Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. Data from the literature show that systemic immune activation plays a role in ALS. OX40 (CD134) is member of the tumor necrosis factor receptor family and is expressed selectively on activated T lymphocytes. The aim of the study was to measure serum soluble OX40 (sOX40) levels in patients with ALS. The study included 25 ALS patients and 15 control subjects. Serum sOX40 levels were determined by the enzyme-linked immunosorbent method. Study showed that sOX40 levels were significantly decreased in serum of ALS patients compared with controls (p=0.05). There was no significant correlation between serum sOX40 levels and clinical parameters of ALS such as severity of the ALS patient clinical state and duration of the disease (p>0.05). In conclusion, decrease in serum sOX40 levels in patients with ALS suggests that this cytokine may be implicated in the pathomechanisms of this disease.Amiotrofična lateralna skleroza (ALS) je neurodegenerativna bolest. Literaturni podaci pokazuju da sistemsko aktiviranje imuno sustava ima ulogu kod ALS. OX40 (CD134) pripada obitelji receptora faktora tumorske nekroze (TN F), a izražen je selektivno na aktiviranim T limfocitima. Cilj studije bio je izmjeriti razine OX40 topljivog u serumu (sOX40) kod bolesnika s ALS. U studiju je bilo uključeno 25 bolesnika s ALS i 15 kontrolnih osoba. Razine sOX40 u serumu mjerene su metodom ELI SA. Rezultati su pokazali da su razine sOX40 značajno snižene u serumu bolesnika s ALS u usporedbi s kontrolnim osobama (P=0,05). Nije bilo značajne korelacije između serumskih razina sOX40 i kliničkih parametara ALS, kao što su težina kliničkog stanja bolesnika s ALS i trajanje bolesti (P>0,05). U zaključku, serumske razine sOX40 kod bolesnika s ALS ukazuju na to da bi ovaj citokin mogao biti upleten u patomehanizme ove bolesti

Joanna Iłżecka

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Acta Clin Croat,  Vol. 51,  No. 1,  2012 3Acta Clin Croat 2012; 51:3-7 Original Scientific PaperSerum SOluble OX40 in PAtientS with AmyOtrOPhiC lAterAl SClerOSiSJoanna iłżeckaDepartment of neurological rehabilitation, medical university of lublin, lublin, PolandSummAry – Amyotrophic lateral sclerosis (AlS) is a neurodegenerative disease. Data from the literature show that systemic immune activation plays a role in AlS. OX40 (CD134) is member of the tumor necrosis factor  receptor family and is expressed selectively on activated t lymphocytes. The aim of the study was to measure serum soluble OX40 (sOX40) levels in patients with AlS. The study included 25 AlS patients and 15 control subjects. Serum sOX40 levels were determined by the enzyme-linked immunosorbent method. Study showed that sOX40 levels were significantly decreased in serum of AlS patients compared with controls (p=0.05). There was no significant correlation between serum sOX40 levels and clinical parameters of AlS such as severity of the AlS patient clinical state and duration of the disease (p>0.05). in conclusion, decrease in serum sOX40 levels in patients with AlS suggests that this cytokine may be implicated in the pathomechanisms of this disease. Key words: Amyotrophic lateral sclerosis; Neurodegeneration; Neuroprotection; Serum; Soluble OX40Correspondence to: Joanna Iłżecka, MD, phD, Szerokie 6b, 20-050 lublin, Polande-mail: ilzecka@onet.pl received January 9, 2009, accepted march 28, 2012IntroductionData from the literature show that systemic im-mune activation plays a role in amyotrophic lateral sclerosis (AlS)1. According to Alexianu et al.2, the up-regulation of proinflammatory factors during early presymptomatic stages as well as the expansion of im-mune activation as the disease progresses in mutant SOD transgenic mice, an animal model of AlS, sug-gest that immune-inflammatory mechanisms could contribute to the