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Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton.

Dale RC, Tantsis EM, Merheb V, Kumaran RY, Sinmaz N, Pathmanandavel K, Ramanathan S, Booth DR, Wienholt LA, Prelog K, Clark DR, Guillemin GJ, Lim CK, Mathey EK, Brilot F - Neurol Neuroimmunol Neuroinflamm (2014)

Bottom Line: We used MO3.13 cells to examine immunoglobulin (Ig) G effects on oligodendrocyte cytoskeleton using 3D deconvolution imaging.MOG antibodies were found in 31/73 patients with DEM (42%) but in 0/24 controls.MOG antibody has functional effects on oligodendrocyte cytoskeleton.

View Article: PubMed Central - PubMed

Affiliation: Neuroimmunology Group (R.C.D., E.M.T., V.M., R.-Y.A.K., N.S., K. Pathmanandavel, S.R., F.B.), Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, Westmead, Australia; Institute for Immunology and Allergy Research (D.R.B.), Westmead Millenium Institute for Medical Research, University of Sydney, Westmead, Australia; Clinical Immunology (L.A.W.), Royal Prince Alfred Hospital, Sydney Medical School Immunology & Infectious Diseases, University of Sydney, Camperdown, Australia; Department of Radiology (K. Prelog), the Children's Hospital at Westmead, Australia; Department of Paediatric Neurology (D.R.C.), Women's and Children's Hospital, North Adelaide, Australia; Neuroinflammation Group (G.J.G., C.K.L.), MND and Neurodegenerative Diseases Research Centre, Macquarie University, Australian School of Advanced Medicine, North Ryde, Australia; and Neuroinflammation Group (E.K.M.), Brain and Mind Research Institute, University of Sydney, Camperdown, Australia.

ABSTRACT

Objective: To examine the clinical features of pediatric CNS demyelination associated with positive myelin oligodendrocyte glycoprotein (MOG) antibodies and to examine the functional effects of MOG antibody on oligodendrocyte cytoskeleton.

Methods: We measured MOG antibody using a fluorescence-activated cell sorting live cell-based assay in acute sera of 73 children with CNS demyelination (DEM) (median age 8 years, range 1.3-15.3) followed for a median of 4 years. We used MO3.13 cells to examine immunoglobulin (Ig) G effects on oligodendrocyte cytoskeleton using 3D deconvolution imaging.

Results: MOG antibodies were found in 31/73 patients with DEM (42%) but in 0/24 controls. At first presentation, MOG antibody-positive patients were more likely to have bilateral than unilateral optic neuritis (ON) (9/10 vs 1/5, respectively, p = 0.03), less likely to have brainstem findings (2/31 vs 16/42, p = 0.005), more likely to have a raised erythrocyte sedimentation rate >20 mm/h (9/19 vs 3/21, p = 0.05), less likely to have intrathecal oligoclonal bands (0/16 vs 5/27, p = 0.18), and less likely to be homozygous or heterozygous for human leukocyte antigen DRB1*1501 (3/18 vs 7/22, p = 0.46). MOG antibody positivity varied according to clinical phenotype, with ON and relapsing ON most likely to be seropositive. Two relapsing MOG antibody-positive patients treated with mycophenolate mofetil remain in remission and have become MOG antibody seronegative. Oligodendrocytes incubated with purified IgG from MOG antibody-positive patients showed a striking loss of organization of the thin filaments and the microtubule cytoskeleton, as evidenced by F-actin and β-tubulin immunolabelings.

Conclusions: MOG antibody may define a separate demyelination syndrome, which has therapeutic implications. MOG antibody has functional effects on oligodendrocyte cytoskeleton.

No MeSH data available.


