Abstract
Background: ß2 Adrenoreceptor expression on peripheral blood mononuclear cells is increased in progressive multiple sclerosis. This increase has been correlated with disease activity in relapsing-remitting multiple sclerosis.
Objective: To determine the ß2 adrenoreceptor expression in primary and secondary progressive multiple sclerosis in relation to findings on magnetic resonance imaging (MRI) and clinical disease activity.
Methods: 10 patients with multiple sclerosis were studied (five with primary progressive and five with secondary progressive forms of the disease) over a period of six months. Monthly clinical and MRI assessments of the brain and spinal cord were carried out. ß2 Adrenoreceptor expression was assessed monthly using a ligand binding assay with [125I]iodocyanopindolol. Expression of ß2 adrenoceptors on peripheral blood mononuclear cells was also assessed in five normal controls over a similar period.
Results: The mean (SEM) value of ß2 adrenoreceptor density for the five normal controls was 1346 (183) sites/cell, with affinity Kd of 120 (40) pM. MRI disease activity in primary progressive multiple sclerosis was reported on two occasions and on those occasions the expression of ß2 adrenoreceptors was increased in excess of 1900 sites/cell; in the remaining 28 observations ß2 adrenoreceptor expression was within the normal range (800 to 1900 sites/cell). In patients with secondary progressive disease, MRI disease activity was observed on 16 occasions. In these patients expression of ß2 adrenoreceptors was increased in excess of 2000 sites/cell in all measurements except in one subject who did not show MRI activity throughout the six months period of study. The affinity of the receptors was within the normal range in all cases.
Conclusions: Increased expression of ß2 adrenoreceptors was correlated with MRI disease activity in two patients with primary progressive multiple sclerosis. In secondary progressive multiple sclerosis, increased expression of ß2 adrenoreceptors tended not to correlate with MRI disease activity. This may reflect a persistent Th1 immune reaction in the secondary progressive form of the disease.
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- Beck J., Rondot P., Catinot L., Falcoff E., Kirchner H., Wietzerbin J. Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand. 1988 Oct;78(4):318–323. doi: 10.1111/j.1600-0404.1988.tb03663.x. [DOI] [PubMed] [Google Scholar]
- Borger P., Hoekstra Y., Esselink M. T., Postma D. S., Zaagsma J., Vellenga E., Kauffman H. F. Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Am J Respir Cell Mol Biol. 1998 Sep;19(3):400–407. doi: 10.1165/ajrcmb.19.3.2765. [DOI] [PubMed] [Google Scholar]
- Byskosh P. V., Reder A. T. Interferon beta-1b effects on cytokine mRNA in peripheral mononuclear cells in multiple sclerosis. Mult Scler. 1996 Apr;1(5):262–269. doi: 10.1177/135245859600100502. [DOI] [PubMed] [Google Scholar]
- Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
- Durán I., Martínez-Cáceres E. M., Río J., Barberà N., Marzo M. E., Montalban X. Immunological profile of patients with primary progressive multiple sclerosis. Expression of adhesion molecules. Brain. 1999 Dec;122(Pt 12):2297–2307. doi: 10.1093/brain/122.12.2297. [DOI] [PubMed] [Google Scholar]
- Elenkov I. J., Haskó G., Kovács K. J., Vizi E. S. Modulation of lipopolysaccharide-induced tumor necrosis factor-alpha production by selective alpha- and beta-adrenergic drugs in mice. J Neuroimmunol. 1995 Sep;61(2):123–131. doi: 10.1016/0165-5728(95)00080-l. [DOI] [PubMed] [Google Scholar]
- Elenkov I. J., Papanicolaou D. A., Wilder R. L., Chrousos G. P. Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. Proc Assoc Am Physicians. 1996 Sep;108(5):374–381. [PubMed] [Google Scholar]
- Giovannoni G., Lai M., Thorpe J., Kidd D., Chamoun V., Thompson A. J., Miller D. H., Feldmann M., Thompson E. J. Longitudinal study of soluble adhesion molecules in multiple sclerosis: correlation with gadolinium enhanced magnetic resonance imaging. Neurology. 1997 Jun;48(6):1557–1565. doi: 10.1212/wnl.48.6.1557. [DOI] [PubMed] [Google Scholar]