disease progression.OX40 (CD134) is member of the tumor necrosis factor (tnF) receptor family and is expressed selec-tively on activated t lymphocytes. The interaction with OX40 ligand (OX40 l) delivers costimulatory signals to t cells3. This cytokine regulates survival and func-tions of depletion-resistant t cells4. it is known that t cells play an important role during inflammation5.The OX40/OX40 l interaction induces auto-immune-like diseases6. blockade of the interaction between OX40 and OX40 l inhibited immune re-sponses in both mouse and nonhuman primate mod-els of allergic inflammation7. According to tateyama et al.8 OX40 is expressed on activated t cells, which may play an important role in autoimmune diseases such as polymyositis and granulomatous myopathy. A study conducted by Xiaoyan et al.9 showed that freshly isolated CD4+ t-cells from patients with myasthe-nia gravis expressed OX40 to a greater extent than cells from healthy individuals. moreover, CD134 is up-regulated in the central nervous system (CnS) of patients with multiple sclerosis10. OX40 may have a proinflammatory function during immune activation and is expressed on a variety of leukocytes within the body11. The OX40 receptor is expressed on autoreactive CD4+ t cells isolated from the site of inflammation in rats with clinical signs of experimental autoimmune encephalomyelitis12. OX40 can also control prolifera-tion, survival, and production of cytokines13,14. The aim of the study was to measure soluble OX40 (sOX40) levels in serum samples from patients with 4 Acta Clin Croat,  Vol. 51,   No. 1,  2012Joanna iłżecka Soluble OX40 in amyotrophic lateral sclerosisAlS and to investigate whether there is a relation-ship between the concentration of sOX40 and clinical parameters of the disease.Material and Methodstwenty-five (14 male/11 female) AlS patients (average age 57, range 34-74 years) were diagnosed according to the el escorial criteria of AlS15. The clinical condition of patients was measured by the Amyotrophic lateral Sclerosis Functional rating Scale (AlSFrS)16. According to this scale, AlS pa-tients scored from 8 to 36 points and were divided into two subgroups: those with a mild clinical state (over 25 points), 15 patients; and those with a severe clinical state (up to 25 points), 10 patients. The aver-age duration of the disease was 16 months (3 months to 8 years). The AlS patients were also divided into two subgroups according to the duration of AlS (14 patients with short duration ≤12 months/11 patients with long duration >12 months) and according to type of AlS onset (15 patients with limb-onset/10 patients with bulbar-onset). The age-matched control group consisted of 15 (8 male/7 female) patients with lumbosacral disk disease. The study was approved by the medical university ethics Committee and performed in accordance with the ethical standards established in helsinki. Serum samples from AlS patients and control subjects were collected into plastic tubes and centri-fuged rapidly. The samples were stored at -70 ºC until analysis. The sOX40 levels were measured by the en-zyme-linked immunosorbent method aided commer-cial eliSA kit for human sCD134 (OX40) (bender medSystems Diagnostics Gmbh, Vienna, Austria) in accordance with the manufacturer’s instructions. On statistical analysis, nonparametric mann-whitney rank sum test was used to examine differ-ences between the groups. Correlation analysis was performed by using Spearman rank correlation. The values were expressed in pg/ml, as median and range. p values ≤0.05 were considered significant.ResultsStudy results showed that serum sOX40 levels were significantly decreased in the overall AlS pa-tient group compared with controls (p=0.05). The sOX40 levels were also significantly decreased in pa-tients with bulbar onset of AlS compared to controls (p=0.02). There