Related in: MedlinePlus

Temporal distribution of MOG antibody in serum of 2 relapsing patients with demyelinating diseasesIn both patient A (A) and patient B (B), upon treatment mycophenolate mofetil (MMF), myelin oligodendrocyte glycoprotein (MOG) antibody decreased to within the healthy control range (below threshold of positivity), and these low titers were associated with remission. Representative dot plot out of 3 experiments is shown. Magenta lines on graphs represent the positivity threshold (obtained with 24 control samples). Black squares represent serum analysis during acute demyelination episodes, and black circles represent sera during remission. Type of demyelinating episode is shown on graph. (C, D) Representative T2 axial MRI scans demonstrate demyelinating lesions during the first acute event and during convalescence. Patient A (C) had globular deep white matter lesions on acute scan (left panel), which show residual gliosis on convalescent scan and no new lesions (right panel). Patient B (D) had inflammatory lesions in basal ganglia and white matter on acute scan (left panel), with complete resolution on convalescent scan and no new lesions (right panel). Ab = antibody; ADEM = acute disseminated encephalomyelitis; CEREB = cerebellar episode; Ig = immunoglobulin; MFI = mean fluorescence intensity; ON = optic neuritis; TM = transverse myelitis.
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Figure 2: Temporal distribution of MOG antibody in serum of 2 relapsing patients with demyelinating diseasesIn both patient A (A) and patient B (B), upon treatment mycophenolate mofetil (MMF), myelin oligodendrocyte glycoprotein (MOG) antibody decreased to within the healthy control range (below threshold of positivity), and these low titers were associated with remission. Representative dot plot out of 3 experiments is shown. Magenta lines on graphs represent the positivity threshold (obtained with 24 control samples). Black squares represent serum analysis during acute demyelination episodes, and black circles represent sera during remission. Type of demyelinating episode is shown on graph. (C, D) Representative T2 axial MRI scans demonstrate demyelinating lesions during the first acute event and during convalescence. Patient A (C) had globular deep white matter lesions on acute scan (left panel), which show residual gliosis on convalescent scan and no new lesions (right panel). Patient B (D) had inflammatory lesions in basal ganglia and white matter on acute scan (left panel), with complete resolution on convalescent scan and no new lesions (right panel). Ab = antibody; ADEM = acute disseminated encephalomyelitis; CEREB = cerebellar episode; Ig = immunoglobulin; MFI = mean fluorescence intensity; ON = optic neuritis; TM = transverse myelitis.

Mentions: Two recent patients (figure 2 and appendix e-2) with positive MOG antibodies who fulfilled 2013 criteria for MS18 were treated with mycophenolate mofetil (MMF), which produced clinical remission, no new lesions on follow-up MRI scans, and normalization of MOG antibodies (figure 2 and appendix e-2). In both patients, upon treatment with MMF, MOG antibody decreased below the threshold of positivity (figure 2, A and B).


Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton.

Dale RC, Tantsis EM, Merheb V, Kumaran RY, Sinmaz N, Pathmanandavel K, Ramanathan S, Booth DR, Wienholt LA, Prelog K, Clark DR, Guillemin GJ, Lim CK, Mathey EK, Brilot F - Neurol Neuroimmunol Neuroinflamm (2014)

Temporal distribution of MOG antibody in serum of 2 relapsing patients with demyelinating diseasesIn both patient A (A) and patient B (B), upon treatment mycophenolate mofetil (MMF), myelin oligodendrocyte glycoprotein (MOG) antibody decreased to within the healthy control range (below threshold of positivity), and these low titers were associated with remission. Representative dot plot out of 3 experiments is shown. Magenta lines on graphs represent the positivity threshold (obtained with 24 control samples). Black squares represent serum analysis during acute demyelination episodes, and black circles represent sera during remission. Type of demyelinating episode is shown on graph. (C, D) Representative T2 axial MRI scans demonstrate demyelinating lesions during the first acute event and during convalescence. Patient A (C) had globular deep white matter lesions on acute scan (left panel), which show residual gliosis on convalescent scan and no new lesions (right panel). Patient B (D) had inflammatory lesions in basal ganglia and white matter on acute scan (left panel), with complete resolution on convalescent scan and no new lesions (right panel). Ab = antibody; ADEM = acute disseminated encephalomyelitis; CEREB = cerebellar episode; Ig = immunoglobulin; MFI = mean fluorescence intensity; ON = optic neuritis; TM = transverse myelitis.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4202678&req=5

