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MND: a global neurodegeneration with retroviral involvement?
JOURNAL OF THE
NEUROLOGICAL SCIENCES
ELSEVIER
Journal of the Neurological Sciences 129 (Suppl.) (1995) 145-147
Sporadic ALS/MND" a global neurodegeneration with retroviral involvement? Martin Egon Westarp ~'*, Pasquale Ferrante b, Herv6 Perron c, Peter Bartmann d, Hans Helmut Kornhuber a " Department of Neurology, University of Ulm, RKU Oberer Eselsberg 45, D-89081 Ulm, Germany b Fondazione "Don Gnocchi", 66 L,ia Capecelatro, 1-20148 Milan, Italy CNRS-Biom~rieux, ENSL. 46 All~e d'ltalie, F-69364 Lyon, France d Department of Paediatrics, Bonn Universi~, Konrad-Adenauer-Allee 119, D-53113 Bonn, Germany
Accepted 21 February 1995
Abstract
Sporadic amyotrophic lateral sclerosis may be an aetiologically heterogenous disease. We confirmed elevated circulating IgG immune complexes, and altered IgG seroreactivities against human retroviral antigens (HIV-2 and HTLV immunoblots) in overlapping subgroups of patients. Together with preliminary findings of a positive polymerase chain reactivity for human T-lymphotropic virus (HTLV.tax/rex) in blood leukocytes of 5 out of 14 sALS patients, we interpret this as evidence for a retroviral involvement in this relentlessly progressive, often asymmetrically spreading neurodegeneration. The possibility of a secondary phenomenon seems unlikely, yet cannot be completely ruled out. Keywords: Amyotrophic lateral sclerosis; Autosomal gene transfer; Human T lymphotropic virus (HTLV); Neurotoxicity;
Retroviral antibodies; Parkinson's disease; Circulating IgG-immunocomplexes; HIV-1; HIV-2
1. Introduction
Amyotrophic lateral sclerosis (ALS, motor neuron disease, M N D ) is characterized by an idiopathic upper and lower motor neuron degeneration, ultrastructural (Westarp et al., 1992; Ono et al., 1989; Ono and Yamauchi, 1994) and functional skin changes (Charcot, 1880), and a variety of immunological alterations without response to immunosuppressive treatment. The frequent coincidence of bulbar onset and dementing disorder (Tandan, 1994), the often asymmetrical and segmental spread of paresis over the patient's body, as well as an inverse correlation of age at begin and total duration of the disease suggest a pathogenic process or co-factor affecting the central nervous system. While no viral particle or immune response against known exogenous agent have ever been identified, unknown slow viruses would fit models of murine motor neuron
* Corresponding author. Tel.: (+49-731) 177 521; Fax: (+49-731) 177 558. 0022-510X/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0022-510X(95)00087-9
disease (Gardner, 1991; Contag and Plagemann, 1989). Epidemiology would be compatible with an optionally pathogenic agent, and endogenous retroviral elements may be involved.
2. Patients, materials and methods
With their informed consent, we examined sera from 50 consecutive sALS in-patients of the Ulm University D e p a r t m e n t of Neurology ( R K U ) (age at onset 19-77 years (mean 56.9 years), first symptoms bulbar (n = 7), in upper extremities (n = 25), and lower extremities (n = 18) diagnosed as definite idiopathic amyotrophic lateral sclerosis (ALS according to Eseorial criteria) between 1990 and 1993), excluding monoclonal gammopathy, antibodies to gangliosides, T r e p o n e m a p a l l i d u m , and Borrelia. All patients were European Caucasians, had been tested HIV-1, HIV-2 and H T L V seronegative by ELISA, and had not travelled to areas where H T L V is endemic. Six sALS patients were examined by HIV-2 immunoblot (New LAV Blot I1 #63,
146
M.E. Westarp et al. /Journal of the Neurological Sciences 129 (Suppl.) (1905) 145-147
Diagnostics Pasteur as described by Perron et al. (1991)), and 50 sALS patients from Ulm by H T L V - 1 / 2 immunoblot (Western Blot 2.3 Kit from Diagnostics Biotechnology, Singapore, with H T L V p19, gp21, p24,p26, p28 plus recombinant gp21). Twenty healthy controls did not react in either immunoblot, and 6 MS patients serving as controls did not react in the HIV-2 immunoblot. Only 1 out of 20 HIV-1 seropositive Italians taken as controls for the H T L V immunoblot recognized one HTLV.gp21 band. To preserve antibody avidity, we only used fresh sera kept at 4°C for both assays. IgG subclasses were quantified in 46 consecutive sALS patients with normal (8-17 g / l ) and 2 patients with reduced total serum IgG. Circulating lgG immune complexes (CIC Raji cell assay measuring both Fc-bound and complement C3-bound complexes) were examined in 27 sALS patients and 72 other neurological patients (done in these controls for suspicion of vasculitis or collagenosis); methods have been published elsewhere (Westarp et al., 1992).
