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Article ; Online: The effect of disease modifying therapies on fatigue in multiple sclerosis.

Cruz Rivera, Samantha / Aiyegbusi, Olalekan Lee / Piani Meier, Daniela / Dunne, Achille / Harlow, Danielle E / Henke, Christian / Kamudoni, Paul / Calvert, Melanie J

Multiple sclerosis and related disorders

2023 Volume 79, Page(s) 105065

Abstract: Introduction: Fatigue is one of the most common and debilitating symptoms in people with multiple sclerosis (PwMS). Disease-modifying therapies (DMTs) are currently the gold standard in the treatment of MS and their effectiveness has been assessed ... ...

Abstract	Introduction: Fatigue is one of the most common and debilitating symptoms in people with multiple sclerosis (PwMS). Disease-modifying therapies (DMTs) are currently the gold standard in the treatment of MS and their effectiveness has been assessed through randomized clinical trials (RCTs). However, there is limited evidence on the impact of DMTs on fatigue in (PwMS). We conducted a systematic review to 1) understand whether fatigue is included as an outcome in MS trials of DMTs; 2) determine the effects on fatigue of treating MS with DMTs and 3) assess the quality of MS trials including fatigue as an outcome. Methods: Two independent researchers systematically searched MEDLINE, EMBASE and ClinicalTrials.gov from 1993 to January 2023 for RCTs that measured fatigue as an outcome. Adherence to reporting standards was assessed with the Consolidated Standards of Reporting Trials (CONSORT)-Patient-Reported Outcomes (PRO), while the risk of bias (RoB) was assessed with the RoB 2 tool by the Cochrane Handbook for Systematic Reviews of Interventions. The systematic review protocol was registered in PROSPERO (CRD42022383321). Results: The search strategy identified 130 RCTs of DMTs of which 7 (5%) assessed fatigue as an outcome. Of the 7 trials, only two presented statistically significant results. In addition, the reporting of fatigue among RCTs was suboptimal with a mean adherence to the CONSORT-PRO Statement of 36% across all trials. Of the 7 trials included, four were assessed as 'high' RoB.. Conclusions: Fatigue has a major impact on PwMS yet there is limited trial-based evidence on the impact of DMTs on fatigue. Assessment of fatigue as an outcome is underrepresented in trials of DMTs and the reporting of PRO trial data is suboptimal. Thus, it is imperative that MS researchers conduct RCTs that include fatigue as an outcome, to support clinicians and people with MS (PwMS) to consider the impact of the different DMTs on fatigue.
MeSH term(s)	Humans ; Fatigue/drug therapy ; Fatigue/etiology ; Multiple Sclerosis/complications ; Multiple Sclerosis/therapy ; Patient Reported Outcome Measures ; Reference Standards ; Systematic Reviews as Topic
Language	English
Publishing date	2023-10-10
Publishing country	Netherlands
Document type	Journal Article ; Review ; Systematic Review
ZDB-ID	2645330-7
ISSN	2211-0356 ; 2211-0348
ISSN (online)	2211-0356
ISSN	2211-0348
DOI	10.1016/j.msard.2023.105065
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Article ; Online: Efficacy and safety results after >3.5 years of treatment with the Bruton's tyrosine kinase inhibitor evobrutinib in relapsing multiple sclerosis: Long-term follow-up of a Phase II randomised clinical trial with a cerebrospinal fluid sub-study.

Montalban, Xavier / Piasecka-Stryczynska, Karolina / Kuhle, Jens / Benkert, Pascal / Arnold, Douglas L / Weber, Martin S / Seitzinger, Andrea / Guehring, Hans / Shaw, Jamie / Tomic, Davorka / Hyvert, Yann / Harlow, Danielle E / Dyroff, Martin / Wolinsky, Jerry S

Multiple sclerosis (Houndmills, Basingstoke, England)

2024 Volume 30, Issue 4-5, Page(s) 558–570

Abstract: Background: Evobrutinib - an oral, central nervous system (CNS)-penetrant, and highly selective Bruton's tyrosine kinase inhibitor - has shown efficacy in a 48-week, double-blind, Phase II trial in patients with relapsing MS.: Objective: Report ... ...

