Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial

Kappos, Ludwig; Li, David; Calabresi, Peter A.; O’Connor, Paul; Bar‐Or, Amit; Barkhof, Frederik; Yin, Ming; Leppert, David; Glanzman, Robert; Tinbergen, Jeroen; Hauser, Stephen L.

doi:10.1016/s0140-6736(11)61649-8

Cited by 676 publications

(608 citation statements)

References 28 publications

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“…MS GWAS [2] identified risk genes are predominantly expressed in other immune cell subsets [10]; and the success of B cell specific therapies [35], and master-regulation of other immune cell types by myeloid cells [36] support their fundamental roles in MS. Eomes and Tbet are most highly expressed by NK cells, which have already been implicated as pathogenically significant, in that their numbers are reduced in MS [37] and their killing of activated T cells and macrophages [38] is important in therapy. It was recently reported that the CD8 effector memory population (both CD45RA+ and CD45RA-) is also deficient in MS, and that this is an early and persistent feature [39], possibly also contributing to the reduction in Eomes and Tbet in MS peripheral blood, and consistent with a longitudinally stable phenotype.…”

Section: Discussionmentioning

confidence: 99%

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies

McKay

Gatt

Fewings

et al. 2016

Clinical Immunology

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Multiple Sclerosis (MS) is an autoimmune disease treated by therapies targeting peripheral blood cells. We previously identified that expression of two MS-risk genes, the transcription factors EOMES and TBX21 (ET), was low in blood from MS and stable over time. Here we replicated the low ET expression in a new MS cohort (p<0.0007 for EOMES, p < 0.028 for TBX21) and demonstrate longitudinal stability (p<10 -4 ) and high heritability (h 2 =0.48 for EOMES) for this molecular phenotype. Genes whose expression correlated with ET, especially those controlling cell migration, further defined the phenotype. CD56+ cells and other subsets expressed lower levels of Eomes or T-bet protein and/or were underrepresented in MS. EOMES and TBX21 risk SNP genotypes, and serum EBNA-1 titres were not correlated with ET expression, but HLA-DRB1*1501 genotype was. ET expression was normalised to healthy control levels with natalizumab, and was highly variable for glatiramer acetate, fingolimod, interferon-beta, dimethyl fumarate.

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Section: Discussionmentioning

confidence: 99%

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies

McKay

Gatt

Fewings

et al. 2016

Clinical Immunology

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“…Several drugs target CD20 and have been shown through phase II clinical trials to decrease new MS disease activity: rituximab [84][85][86], ocrelizumab [87], and ofatumumab (A. Bar-Or et al, in preparation). The effect of these drugs on Bcell depletion does not appear to affect significantly the abnormal antibodies (IgG), OCB number and pattern, or antibody synthesis rates in the CSF of treated patients [88][89][90].…”

Section: B-cell Depletion In Msmentioning

confidence: 99%

Neuroinflammation: Ways in Which the Immune System Affects the Brain

et al. 2015

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Neuroinflammation is the response of the central nervous system (CNS) to disturbed homeostasis and typifies all neurological diseases. The main reactive components of the CNS include microglial cells and infiltrating myeloid cells, astrocytes, oligodendrocytes, and the blood-brain b a r r i e r , c y t o k i n e s , a n d c y t o k i n e s i g n a l i n g . Neuroinflammatory responses may be helpful or harmful, as mechanisms associated with neuroinflammation are involved in normal brain development, as well as in neuropathological processes. This review examines the roles of various cell types that contribute to the immune dysregulation associated with neuroinflammation. Microglia enter the CNS very early in embryonic development and, as such, play an essential role in both the healthy and diseased brain. B-cell diversity contributes to CNS disease through both antibody-dependent and antibody-independent mechanisms. The influences of these B-cell mechanisms on other cell types, including myeloid cells and T cells, are reviewed in relationship to antibody-mediated CNS disorders, paraneoplastic neurological diseases, and multiple sclerosis. New insights into neuroinflammation offer exciting opportunities to investigate potential therapeutic targets for debilitating CNS diseases.