3. Results
HIV-2 seroreactiL'ity As had been the case in 3 of 6 sALS patients examined earlier as controls for an MS study (Perron et al., 1991), 3 out of 6 sALS sera from Ulm recognized HIV-2 antigens. One 65-year-old man reacted with two immunoblot bands, and 2 patients, aged 68 and 80, recognized one single antigen each, i.e. one 8 kDa HIV-2 antigen was identified twice, and 26 kDa and 52 kDa antigen once. No patient demonstrated any sign of immunosuppression, and none fulfilled the criteria for a definite HTLV-immunoblot seropositivity (reacting with at least one enc- and one gag- antigen simultaneously). None of the patients had been immunized recently (Lee et al., 1992), suffered from lupus erythematosus (Talal et al., 1990; Jindal et al., 1993), or had received retinoic acid medication. An 18-kDa HIV-1 protein reported as false-positive recognized by up to 6% seroconverting patients (Courouc6 et al., 1986) was not recognized. HTL V seroreactit'ity Twenty healthy adults did not show IgG serum antibodies to H T L V - 1 / 2 in the immunoblot used. One out of twenty HIV-infected individuals recognized HTLV.gp21 glycoprotein, i.e. a s "indeterminate reactivity" different from definite HTLV seropositivity (according to DIN 58969 Part 41 Oct. 1992). In total, 25 out of 50 sALS patients demonstrated H T L V immunoblot seroreactivity, i.e. 16 men and 9 women (50%). Four out of 10 repetitively examined patients had changed their seroreactivity in the course of time, yet without recognizable correlation to clinical progres-
sion. The most frequently identified H T L V antigens were: HTLV.Rgp2118 × (18 X recombinant Rgp21, 5 times gp21) HTLV.p1916 × HTLV.p2613 X H T L V p2812 x Seven sALS patients recognized a high molecular weight antigen (60-65 kDa) not described in the test instruction, and similar to the bands reported in subjectively healthy HIV-1 seropositives (110 kDa). HTLV.gp21 sequences accounted for one quarter of all immunoblot bands in sALS (23 of 90, i.e. 25%), being present (Rgp21 or gp21) in 20 of 50 sALS patients (40%). For the report on HTLV-tax-rex D N A in peripheral blood leukocytes in 5 out of 14 sALS patients see Ferrante et al.
Circulating IgG immune complexes CIC levels exceeded 14 mg/1 in 6 of the 72 neurological control patients, and in 9 of the 27 sALS patients ( p < 0.05). CIC levels usually ranged from 2.5 to 150 m g / l , all seven maximal quantifications with IgG-CIC > 125 m g / l came from sALS patients (aged 18-74 years, range 129.0-1012.0 mg/1). Systemic lupus erythematosus, apparent vasculitis, rheumatoid arthritis, Wegener granulomatosis, Sj6gren's syndrome, paraproteinemia or mucocutaneous T-cell dysplasia had been excluded in all sALS patients. In contrast to the general population (Kingsmore et al., 1989), we observed no positive correlation of CIC and age. Patients seronegative for antiretroviral antibodies did not have higher immune complex levels, suggesting a sequestration of specific antibodies as in neuroborreliosis (Schutzer et al., 1990). No coincidence of anti-nuclear antibodies and elevated CIC levels was documented. The mean total immunoglobulin concentrations did not differ between sALS for IgG (n = 44 men; 10.9 g/l, n = 14 women; 11.0 g / l ) and age-matched Parkinson patients (n = 11 men; 12.0 g/l, n = 5 women; 11.4 g/l), IgA (mean in both groups = 2.6 g / l ) or IgM (sALS = 1.2 g / l , Parkinson = 0.9 g/l).
