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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

Distribution of MOG IgG antibody in pediatric demyelinating diseases(A) Antibody reactivity to myelin oligodendrocyte glycoprotein (MOG) was determined by flow cytometry live cell-based assay. (B) Representative example of flow cytometry histograms for one MOG antibody–positive patient with a very high ΔMFI and (C) an intermediate ΔMFI. MFI values are noted in the legend. (D) Human surface MOG IgG antibody was detected in 31/73 sera from patients with demyelinating diseases (DEM) and 0/24 controls (CTL). Magenta line on graph represents the positivity threshold. MOG antibody positivity is shown between brackets. (E) Surface MOG antibody was detected in 3/22 CSF from patients with DEM and 0/20 CSF from patients with other neurologic diseases (CTL). Black circles represent patients with positive MOG antibody in CSF and in serum. (F) Distribution and number of MOG antibody–positive patients in optic neuritis (ON). (G) Correlation between erythrocyte sedimentation rate and age in MOG antibody–positive patients. (H) Distribution and (I) number of MOG antibody–positive patients in demyelinating diseases at follow-up. Ab = antibody; ADEM = acute disseminated encephalomyelitis; CIS = clinically isolated syndrome; BON = bilateral optic neuritis; HEK = human embryonic kidney; Ig = immunoglobulin; MFI = mean fluorescence intensity; MS = multiple sclerosis; TM = transverse myelitis; UON = unilateral optic neuritis.
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Figure 1: Distribution of MOG IgG antibody in pediatric demyelinating diseases(A) Antibody reactivity to myelin oligodendrocyte glycoprotein (MOG) was determined by flow cytometry live cell-based assay. (B) Representative example of flow cytometry histograms for one MOG antibody–positive patient with a very high ΔMFI and (C) an intermediate ΔMFI. MFI values are noted in the legend. (D) Human surface MOG IgG antibody was detected in 31/73 sera from patients with demyelinating diseases (DEM) and 0/24 controls (CTL). Magenta line on graph represents the positivity threshold. MOG antibody positivity is shown between brackets. (E) Surface MOG antibody was detected in 3/22 CSF from patients with DEM and 0/20 CSF from patients with other neurologic diseases (CTL). Black circles represent patients with positive MOG antibody in CSF and in serum. (F) Distribution and number of MOG antibody–positive patients in optic neuritis (ON). (G) Correlation between erythrocyte sedimentation rate and age in MOG antibody–positive patients. (H) Distribution and (I) number of MOG antibody–positive patients in demyelinating diseases at follow-up. Ab = antibody; ADEM = acute disseminated encephalomyelitis; CIS = clinically isolated syndrome; BON = bilateral optic neuritis; HEK = human embryonic kidney; Ig = immunoglobulin; MFI = mean fluorescence intensity; MS = multiple sclerosis; TM = transverse myelitis; UON = unilateral optic neuritis.

Mentions: In order to align our detection method to recent reports, we first detected MOG antibody in serum using FACS assay and HEK cells expressing human MOG.11,14,16,31,32 The mean fluorescence intensity correlated with antibody concentration (figure 1A). Using the mean plus 3 SDs to establish the threshold for positivity, MOG antibodies were found in 31/73 (42%) of the DEM group but in 0/24 controls (figure 1, B–D, p = 0.000). We have tested 57 other medical and neurologic controls, and all were negative. We also tested MOG antibody in CSF (figure 1E). We had CSF available in 22 patients with DEM, of which 5 were positive for MOG antibody in serum. Only 3/22 CSF samples were positive, 2 of which were serum positive and 1 of which was serum negative (figure 1E). Serologic testing for AQP4 antibodies was performed in 64 patients with DEM and was negative in all (data not shown).


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)

Distribution of MOG IgG antibody in pediatric demyelinating diseases(A) Antibody reactivity to myelin oligodendrocyte glycoprotein (MOG) was determined by flow cytometry live cell-based assay. (B) Representative example of flow cytometry histograms for one MOG antibody–positive patient with a very high ΔMFI and (C) an intermediate ΔMFI. MFI values are noted in the legend. (D) Human surface MOG IgG antibody was detected in 31/73 sera from patients with demyelinating diseases (DEM) and 0/24 controls (CTL). Magenta line on graph represents the positivity threshold. MOG antibody positivity is shown between brackets. (E) Surface MOG antibody was detected in 3/22 CSF from patients with DEM and 0/20 CSF from patients with other neurologic diseases (CTL). Black circles represent patients with positive MOG antibody in CSF and in serum. (F) Distribution and number of MOG antibody–positive patients in optic neuritis (ON). (G) Correlation between erythrocyte sedimentation rate and age in MOG antibody–positive patients. (H) Distribution and (I) number of MOG antibody–positive patients in demyelinating diseases at follow-up. Ab = antibody; ADEM = acute disseminated encephalomyelitis; CIS = clinically isolated syndrome; BON = bilateral optic neuritis; HEK = human embryonic kidney; Ig = immunoglobulin; MFI = mean fluorescence intensity; MS = multiple sclerosis; TM = transverse myelitis; UON = unilateral optic neuritis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: Distribution of MOG IgG antibody in pediatric demyelinating diseases(A) Antibody reactivity to myelin oligodendrocyte glycoprotein (MOG) was determined by flow cytometry live cell-based assay. (B) Representative example of flow cytometry histograms for one MOG antibody–positive patient with a very high ΔMFI and (C) an intermediate ΔMFI. MFI values are noted in the legend. (D) Human surface MOG IgG antibody was detected in 31/73 sera from patients with demyelinating diseases (DEM) and 0/24 controls (CTL). Magenta line on graph represents the positivity threshold. MOG antibody positivity is shown between brackets. (E) Surface MOG antibody was detected in 3/22 CSF from patients with DEM and 0/20 CSF from patients with other neurologic diseases (CTL). Black circles represent patients with positive MOG antibody in CSF and in serum. (F) Distribution and number of MOG antibody–positive patients in optic neuritis (ON). (G) Correlation between erythrocyte sedimentation rate and age in MOG antibody–positive patients. (H) Distribution and (I) number of MOG antibody–positive patients in demyelinating diseases at follow-up. Ab = antibody; ADEM = acute disseminated encephalomyelitis; CIS = clinically isolated syndrome; BON = bilateral optic neuritis; HEK = human embryonic kidney; Ig = immunoglobulin; MFI = mean fluorescence intensity; MS = multiple sclerosis; TM = transverse myelitis; UON = unilateral optic neuritis.
Mentions: In order to align our detection method to recent reports, we first detected MOG antibody in serum using FACS assay and HEK cells expressing human MOG.11,14,16,31,32 The mean fluorescence intensity correlated with antibody concentration (figure 1A). Using the mean plus 3 SDs to establish the threshold for positivity, MOG antibodies were found in 31/73 (42%) of the DEM group but in 0/24 controls (figure 1, B–D, p = 0.000). We have tested 57 other medical and neurologic controls, and all were negative. We also tested MOG antibody in CSF (figure 1E). We had CSF available in 22 patients with DEM, of which 5 were positive for MOG antibody in serum. Only 3/22 CSF samples were positive, 2 of which were serum positive and 1 of which was serum negative (figure 1E). Serologic testing for AQP4 antibodies was performed in 64 patients with DEM and was negative in all (data not shown).

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