Abstract	Background: Evobrutinib - an oral, central nervous system (CNS)-penetrant, and highly selective Bruton's tyrosine kinase inhibitor - has shown efficacy in a 48-week, double-blind, Phase II trial in patients with relapsing MS. Objective: Report results of the Phase II open-label extension (OLE; up to week 192 from randomisation) and a cerebrospinal fluid (CSF) sub-study. Methods: In the 48-week double-blind period (DBP), patients received evobrutinib 25 mg once-daily, 75 mg once-daily, 75 mg twice-daily or placebo (switched to evobrutinib 25 mg once-daily after week 24). Patients could then enter the OLE, receiving evobrutinib 75 mg once-daily (mean (± standard deviation (SD)) duration = 50.6 weeks (±6.0)) before switching to 75 mg twice-daily. Results: Of 164 evobrutinib-treated patients who entered the OLE, 128 (78.0%) completed ⩾192 weeks of treatment. Patients receiving DBP evobrutinib 75 mg twice-daily: annualised relapse rate at week 48 (0.11 (95% confidence interval (CI) = 0.04-0.25)) was maintained with the OLE twice-daily dose up to week 192 (0.11 (0.05-0.22)); Expanded Disability Status Scale score remained stable; serum neurofilament light chain fell to levels like a non-MS population ( Conclusion: Long-term evobrutinib treatment was well tolerated and associated with a sustained low level of disease activity. Evobrutinib was present in CSF at concentrations similar to plasma.
MeSH term(s)	Humans ; Multiple Sclerosis/drug therapy ; Tyrosine Kinase Inhibitors ; Follow-Up Studies ; Recurrence ; Double-Blind Method ; Treatment Outcome ; Piperidines ; Pyrimidines
Chemical Substances	evobrutinib (ZA45457L1K) ; Tyrosine Kinase Inhibitors ; Piperidines ; Pyrimidines
Language	English
Publishing date	2024-03-04
Publishing country	England
Document type	Randomized Controlled Trial ; Clinical Trial, Phase II ; Journal Article
ZDB-ID	1290669-4
ISSN	1477-0970 ; 1352-4585
ISSN (online)	1477-0970
ISSN	1352-4585
DOI	10.1177/13524585241234783
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Article: Static and group-based trajectory analyses of factors associated with non-adherence in patients with multiple sclerosis newly-initiating once- or twice-daily oral disease-modifying therapy.

Nicholas, Jacqueline A / Edwards, Natalie C / Edwards, Roger A / Dellarole, Anna / Manca, Luigi / Harlow, Danielle E / Phillips, Amy L

Multiple sclerosis journal - experimental, translational and clinical

2022 Volume 8, Issue 2, Page(s) 20552173221101150

Abstract: Background: Increased understanding of adherence may facilitate optimal targeting of interventions.: Objective: To utilize group-based trajectory modeling (GBTM) to understand longitudinal patterns of adherence and factors associated with non- ... ...

Abstract	Background: Increased understanding of adherence may facilitate optimal targeting of interventions. Objective: To utilize group-based trajectory modeling (GBTM) to understand longitudinal patterns of adherence and factors associated with non-adherence in patients with multiple sclerosis (MS) newly-initiating once-/twice-daily oral disease-modifying therapy (DMT) (fingolimod, dimethyl fumarate, or teriflunomide). Methods: Commercial plan data were analyzed using proportion of days covered (PDC) to evaluate factors associated with non-adherence. GBTM clustered patient subgroups with similar longitudinal patterns of adherence measured by monthly PDC (≥80%) and multinomial logistic regression identified factors associated with adherence trajectory subgroups. Results: Among 7689 patients, 39.5% were non-adherent to once-/twice-daily oral DMTs. Characteristics associated with non-adherence (PDC<80%) included younger age, female, depression or migraine, switching during follow-up, more frequent dosing, relapse, and absence of magnetic resonance imaging. GBTM elucidated three adherence subgroups: Immediately Non-Adherent (14.9%); Gradually Non-Adherent (19.5%), and Adherent (65.6%). Additional factors associated with adherence (i.e. region, chronic lung disease) were identified and factors differed among trajectory subgroups. Conclusion: These analyses confirmed that a significant proportion of patients with MS are non-adherent to once-/twice-daily oral DMTs. Unique patterns of non-adherence and factors associated with patterns of adherence emerged. The approach demonstrated how quantitative trajectories can help clinicians develop tailored interventions.
Language	English
Publishing date	2022-06-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2841884-0
ISSN	2055-2173 ; 2055-2173
ISSN (online)	2055-2173
ISSN	2055-2173
DOI	10.1177/20552173221101150
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Article ; Online: Inhibitors of myelination: ECM changes, CSPGs and PTPs.