4. Discussion
In mice, an exogenous (Gardner et al., 1973; Jolicoeur et al., 1991) or endogenous (Contag and Plagemann, 1989) retrovirus is necessary, though not sufficient, to induce motor neuron disease. We have qualitatively identified immunoblot antibody reactivities against H T L V - 1 / 2 antigens (in 50% patients) and single HIV-2 antigens (in 6 of 12 patients). Dutch blood donors reach 0.01% immunoblot H T L V seropositivity (Zaaijer et al., 1993), and HIV-infected controls had been largely negative. H T L V is transmitted by saliva (Taniguchi et al., 1993), optionally pathogenic, and has been associated with myeloma and myelopathy, as well as alterations in parathyroid hormone regulation
M.E. Westarp et al. /Journal of the Neurological Sciences 129 (SuppL) (1995) 145-147
( Y o s h i d a et al., 1993). M o t o r n e u r o n d y s f u n c t i o n a n d PTH dysregulation may casuistically correlate (Breuer a n d A t k i n s o n , 1988), a n d m o t o r n e u r o n d i s e a s e c a n b e m i m i c k e d by l y m p h o m a ( Y o u n g e r et al., 1991). I n s p i n a l m o t o r n e u r o n s m u r i n e r e t r o v i r u s as w e l l as H I V g e n e e x p r e s s i o n is n e u r o t o x i c in m i c e ( T h o m a s et al., 1994). F r o m d i f f e r e n t " i n d e t e r m i n a t e " a n t i r e t r o v i r a l s e r o r e a c t i v i t i e s in s A L S ( W e s t a r p et al,, 1994b) t h e i n v o l v e m e n t o f a n u n c h a r a c t e r i z e d r e t r o v i r a l g e n e exp r e s s i o n in a p r o p o r t i o n o f p a t i e n t s w i t h s A L S w o u l d b e s u r p r i s i n g . F u r t h e r w o r k will s h o w w h e t h e r an antisynthetic peptide reactivity can be delineated (Westarp et al., 1994a), a n d a s p e c i f i c l g G s u b c l a s s r e d u c t i o n b e s u b s t a n t i a t e d in s A L S ( W e s t a r p et al., 1994c). A slow v i r a l g e n e p r o d u c t w o u l d e l e g a n t l y e x p l a i n b o t h clinical expansion of sALS, and the neurotoxic properties of s e r u m ( M a r t i - F a b r e g a s et al., 1992) a n d C S F ( C o u r a t i e r et al., 1993; N a g a r a et al., 1994) f r o m s A L S patients. C u r r e n t m o d e l s d o n o t n e c e s s a r i l y c o n t r a d i c t a r e t r o v i r a l i n v o l v e m e n t ( E n g e l , 1991).
References Breuer, A.C. and Atkinson, M.B. (1988) Fast axonal transport alterations in amyotrophic lateral sclerosis (ALS) and in parathyroid hormone (PTH)-treated axons. Cell Motil. Cytoskel., 10: 321-330. Charcot, J.M. (1880) Lecon sur les Maladies du Syst6me Nerveux Faites h la Salpl~tri~re, vol. II, p, 237, Paris. Contag, C.H. and Plagemann, P.G. (1989) Age-dependent poliomyelitis of mice: expression of endogenous retrovirus correlates with cytocidal replication of lactate dehydrogenase-elevating virus in motor neurons. J. Virol., 63: 4362-4369. Couratier, P., J. Hugon, P. Sindou, J.M. Vallat and M. Dumas (1993) Cell culture evidence for neuronal degeneration in amyotrophic lateral sclerosis being linked to glutamate AMPA/kainate receptors. Lancet, 341: 265-268. Courouc~, A.M., Muller, J.Y. and Richard, D. (1986) False-positive western blot reactions to human immunodeficiency virus in blood donors. Lancet, ii: 921-922. Engel, W.K. (1991) Does a retrovirus cause amyotrophic lateral sclerosis? Ann. Neurol., 30: 431-433. Gardner, M.B. (1991) Retroviral leukemia and lower motor neuron disease in wild mice: natural history, pathogenesis, and genetic resistance. Adv. Neurol., 56: 473-479. Gardner, M.B., Henderson, B.E., Estes, J.D., Menck, H., Parker, J.C. and Huebner, R.J. (1973) Unusually high incidence of spontaneous lymphomas in wild house mice. J. Natl. Cancer Inst., 50: 1571-1572. Jindal, R., Solomon, M. and Burrows, L. (1993) False positive test for HIV in a woman with lupus and renal failure. N. Engl. J. Med., 328: 1281-1282. Jolicoeur, P., Rassart, E., DesGroseillers, L., Robitaille, Y., Paquette, Y. and Kay, D.G. (1991) Retrovirus-induced motor neuron disease of mice: molecular basis of neurotropism and paralysis. Adv. Neurol., 56: 481-493. Kingsmore, S.F., Thompson, J.M., Crockard, A.D., Todd, D., McKirsan, J., Patterson, C., Fay, A.C. and McNeill, T.A. (1989) Measurement of circulating immune complexes containing IgG, IgM, lgA and IgE by flow cytometry: correlation with disease activity in patients with systemic lupus erythematosus. J. Clin. Lab. Immunol., 30: 45-52. Lee, D.A., Eby, W.C. and Molinaro, G.A. (1992) HIV false positivity after hepatitis B vaccination [letter]. Lancet, 339: 1060.
