Antibodies
against Gangliosides in Patients Neurological Manifestations
with SLE and
MARTINEZ*, M. TINTORE**, J. MONTALBAN**, J. ORDI*, M. VILARDELL* and A. CODINA** *Department of Internal Medicine, and **Unit of Neurological Research, Department of Neurology, Hospital General Vall d’Hebron,
X.
Barcelona, Spain
Pathogenesis of neuropsychiatric manifestations of systemic lupus erythematosus (SLE) has not been clearly defined, and the search for pathogenic mechanisms has focused on the importance of several autoantibodies. There is increasing evidence that antibodies against
gangliosides may have a pathogenic role in some neurological disorders. The aim of the present study was to examine the association between antibodies against gangliosides and neuropsychiatric SLE. We found anti-type II ganglioside antibodies in two out of 32 patients with multiple sclerosis (6.25%) and in 10 out of 60 patients with SLE (16.6%); five of 17 patients with neurological abnormalities also had high levels of these antibodies (29.4%). Five of the 10 patients with SLE and positive antiganglioside antibody assays had only IgM antibodies, three had IgG antibodies and two had both isotypes. By chi-square analysis, the incidence of anti-type II ganglioside antibodies was not significantly higher in patients with symptoms related to the nervous system than in SLE patients without neurological involvement (P > 0.2). No clear correlation was found between antibodies against gangliosides and cardiolipin. Key Words : Neuropsychiatric Lupus Demyelination
Introduction Abnormalities of the nervous-system function occur in about 50% of all cases of systemic lupus erythematosus 1-3. In recent years, the search for pathogenic mechanisms in the development of central nervous system (CNS) SLE has focused on the importance of autoantibodies to neuronal membrane antigens. The potential pathogenic role of neuron-reactive antibodies is supported by the observation that these antibodies are present in the nervous systems of patients with CNS involvement. The association is particularly strong in
patients
with
organic brain syndromes, psychosis
or
seizures 4. Bonfa et at. have documented a striking association between lupus psychosis and autoantibodies to ribosomal P protein~. Anticardiolipin antibodies have been related to venous and arterial cerebral thrombosis and chorea~. Nevertheless, the pathogenesis of neuromanifestations of SLE has not been defined and it unlikely that a single pathologic process can explain the diversity of clinical CNS
and some glycoproteins). Glycosphingolipids be divided into gangliosides and neutral glycolipids such as cerebrosides. There is increasing evidence that antibodies against gangliosides may have a pathogenic role in some neurological disorders. Antibodies against gangliosides have been detected in relatively levels in 20% of Guillain-Barré syndrome patients~, and in patients with chronic idiopathic demyelinating polyradiculoneuropathy9, motoneuron disease&dquo; and multiple sclerosis (MS)&dquo;. The aim of the present study was to examine the association between antibodies against
protein can
and SLE. Patients and methods Sera from 132 were studied. were kept frozen at -80°C until use. Included in this study were 60 patients with SLE who fulfilled the 1982 American Rheumatism Association’s revised criteria for SLE 12; 17 patients had experienced neuropsychiatric manifestations (Table 1) and 43 had no previous or current
dysfunction. Human CNS
19.4%) and 30Vo proteins (the bulk of myelin proteins be accounted for by proteolipid protein (PLP), myelin basic protein (MBP), and a fraction of highmolecular-weight proteins that include the Wolfgram can
consists of 70% Mpids (phospho-
lipids 30.2%, glycosphingolipids 19.,2% and cholesterol
Correspondence: Dr. J. Montalbán, M.D., Ph.D., Department of Neurology, Hospital General Vall d’Hebron, Psg Vall d’Hebron s/n, 08035-Barcelona, Spain.
neurological involvement. Thirty-two subjects were used as patients with evidence
of
MS and 40 normal
controls.
