ORIGINAL CONTRIBUTION Elevated Levels of to Glycoprotein Is Not Specific for Patients With

Arnon Karni, MD; Ronit Bakimer-Kleiner, PhD; Oded Abramsky, MD, PhD; Avraham Ben-Nun, PhD

Objective: To evaluate the presence and specificity of and to myelin basic were significantly higher in anti–myelin oligodendrocyte glycoprotein (MOG) anti- patients with MS (PϽ.001 and P = .001, respectively) and body in the cerebrospinal fluid and plasma of patients patients with ONDs (P = .005 and P = .03, respectively) with multiple sclerosis (MS). compared with controls; frequency of to MOG, but not to myelin basic protein, was higher in patients Design: Case-control study of patients with clinically with MS and patients with ONDs (P = .01 and P = .003, definite MS compared with patients with other neuro- respectively, for the frequency of anti-MOG antibody, and logic diseases (ONDs) of the central and P = .65 and P = .41, respectively, for the frequency of anti- control subjects. myelin basic protein antibody). Plasma levels of anti- bodies to MOG and to myelin basic protein were higher Setting: Referral center in the Department of Neurol- in patients with MS compared with patients with ONDs ogy of Hadassah University Hospital, greater Jerusalem (P = .003 for both comparisons) and with controls (P =.03 area, Israel. and P = .04, respectively); however, the frequency of an- tibodies to MOG and myelin basic protein was similar Participants: Consecutive cerebrospinal fluid samples in patients with MS, patients with ONDs (P = .54 and from 31 patients with MS, 31 patients with ONDs, and P = .82, respectively), and controls (P = .50 and P = .14, 28 healthy controls; and plasma samples from 33 pa- respectively). tients with MS, 28 patients with ONDs, and 31 healthy controls were taken from the cerebrospinal fluid and Conclusions: The elevated presence of anti-MOG anti- plasma bank of the Department of Neurology, Hadassah body is not specific for MS because a similar appearance University Hospital. was also demonstrated in patients with ONDs. There- fore, it is not clear whether this antibody is pathogenic Main Outcome Measures: Levels and frequencies of in MS or, on the contrary, has a defensive role against anti-MOG antibody in patients with MS, as defined by further immune-mediated damage after myelin break- -linked immunosorbent assay. down.

Results: Cerebrospinal fluid levels of antibodies to MOG Arch Neurol. 1999;56:311-315