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Marti-Fabregas, J., R. Soler, J. Esquerda, J.M. Grau, J. Pradas and I. Ilia (1992) Clinical status of motoneuron disease does not correlate with serum neurotoxicity on cultured neurons. Acta Neurol. Scand., 85: 219-223. Nagara, T.N., Gourie-Devi, M., Nalini, A. and Raju, T.R. (1994) Neurofilament phosphorylation is enhanced in cultured chick spinal cord neurons exposed to cerebrospinal fluid from amyotropbic lateral sclerosis patients. Acta Neuropathol., 88: 349352. Ono, S., Mannen, T. and Toyokura, Y. (1989) Differential diagnosis between amyotrophic lateral sclerosis and spinal muscular atrophy by skin involvement. J. Neurol. Sci., 91: 301-310. Ono, S. and Yamauchi, M. (1994) Elastin cross-linking in the skin from patients with amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiat., 57: 94-96. Perron, H., Geny, C., Genoulaz, O., Pellat, J., Perret, J. and Seigneurin, J.M. (1991) Antibody to reverse transcriptase of human retroviruses in multiple sclerosis. Acta Neurol. Scand., 84: 507-513. Schutzer, S.E., Coyle, P.K., Belman, A.L., Golightly, M.G. and Drulle, J. (1990) Sequestration of antibody to Borrelia burgdorferi in immune complexes in seronegative Lyme disease. Lancet, 335: 312-315. Talal, N., Garry, R.F., Schur, P.H., Alexander, S., Dauphin~e, M.J,, Livas, I.H., Ballester, A., Takei, M. and Dang, H. (1990) A conserved idiotype and antibodies to retroviral proteins in systemic lupus erythematosus. J. Clin. Invest., 85: 1866-1878. Tandan, R. (1994) Clinical features and differential diagnosis of classical motor neuron disease. In: Williams, A.C. (Ed.), Motor Neuron Disease, Chapman and Hall, London, pp. 3-27. Taniguchi, S., Maekawa, N, Yashiro, N. and Hamada, T. (1993) Detection of human T-cell lymphotropic virus type-i proviral DNA in the saliva of an adult T-cell leukaemia/lymphoma patient using the polymerase chain reaction. Br. J. Dermatol., 129: 637-641. Thomas, F.P., Chalk, C., Lalonde, R., Robitaille, Y. and Jolicoeur, P. (1994) Expression of human immunodeficiency virus type 1 in the nervous system of transgenic mice leads to neurological disease. J. Virol., 68: 7099-7107. Westarp, M.E., Kolde, G., Westphal, K.P., Hiilser, P.-J., Westarp, M.P., Wollinsky, K.H. and Kornhuber, H.H. (1992) Amyotrophic lateral sclerosis, Dermal and body fluid alterations with and without intrathecal interferon-beta treatment. Neurol. Psychiat. Brain Res., 1: 67-75. Westarp, M.E., F6hring, B., Rasmussen, H., Schraff, S., Mertens, T. and Kornhuber, H.H. (1994a) Retroviral synthetic peptide serum antibodies in human sporadic amyotrophic lateral sclerosis. Peptides, 15: 207-214. Westarp, M.E., Ferrante, P., Perron, H., Schraff, S., Westarp, M.P. and Kornhuher, H.H. (1994b) Antiretroviral seroreactivity in sporadic adult amyotrophic lateral sclerosis. Neurol. Psychiat. Brain Res., 3: 191-196. Westarp, M.E., Bartmann, P. and Kornhuber, H.H. (1994c) Immunoglobulin-G isotype changes in human sporadic amyotrophic lateral sclerosis (sALS). Neurosci. Lett., 173: 124-126. Yoshida, Y., Sakamoto, Y., Yoshimine, A., Maruyama, Y., Ikegami, N., Inose, M., Imamura, H., Nakahara, K., Nakagawa, M. and