299
Downloaded from lup.sagepub.com at UNIV OF MONTANA on April 8, 2015
Table I
aGG:
Clinical and
serological data of patients with SLE
antiganglioside antibodies;
aCL:
anticardiolipin antibodies;
and
Pos:
All serum samples were tested by enzyme-linked immunosorbent assay (ELISA) for IgG and IgM reactivity with a pool of ganglioside extracted from bovine brain (type II ganglioside, Sigma G2250). Microwells in a flat-bottom 96-well ELISA plate (Flow) were coated with ethanol (100 pol) containing 10 pog/ml of ganglioside, and the ethanol was allowed to evaporate overnight. Wells were then blocked with 200 pol of 1 % bovine serum albumin (BSA) in phosphate buffered saline (PBS) for 4 h at room temperature. Wells were washed four times with PBS (200 pol), and patient serum (50 pol) was added in triplicate to the wells at the serum dilution of i ~ 50 and incubated for 16 h at 4°C. Sera from controls were also added to microwells not coated with antigen to determine non-specific binding. The plates were then washed four times in PBS solution, and alkaline-phosphatase conjugated anti-human IgG (Sigma A5403) or IgM (Sigma A3275) diluted 1:1000 in PBS-ST solution was added. After It h at room temperature the plates were washed four times, and substrate solution {5~l pol) containing p-nitrophenylphosphate with diethanolamine (I mg/ml), pH 9.8, was added to the wells. Reaction products were measured spectrophotometrically at 405 nm in a Biotek EIA reader. Serum was considered positive when the mean absorbances obtained from the wells coated with type 11 ganglioside exceeded by more than three standard deviations the mean binding activities of serum from the control group. Various time intervals were studied to determine the optimal times for reading the last incubation step. To compare data from different experiments, six dilutions of a standard serum from a patient with high antibody titers were used in each assay (Figure I ~, and reading was performed when the optical density in type 11 gangliosidecoated wells incubated with the positive control reached
neurological involvement.
positive; Neg: negative.
I Serum serial dilutions from side antibodies.
Figure
a
patient with IgM antiganglio-
reading of 1.0, usually corresponding to an interval of 10-20 min. Concentrations of anticardiolipin antibodies were measured by a standardized ELISA as devised by Gharavi et al.13 and results were expressed according to the standardization 14. a
Results 16 In the SLE group, the mean age was 38.7 years (SD years, maximum 73, minimum 15). The mean age at diagnosis of SLE was 32.6 years (SD 16.1 years, maximum 71, minimum 8). Other immunological diseases were found in 22% of the patients. The following neurological disorders related to SLE were found in 17 =
=
300
Downloaded from lup.sagepub.com at UNIV OF MONTANA on April 8, 2015
patients (2~~10): 1 stroke, two multi-infarctic dementia, three seizures, two myelitis, two psychosis, one nonmetabolic coma, two cranial multineuritis, one meningoencephaloradiculitis, one my~sitis and one aseptic
meningitis (Table I). We found anti-type II ganglioside antibodies in two patients with MS ~~.~~~1~~ and 10 patients with SLE ~1~.6~0); 5 of these had neurological abnormalities (29.4Vo ; Table II). Five of the 10 patients with SLE and positive antiganglioside antibody assays had only IgM antibodies, three had IgG antibodies and two had both isotypes. By chi-square analysis, the incidence of anti-type II ganglioside antibodies was not significantly higher in patients with symptoms related to the nervous system than in SLE patients without neurological involvement (P > 0.2). Although anti-type II ganglioside antibodies were found more frequently in SLE compared to MS patients and healthy individuals, a relationship between the presence of these
antibodies and cerebral SLE was not found. Fifteen patients had anticardiolipin antibodies ~~5~’~~; six of these patients had neurological involvement (Table II). No clear correlation was found between antibodies against gangliosides and cardiolipin. Table II
Antiganglioside antibodies
aGG: antibodies against gangliosides. I Group 1: Healthy individuals. ~I Group 2: Multiple sclerosis patients. Group 3: SLE patients. d 5 IgG and 8 IgM, from’the 12 aGG-positive and 3.
