{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T16:28:03Z","timestamp":1774542483293,"version":"3.50.1"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The relapsing-remitting dynamics is a hallmark of autoimmune diseases such as Multiple Sclerosis (MS). Although current understanding of both cellular and molecular mechanisms involved in the pathogenesis of autoimmune diseases is significant, how their activity generates this prototypical dynamics is not understood yet. In order to gain insight about the mechanisms that drive these relapsing-remitting dynamics, we developed a computational model using such biological knowledge. We hypothesized that the relapsing dynamics in autoimmunity can arise through the failure in the mechanisms controlling cross-regulation between regulatory and effector T cells with the interplay of stochastic events (e.g. failure in central tolerance, activation by pathogens) that are able to trigger the immune system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The model represents five concepts: central tolerance (T-cell generation by the thymus), T-cell activation, T-cell memory, cross-regulation (negative feedback) between regulatory and effector T-cells and tissue damage. We enriched the model with reversible and irreversible tissue damage, which aims to provide a comprehensible link between autoimmune activity and clinical relapses and active lesions in the magnetic resonances studies in patients with Multiple Sclerosis. Our analysis shows that the weakness in this negative feedback between effector and regulatory T-cells, allows the immune system to generate the characteristic relapsing-remitting dynamics of autoimmune diseases, without the need of additional environmental triggers. The simulations show that the timing at which relapses appear is highly unpredictable. We also introduced targeted perturbations into the model that mimicked immunotherapies that modulate effector and regulatory populations. The effects of such therapies happened to be highly dependent on the timing and\/or dose, and on the underlying dynamic of the immune system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The relapsing dynamic in MS derives from the emergent properties of the immune system operating in a pathological state, a fact that has implications for predicting disease course and developing new therapies for MS.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1752-0509-5-114","type":"journal-article","created":{"date-parts":[[2011,7,15]],"date-time":"2011-07-15T18:22:31Z","timestamp":1310754151000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Modeling the effector - regulatory T cell cross-regulation reveals the intrinsic character of relapses in Multiple Sclerosis"],"prefix":"10.1186","volume":"5","author":[{"given":"Nieves","family":"V\u00e9lez de Mendiz\u00e1bal","sequence":"first","affiliation":[]},{"given":"Jorge","family":"Carneiro","sequence":"additional","affiliation":[]},{"given":"Ricard V","family":"Sol\u00e9","sequence":"additional","affiliation":[]},{"given":"Joaqu\u00edn","family":"Go\u00f1i","sequence":"additional","affiliation":[]},{"given":"Jean","family":"Bragard","sequence":"additional","affiliation":[]},{"given":"Ivan","family":"Martinez-Forero","sequence":"additional","affiliation":[]},{"given":"Sara","family":"Martinez-Pasamar","sequence":"additional","affiliation":[]},{"given":"Jorge","family":"Sepulcre","sequence":"additional","affiliation":[]},{"given":"Javier","family":"Torrealdea","sequence":"additional","affiliation":[]},{"given":"Francesca","family":"Bagnato","sequence":"additional","affiliation":[]},{"given":"Jordi","family":"Garcia-Ojalvo","sequence":"additional","affiliation":[]},{"given":"Pablo","family":"Villoslada","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2011,7,15]]},"reference":[{"issue":"9648","key":"719_CR1","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1016\/S0140-6736(08)61620-7","volume":"372","author":"A Compston","year":"2008","unstructured":"Compston A, Coles A: Multiple sclerosis. Lancet. 2008, 372 (9648): 1502-1517. 