Harlow, Danielle E / Macklin, Wendy B

Experimental neurology

2013 Volume 251, Page(s) 39–46

Abstract: After inflammation-induced demyelination, such as in the disease multiple sclerosis, endogenous remyelination often fails. However, in animal models of demyelination induced with toxins, remyelination can be quite robust. A significant difference between ...

Abstract	After inflammation-induced demyelination, such as in the disease multiple sclerosis, endogenous remyelination often fails. However, in animal models of demyelination induced with toxins, remyelination can be quite robust. A significant difference between inflammation-induced and toxin-induced demyelination is the response of local cells within the lesion, including astrocytes, oligodendrocytes, microglia/macrophages, and NG2+ cells, which respond to inflammatory stimuli with increased extracellular matrix (ECM) protein and chondroitin sulfate proteoglycan (CSPG) production and deposition. Here, we summarize current knowledge of ECM changes in demyelinating lesions, as well as oligodendrocyte responses to aberrant ECM proteins and CSPGs after various types of demyelinating insults. The discovery that CSPGs act through the receptor protein tyrosine phosphatase sigma (PTPσ) and the Rho-ROCK pathway to inhibit oligodendrocyte process extension and myelination, but not oligodendrocyte differentiation (Pendleton et al., Experimental Neurology (2013) vol. 247, pp. 113-121), highlights the need to better understand the ECM changes that accompany demyelination and their influence on oligodendrocytes and effective remyelination.
MeSH term(s)	Animals ; Chondroitin Sulfate Proteoglycans/pharmacology ; Gene Expression Regulation/drug effects ; Myelin Sheath/drug effects ; Oligodendroglia/drug effects ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism
Chemical Substances	Chondroitin Sulfate Proteoglycans ; Receptor-Like Protein Tyrosine Phosphatases, Class 2 (EC 3.1.3.48)
Language	English
Publishing date	2013-11-04
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2013.10.017
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Zs.A 184: Show issues

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Article: Remyelination Therapy in Multiple Sclerosis.

Harlow, Danielle E / Honce, Justin M / Miravalle, Augusto A

Frontiers in neurology

2015 Volume 6, Page(s) 257

Abstract: Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system that results in destruction of the myelin sheath that surrounds axons and eventual neurodegeneration. Current treatments approved for the treatment of relapsing forms of ...

Abstract	Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system that results in destruction of the myelin sheath that surrounds axons and eventual neurodegeneration. Current treatments approved for the treatment of relapsing forms of MS target the aberrant immune response and successfully reduce the severity of attacks and frequency of relapses. Therapies are still needed that can repair damage particularly for the treatment of progressive forms of MS for which current therapies are relatively ineffective. Remyelination can restore neuronal function and prevent further neuronal loss and clinical disability. Recent advancements in our understanding of the molecular and cellular mechanisms regulating myelination, as well as the development of high-throughput screens to identify agents that enhance myelination, have lead to the identification of many potential remyelination therapies currently in preclinical and early clinical development. One problem that has plagued the development of treatments to promote remyelination is the difficulty in assessing remyelination in patients with current imaging techniques. Powerful new imaging technologies are making it easier to discern remyelination in patients, which is critical for the assessment of these new therapeutic strategies during clinical trials. This review will summarize what is currently known about remyelination failure in MS, strategies to overcome this failure, new therapeutic treatments in the pipeline for promoting remyelination in MS patients, and new imaging technologies for measuring remyelination in patients.
Language	English
Publishing date	2015-12-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2015.00257
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Article ; Online: Myelin Proteolipid Protein Complexes with αv Integrin and AMPA Receptors In Vivo and Regulates AMPA-Dependent Oligodendrocyte Progenitor Cell Migration through the Modulation of Cell-Surface GluR2 Expression.

Harlow, Danielle E / Saul, Katherine E / Komuro, Hitoshi / Macklin, Wendy B

The Journal of neuroscience : the official journal of the Society for Neuroscience

2015 Volume 35, Issue 34, Page(s) 12018–12032

Abstract: In previous studies, stimulation of ionotropic AMPA/kainate glutamate receptors on cultured oligodendrocyte cells induced the formation of a signaling complex that includes the AMPA receptor, integrins, calcium-binding proteins, and, surprisingly, the ... ...