ULTIPLE SCLEROSIS elin oligodendrocyte antigens, such as my- (MS) is an acquired elin basic protein (MBP) and galactocere- and chronic white brosidase in serum and cerebrospinal fluid matter disease of pre- (CSF), show that elevated titers of these sumed autoimmune antibodies are not specific for MS. This pathogenesis. Results of pathologic stud- raises the dilemma of whether these anti- M1-4 ies of the disease and of the animal bodies are deleterious or play a defensive From the Department of model—experimental autoimmune en- role against further autoimmune attack af- Neurology, Hadassah cephalomyelitis—emphasize mainly a T- ter myelin breakdown.11 University Hospital, Hebrew basis for an inflammatory reaction of Myelin oligodendrocyte glycopro- University Hadassah Medical demyelinating plaques. However, be- tein (MOG) is a minor component of my- School, Jerusalem yond the well-known intrathecal overpro- elin proteins12 that is restricted to the cen- (Drs Karni and Abramsky), duction of immunoglobulins in patients tral nervous system (CNS)13-16 and is and the Department of 5 Immunology, The Weizmann with MS, there is also clear evidence of located in the outermost region of the my- 14,17,18 Institute of Science, Rehovot humoral immune activity in these elin sheath. Results of several inves- (Drs Bakimer-Kleiner and plaques.6,7 Results of previous studies8-10 tigations4,19 suggest this antigen may be a Ben-Nun), Israel. of the frequency of antibodies against my- primary target of the humoral autoim-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 PATIENTS, MATERIALS, solution in phosphate-buffered saline solution (PBS), pH 7.4, overnight at 4°C. Unreactive sites were saturated with AND METHODS 10% filtered fetal calf serum (150 µL) in carbonate buffer, pH 9.6, for 2 hours at 37°C. A 75-µL volume of CSF (di- PATIENTS luted 1:5 in PBS with 1% bovine serum albumin [BSA] and 0.05% Tween-20) or plasma (diluted 1:200 in the same so- Samples of CSF and plasma were obtained from 31 and 33 lution) was added to each well, and the plates were kept at patients with clinically definite28 MS, respectively. Clini- room temperature for 1 hour. After washing, goat biotin- cal and laboratory data are presented in Table 1. ylated antihuman IgG (75 µL), diluted 1:4000 in PBS and Cerebrospinal fluid samples were also obtained from 3% BSA or antihuman IgA, IgG and IgM conjugated to per- 31 patients with ONDs of the CNS and from 28 controls oxidase (75 µL), diluted 1:2000 in PBS and 1% BSA and who were examined for headache. The ONDs group in- 0.05% Tween-20 were added to each well of the tested CSF cluded 6 patients with degenerative dementia, 3 patients and plasma samples, respectively, and the plates were in- with primary CNS lymphoma, 3 patients with Behc¸et dis- cubated for an additional 2 hours at room temperature. Bo- ease, 3 patients with acute meningitis, 3 patients with mo- vine serum albumin was included to reduce nonspecific tor neuron disease, 2 patients with multisystem atrophy, binding. The CSF plates were washed again, then peroxi- 2 patients with extrapyramidal syndromes, 2 patients with dase (75 µL) that was conjugated to streptavidin and di- acute encephalitis, 2 patients with intracerebral hemor- luted 1:2000 in PBS and 1% BSA was added to each well, rhage, 1 patient with acute cerebral infarct, l patient with and the plates were incubated for 30 minutes at 37°C. Af- Wilson disease, 1 patient with type C Niemann-Pick dis- terward, all plates were washed and a 2,2Ј-Azinobis (3- ease, 1 patient with focal epilepsy, and l patient with Frie- ethylbenzthiazoline-sulfonic acid) (ABTS; Sigma-Aldrich dreich ataxia. Corp, St Louis, Mo) substrate was added. The developing Plasma samples were also obtained from 31 healthy color was read as an optical density at 405 nm (OD405). Each individuals and 28 patients with ONDs of the CNS (Table CSF and plasma specimen was tested in duplicate (2 1). The latter comprised 11 patients with acute cerebral in- samples), so the results for every specimen express the av- farct, 3 patients with intracerebral hemorrhage, 2 patients erage value of the OD readings. The within-assay varia- with degenerative dementia, 2 patients with cryptogenic tion was consistently less than 15%. Specimens were con- generalized epilepsy, 2 patients with Behc¸et disease, 2 pa- sidered positive if their average OD reading was higher than tients with brain vasculitis, 2 patients with acute encepha- the mean OD405 level +2 SDs of controls. Results of pre- litis, 1 patient with acute meningitis, 1 patient with Wil- liminary tests done twice with 30 patients with MS, 20 pa- son disease, 1 patient with type C Niemann-Pick disease, tients with ONDs, and 10 controls show a complete match- and 1 patient with Sydenham chorea. None of the partici- ing of positive specimens for anti-MOG antibodies. pants were being treated with immunosuppressive or im- munomodulatory drugs during CSF or blood sampling. CSF OLIGOCLONAL BANDS