patients in Groups
2
Discussion
Sergott et al. observed that antiserum to the myelin glycosphingolipid galactocerebroside (GAIC) causes rapidly focal when injected into pig optic nerves. The capacity of antiGAIC to induce CNS was complement dependent and to result from primary damage to ohgodendrocytes ~~ ~ Roth et al. reported that cultures of mouse spinal cord tissue, to antisera against GAIC and two (GM1 and GM4), showed demyelination changes 16. Anti-GalC antibodies were detected in 50% of experimental allergic neuritis rabbits 17. A high incidence of autoantibody against glycosphingolipids and in particular against ’asialoGM1* was observed by Hirano et al. in sera from patients with SLE with neurological disorders, using an immuno-
flocculation test. The sera from 14 out of 17 patients with SLE and neurological involvement reacted with asialo--MM 1 bnt showed no activity against other glycosphingolipids such as GM I, asialo-GM2 and !Gal~. In 87 SLE patients without neurological abnormalities, as well as in 61 cases of other autoimmune diseases and 20 cases of different neurologic diseases, no antibodies could be detected 18. Later on, the same author reported similar results using an ELISA technique 19. The results found by Hirano et al. suggested that antiganglioside antibodies and in particular anti-asialo~r~ antibodies could play a role in the pathogenesis of neurological complications accompanying SLE. Costallat et al. found a strong correlation between IgM antigangliosides and anti-GaIC antibodies and neuropsychiatric manifestations. These authors concluded that these antibodies showed an important predictive role for neurological abnormalities in SLE 20. On the other hand, Endo etal. observed that the occurrence of anti-asialo-GM I, but not of anti-GM I, was significantly more frequent in patients with SLE than in those with MS. However, these authors found no correlation between the presence of antiglycosphingolipid antibodies and symptoms related to the nervous system in patients with SLE, using a liposome lysis assay21. For these authors, the presence of antibodies in the sera of other patients who have traumatic or ischemic injury to the CNS suggests that these antibodies can arise in response to inflammation and damage of neural tissues. As we have previously mentioned, the major lipids in myelin are phospholipids, glycosphingolipids and cholesterol. Glycosphingolipids constitute approximately 20% of the total myelin lipids; gangliosides account for less than 1070 of this fraction. Although GM 1 is not the most abundant brain gangliosides, and asialoC~~ 1 is present only in trace amounts in brain ganglioside preparations, it seems that antibodies against these compounds could have a role in producing lesions in the central and peripheral nervous systems, mainly of the demyelinating type such as myelitis, optic neuritis, cranial multineuritis, and other focal non-ischemic neurological deficits. Although our results do not demonstrate a relationship between antibodies against
ant manifestations, study of a number of with SLE and symptoms related to the nervous system and/or determination of other types of antiganglioside antibodies could clarify the pathogenic significance of these antibodies.
Acknowledgements This study has been supported in part by Grantt No. 91/00300500 from the Fondo de Investigaciones Sanitarias (Ministry of Health of Spain). We are
301
Downloaded from lup.sagepub.com at UNIV OF MONTANA on April 8, 2015
indebted to Ms M. José Vicente for her technical assistance.