were no significant differences in serum sOX40 levels between the subgroups of AlS patients according to their clinical state, type of AlS onset and disease duration (p>0.05). The median val-ues of serum sOX40 levels and comparative analysis between subgroups are presented in table 1. DiscussionData from the literature show that chronic inflam-mation is associated with neurodegenerative diseases, Table 1. Serum soluble OX40 (sOX40) levels and comparative between-group analysis        Group                          sOX40 level (pg/ml)                                                 median (range) ComparisonControl                                  1300  (747-1607) Control vs. AlS total                 p=0.05*AlS – total                            1149  (464-1711)AlS – short duration             1119 (464-1711) AlS short vs. long duration                 p=0.44      AlS – long duration              1241 (622-1412) AlS – bulbar onset                1129 (471-1458) AlS bulbar vs. limb onset                 p=0.29AlS – limb onset                   1241 (464-1711)AlS - mild clinical state        1129  (464-1711) AlS mild vs. severe clinical state                 p=0.56AlS – severe clinical state     1231  (622-1458)Data are expressed as median and range; AlS = amyotrophic lateral sclerosis; *statistical significance P≤0.05; mann-whitney rank sum testActa Clin Croat,  Vol. 51,  No. 1,  2012 5Joanna iłżecka Soluble OX40 in amyotrophic lateral sclerosisincluding AlS17,18. Zhang et al.19 observed activated monocyte/macrophages in serum of patients with AlS and their activation was related to the rate of AlS disease progression. immunohistochemical studies demonstrated the presence of t-cell lympho-cytes in the spinal cord of AlS patients. According to engelhardt et al.20, t-helper cells were observed in the proximity to corticospinal tract degeneration, while t-helper and t-suppressor cytotoxic cells were found in ventral horns. Graves et al.21 revealed the inflam-mation in AlS spinal cord and brain to be mediated by activated macrophages, mast cells and t cells.holmoy states that the inflammatory process in AlS involves infiltration of t cells and activation of antigen presenting cells co-localizing with motor neu-ron damage in the brain and spinal cord22. The role of t cells in this process is unclear. Probably, t cells may damage motor neurons by the cell-cell contact or cytokine secretion, or contribute indirectly to motor neuron damage through activation of microglia and macrophages. it cannot be excluded that t cell infiltra-tion may be secondary process to the death of motor neurons. On the other hand, there is evidence that t cell responses may play a neuroprotective role in AlS. Shi et al.23 observed a significant positive correla-tion of t cell percentage with the AlS progression rate. A systemic low-grade inflammation was detected in patients with AlS and was correlated with their de-gree of disability24. moreover, elevation of inflamma-tory markers such as tnF-alpha, interferon-gamma (iFn-γ) and nitric oxide was demonstrated in serum of AlS patients compared to normal controls25.According to troost et al.26, the majority of many diffusely scattered lymphocytes seen in the anterior and lateral corticospinal tracts and anterior horns be-longed to the suppressor/cytotoxicity t cell subset. The circulating autoreactive lymphocytes of patients with AlS were isolated and activated in vitro. it was observed that autoreactive cells may induce differen-tiation of mesenchymal stem cells to neuronal stem cells and this is a protective physiologic mechanism to nerve tissue repair27.it was observed that t cell-dependent immunity in the CnS is beneficial for neuroprotection and neu-rogenesis. The expression of OX40 l in microglia provides a molecular basis for the maintenance of t cell