ANTIGENS Cerebrospinal fluid oligoclonal bands were detected by elec- trophoresis of unconcentrated CSF on agarose gel (Pana- Human MOG, a recombinant MOG that represents the im- gel; Princeton Separations Inc, Freehold, NJ) slides, fol- munoglobulinlike domain of the MOG molecule, was pre- lowed by fixation using picric acid, drying, and staining with pared as described previously.31 The specific peptide sequence amido black. is GQFRVIGPRHPIRALVGDEVELPCRISPGKNATGMEV- GWYRPPFSRVVHLYRNGKDQDGDQAPEYRGRTELLKD- CSF IgG CONCENTRATIONS AIGEGKVTLRIRNVRFSDEGGFTCFFRDHSYQEEAAME- LKVEDPFYWVS. The CSF IgG concentrations of patients with MS, patients Human MBP was purified from neurologically healthy with ONDs, and controls were measured in immunodif- according to Dunkley and Carnegie.32 fusion plates (Behringwerke AG, Marburg, Germany). Mea- surement was done to check whether the anti-MOG and ANTIBODY DETERMINATION anti-MBP levels obtained were specific for the antigen tested or were attributable to the total IgG concentrations. Cerebrospinal fluid and plasma samples were tested for lev- els of anti-MOG and anti-MBP antibodies of the IgA, IgG, STATISTICAL ANALYSIS and IgM isotypes. The CSF levels were measured by a modi- fied enzyme-linked immunosorbent assay with avidin- Comparisons were made among patients with MS, pa- biotin amplification12 and the plasma levels were mea- tients with ONDs, and controls for anti-MOG and anti- sured using standard enzyme-linked immunosorbent assay. MBP antibody levels and for CSF IgG concentrations us- Briefly, 96-well microtiter plates (Nunc-Immuno plates; ing the Wilcoxon rank sum test. Comparisons of the Nunc Als, Roskilde, Denmark) were coated with 100 µL frequency of positive patients were made with Yates cor- of a 10-µg/mL antigen (recombinant human MOG or MBP) rected ␹2 test. PϽ.05 was considered significant.

mune process in MS. Anti-MOG antibody—but not an- mune encephalomyelitis resulted in new and enlarged de- tibodies against other myelin —was capable of myelinative plaques, respectively.17,21-23 Moreover, in causing demyelination in brain cell cultures.20 Anti- chronic relapsing experimental autoimmune encepha- MOG antibody injected intrathecally into healthy rats and lomyelitis, serum demyelinating activity correlated with intravenously into animals with experimental autoim- the anti-MOG antibody titer;24 in a nonhuman primate

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 1. Clinical and Laboratory Data for Patients With MS, Table 2. Anti-MOG and Anti-MBP Antibody Levels in the Patients With ONDs, and Controls* CSF of Patients With MS, Patients With ONDs of the CNS, and Controls* Patients Patients With MS With ONDs Controls Positive Patients, OD , Patients, CSF donors, No. 31 (10:21) 31 (12:19) 28 (11:17) 405 Diagnosis No. Mean ± SD P† No. (%) P‡ (males:females)

Age of CSF donors, 16-58 (36.7) 15-86 (49.1) 19-72 (36.1) Anti-MOG Antibody (Cutoff Value, 0.781 OD405) range (mean), y MS 31 0.793 ± 0.522 Ͻ.01 10 (32) .01§ Plasma donors, No. 33 (13:20) 28 (9:19) 31 (13:18) ONDs 31 0.794 ± 0.459 .005࿣ 12 (39) .003࿣ (males:females) Healthy 28 0.470 ± 0.156 . . . 1 (4) . . . Age of plasma donors, 18-57 (41.5) 14-82 (50.1) 22-54 (35.5) range (mean), y Anti-MBP Antibody (Cutoff Value, 1.070 OD405) Positive CSF OCBs 19 ...... MS 30 0.925 ± 0.201 .001§ 3 (10) .65 RR/SP disease course ONDs 31 0.896 ± 0.174 .03࿣ 4 (13) .41 CSF donors 21/10 ...... Healthy 28 0.804 ± 0.133 . . . 1 (4) . . . Plasma donors 19/14 ...... EDSS score, *MOG indicates myelin oligodendrocyte glycoprotein; MBP, myelin basic range (mean) protein; CSF, cerebrospinal fluid; MS, multiple sclerosis; ONDs, other neurologic diseases; CNS, ; OD , optical density at CSF donors 1.0-7.0 (3.6) ...... 405 405 nm. No significant statistical differences were found between patients Plasma donors 1.0-7.0 (4.3) ...... with MS and patients with ONDs for the levels and frequency of positive Disease duration, patients of anti-MOG and anti-MBP antibodies; and ellipses, data not range (mean), y applicable. CSF donors 1-30 (7.0) ...... †Levels of antibodies were compared using the Wilcoxon rank sum test. Plasma donors 1-28 (11.9) ...... ‡Positive frequencies were compared according to the Yates corrected ␹2 test. *MS indicates multiple sclerosis; ONDs, other neurologic diseases; §MS vs healthy. CSF, cerebrospinal fluid; OCBs, oligoclonal bands; RR/SP, ࿣ONDs vs healthy. relapsing-remitting/secondary progressive29; EDSS, Expanded Disability Status Scale according to Kurtzke30; and ellipses, data not applicable. Table 3. Anti-MOG and Anti-MBP Antibody Levels in the Plasma of Patients With MS, Patients model of experimental autoimmune encephalomyelitis With ONDs of the CNs, and Controls* induced by MOG, exacerbations correlated with an en- 25 hanced production of anti-MOG antibody. Positive