References 1. Johnson RT, Richardson EP Jr. The neurological manifestations of systemic lupus erythematosus: a clinical-pathological study of 24 cases and review of the literature. Medicine (Baltimore) 1968; 47: 337-69. 2. Feinglass EJ, Arnett FC, Dorsch CA, Zizic TM, Stevens MB. Neuropsychiatric manifestations of systemic lupus erythematosus: diagnosis, clinical spectrum, and relationship to other features of the disease. Medicine (Baltimore ) 1976; 55: 323-39. 3. Kaell AT, Shetty M, Lee BCP, Lockshin MD. The diversity of neurologic events in systemic lupus erythematosus. Arch Neurol 1986; 43: 273-6. 4. Bluenstein HG, Williams GV, Steinberg AD. Cerobrospinal fluid antibodies to neuronal cells: association with neuropsychiatric manifestations of systemic lupus erythematosus. Am J Med 1981; 70: 240-6. 5. Bonfa E, Golombek SJ, Kaufman LD et al. Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl JMed 1987; 317:265-71. 6. Harris EN, Gharavi AE, Asherson RA, Boey ML, Hughes GRV. Cerebral infarction in systemic lupus erythematosus: association with anticardiolipin antibodies. Clin Exp Rheum 1984; 2 :47-51. 7. Asherson RA, Berksen RHWM, Harris EN et al. Chorea in systemic lupus erythematosus and ’lupus-like’ disease: association with antiphospholipid antibodies. Sem Arthritis Rheum 1987; 16: 253-9. 8. Ilyas AA, Willison HJ, Quarles RJ et al. Serum antibodies to gangliosides in Guillain-Barré syndrome. Ann Neurol 1988; 23:440-7. 9. Sindern E, Stark E, Haas J, Steck AJ. Serum antibodies to GM1 and GM3-gangliosides in systemic lupus erythematosus with chronic inflammatory demyelinating polyradiculoneuropathy. Acta Neurol Scand 1991; 83: 399-402. 10. Pestronk A, Adams RN, Clawson L et al. Serum antibodies to GM1 gangliosides in amyotrophic lateral sclerosis. Neurology 1988; 38: 1457-61.
11. Arnon R, Crisp E, Kelley R, Ellison GW, Myers LW, Tourtellotte WW. Anti-ganglioside antibodies in multiple sclerosis. J Neurol
Sci 1980; 46: 179-86. 12. Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-7. 13. Gharavi AE, Harris EN, Asherson RA, Hughes GRV. Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis 1987; 46: 1-6. 14. Harris EN, Gharavi AE, Patel SP, Hughes GRV. Evaluation of the anticardiolipin antibody test: report of an international workshop held 4th April 1986. Clin Exp Immunol 1987; 68: 215-22. 15. Sergott RC, Brown MJ, Silberberg DH, Lisak RP. Antigalactocerebroside serum demyelinates optic nerve in vivo. J Neurol Sci 1984; 64:297-303. 16. Rott GA, Roytta M, Yu RK, Raine CS, Bornstein MB. Antisera to different glycolipids induce myelin alterations in mouse spinal cord tissue cultures. Brain Res 1985; 339: 9-18. 17. Irie H, Yorita T, Takahashi K. Anti-galactocerebroside antibody in rabbits with experimental allergic neuritis. Japan J Exp Med 1986; 56: 43-9. 18. Hirano T, Hashimoto H, Shiokawa Y et al. Antiglycolipid autoantibody detected in the sera from systemic lupus, erythematosus patients. J Clin Invest 1980; 66: 1437-40. 19. Hirano T, Miyahima H, Taniguchi 0 et al. Anti asialo GM1 antibody detected in the patients’ sera from systemic lupus erythematosus and Behcet’s disease with neurological manifestations. Jpn J Med 1988; 27: 167-7 1. 20. Costallat LT, de Oliveira RM, Santiago MB, Cossermelli W. Samara AM. Neuropsychiatric manifestations of systemic lupus erythematosus: the value of anticardiolipin, antiganglioside, and antigalactocerebroside antibodies. Clin Rheumatol (Belgium) 1990; 9: 489-97. 21. Endo T, Scott DD, Stewart SS, Kundu SK, Marcus DM. Antibodies to glycosphingolipids in patients with multiple sclerosis and SLE. J Immunol 1984; 132: 1793-7.