Figure 2: Temporal distribution of MOG antibody in serum of 2 relapsing patients with demyelinating diseasesIn both patient A (A) and patient B (B), upon treatment mycophenolate mofetil (MMF), myelin oligodendrocyte glycoprotein (MOG) antibody decreased to within the healthy control range (below threshold of positivity), and these low titers were associated with remission. Representative dot plot out of 3 experiments is shown. Magenta lines on graphs represent the positivity threshold (obtained with 24 control samples). Black squares represent serum analysis during acute demyelination episodes, and black circles represent sera during remission. Type of demyelinating episode is shown on graph. (C, D) Representative T2 axial MRI scans demonstrate demyelinating lesions during the first acute event and during convalescence. Patient A (C) had globular deep white matter lesions on acute scan (left panel), which show residual gliosis on convalescent scan and no new lesions (right panel). Patient B (D) had inflammatory lesions in basal ganglia and white matter on acute scan (left panel), with complete resolution on convalescent scan and no new lesions (right panel). Ab = antibody; ADEM = acute disseminated encephalomyelitis; CEREB = cerebellar episode; Ig = immunoglobulin; MFI = mean fluorescence intensity; ON = optic neuritis; TM = transverse myelitis.
Mentions: Two recent patients (figure 2 and appendix e-2) with positive MOG antibodies who fulfilled 2013 criteria for MS18 were treated with mycophenolate mofetil (MMF), which produced clinical remission, no new lesions on follow-up MRI scans, and normalization of MOG antibodies (figure 2 and appendix e-2). In both patients, upon treatment with MMF, MOG antibody decreased below the threshold of positivity (figure 2, A and B).

Bottom Line: We used MO3.13 cells to examine immunoglobulin (Ig) G effects on oligodendrocyte cytoskeleton using 3D deconvolution imaging.MOG antibodies were found in 31/73 patients with DEM (42%) but in 0/24 controls.MOG antibody has functional effects on oligodendrocyte cytoskeleton.

View Article: PubMed Central - PubMed

Affiliation: Neuroimmunology Group (R.C.D., E.M.T., V.M., R.-Y.A.K., N.S., K. Pathmanandavel, S.R., F.B.), Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, Westmead, Australia; Institute for Immunology and Allergy Research (D.R.B.), Westmead Millenium Institute for Medical Research, University of Sydney, Westmead, Australia; Clinical Immunology (L.A.W.), Royal Prince Alfred Hospital, Sydney Medical School Immunology & Infectious Diseases, University of Sydney, Camperdown, Australia; Department of Radiology (K. Prelog), the Children's Hospital at Westmead, Australia; Department of Paediatric Neurology (D.R.C.), Women's and Children's Hospital, North Adelaide, Australia; Neuroinflammation Group (G.J.G., C.K.L.), MND and Neurodegenerative Diseases Research Centre, Macquarie University, Australian School of Advanced Medicine, North Ryde, Australia; and Neuroinflammation Group (E.K.M.), Brain and Mind Research Institute, University of Sydney, Camperdown, Australia.

ABSTRACT

Objective: To examine the clinical features of pediatric CNS demyelination associated with positive myelin oligodendrocyte glycoprotein (MOG) antibodies and to examine the functional effects of MOG antibody on oligodendrocyte cytoskeleton.

Methods: We measured MOG antibody using a fluorescence-activated cell sorting live cell-based assay in acute sera of 73 children with CNS demyelination (DEM) (median age 8 years, range 1.3-15.3) followed for a median of 4 years. We used MO3.13 cells to examine immunoglobulin (Ig) G effects on oligodendrocyte cytoskeleton using 3D deconvolution imaging.

Results: MOG antibodies were found in 31/73 patients with DEM (42%) but in 0/24 controls. At first presentation, MOG antibody-positive patients were more likely to have bilateral than unilateral optic neuritis (ON) (9/10 vs 1/5, respectively, p = 0.03), less likely to have brainstem findings (2/31 vs 16/42, p = 0.005), more likely to have a raised erythrocyte sedimentation rate >20 mm/h (9/19 vs 3/21, p = 0.05), less likely to have intrathecal oligoclonal bands (0/16 vs 5/27, p = 0.18), and less likely to be homozygous or heterozygous for human leukocyte antigen DRB1*1501 (3/18 vs 7/22, p = 0.46). MOG antibody positivity varied according to clinical phenotype, with ON and relapsing ON most likely to be seropositive. Two relapsing MOG antibody-positive patients treated with mycophenolate mofetil remain in remission and have become MOG antibody seronegative. Oligodendrocytes incubated with purified IgG from MOG antibody-positive patients showed a striking loss of organization of the thin filaments and the microtubule cytoskeleton, as evidenced by F-actin and β-tubulin immunolabelings.

Conclusions: MOG antibody may define a separate demyelination syndrome, which has therapeutic implications. MOG antibody has functional effects on oligodendrocyte cytoskeleton.

No MeSH data available.


Related in: MedlinePlus