Patients with MS had higher titers of CSF anti- Patients, OD405, Patients, MOG antibody, and more anti-MOG IgG antibody- Diagnosis No. Mean ± SD P† No. (%) P‡ 26,27 secreting cells, in CSF and blood than did controls. Anti-MOG Antibody (Cutoff Value, 0.451 OD405) To evaluate whether the presence of anti-MOG anti- MS 33 0.295 ± 0.080 .03§ 2 (6) .50 body is specific to MS, we compared the levels of CSF ONDs 28 0.226 ± 0.064 .27 0 (0) .99 and plasma anti-MOG antibody in patients with MS and Healthy 31 0.261 ± 0.095 . . . 1 (3) . . . the frequencies of patients with MS positive for this an- Anti-MBP Antibody (Cutoff Value, 1.554 OD405) tibody with those of patients with other neurologic dis- MS 33 0.414 ± 0.140 .04§ 4 (12) .14 eases (ONDs) of the CNS and healthy control subjects. ONDs 28 0.300 ± 0.127 .27࿣ 2 (7) .43 ... We also compared the frequencies of anti-MOG anti- Healthy 31 0.351 ± 0.101 . . . 1 (3) body with those of anti-MBP antibody in the same groups. *MOG indicates myelin oligodendrocyte glycoprotein; MBP, myelin basic RESULTS protein; MS, multiple sclerosis; ONDs, other neurologic diseases; CNS, central nervous system; OD405, optical density at 405 nm; and ellipses, data not applicable. No significant statistical differences were found between Levels of anti-MOG and anti-MBP antibodies were deter- patients with MS and patients with ONDs for the levels and frequency of mined in CSF and plasma samples from patients with MS, positive patients with anti-MOG and anti-MBP antibodies. patients with ONDs, and controls. We compared overall †Antibody levels were compared using the Wilcoxon rank sum test. ‡Positive frequencies were compared according to the Yates corrected ␹2 values of the antibodies and frequency of positive pa- test. tients. The cutoff value above which patients were con- §MS vs healthy. sidered positive for CSF antibodies was set as the mean ࿣ONDs vs healthy. value for controls +2 SDs: 0.781 OD405 for the anti-MOG antibody and 1.070 OD405 for the anti-MBP antibody. The MBP antibody) was higher in the MS and ONDs groups cutoff value above which patients were considered posi- than in controls. There were no significant differences tive for plasma antibodies was set as the mean value for in anti-MOG and anti-MBP antibody levels between the controls +2 SDs: 0.451 OD405 for the anti-MOG antibody MS and ONDs groups. and 0.554 OD405 for the anti-MBP antibody. Plasma levels of anti-MOG and anti-MBP antibodies As shown in Table 2, CSF levels of anti-MOG and of patients with MS were significantly higher than those anti-MBP antibodies of patients with MS and patients with of patients with ONDs and controls (Table 3). There were ONDs were significantly higher than those of controls. no significant differences in percentage of patients who were However, only the frequency of patients who were posi- positive for anti-MOG or anti-MBP antibodies among pa- tive for the anti-MOG antibody (but not for the anti- tients with MS, patients with ONDs, and controls.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 To check whether the differences in levels of CSF There was no correlation between CSF anti-MOG antibodies can be attributed to levels of CSF immuno- antibody levels and CSF IgG concentrations. This result globulins, we measured CSF IgG concentrations. Range indicated that the detected antibodies were specific for of CSF IgG concentrations in patients with MS was 0.002 the antigens we tested. to 0.15 g/L (mean, 0.05 g/L). Mean CSF IgG concentra- Although the plasma levels of the anti-MOG and anti- tion of the 10 anti-MOG