302
Downloaded from lup.sagepub.com at UNIV OF MONTANA on April 8, 2015
(Received 31 March 1992) (Accepted 22 July 1992)
against Gangliosides in Patients Neurological Manifestations
with SLE and
MARTINEZ*, M. TINTORE**, J. MONTALBAN**, J. ORDI*, M. VILARDELL* and A. CODINA** *Department of Internal Medicine, and **Unit of Neurological Research, Department of Neurology, Hospital General Vall d’Hebron,
X.
Barcelona, Spain
Pathogenesis of neuropsychiatric manifestations of systemic lupus erythematosus (SLE) has not been clearly defined, and the search for pathogenic mechanisms has focused on the importance of several autoantibodies. There is increasing evidence that antibodies against
gangliosides may have a pathogenic role in some neurological disorders. The aim of the present study was to examine the association between antibodies against gangliosides and neuropsychiatric SLE. We found anti-type II ganglioside antibodies in two out of 32 patients with multiple sclerosis (6.25%) and in 10 out of 60 patients with SLE (16.6%); five of 17 patients with neurological abnormalities also had high levels of these antibodies (29.4%). Five of the 10 patients with SLE and positive antiganglioside antibody assays had only IgM antibodies, three had IgG antibodies and two had both isotypes. By chi-square analysis, the incidence of anti-type II ganglioside antibodies was not significantly higher in patients with symptoms related to the nervous system than in SLE patients without neurological involvement (P > 0.2). No clear correlation was found between antibodies against gangliosides and cardiolipin. Key Words : Neuropsychiatric Lupus Demyelination
Introduction Abnormalities of the nervous-system function occur in about 50% of all cases of systemic lupus erythematosus 1-3. In recent years, the search for pathogenic mechanisms in the development of central nervous system (CNS) SLE has focused on the importance of autoantibodies to neuronal membrane antigens. The potential pathogenic role of neuron-reactive antibodies is supported by the observation that these antibodies are present in the nervous systems of patients with CNS involvement. The association is particularly strong in
patients
with
organic brain syndromes, psychosis
or
seizures 4. Bonfa et at. have documented a striking association between lupus psychosis and autoantibodies to ribosomal P protein~. Anticardiolipin antibodies have been related to venous and arterial cerebral thrombosis and chorea~. Nevertheless, the pathogenesis of neuromanifestations of SLE has not been defined and it unlikely that a single pathologic process can explain the diversity of clinical CNS
and some glycoproteins). Glycosphingolipids be divided into gangliosides and neutral glycolipids such as cerebrosides. There is increasing evidence that antibodies against gangliosides may have a pathogenic role in some neurological disorders. Antibodies against gangliosides have been detected in relatively levels in 20% of Guillain-Barré syndrome patients~, and in patients with chronic idiopathic demyelinating polyradiculoneuropathy9, motoneuron disease&dquo; and multiple sclerosis (MS)&dquo;. The aim of the present study was to examine the association between antibodies against
protein can
and SLE. Patients and methods Sera from 132 were studied. were kept frozen at -80°C until use. Included in this study were 60 patients with SLE who fulfilled the 1982 American Rheumatism Association’s revised criteria for SLE 12; 17 patients had experienced neuropsychiatric manifestations (Table 1) and 43 had no previous or current
dysfunction. Human CNS
19.4%) and 30Vo proteins (the bulk of myelin proteins be accounted for by proteolipid protein (PLP), myelin basic protein (MBP), and a fraction of highmolecular-weight proteins that include the Wolfgram can
consists of 70% Mpids (phospho-
lipids 30.2%, glycosphingolipids 19.,2% and cholesterol
Correspondence: Dr. J. Montalbán, M.D., Ph.D., Department of Neurology, Hospital General Vall d’Hebron, Psg Vall d’Hebron s/n, 08035-Barcelona, Spain.
neurological involvement. Thirty-two subjects were used as patients with evidence
of
MS and 40 normal
controls.