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“…It is therefore possible that by examining more OCB from additional MS patients some of those OCB antibodies might recognize myelin or neuronal proteins. One might also question the importance of identifying the specificity of OCB antibodies in MS. Clinical trials have shown that the anti-CD20 B-cell-depleting antibody ocrelizumab is remarkably effective in treatment of relapsing-remitting (18) and primary progressive MS (19). However, such clinical benefit occurs soon after B-cell depletion without evident changes in antibodies, and therefore likely reflects a loss in B-cell antigen-presenting cell (APC) function (20).…”

mentioning

confidence: 99%

Antibodies in multiple sclerosis oligoclonal bands target debris

Winger

Zamvil

2016

Proc. Natl. Acad. Sci. U.S.A.

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IgG oligoclonal bands (OCB) are detected in the cerebrospinal fluid (CSF) of more than 90% of multiple sclerosis (MS) patients and are considered the immunological hallmark that supports MS diagnosis. OCB are not unique to MS but are also observed in chronic CNS infections, where they target their causative agents (1-3). However, the target specificities of the IgG within OCB in MS have remained a mystery. Identification of those antigens recognized by OCB antibodies is thought to hold fundamental clues to the pathogenesis of MS. In a recent PNAS publication, Brändle et al. (4) provide evidence that OCB in MS target ubiquitous intracellular antigens released in cellular debris.In 1942, Kabat et al. (5) established the diagnostic value of quantitative determinations of CSF gamma globulins in clinical neurology, and particularly in MS. They observed that changes in CSF IgG were independent of those in serum, suggesting that this Ig production was compartmentalized to the CNS. Advances in CSF analytics and gel electrophoresis led to the identification of OCB in 1959 (6). CSF OCB in MS patients are persistent, which is thought to be a reflection of both ongoing CNS inflammation and immunologic memory. Understanding the specificity of OCB has since captivated the interest of clinical neurologists and scientists alike. It has been assumed that the OCB target antigens are relevant to MS pathogenesis. The most popular theory contends that IgG within OCB target myelin autoantigens and/or viruses that may elicit CNS damage directly or indirectly via molecular mimicry. Some earlier studies that evaluated whole CSF IgG from MS patients identified antibodies to several different viruses, such as measles, varicella zoster, human T-lymphocytic virus 1, and human hepatitis virus 6 (7), whereas other investigations found antibodies targeting major myelin proteins, myelin basic protein (MBP) and myelin oligodencrocyte glycoprotein (MOG) (8, 9) as well as glycolipids, fatty acids, and neurofilament proteins (10). Similarly, more recent investigations that have applied single-cell PCR cloning to individual CSF B cells in MS have detected antibodies to certain viruses or myelin proteins (11-13). However, it has been impossible to match specificity of antibodies identified in CSF to OCB by studying whole CSF IgG or recombinant antibodies constructed from rearranged Ig heavy-and light-chain genes in individual B cells.Dornmair and coworkers used a combination of new biochemical, proteomic, and transcriptomic approaches (4, 14) to examine the specificity of antibodies in MS OCB. Disulfide-linked IgG heavy-(IgH) and IgG light-(IgL) chain complexes were purified from single OCB spots using affinity chromatography and two-dimensional gel electrophoresis. Those antibody (IgH 2 IgL 2 ) complexes were then analyzed by mass spectrometry to generate patient-specific Ig peptidomes. In parallel, IgH and IgL genes, including the unique complementarity-determining region 3, from CSF B cells isolated from the corresponding patient were sequenced ...

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Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial

Cited by 676 publications

References 28 publications

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies

Neuroinflammation: Ways in Which the Immune System Affects the Brain

Antibodies in multiple sclerosis oligoclonal bands target debris

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