antibody–positive patients with MBP antibodies of patients with MS were significantly MS was 0.06 g/L, whereas mean CSF IgG concentra- higher than the antibody levels of patients with ONDs tions of the 21 anti-MOG antibody–negative patients with and controls, these levels were usually not higher than MS was 0.06 g/L. There was no significant difference be- the cutoff value for controls. tween these 2 subgroups of patients with MS. Anti-MOG antibody has been suggested to be in- Range of CSF IgG concentrations in patients with volved in the formation of demyelinative MS plaques.14-18 ONDs was 0.002 to 0.12 g/L (mean, 0.03 g/L). Mean CSF However, we found that this antibody was also present IgG concentrations of the 12 anti-MOG antibody– in ONDs with no demyelinating lesions. Therefore, our positive patients with ONDs was 0.04 g/L, whereas mean study shows that measuring anti-MOG antibody cannot CSF IgG concentrations of the 19 anti-MOG antibody– serve as a diagnostic tool for MS and does not support negative patients with ONDs was 0.04 g/L. There was no the notion that anti-MOG antibody is primarily respon- significant difference in IgG concentration between these sible for demyelination in MS. 2 subgroups of patients with ONDs. Our findings support the possibility that increased Similarly, no significant difference in anti-MOG and levels of anti-MOG antibody in MS may represent a sec- anti-MBP antibodies was found between 19 patients with ondary phenomenon related to myelin damage in this dis- MS with CSF oligoclonal bands and 12 patients with MS ease. Taking into account its demyelinative prop- without CSF oligoclonal bands. erty,17,20-23 this antibody may be pathogenic in the setting Because the relative frequency of immunoglobulin- of blood-brain barrier breach, complement, and inflam- producing B cells and plasma cells is higher in the late matory infiltrates that occur in acute MS lesions. How- stages of MS,33 we analyzed the levels and frequencies of ever, it may serve as a defense line against immune- anti-MOG and anti-MBP in patients with MS according mediated damage after myelin breakdown11 by opsonization to disease course (relapsing-remitting vs secondary pro- of myelin debris to allow phagocytosis by macrophages gressive), degree of disability (evaluated by the Ex- and microglial cells. Therefore, as with other MS nonspe- panded Disability Status Scale of Kurtzke30), and dis- cific autoantibodies, the meaning of elevated anti-MOG ease duration. No significant differences in the levels and antibody levels in CSF is not straightforward. frequencies of CSF anti-MOG and anti-MBP antibodies were noted on the basis of the above-mentioned clinical Accepted for publication July 14, 1998. features of MS. However, 50% (6/12) of the patients with This work was supported in part by the Hilda Katz MS with a disease duration of 5 years or more were posi- Blaustein, the Zeev Aram, and the Lena P. Harvey endow- tive for the anti-MOG antibody compared with only 21% ment funds. (4/19) of the patients with MS with a disease duration of Corresponding author: Arnon Karni, MD, Depart- less than 5 years (P = .20). ment of Neurology, Hadassah University Hospital, PO Similar to the CSF, no significant differences in the Box 12000, Jerusalem 91120, Israel (e-mail: akarni levels and frequencies of the plasma anti-MOG and anti- @cc.huji.ac.il). MBP antibodies were found by subdividing the patients with MS according to disease course, degree of disabil- ity, or disease duration. REFERENCES

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