299
Downloaded from lup.sagepub.com at UNIV OF MONTANA on April 8, 2015
Table I
aGG:
Clinical and
serological data of patients with SLE
antiganglioside antibodies;
aCL:
anticardiolipin antibodies;
and
Pos:
All serum samples were tested by enzyme-linked immunosorbent assay (ELISA) for IgG and IgM reactivity with a pool of ganglioside extracted from bovine brain (type II ganglioside, Sigma G2250). Microwells in a flat-bottom 96-well ELISA plate (Flow) were coated with ethanol (100 pol) containing 10 pog/ml of ganglioside, and the ethanol was allowed to evaporate overnight. Wells were then blocked with 200 pol of 1 % bovine serum albumin (BSA) in phosphate buffered saline (PBS) for 4 h at room temperature. Wells were washed four times with PBS (200 pol), and patient serum (50 pol) was added in triplicate to the wells at the serum dilution of i ~ 50 and incubated for 16 h at 4°C. Sera from controls were also added to microwells not coated with antigen to determine non-specific binding. The plates were then washed four times in PBS solution, and alkaline-phosphatase conjugated anti-human IgG (Sigma A5403) or IgM (Sigma A3275) diluted 1:1000 in PBS-ST solution was added. After It h at room temperature the plates were washed four times, and substrate solution {5~l pol) containing p-nitrophenylphosphate with diethanolamine (I mg/ml), pH 9.8, was added to the wells. Reaction products were measured spectrophotometrically at 405 nm in a Biotek EIA reader. Serum was considered positive when the mean absorbances obtained from the wells coated with type 11 ganglioside exceeded by more than three standard deviations the mean binding activities of serum from the control group. Various time intervals were studied to determine the optimal times for reading the last incubation step. To compare data from different experiments, six dilutions of a standard serum from a patient with high antibody titers were used in each assay (Figure I ~, and reading was performed when the optical density in type 11 gangliosidecoated wells incubated with the positive control reached
neurological involvement.
positive; Neg: negative.
I Serum serial dilutions from side antibodies.
Figure
a
patient with IgM antiganglio-
reading of 1.0, usually corresponding to an interval of 10-20 min. Concentrations of anticardiolipin antibodies were measured by a standardized ELISA as devised by Gharavi et al.13 and results were expressed according to the standardization 14. a
Results 16 In the SLE group, the mean age was 38.7 years (SD years, maximum 73, minimum 15). The mean age at diagnosis of SLE was 32.6 years (SD 16.1 years, maximum 71, minimum 8). Other immunological diseases were found in 22% of the patients. The following neurological disorders related to SLE were found in 17 =
=
300
Downloaded from lup.sagepub.com at UNIV OF MONTANA on April 8, 2015
patients (2~~10): 1 stroke, two multi-infarctic dementia, three seizures, two myelitis, two psychosis, one nonmetabolic coma, two cranial multineuritis, one meningoencephaloradiculitis, one my~sitis and one aseptic
meningitis (Table I). We found anti-type II ganglioside antibodies in two patients with MS ~~.~~~1~~ and 10 patients with SLE ~1~.6~0); 5 of these had neurological abnormalities (29.4Vo ; Table II). Five of the 10 patients with SLE and positive antiganglioside antibody assays had only IgM antibodies, three had IgG antibodies and two had both isotypes. By chi-square analysis, the incidence of anti-type II ganglioside antibodies was not significantly higher in patients with symptoms related to the nervous system than in SLE patients without neurological involvement (P > 0.2). Although anti-type II ganglioside antibodies were found more frequently in SLE compared to MS patients and healthy individuals, a relationship between the presence of these
antibodies and cerebral SLE was not found. Fifteen patients had anticardiolipin antibodies ~~5~’~~; six of these patients had neurological involvement (Table II). No clear correlation was found between antibodies against gangliosides and cardiolipin. Table II
Antiganglioside antibodies
aGG: antibodies against gangliosides. I Group 1: Healthy individuals. ~I Group 2: Multiple sclerosis patients. Group 3: SLE patients. d 5 IgG and 8 IgM, from’the 12 aGG-positive and 3.