Abstract	In previous studies, stimulation of ionotropic AMPA/kainate glutamate receptors on cultured oligodendrocyte cells induced the formation of a signaling complex that includes the AMPA receptor, integrins, calcium-binding proteins, and, surprisingly, the myelin proteolipid protein (PLP). AMPA stimulation of cultured oligodendrocyte progenitor cells (OPCs) also caused an increase in OPC migration. The current studies focused primarily on the formation of the PLP-αv integrin-AMPA receptor complex in vivo and whether complex formation impacts OPC migration in the brain. We found that in wild-type cerebellum, PLP associates with αv integrin and the calcium-impermeable GluR2 subunit of the AMPA receptor, but in mice lacking PLP, αv integrin did not associate with GluR2. Live imaging studies of OPC migration in ex vivo cerebellar slices demonstrated altered OPC migratory responses to neurotransmitter stimulation in the absence of PLP and GluR2 or when αv integrin levels were reduced. Chemotaxis assays of purified OPCs revealed that AMPA stimulation was neither attractive nor repulsive but clearly increased the migration rate of wild-type but not PLP null OPCs. AMPA receptor stimulation of wild-type OPCs caused decreased cell-surface expression of the GluR2 AMPA receptor subunit and increased intracellular Ca(2+) signaling, whereas PLP null OPCs did not reduce GluR2 at the cell surface or increase Ca(2+) signaling in response to AMPA treatment. Together, these studies demonstrate that PLP is critical for OPC responses to glutamate signaling and has important implications for OPC responses when levels of glutamate are high in the extracellular space, such as following demyelination. Significance statement: After demyelination, such as occurs in multiple sclerosis, remyelination of axons is often incomplete, leading to loss of neuronal function and clinical disability. Remyelination may fail because oligodendrocyte precursor cells (OPCs) do not completely migrate into demyelinated areas or OPCs in lesions may not mature into myelinating oligodendrocytes. We have found that the myelin proteolipid protein is critical to regulating OPC migratory responses to the neurotransmitter glutamate through modulation of cell-surface expression of the calcium-impermeable GluR2 subunit of the AMPA glutamate receptor and increased intercellular Ca(2+) signaling. Altered glutamate homeostasis has been reported in demyelinated lesions. Therefore, understanding how OPCs respond to glutamate has important implications for treatment after white matter injury and disease.
MeSH term(s)	Animals ; Calcium Signaling/physiology ; Cell Membrane/metabolism ; Cell Movement/physiology ; Cells, Cultured ; Cerebellum/metabolism ; Female ; Integrin alphaV/metabolism ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Myelin Proteolipid Protein/metabolism ; Oligodendroglia/metabolism ; Protein Binding/physiology ; Receptors, AMPA/biosynthesis ; Receptors, AMPA/metabolism ; Stem Cells/metabolism
Chemical Substances	Integrin alphaV ; Myelin Proteolipid Protein ; Receptors, AMPA ; glutamate receptor ionotropic, AMPA 2 (P6W5IXV8V9)
Language	English
Publishing date	2015-06-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.5151-14.2015
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Article ; Online: CLICK-MS and MASTER-2 Phase IV trial design: cladribine tablets in suboptimally controlled relapsing multiple sclerosis.

Miravalle, Augusto A / Katz, Joshua / Robertson, Derrick / Hayward, Brooke / Harlow, Danielle E / Lebson, Lori A / Sloane, Jacob A / Bass, Ann D / Fox, Edward J

Neurodegenerative disease management

2021 Volume 11, Issue 2, Page(s) 99–111

Abstract: Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) are approved for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting MS and active secondary progressive MS. However, real-world data on cladribine ... ...

Abstract	Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) are approved for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting MS and active secondary progressive MS. However, real-world data on cladribine tablets are limited. CLICK-MS and MASTER-2 are single arm, observational, 30-month, Phase IV studies in the US evaluating the effectiveness and safety of cladribine tablets 3.5 mg/kg in patients with relapsing-remitting MS or active secondary progressive MS who had suboptimal response to prior injectable (CLICK-MS), or infusion/oral (MASTER-2) disease-modifying therapy. The primary end point is 24-month annualized relapse rate. Key secondary end points include patient-reported outcomes on quality of life measures, treatment adherence and adverse events. Studies began in 2019 and are expected to be completed in 2023.
MeSH term(s)	Female ; Humans ; Male ; Administration, Oral ; Cladribine/therapeutic use ; Immunosuppressive Agents/therapeutic use ; Multiple Sclerosis, Chronic Progressive/drug therapy ; Multiple Sclerosis, Relapsing-Remitting/drug therapy ; Prospective Studies ; Quality of Life ; Tablets ; Observational Studies as Topic ; Clinical Trials, Phase IV as Topic ; Multicenter Studies as Topic
Chemical Substances	Cladribine (47M74X9YT5) ; Immunosuppressive Agents ; Tablets
Language	English
Publishing date	2021-02-01
Publishing country	England
Document type	Clinical Trial Protocol ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2608846-0
ISSN	1758-2032 ; 1758-2024
ISSN (online)	1758-2032
ISSN	1758-2024
DOI	10.2217/nmt-2020-0059
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Article: Embryonic origin of gustatory cranial sensory neurons.

