Cortical demyelination occurs early, becomes more extensive with time and eventually exceeds the extent of white matter pathology in progressive disease. However our understanding of the mechanisms driving cortical demyelination remains poor. As a result, we lack the therapeutic targets that could enable cortical disease burden to be reduced and disease progression to be halted. A greater knowledge of the factors that drive pathology in the MS cortex is therefore desperately needed in order to develop novel medicines that can ameliorate disease burden in the progressive stage. Our group has recently demonstrated an important role for human leukocyte antigen (HLA) molecules in cortical lesion pathogenesis by showing that carriage of HLA-DRB1*15, the primary genetic risk factor for MS, is associated with more severe cortical inflammation and demyelination.1 Although our study was the first to link genetic variation with pathologic phenotypes in the cortex, it was necessarily limited to end-stage disease by virtue of a post-mortem cohort. It has heretofore remained unknown to what extent HLA genotypes influence cortical tissue injury during earlier stages of MS. To this end, a large (n = 92) magnetic resonance imaging (MRI) study published in this journal by Shinoda et al.2 extends our work and associates HLA genotype with in vivo disease. They report that HLADRB1*1501 carriers have an increased number of MRI-defined cortical lesions and also that a higher proportion of HLA-DRB1*1501 carriers have cortical lesions compared to non-carriers. Conversely, carriage of HLA-DRB1*0405 was found to have a protective effect on cortical lesion burden. Taken together, these findings provide support to the notion that HLA genotype is associated with the extent of cortical disease and may suggest that HLA molecules contribute to cortical lesion aetiology. Current consensus suggests that cortical lesions are driven by immune activation in the meninges, with
the diffusion of myelinotoxic mediators into the underlying cortical parenchyma mediating demyelination. While HLA-DRB1*15 may influence meningeal inflammation and secondarily impact cortical disease via diffusible factors, this is likely an oversimplification. Our group has recently demonstrated deposition of fibrin(ogen) in the MS cortex, suggestive of cortical blood–brain barrier (BBB) disruption.3 Given that the perivascular spaces of penetrating subpial vessels are continuous with the subarachnoid space, immune activation in the meninges cannot be disentangled from that in the perivasculature. HLADRB1*15 has been demonstrated to increase the extent of T-cell proliferation throughout the central nervous system (CNS),4 and so autoreactive perivascular T-cell activation in the setting of a disrupted cortical BBB may increase the odds of lesion initiation and expansion. Indeed, a proportion of cortical plaques may actually begin as small perivascular lesions and subsequently coalesce to become larger, subpial lesions. This view is consistent with in vivo work showing demyelination around central cortical veins5 and gadolinium enhancement within cortical lesions on MRI.6 Higher resolution MRI techniques that can track the development of cortical lesions in vivo are desperately needed in order to resolve these gaps in our understanding, but meanwhile, it will be important to remain open-minded.
Multiple Sclerosis Journal 1–2 DOI: 10.1177/ https://doi.org/10.1177/1352458517734071 1352458517734071 https://doi.org/10.1177/1352458517734071 © The Author(s), 2017. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Shinoda et al.2 provide new MRI evidence that HLADRB1*15 influences cortical lesional burden and extends our own work showing that HLA genotype is associated with post-mortem cortical pathologic outcome. That an allele known to increase disease susceptibility and worsen clinical outcome should also influence the extent of cortical disease is likely an important clue to pathologic mechanisms underlying progressive MS. Future studies are now urgently needed to elucidate the mechanism by which HLADRB1*15 exerts these effects, so that novel druggable targets can be identified that reduce the burden of this often devastating disease. Declaration of Conflicting Interests G.C.D. is supported by the NIHR Biomedical Research Centre (BRC), Oxford, and has research funding from the Oxford BRC, MRC(UK) and Merck-Serono. He has received travel expenses from Bay Schering, Biogen Idec, Genzyme, Merck Serono and Nova.
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Multiple Sclerosis Journal 00(0) Funding The author(s) received no financial support for the research, authorship and/or publication of this article.