patients in Groups
2
Discussion
Sergott et al. observed that antiserum to the myelin glycosphingolipid galactocerebroside (GAIC) causes rapidly focal when injected into pig optic nerves. The capacity of antiGAIC to induce CNS was complement dependent and to result from primary damage to ohgodendrocytes ~~ ~ Roth et al. reported that cultures of mouse spinal cord tissue, to antisera against GAIC and two (GM1 and GM4), showed demyelination changes 16. Anti-GalC antibodies were detected in 50% of experimental allergic neuritis rabbits 17. A high incidence of autoantibody against glycosphingolipids and in particular against ’asialoGM1* was observed by Hirano et al. in sera from patients with SLE with neurological disorders, using an immuno-
flocculation test. The sera from 14 out of 17 patients with SLE and neurological involvement reacted with asialo--MM 1 bnt showed no activity against other glycosphingolipids such as GM I, asialo-GM2 and !Gal~. In 87 SLE patients without neurological abnormalities, as well as in 61 cases of other autoimmune diseases and 20 cases of different neurologic diseases, no antibodies could be detected 18. Later on, the same author reported similar results using an ELISA technique 19. The results found by Hirano et al. suggested that antiganglioside antibodies and in particular anti-asialo~r~ antibodies could play a role in the pathogenesis of neurological complications accompanying SLE. Costallat et al. found a strong correlation between IgM antigangliosides and anti-GaIC antibodies and neuropsychiatric manifestations. These authors concluded that these antibodies showed an important predictive role for neurological abnormalities in SLE 20. On the other hand, Endo etal. observed that the occurrence of anti-asialo-GM I, but not of anti-GM I, was significantly more frequent in patients with SLE than in those with MS. However, these authors found no correlation between the presence of antiglycosphingolipid antibodies and symptoms related to the nervous system in patients with SLE, using a liposome lysis assay21. For these authors, the presence of antibodies in the sera of other patients who have traumatic or ischemic injury to the CNS suggests that these antibodies can arise in response to inflammation and damage of neural tissues. As we have previously mentioned, the major lipids in myelin are phospholipids, glycosphingolipids and cholesterol. Glycosphingolipids constitute approximately 20% of the total myelin lipids; gangliosides account for less than 1070 of this fraction. Although GM 1 is not the most abundant brain gangliosides, and asialoC~~ 1 is present only in trace amounts in brain ganglioside preparations, it seems that antibodies against these compounds could have a role in producing lesions in the central and peripheral nervous systems, mainly of the demyelinating type such as myelitis, optic neuritis, cranial multineuritis, and other focal non-ischemic neurological deficits. Although our results do not demonstrate a relationship between antibodies against
ant manifestations, study of a number of with SLE and symptoms related to the nervous system and/or determination of other types of antiganglioside antibodies could clarify the pathogenic significance of these antibodies.
Acknowledgements This study has been supported in part by Grantt No. 91/00300500 from the Fondo de Investigaciones Sanitarias (Ministry of Health of Spain). We are
301
Downloaded from lup.sagepub.com at UNIV OF MONTANA on April 8, 2015
indebted to Ms M. José Vicente for her technical assistance.