Osame, M. (1993) Three cases of juvenile onset HTLV-I-associated myelopathy with pseudohypo-parathyroidism. J. Neurol. Sci., 118: 145-149. Younger, D.S., Rowland, L.P. and Latov, N. (1991) Lymphoma, motor neuron diseases, and amyotrophic lateral sclerosis. Ann. Neurol., 29: 78-86. Zaaijer, H.L., Dudok-de Wit, C., Cuypers, H.T., Winkel, I.N. and Lelie, P.N. (1993) Prevalence of human T-cell lymphotropic virus type I among Dutch blood donors. Ned. Tijdschr. Geneeskd., 137: 2541-2543.
NEUROLOGICAL SCIENCES
ELSEVIER
Journal of the Neurological Sciences 129 (Suppl.) (1995) 145-147
Sporadic ALS/MND" a global neurodegeneration with retroviral involvement? Martin Egon Westarp ~'*, Pasquale Ferrante b, Herv6 Perron c, Peter Bartmann d, Hans Helmut Kornhuber a " Department of Neurology, University of Ulm, RKU Oberer Eselsberg 45, D-89081 Ulm, Germany b Fondazione "Don Gnocchi", 66 L,ia Capecelatro, 1-20148 Milan, Italy CNRS-Biom~rieux, ENSL. 46 All~e d'ltalie, F-69364 Lyon, France d Department of Paediatrics, Bonn Universi~, Konrad-Adenauer-Allee 119, D-53113 Bonn, Germany
Accepted 21 February 1995
Abstract
Sporadic amyotrophic lateral sclerosis may be an aetiologically heterogenous disease. We confirmed elevated circulating IgG immune complexes, and altered IgG seroreactivities against human retroviral antigens (HIV-2 and HTLV immunoblots) in overlapping subgroups of patients. Together with preliminary findings of a positive polymerase chain reactivity for human T-lymphotropic virus (HTLV.tax/rex) in blood leukocytes of 5 out of 14 sALS patients, we interpret this as evidence for a retroviral involvement in this relentlessly progressive, often asymmetrically spreading neurodegeneration. The possibility of a secondary phenomenon seems unlikely, yet cannot be completely ruled out. Keywords: Amyotrophic lateral sclerosis; Autosomal gene transfer; Human T lymphotropic virus (HTLV); Neurotoxicity;
Retroviral antibodies; Parkinson's disease; Circulating IgG-immunocomplexes; HIV-1; HIV-2
1. Introduction
Amyotrophic lateral sclerosis (ALS, motor neuron disease, M N D ) is characterized by an idiopathic upper and lower motor neuron degeneration, ultrastructural (Westarp et al., 1992; Ono et al., 1989; Ono and Yamauchi, 1994) and functional skin changes (Charcot, 1880), and a variety of immunological alterations without response to immunosuppressive treatment. The frequent coincidence of bulbar onset and dementing disorder (Tandan, 1994), the often asymmetrical and segmental spread of paresis over the patient's body, as well as an inverse correlation of age at begin and total duration of the disease suggest a pathogenic process or co-factor affecting the central nervous system. While no viral particle or immune response against known exogenous agent have ever been identified, unknown slow viruses would fit models of murine motor neuron
* Corresponding author. Tel.: (+49-731) 177 521; Fax: (+49-731) 177 558. 0022-510X/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0022-510X(95)00087-9
disease (Gardner, 1991; Contag and Plagemann, 1989). Epidemiology would be compatible with an optionally pathogenic agent, and endogenous retroviral elements may be involved.