References 1. Yates RL, Esiri MM, Palace J, et al. The influence of HLA-DRB1*15 on motor cortical pathology in multiple sclerosis. Neuropathol Appl Neurobiol 2015; 41(3): 371–384. 2. Shinoda K, Matsushita T, Nakamura Y, et al. HLADRB1*04:05 allele is associated with intracortical lesions on three-dimensional double inversion recovery images in Japanese patients with multiple sclerosis. Mult Scler. Epub ahead of print 1 May 2017. DOI: 10.1177/1352458517707067. 3. Yates RL, Esiri MM, Palace J, et al. Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex. Ann Neurol 2017; 82: 259–270.
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4. Mohme M, Hotz C, Stevanovic S, et al. HLA-DR15derived self-peptides are involved in increased autologous T cell proliferation in multiple sclerosis. Brain 2013; 136(Pt 6): 1783–1798. 5. Mistry N, Dixon J, Tallantyre E, et al. Central veins in brain lesions visualized with high-field magnetic
resonance imaging: A pathologically specific diagnostic biomarker for inflammatory demyelination in the brain. JAMA Neurol 2013; 70(5): 623–628. 6. Maranzano J, Rudko DA, Nakamura K, et al. MRI evidence of acute inflammation in leukocortical lesions of patients with early multiple sclerosis. Neurology. Epub ahead of print 19 July 2017. DOI: 10.1212/ WNL.0000000000004227.
Jonathan I Spencer1, Richard L Yates2, Jack S Bell1 and Gabriele C DeLuca3 1Medical School, University of Oxford, Oxford, UK 2 Medical School, University of Oxford, Oxford, UK/ Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK 3Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK
Correspondence to: GC DeLuca Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Level 1, West Wing, Oxford OX3 9DU, UK. [email protected]
2 journals.sagepub.com/home/msj
research-article2017
MSJ0010.1177/1352458517734071Multiple Sclerosis JournalJI Spencer, RL Yates et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Letter
Cortical lesions and HLA genotype: Still a grey area? Date received: 26 July 2017; accepted: 23 August 2017 Substantial evidence suggests that cortical tissue injury plays a key role in the progression of permanent disability in multiple sclerosis (MS). Cortical demyelination occurs early, becomes more extensive with time and eventually exceeds the extent of white matter pathology in progressive disease. However our understanding of the mechanisms driving cortical demyelination remains poor. As a result, we lack the therapeutic targets that could enable cortical disease burden to be reduced and disease progression to be halted. A greater knowledge of the factors that drive pathology in the MS cortex is therefore desperately needed in order to develop novel medicines that can ameliorate disease burden in the progressive stage. Our group has recently demonstrated an important role for human leukocyte antigen (HLA) molecules in cortical lesion pathogenesis by showing that carriage of HLA-DRB1*15, the primary genetic risk factor for MS, is associated with more severe cortical inflammation and demyelination.1 Although our study was the first to link genetic variation with pathologic phenotypes in the cortex, it was necessarily limited to end-stage disease by virtue of a post-mortem cohort. It has heretofore remained unknown to what extent HLA genotypes influence cortical tissue injury during earlier stages of MS. To this end, a large (n = 92) magnetic resonance imaging (MRI) study published in this journal by Shinoda et al.2 extends our work and associates HLA genotype with in vivo disease. They report that HLADRB1*1501 carriers have an increased number of MRI-defined cortical lesions and also that a higher proportion of HLA-DRB1*1501 carriers have cortical lesions compared to non-carriers. Conversely, carriage of HLA-DRB1*0405 was found to have a protective effect on cortical lesion burden. Taken together, these findings provide support to the notion that HLA genotype is associated with the extent of cortical disease and may suggest that HLA molecules contribute to cortical lesion aetiology. Current consensus suggests that cortical lesions are driven by immune activation in the meninges, with
the diffusion of myelinotoxic mediators into the underlying cortical parenchyma mediating demyelination. While HLA-DRB1*15 may influence meningeal inflammation and secondarily impact cortical disease via diffusible factors, this is likely an oversimplification. Our group has recently demonstrated deposition of fibrin(ogen) in the MS cortex, suggestive of cortical blood–brain barrier (BBB) disruption.3 Given that the perivascular spaces of penetrating subpial vessels are continuous with the subarachnoid space, immune activation in the meninges cannot be disentangled from that in the perivasculature. HLADRB1*15 has been demonstrated to increase the extent of T-cell proliferation throughout the central nervous system (CNS),4 and so autoreactive perivascular T-cell activation in the setting of a disrupted cortical BBB may increase the odds of lesion initiation and expansion. Indeed, a proportion of cortical plaques may actually begin as small perivascular lesions and subsequently coalesce to become larger, subpial lesions. This view is consistent with in vivo work showing demyelination around central cortical veins5 and gadolinium enhancement within cortical lesions on MRI.6 Higher resolution MRI techniques that can track the development of cortical lesions in vivo are desperately needed in order to resolve these gaps in our understanding, but meanwhile, it will be important to remain open-minded.