survival, expansion of t cells and increased secre-tion of growth factors, which may contribute to the protective effect in the CnS28. beers et al.29 showed in a model of chronic neurodegeneration that activa-tion of glia did not predict glial function, and that the presence of CD4+ t cells induced neuroprotection by modulating the trophic/cytotoxic balance of glia. There are no studies published in the literature concerning OX40 in AlS. The present study showed that sOX40 levels in serum of patients with AlS were decreased compared with controls. banerjee et al.30 in-vestigated the role of t cell immunity in human G93A superoxide dismutase 1 (SOD1) transgenic mice and in AlS patients, and demonstrated dysfunction and deficits of t cells. because OX40 can influence t cells, which have a potential protective role in im-mune/inflammatory reactions in the CnS, it cannot be excluded that this cytokine is implicated in neuro-degeneration in AlS. in conditions associated with the activation of immune/inflammatory mechanisms, the sOX40 levels would be increased. Contrary, the present study showed that this cytokine levels were decreased in serum of patients with AlS compared to controls. it cannot be excluded that the lower serum level of this cytokine may be the result of its higher activity in the immune-inflammatory process within the CnS. it was observed that the study parameter of OX40 serum concentration need not reflect its con-centration within the organs31.References1. KAwAmAtA t, AKiyAmA h, yAmADA t, et al. im-munologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol 1992;140:691-707.2. AleXiAnu me, KOZOVSKA m, APPel Sh. immune reactivity in a mouse model of familial AlS correlates with disease progression. neurology 2001;57:1282-9.3. tAylOr l, SChwArZ h. identification of a soluble OX40 isoform: development of a specific and quantitative immunoassay. J immunol methods 2001;255:67-72.4. KrOemer A, XiAO X, Vu mD, et al. OX40 controls functionally different t cell subsets and their resistance to depletion therapy. J immunol 2007;179:5584-91.5. CAVAnAqh mm, huSSell t. it is wise to target the late costimulatory molecule OX40 as a therapeutic target? Arch immunol Ther exp (warsz) 2008;56:291-7.6. murAtA K, nOSe m, nOlhlOVu lC, et al. Consti-tutive OX40/OX40 ligand interaction induces autoimmune-like diseases. J immunol 2002;169:4628-36.6 Acta Clin Croat,  Vol. 51,   No. 1,  2012Joanna iłżecka Soluble OX40 in amyotrophic lateral sclerosis  7. wAnG yh, liu yJ. OX40-OX40l interactions: a prom-ising therapeutic target for allergic diseases? J Clin invest 2007;117:3655-7.  8. tAteyAmA m, FuJihArA K, iShii n, et al. expres-sion of OX40 in muscles of polymyositis and granulomatous myopathy. J neurol Sci 2002;194:29-34.  9. XiAOyAn Z, PirSKAnen r, mAlmStrOm V, et al. expression of OX40 (CD134) on CD4+ t-cells from patients with myasthenia gravis. Clin exp immunol 2006;143:110-6.10. CArbOni S, AbOul-enein F, wAltZinGer C, et al. CD134 plays a crucial role in the pathogenesis of eAe and is upregulated in the CnS of patients with multiple sclerosis. J neuroimmunol 2003;145:1-11.11. weinberG AD, mOntler r. modulation of tnF re-ceptor family members to inhibit autoimmune disease. Curr Drug targets inflamm Allergy 2005;4:195-203.12. KAleebA JAr, OFFner h, VAnDenbArK AA, et al. The OX40 receptor provides a potent co-stimulatory signal capable of inducing encephalitogenicity in myelin-specific CD4+ t cells. int immunol 1998;10:453-61.13. SO t, lee Sw, CrOFt m. immune regulation and control of regulatory t cells by OX40 and 4-1bb. Cytokine Growth Factor rev 2008;19:253-62.14. mOuSAVi SF, SOrOOSh P, tAKAhAShi t, et al. OX40 costimulatory signals potentiate the memory commit-ment of effector CD8+ t cells. J immunol 2008;181:5990-6001.15. brOOKS br. el escorial world Federation of neurology criteria for the diagnosis