2. Patients, materials and methods
With their informed consent, we examined sera from 50 consecutive sALS in-patients of the Ulm University D e p a r t m e n t of Neurology ( R K U ) (age at onset 19-77 years (mean 56.9 years), first symptoms bulbar (n = 7), in upper extremities (n = 25), and lower extremities (n = 18) diagnosed as definite idiopathic amyotrophic lateral sclerosis (ALS according to Eseorial criteria) between 1990 and 1993), excluding monoclonal gammopathy, antibodies to gangliosides, T r e p o n e m a p a l l i d u m , and Borrelia. All patients were European Caucasians, had been tested HIV-1, HIV-2 and H T L V seronegative by ELISA, and had not travelled to areas where H T L V is endemic. Six sALS patients were examined by HIV-2 immunoblot (New LAV Blot I1 #63,
146
M.E. Westarp et al. /Journal of the Neurological Sciences 129 (Suppl.) (1905) 145-147
Diagnostics Pasteur as described by Perron et al. (1991)), and 50 sALS patients from Ulm by H T L V - 1 / 2 immunoblot (Western Blot 2.3 Kit from Diagnostics Biotechnology, Singapore, with H T L V p19, gp21, p24,p26, p28 plus recombinant gp21). Twenty healthy controls did not react in either immunoblot, and 6 MS patients serving as controls did not react in the HIV-2 immunoblot. Only 1 out of 20 HIV-1 seropositive Italians taken as controls for the H T L V immunoblot recognized one HTLV.gp21 band. To preserve antibody avidity, we only used fresh sera kept at 4°C for both assays. IgG subclasses were quantified in 46 consecutive sALS patients with normal (8-17 g / l ) and 2 patients with reduced total serum IgG. Circulating lgG immune complexes (CIC Raji cell assay measuring both Fc-bound and complement C3-bound complexes) were examined in 27 sALS patients and 72 other neurological patients (done in these controls for suspicion of vasculitis or collagenosis); methods have been published elsewhere (Westarp et al., 1992).
3. Results
HIV-2 seroreactiL'ity As had been the case in 3 of 6 sALS patients examined earlier as controls for an MS study (Perron et al., 1991), 3 out of 6 sALS sera from Ulm recognized HIV-2 antigens. One 65-year-old man reacted with two immunoblot bands, and 2 patients, aged 68 and 80, recognized one single antigen each, i.e. one 8 kDa HIV-2 antigen was identified twice, and 26 kDa and 52 kDa antigen once. No patient demonstrated any sign of immunosuppression, and none fulfilled the criteria for a definite HTLV-immunoblot seropositivity (reacting with at least one enc- and one gag- antigen simultaneously). None of the patients had been immunized recently (Lee et al., 1992), suffered from lupus erythematosus (Talal et al., 1990; Jindal et al., 1993), or had received retinoic acid medication. An 18-kDa HIV-1 protein reported as false-positive recognized by up to 6% seroconverting patients (Courouc6 et al., 1986) was not recognized. HTL V seroreactit'ity Twenty healthy adults did not show IgG serum antibodies to H T L V - 1 / 2 in the immunoblot used. One out of twenty HIV-infected individuals recognized HTLV.gp21 glycoprotein, i.e. a s "indeterminate reactivity" different from definite HTLV seropositivity (according to DIN 58969 Part 41 Oct. 1992). In total, 25 out of 50 sALS patients demonstrated H T L V immunoblot seroreactivity, i.e. 16 men and 9 women (50%). Four out of 10 repetitively examined patients had changed their seroreactivity in the course of time, yet without recognizable correlation to clinical progres-
sion. The most frequently identified H T L V antigens were: HTLV.Rgp2118 × (18 X recombinant Rgp21, 5 times gp21) HTLV.p1916 × HTLV.p2613 X H T L V p2812 x Seven sALS patients recognized a high molecular weight antigen (60-65 kDa) not described in the test instruction, and similar to the bands reported in subjectively healthy HIV-1 seropositives (110 kDa). HTLV.gp21 sequences accounted for one quarter of all immunoblot bands in sALS (23 of 90, i.e. 25%), being present (Rgp21 or gp21) in 20 of 50 sALS patients (40%). For the report on HTLV-tax-rex D N A in peripheral blood leukocytes in 5 out of 14 sALS patients see Ferrante et al.