Harlow, Danielle E / Barlow, Linda A

Developmental biology

2007 Volume 310, Issue 2, Page(s) 317–328

Abstract: Cranial nerves VII, IX and X provide both gustatory (taste) and non-gustatory (touch, pain, temperature) innervation to the oral cavity of vertebrates. Gustatory neurons innervate taste buds and project centrally to the rostral nucleus of the solitary ... ...

Abstract	Cranial nerves VII, IX and X provide both gustatory (taste) and non-gustatory (touch, pain, temperature) innervation to the oral cavity of vertebrates. Gustatory neurons innervate taste buds and project centrally to the rostral nucleus of the solitary tract (NTS), whereas neurons providing general epithelial innervation to the oropharynx project to non-gustatory hindbrain regions, i.e., spinal trigeminal nucleus. In addition to this dichotomy in function, cranial ganglia VII, IX and X have dual embryonic origins, comprising sensory neurons derived from both cranial neural crest and epibranchial placodes. We used a fate mapping approach to test the hypothesis that epibranchial placodes give rise to gustatory neurons, whereas the neural crest generates non-gustatory cells. Placodal ectoderm or neural crest was grafted from Green Fluorescent Protein (GFP) expressing salamander embryos into unlabeled hosts, allowing us to discern the postembryonic central and peripheral projections of each embryonic neuronal population. Neurites that innervate taste buds are exclusively placodal in origin, and their central processes project to the NTS, consistent with a gustatory fate. In contrast, neural crest-derived neurons do not innervate taste buds; instead, neurites of these sensory neurons terminate as free nerve endings within the oral epithelium. Further, the majority of centrally directed fibers of neural crest neurons terminate outside the NTS, in regions that receive general epithelial afferents. Our data provide empirical evidence that embryonic origin dictates mature neuron function within cranial sensory ganglia: specifically, gustatory neurons derive from epibranchial placodes, whereas neural crest-derived neurons provide general epithelial innervation to the oral cavity.
MeSH term(s)	Ambystoma mexicanum/embryology ; Ambystoma mexicanum/physiology ; Animals ; Cranial Nerves/cytology ; Cranial Nerves/embryology ; Ectoderm/cytology ; Ectoderm/embryology ; Epithelium/embryology ; Epithelium/innervation ; Neural Crest/cytology ; Neural Crest/embryology ; Neurites/physiology ; Neurons, Afferent/cytology ; Neurons, Afferent/physiology ; Rhombencephalon/cytology ; Rhombencephalon/embryology ; Taste Buds/cytology ; Taste Buds/embryology
Language	English
Publishing date	2007-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2007.07.042
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Article ; Online: The Protein Tyrosine Phosphatase Shp2 Regulates Oligodendrocyte Differentiation and Early Myelination and Contributes to Timely Remyelination.

Ahrendsen, Jared T / Harlow, Danielle E / Finseth, Lisbet T / Bourne, Jennifer N / Hickey, Sean P / Gould, Elizabeth A / Culp, Cecilia M / Macklin, Wendy B

The Journal of neuroscience : the official journal of the Society for Neuroscience

2017 Volume 38, Issue 4, Page(s) 787–802

Abstract: Shp2 is a nonreceptor protein tyrosine phosphatase that has been shown to influence neurogenesis, oligodendrogenesis, and oligodendrocyte differentiation. Furthermore, Shp2 is a known regulator of the Akt/mammalian target of rapamycin and ERK signaling ... ...