References 1. Johnson RT, Richardson EP Jr. The neurological manifestations of systemic lupus erythematosus: a clinical-pathological study of 24 cases and review of the literature. Medicine (Baltimore) 1968; 47: 337-69. 2. Feinglass EJ, Arnett FC, Dorsch CA, Zizic TM, Stevens MB. Neuropsychiatric manifestations of systemic lupus erythematosus: diagnosis, clinical spectrum, and relationship to other features of the disease. Medicine (Baltimore ) 1976; 55: 323-39. 3. Kaell AT, Shetty M, Lee BCP, Lockshin MD. The diversity of neurologic events in systemic lupus erythematosus. Arch Neurol 1986; 43: 273-6. 4. Bluenstein HG, Williams GV, Steinberg AD. Cerobrospinal fluid antibodies to neuronal cells: association with neuropsychiatric manifestations of systemic lupus erythematosus. Am J Med 1981; 70: 240-6. 5. Bonfa E, Golombek SJ, Kaufman LD et al. Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl JMed 1987; 317:265-71. 6. Harris EN, Gharavi AE, Asherson RA, Boey ML, Hughes GRV. Cerebral infarction in systemic lupus erythematosus: association with anticardiolipin antibodies. Clin Exp Rheum 1984; 2 :47-51. 7. Asherson RA, Berksen RHWM, Harris EN et al. Chorea in systemic lupus erythematosus and ’lupus-like’ disease: association with antiphospholipid antibodies. Sem Arthritis Rheum 1987; 16: 253-9. 8. Ilyas AA, Willison HJ, Quarles RJ et al. Serum antibodies to gangliosides in Guillain-Barré syndrome. Ann Neurol 1988; 23:440-7. 9. Sindern E, Stark E, Haas J, Steck AJ. Serum antibodies to GM1 and GM3-gangliosides in systemic lupus erythematosus with chronic inflammatory demyelinating polyradiculoneuropathy. Acta Neurol Scand 1991; 83: 399-402. 10. Pestronk A, Adams RN, Clawson L et al. Serum antibodies to GM1 gangliosides in amyotrophic lateral sclerosis. Neurology 1988; 38: 1457-61.
11. Arnon R, Crisp E, Kelley R, Ellison GW, Myers LW, Tourtellotte WW. Anti-ganglioside antibodies in multiple sclerosis. J Neurol
Sci 1980; 46: 179-86. 12. Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-7. 13. Gharavi AE, Harris EN, Asherson RA, Hughes GRV. Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis 1987; 46: 1-6. 14. Harris EN, Gharavi AE, Patel SP, Hughes GRV. Evaluation of the anticardiolipin antibody test: report of an international workshop held 4th April 1986. Clin Exp Immunol 1987; 68: 215-22. 15. Sergott RC, Brown MJ, Silberberg DH, Lisak RP. Antigalactocerebroside serum demyelinates optic nerve in vivo. J Neurol Sci 1984; 64:297-303. 16. Rott GA, Roytta M, Yu RK, Raine CS, Bornstein MB. Antisera to different glycolipids induce myelin alterations in mouse spinal cord tissue cultures. Brain Res 1985; 339: 9-18. 17. Irie H, Yorita T, Takahashi K. Anti-galactocerebroside antibody in rabbits with experimental allergic neuritis. Japan J Exp Med 1986; 56: 43-9. 18. Hirano T, Hashimoto H, Shiokawa Y et al. Antiglycolipid autoantibody detected in the sera from systemic lupus, erythematosus patients. J Clin Invest 1980; 66: 1437-40. 19. Hirano T, Miyahima H, Taniguchi 0 et al. Anti asialo GM1 antibody detected in the patients’ sera from systemic lupus erythematosus and Behcet’s disease with neurological manifestations. Jpn J Med 1988; 27: 167-7 1. 20. Costallat LT, de Oliveira RM, Santiago MB, Cossermelli W. Samara AM. Neuropsychiatric manifestations of systemic lupus erythematosus: the value of anticardiolipin, antiganglioside, and antigalactocerebroside antibodies. Clin Rheumatol (Belgium) 1990; 9: 489-97. 21. Endo T, Scott DD, Stewart SS, Kundu SK, Marcus DM. Antibodies to glycosphingolipids in patients with multiple sclerosis and SLE. J Immunol 1984; 132: 1793-7.
302
Downloaded from lup.sagepub.com at UNIV OF MONTANA on April 8, 2015
(Received 31 March 1992) (Accepted 22 July 1992)