of amyotrophic lateral sclerosis. J neurol Sci 1994;124 Suppl:96-107.16. GOrDOn Ph, miller rG, mOOre Dh. AlSFrS-r. Amyotroph lateral Scler Other motor neuron Disord 2004;5:90-3.17. mcGeer Pl, mcGeer eG. inflammation and the degen-erative diseases of aging. Ann n y Acad Sci 2004;1035:104-16.18. tilleuX S, hermAnS e. neuroinflammation and reg-ulation of glial glutamate uptake in neurological disorders. J neurosci res 2007;85:2059-70.19. ZhAnG r, GASCOn r, miller rG, et al. evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sAlS). J neuroimmunol 2005;159:215-24.20. enGelhArDt Ji, tAJti J, APPel Sh. lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. Arch neurol 1993;50:30-6.21. GrAVeS mC, FiAlA m, DinGlASAn lA, et al. in-flammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and t cells. Amyotroph lateral Scler Other motor neuron Disord 2004;5:213-9.22. hOlmOy t. t cells in amyotrophic lateral sclerosis. eur J neurol 2008;15:360-6.23. Shi n, KAwAnO y, tAteiShi t, et al. increased il-13-producing t cells in AlS: positive correlations with disease se-verity and progression rate. J neuroimmunol 2007;182:232-5.24. KeiZmAn D, rOGOwSKi O, berliner S, et al. low-grade systemic inflammation in patients with amyotrophic lateral sclerosis. Acta neurol Scand 2009;119:383-9.25. bAbu Gn, KumAr A, ChAnDrA r, et al. elevated in-flammatory markers in a group of amyotrophic lateral sclerosis patients from northern india. neurochem res 2008;33:1145-9.26. trOOSt D, Van den OOrD JJ, ViAnney de JOnG Jm. immunohistochemical characterization of the inflammatory infiltrate in amyotrophic lateral sclerosis. neuropathol Appl neurobiol 1990;16:401-10.27. mOViqliA GA, VArelA G, GAetA CA, et al. Au-toreactive t cells induce in vitro bm mesenchymal stem cell transdifferentiation to neural stem cells. Cytotherapy 2006;8:196-201.28. wAnq y, li m, SOnq m, et al. expression of OX40 ligand in microglia activated by iFn-gamma sustains a protective CD4(+) t-cell response in vitro. Cell immunol 2008;251:86-92.29. beerS Dr, henKel JS, ZhAO w, et al. CD4+ t cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited AlS. Proc natl Acad Sci uSA 2008;105:15558-63.30. bAnerJee r, mOSley rl, reynOlDS AD, et al. Adaptive immune neuroprotection in G93A-SOD1 amyo-trophic lateral sclerosis mice. PloS One 2008;3(7):e2740.31. ŠirAnOVić m, KOVAČ J, GOPČeVić S, et al. human soluble trem-1: lung and serum levels in patients with bacterial ventilator associated pneumonia. Acta Clin Croat 2001;50:345-9.Acta Clin Croat,  Vol. 51,  No. 1,  2012 7Joanna iłżecka Soluble OX40 in amyotrophic lateral sclerosisSažetakOX40 tOPlJiV u Serumu KOD bOleSniKA S AmiOtrOFiČnOm lAterAlnOm SKlerOZOmJ. IłżeckaSummAry – Amiotrofična lateralna skleroza (AlS) je neurodegenerativna bolest. literaturni podaci pokazuju da sistemsko aktiviranje imuno sustava ima ulogu kod AlS. OX40 (CD134) pripada obitelji receptora faktora tumorske ne-kroze (tnF), a izražen je selektivno na aktiviranim t limfocitima. Cilj studije bio je izmjeriti razine OX40 topljivog u se-rumu (sOX40) kod bolesnika s AlS. u studiju je bilo uključeno 25 bolesnika s AlS i 15 kontrolnih osoba. razine sOX40 u serumu mjerene su metodom eliSA. rezultati su pokazali da su razine sOX40 značajno snižene u serumu bolesnika s AlS u usporedbi s kontrolnim osobama (p=0,05). nije bilo značajne korelacije između serumskih razina sOX40 i klinič-kih parametara AlS, kao što su težina kliničkog stanja bolesnika s AlS i trajanje bolesti (p>0,05). u zaključku, serumske razine sOX40 kod bolesnika s AlS ukazuju na to da bi ovaj citokin mogao biti upleten u patomehanizme ove bolesti.Ključne riječi: Amiotrofična lateralna skleroza; Neurodegeneracija; Neuroprotekcija; Serum; Topljivi OX40

OX40 topljiv u serumu kod bolesnika s amiotrofičnom lateralnom sklerozom

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