Abstract	Shp2 is a nonreceptor protein tyrosine phosphatase that has been shown to influence neurogenesis, oligodendrogenesis, and oligodendrocyte differentiation. Furthermore, Shp2 is a known regulator of the Akt/mammalian target of rapamycin and ERK signaling pathways in multiple cellular contexts, including oligodendrocytes. Its role during later postnatal CNS development or in response to demyelination injury has not been examined. Based on the current studies, we hypothesize that Shp2 is a negative regulator of CNS myelination. Using transgenic mouse technology, we show that Shp2 is involved in oligodendrocyte differentiation and early myelination, but is not necessary for myelin maintenance. We also show that Shp2 regulates the timely differentiation of oligodendrocytes following lysolecithin-induced demyelination, although apparently normal remyelination occurs at a delayed time point. These data suggest that Shp2 is a relevant therapeutic target in demyelinating diseases such as multiple sclerosis.
MeSH term(s)	Animals ; Cell Differentiation/physiology ; Female ; Male ; Mice ; Mice, Transgenic ; Myelin Sheath/metabolism ; Neurogenesis/physiology ; Oligodendroglia/cytology ; Oligodendroglia/enzymology ; Oligodendroglia/metabolism ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism ; Zebrafish
Chemical Substances	Protein Tyrosine Phosphatase, Non-Receptor Type 11 (EC 3.1.3.48)
Language	English
Publishing date	2017-12-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.2864-16.2017
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Article ; Online: Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination.

Liu, Yiting / Given, Katherine S / Harlow, Danielle E / Matschulat, Adeline M / Macklin, Wendy B / Bennett, Jeffrey L / Owens, Gregory P

Acta neuropathologica communications

2017 Volume 5, Issue 1, Page(s) 25

Abstract: Intrathecal immunoglobulin G (IgG) synthesis, cerebrospinal fluid (CSF) oligoclonal IgG bands and lesional IgG deposition are seminal features of multiple sclerosis (MS) disease pathology. Both the specific targets and pathogenic effects of MS antibodies ...

Abstract	Intrathecal immunoglobulin G (IgG) synthesis, cerebrospinal fluid (CSF) oligoclonal IgG bands and lesional IgG deposition are seminal features of multiple sclerosis (MS) disease pathology. Both the specific targets and pathogenic effects of MS antibodies remain poorly characterized. We produced IgG1 monoclonal recombinant antibodies (rAbs) from clonally-expanded plasmablasts recovered from MS patient CSF. Among these were a subset of myelin-specific MS rAbs. We examined their immunoreactivity to mouse organotypic cerebellar slices by live binding and evaluated tissue injury in the presence and absence of human complement. Demyelination, glial and neuronal viability, and complement pathway activation were assayed by immunofluorescence microscopy and compared to the effects of an aquaporin-4 water channel (AQP4)-specific rAb derived from a neuromyelitis optica (NMO) patient. MS myelin-specific rAbs bound to discrete surface domains on oligodendrocyte processes and myelinating axons. Myelin-specific MS rAbs initiated complement-dependent cytotoxicity to oligodendrocytes and induced rapid demyelination. Demyelination was accompanied by increased microglia activation; however, the morphology and survival of astrocytes, oligodendrocyte progenitors and neurons remained unaffected. In contrast, NMO AQP4-specific rAb initiated complement-dependent astrocyte damage, followed by sequential loss of oligodendrocytes, demyelination, microglia activation and neuronal death. Myelin-specific MS antibodies cause oligodendrocyte loss and demyelination in organotypic cerebellar slices, which are distinct from AQP4-targeted pathology, and display seminal features of active MS lesions. Myelin-specific antibodies may play an active role in MS lesion formation through complement-dependent mechanisms.
MeSH term(s)	Animals ; Astrocytes/immunology ; Astrocytes/pathology ; Cell Death ; Cerebellum/immunology ; Cerebellum/pathology ; Complement System Proteins/immunology ; Complement System Proteins/metabolism ; Humans ; Immunoglobulin G/immunology ; Immunoglobulin G/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/immunology ; Microglia/pathology ; Multiple Sclerosis/immunology ; Multiple Sclerosis/pathology ; Myelin Proteins/immunology ; Neurons/immunology ; Neurons/pathology ; Oligodendroglia/immunology ; Oligodendroglia/pathology ; Optic Neuritis/immunology ; Optic Neuritis/pathology ; Plasma Cells/immunology ; Recombinant Proteins/metabolism ; Tissue Culture Techniques
Chemical Substances	Immunoglobulin G ; Myelin Proteins ; Recombinant Proteins ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2017-03-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-017-0428-6
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