- Haskó G., Elenkov I. J., Kvetan V., Vizi E. S. Differential effect of selective block of alpha 2-adrenoreceptors on plasma levels of tumour necrosis factor-alpha, interleukin-6 and corticosterone induced by bacterial lipopolysaccharide in mice. J Endocrinol. 1995 Mar;144(3):457–462. doi: 10.1677/joe.0.1440457. [DOI] [PubMed] [Google Scholar]
- Haskó G., Szabó C., Németh Z. H., Salzman A. L., Vizi E. S. Stimulation of beta-adrenoceptors inhibits endotoxin-induced IL-12 production in normal and IL-10 deficient mice. J Neuroimmunol. 1998 Aug 1;88(1-2):57–61. doi: 10.1016/s0165-5728(98)00073-3. [DOI] [PubMed] [Google Scholar]
- Hellstrand K., Hermodsson S. An immunopharmacological analysis of adrenaline-induced suppression of human natural killer cell cytotoxicity. Int Arch Allergy Appl Immunol. 1989;89(4):334–341. doi: 10.1159/000234972. [DOI] [PubMed] [Google Scholar]
- Karaszewski J. W., Reder A. T., Anlar B., Kim W. C., Arnason B. G. Increased lymphocyte beta-adrenergic receptor density in progressive multiple sclerosis is specific for the CD8+, CD28- suppressor cell. Ann Neurol. 1991 Jul;30(1):42–47. doi: 10.1002/ana.410300109. [DOI] [PubMed] [Google Scholar]
- Karaszewski J. W., Reder A. T., Maselli R., Brown M., Arnason B. G. Sympathetic skin responses are decreased and lymphocyte beta-adrenergic receptors are increased in progressive multiple sclerosis. Ann Neurol. 1990 Apr;27(4):366–372. doi: 10.1002/ana.410270404. [DOI] [PubMed] [Google Scholar]
- Kidd D., Thorpe J. W., Kendall B. E., Barker G. J., Miller D. H., McDonald W. I., Thompson A. J. MRI dynamics of brain and spinal cord in progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 1996 Jan;60(1):15–19. doi: 10.1136/jnnp.60.1.15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kidd D., Thorpe J. W., Thompson A. J., Kendall B. E., Moseley I. F., MacManus D. G., McDonald W. I., Miller D. H. Spinal cord MRI using multi-array coils and fast spin echo. II. Findings in multiple sclerosis. Neurology. 1993 Dec;43(12):2632–2637. doi: 10.1212/wnl.43.12.2632. [DOI] [PubMed] [Google Scholar]
- Kurtzke J. F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983 Nov;33(11):1444–1452. doi: 10.1212/wnl.33.11.1444. [DOI] [PubMed] [Google Scholar]
- Lu C. Z., Jensen M. A., Arnason B. G. Interferon gamma- and interleukin-4-secreting cells in multiple sclerosis. J Neuroimmunol. 1993 Jul;46(1-2):123–128. doi: 10.1016/0165-5728(93)90241-p. [DOI] [PubMed] [Google Scholar]
- Lucchinetti C. F., Brück W., Rodriguez M., Lassmann H. Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol. 1996 Jul;6(3):259–274. doi: 10.1111/j.1750-3639.1996.tb00854.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Makhlouf K., Comabella M., Imitola J., Weiner H. L., Khoury S. J. Oral salbutamol decreases IL-12 in patients with secondary progressive multiple sclerosis. J Neuroimmunol. 2001 Jul 2;117(1-2):156–165. doi: 10.1016/s0165-5728(01)00322-8. [DOI] [PubMed] [Google Scholar]
- Makhlouf Karim, Weiner Howard L., Khoury Samia J. Potential of beta2-adrenoceptor agonists as add-on therapy for multiple sclerosis: focus on salbutamol (albuterol). CNS Drugs. 2002;16(1):1–8. doi: 10.2165/00023210-200216010-00001. [DOI] [PubMed] [Google Scholar]
- Martin R., McFarland H. F., McFarlin D. E. Immunological aspects of demyelinating diseases. Annu Rev Immunol. 1992;10:153–187. doi: 10.1146/annurev.iy.10.040192.001101. [DOI] [PubMed] [Google Scholar]
- McDonnell G. V., McMillan S. A., Douglas J. P., Droogan A. G., Hawkins S. A. Serum soluble adhesion molecules in multiple sclerosis: raised sVCAM-1, sICAM-1 and sE-selectin in primary progressive disease. J Neurol. 1999 Feb;246(2):87–92. doi: 10.1007/s004150050313. [DOI] [PubMed] [Google Scholar]
- Panina-Bordignon P., Mazzeo D., Lucia P. D., D'Ambrosio D., Lang R., Fabbri L., Self C., Sinigaglia F. Beta2-agonists prevent Th1 development by selective inhibition of interleukin 12. J Clin Invest. 1997 Sep 15;100(6):1513–1519. doi: 10.1172/JCI119674. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Poser C. M., Paty D. W., Scheinberg L., McDonald W. I., Davis F. A., Ebers G. C., Johnson K. P., Sibley W. A., Silberberg D. H., Tourtellotte W. W. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983 Mar;13(3):227–231. doi: 10.1002/ana.410130302. [DOI] [PubMed] [Google Scholar]
- Prat A., Pelletier D., Duquette P., Arnold D. L., Antel J. P. Heterogeneity of T-lymphocyte function in primary progressive multiple sclerosis: relation to magnetic resonance imaging lesion volume. Ann Neurol. 2000 Feb;47(2):234–237. [PubMed] [Google Scholar]