Multiple Sclerosis Journal 1–2 DOI: 10.1177/ https://doi.org/10.1177/1352458517734071 1352458517734071 https://doi.org/10.1177/1352458517734071 © The Author(s), 2017. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Shinoda et al.2 provide new MRI evidence that HLADRB1*15 influences cortical lesional burden and extends our own work showing that HLA genotype is associated with post-mortem cortical pathologic outcome. That an allele known to increase disease susceptibility and worsen clinical outcome should also influence the extent of cortical disease is likely an important clue to pathologic mechanisms underlying progressive MS. Future studies are now urgently needed to elucidate the mechanism by which HLADRB1*15 exerts these effects, so that novel druggable targets can be identified that reduce the burden of this often devastating disease. Declaration of Conflicting Interests G.C.D. is supported by the NIHR Biomedical Research Centre (BRC), Oxford, and has research funding from the Oxford BRC, MRC(UK) and Merck-Serono. He has received travel expenses from Bay Schering, Biogen Idec, Genzyme, Merck Serono and Nova.
journals.sagepub.com/home/msj 1
Multiple Sclerosis Journal 00(0) Funding The author(s) received no financial support for the research, authorship and/or publication of this article.
References 1. Yates RL, Esiri MM, Palace J, et al. The influence of HLA-DRB1*15 on motor cortical pathology in multiple sclerosis. Neuropathol Appl Neurobiol 2015; 41(3): 371–384. 2. Shinoda K, Matsushita T, Nakamura Y, et al. HLADRB1*04:05 allele is associated with intracortical lesions on three-dimensional double inversion recovery images in Japanese patients with multiple sclerosis. Mult Scler. Epub ahead of print 1 May 2017. DOI: 10.1177/1352458517707067. 3. Yates RL, Esiri MM, Palace J, et al. Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex. Ann Neurol 2017; 82: 259–270.
Visit SAGE journals online journals.sagepub.com/ home/msj
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4. Mohme M, Hotz C, Stevanovic S, et al. HLA-DR15derived self-peptides are involved in increased autologous T cell proliferation in multiple sclerosis. Brain 2013; 136(Pt 6): 1783–1798. 5. Mistry N, Dixon J, Tallantyre E, et al. Central veins in brain lesions visualized with high-field magnetic
resonance imaging: A pathologically specific diagnostic biomarker for inflammatory demyelination in the brain. JAMA Neurol 2013; 70(5): 623–628. 6. Maranzano J, Rudko DA, Nakamura K, et al. MRI evidence of acute inflammation in leukocortical lesions of patients with early multiple sclerosis. Neurology. Epub ahead of print 19 July 2017. DOI: 10.1212/ WNL.0000000000004227.
Jonathan I Spencer1, Richard L Yates2, Jack S Bell1 and Gabriele C DeLuca3 1Medical School, University of Oxford, Oxford, UK 2 Medical School, University of Oxford, Oxford, UK/ Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK 3Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK
Correspondence to: GC DeLuca Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Level 1, West Wing, Oxford OX3 9DU, UK. [email protected]
2 journals.sagepub.com/home/msj