Circulating IgG immune complexes CIC levels exceeded 14 mg/1 in 6 of the 72 neurological control patients, and in 9 of the 27 sALS patients ( p < 0.05). CIC levels usually ranged from 2.5 to 150 m g / l , all seven maximal quantifications with IgG-CIC > 125 m g / l came from sALS patients (aged 18-74 years, range 129.0-1012.0 mg/1). Systemic lupus erythematosus, apparent vasculitis, rheumatoid arthritis, Wegener granulomatosis, Sj6gren's syndrome, paraproteinemia or mucocutaneous T-cell dysplasia had been excluded in all sALS patients. In contrast to the general population (Kingsmore et al., 1989), we observed no positive correlation of CIC and age. Patients seronegative for antiretroviral antibodies did not have higher immune complex levels, suggesting a sequestration of specific antibodies as in neuroborreliosis (Schutzer et al., 1990). No coincidence of anti-nuclear antibodies and elevated CIC levels was documented. The mean total immunoglobulin concentrations did not differ between sALS for IgG (n = 44 men; 10.9 g/l, n = 14 women; 11.0 g / l ) and age-matched Parkinson patients (n = 11 men; 12.0 g/l, n = 5 women; 11.4 g/l), IgA (mean in both groups = 2.6 g / l ) or IgM (sALS = 1.2 g / l , Parkinson = 0.9 g/l).
4. Discussion
In mice, an exogenous (Gardner et al., 1973; Jolicoeur et al., 1991) or endogenous (Contag and Plagemann, 1989) retrovirus is necessary, though not sufficient, to induce motor neuron disease. We have qualitatively identified immunoblot antibody reactivities against H T L V - 1 / 2 antigens (in 50% patients) and single HIV-2 antigens (in 6 of 12 patients). Dutch blood donors reach 0.01% immunoblot H T L V seropositivity (Zaaijer et al., 1993), and HIV-infected controls had been largely negative. H T L V is transmitted by saliva (Taniguchi et al., 1993), optionally pathogenic, and has been associated with myeloma and myelopathy, as well as alterations in parathyroid hormone regulation
M.E. Westarp et al. /Journal of the Neurological Sciences 129 (SuppL) (1995) 145-147
( Y o s h i d a et al., 1993). M o t o r n e u r o n d y s f u n c t i o n a n d PTH dysregulation may casuistically correlate (Breuer a n d A t k i n s o n , 1988), a n d m o t o r n e u r o n d i s e a s e c a n b e m i m i c k e d by l y m p h o m a ( Y o u n g e r et al., 1991). I n s p i n a l m o t o r n e u r o n s m u r i n e r e t r o v i r u s as w e l l as H I V g e n e e x p r e s s i o n is n e u r o t o x i c in m i c e ( T h o m a s et al., 1994). F r o m d i f f e r e n t " i n d e t e r m i n a t e " a n t i r e t r o v i r a l s e r o r e a c t i v i t i e s in s A L S ( W e s t a r p et al,, 1994b) t h e i n v o l v e m e n t o f a n u n c h a r a c t e r i z e d r e t r o v i r a l g e n e exp r e s s i o n in a p r o p o r t i o n o f p a t i e n t s w i t h s A L S w o u l d b e s u r p r i s i n g . F u r t h e r w o r k will s h o w w h e t h e r an antisynthetic peptide reactivity can be delineated (Westarp et al., 1994a), a n d a s p e c i f i c l g G s u b c l a s s r e d u c t i o n b e s u b s t a n t i a t e d in s A L S ( W e s t a r p et al., 1994c). A slow v i r a l g e n e p r o d u c t w o u l d e l e g a n t l y e x p l a i n b o t h clinical expansion of sALS, and the neurotoxic properties of s e r u m ( M a r t i - F a b r e g a s et al., 1992) a n d C S F ( C o u r a t i e r et al., 1993; N a g a r a et al., 1994) f r o m s A L S patients. C u r r e n t m o d e l s d o n o t n e c e s s a r i l y c o n t r a d i c t a r e t r o v i r a l i n v o l v e m e n t ( E n g e l , 1991).
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