- Rieckmann P., Albrecht M., Kitze B., Weber T., Tumani H., Broocks A., Lüer W., Helwig A., Poser S. Tumor necrosis factor-alpha messenger RNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity. Ann Neurol. 1995 Jan;37(1):82–88. doi: 10.1002/ana.410370115. [DOI] [PubMed] [Google Scholar]
- Sanders V. M., Baker R. A., Ramer-Quinn D. S., Kasprowicz D. J., Fuchs B. A., Street N. E. Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help. J Immunol. 1997 May 1;158(9):4200–4210. [PubMed] [Google Scholar]
- Stevenson V. L., Miller D. H., Leary S. M., Rovaris M., Barkhof F., Brochet B., Dousset V., Filippi M., Hintzen R., Montalban X. One year follow up study of primary and transitional progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2000 Jun;68(6):713–718. doi: 10.1136/jnnp.68.6.713. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thompson A. J., Kermode A. G., MacManus D. G., Kendall B. E., Kingsley D. P., Moseley I. F., McDonald W. I. Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. BMJ. 1990 Mar 10;300(6725):631–634. doi: 10.1136/bmj.300.6725.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thompson A. J., Kermode A. G., Wicks D., MacManus D. G., Kendall B. E., Kingsley D. P., McDonald W. I. Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann Neurol. 1991 Jan;29(1):53–62. doi: 10.1002/ana.410290111. [DOI] [PubMed] [Google Scholar]
- Thompson A. J., Polman C. H., Miller D. H., McDonald W. I., Brochet B., Filippi M Montalban X., De Sá J. Primary progressive multiple sclerosis. Brain. 1997 Jun;120(Pt 6):1085–1096. doi: 10.1093/brain/120.6.1085. [DOI] [PubMed] [Google Scholar]
- Thorpe J. W., Kidd D., Moseley I. F., Thompson A. J., MacManus D. G., Compston D. A., McDonald W. I., Miller D. H. Spinal MRI in patients with suspected multiple sclerosis and negative brain MRI. Brain. 1996 Jun;119(Pt 3):709–714. doi: 10.1093/brain/119.3.709. [DOI] [PubMed] [Google Scholar]
- Waxman S. G. Demyelinating diseases--new pathological insights, new therapeutic targets. N Engl J Med. 1998 Jan 29;338(5):323–325. doi: 10.1056/NEJM199801293380610. [DOI] [PubMed] [Google Scholar]
- Whalen M. M., Bankhurst A. D. Effects of beta-adrenergic receptor activation, cholera toxin and forskolin on human natural killer cell function. Biochem J. 1990 Dec 1;272(2):327–331. doi: 10.1042/bj2720327. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Windhagen A., Newcombe J., Dangond F., Strand C., Woodroofe M. N., Cuzner M. L., Hafler D. A. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. J Exp Med. 1995 Dec 1;182(6):1985–1996. doi: 10.1084/jem.182.6.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Woiciechowsky C., Asadullah K., Nestler D., Eberhardt B., Platzer C., Schöning B., Glöckner F., Lanksch W. R., Volk H. D., Döcke W. D. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med. 1998 Jul;4(7):808–813. doi: 10.1038/nm0798-808. [DOI] [PubMed] [Google Scholar]
- Woodroofe M. N., Cuzner M. L. Cytokine mRNA expression in inflammatory multiple sclerosis lesions: detection by non-radioactive in situ hybridization. Cytokine. 1993 Nov;5(6):583–588. doi: 10.1016/s1043-4666(05)80008-0. [DOI] [PubMed] [Google Scholar]
- Zoukos Y., Kidd D., Woodroofe M. N., Kendall B. E., Thompson A. J., Cuzner M. L. Increased expression of high affinity IL-2 receptors and beta-adrenoceptors on peripheral blood mononuclear cells is associated with clinical and MRI activity in multiple sclerosis. Brain. 1994 Apr;117(Pt 2):307–315. doi: 10.1093/brain/117.2.307. [DOI] [PubMed] [Google Scholar]
- Zoukos Y., Leonard J. P., Thomaides T., Thompson A. J., Cuzner M. L. beta-Adrenergic receptor density and function of peripheral blood mononuclear cells are increased in multiple sclerosis: a regulatory role for cortisol and interleukin-1. Ann Neurol. 1992 Jun;31(6):657–662. doi: 10.1002/ana.410310614. [DOI] [PubMed] [Google Scholar]
- Zoukos Y., Thomaides T., Mathias C. J., Cuzner M. L. High beta-adrenoceptor density on peripheral blood mononuclear cells in progressive multiple sclerosis: a manifestation of autonomic dysfunction? Acta Neurol Scand. 1994 Dec;90(6):382–387. doi: 10.1111/j.1600-0404.1994.tb02745.x. [DOI] [PubMed] [Google Scholar]