10.1016\/S0140-6736(08)61620-7","journal-title":"Lancet"},{"issue":"Suppl 1","key":"719_CR2","doi-asserted-by":"publisher","first-page":"S5","DOI":"10.1016\/j.jns.2007.01.065","volume":"256","author":"T Vollmer","year":"2007","unstructured":"Vollmer T: The natural history of relapses in multiple sclerosis. J Neurol Sci. 2007, 256 (Suppl 1): S5-13.","journal-title":"J Neurol Sci"},{"issue":"5","key":"719_CR3","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1002\/ana.410370511","volume":"37","author":"LA Stone","year":"1995","unstructured":"Stone LA, Frank JA, Albert PS, Bash C, Smith ME, Maloni H, McFarland HF: The effect of interferon-beta on blood-brain barrier disruptions demonstrated by contrast-enhanced magnetic resonance imaging in relapsing-remitting multiple sclerosis. Ann Neurol. 1995, 37 (5): 611-619. 10.1002\/ana.410370511","journal-title":"Ann Neurol"},{"issue":"1","key":"719_CR4","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1001\/archneur.66.1.noc80047","volume":"66","author":"AW Chiu","year":"2009","unstructured":"Chiu AW, Richert N, Ehrmantraut M, Ohayon J, Gupta S, Bomboi G, Gaindh D, Cantor FK, Frank JA, McFarland HF, et al.: Heterogeneity in Response to Interferon Beta in Patients With Multiple Sclerosis. Arch Neurol. 2009, 66 (1): e1-5. 10.1002\/ana.21759.","journal-title":"Arch Neurol"},{"issue":"7","key":"719_CR5","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1212\/WNL.59.7.1006","volume":"59","author":"A Boiko","year":"2002","unstructured":"Boiko A, Vorobeychik G, Paty D, Devonshire V, Sadovnick D: Early onset multiple sclerosis: a longitudinal study. Neurology. 2002, 59 (7): 1006-1010.","journal-title":"Neurology"},{"issue":"9","key":"719_CR6","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1038\/ni0901-762","volume":"2","author":"L Steinman","year":"2001","unstructured":"Steinman L: Multiple sclerosis: a two-stage disease. Nat Immunol. 2001, 2 (9): 762-764. 10.1038\/ni0901-762","journal-title":"Nat Immunol"},{"issue":"20","key":"719_CR7","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1056\/NEJM200011163432001","volume":"343","author":"C Confavreux","year":"2000","unstructured":"Confavreux C, Vukusic S, Moreau T, Adeleine P: Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000, 343 (20): 1430-1438. 10.1056\/NEJM200011163432001","journal-title":"N Engl J Med"},{"issue":"Pt 5","key":"719_CR8","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1093\/brain\/awf098","volume":"125","author":"D Buljevac","year":"2002","unstructured":"Buljevac D, Flach HZ, Hop WC, Hijdra D, Laman JD, Savelkoul HF, Der Meche FG, van Doorn PA, Hintzen RQ: Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain. 2002, 125 (Pt 5): 952-960.","journal-title":"Brain"},{"issue":"7416","key":"719_CR9","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1136\/bmj.327.7416.646","volume":"327","author":"D Buljevac","year":"2003","unstructured":"Buljevac D, Hop WC, Reedeker W, Janssens AC, van der Meche FG, van Doorn PA, Hintzen RQ: Self reported stressful life events and exacerbations in multiple sclerosis: prospective study. BMJ. 2003, 327 (7416): 646- 10.1136\/bmj.327.7416.646","journal-title":"BMJ"},{"key":"719_CR10","first-page":"153","volume":"10","author":"R Martin","year":"1992","unstructured":"Martin R, McFarland HF, McFarlin DE: Immunological aspects of demyelinating diseases. AnnuRevImmunol. 1992, 10: 153-187.","journal-title":"AnnuRevImmunol"},{"issue":"1","key":"719_CR11","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.neuron.2006.09.011","volume":"52","author":"SL Hauser","year":"2006","unstructured":"Hauser SL, Oksenberg JR: The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006, 52 (1): 61-76. 10.1016\/j.neuron.2006.09.011","journal-title":"Neuron"},{"issue":"1","key":"719_CR12","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/S0165-5728(99)00099-5","volume":"99","author":"P Diaz-Villoslada","year":"1999","unstructured":"Diaz-Villoslada P, Shih A, Shao L, Genain CP, Hauser SL: Autoreactivity to myelin antigens: myelin\/oligodendrocyte glycoprotein is a prevalent autoantigen. JNeuroimmunol. 1999, 99 (1): 36-43. 10.1016\/S0165-5728(99)00099-5.","journal-title":"JNeuroimmunol"},{"issue":"10","key":"719_CR13","doi-asserted-by":"publisher","first-page":"2942","DOI":"10.1002\/1521-4141(2001010)31:10<2942::AID-IMMU2942>3.0.CO;2-M","volume":"31","author":"P Villoslada","year":"2001","unstructured":"Villoslada P, Abel K, Heald N, Goertsches R, Hauser SL, Genain CP: Frequency, heterogeneity and encephalitogenicity of T cells specific for myelin oligodendrocyte glycoprotein in naive outbred primates. Eur J Immunol. 2001, 31 (10): 2942-2950. 10.1002\/1521-4141(2001010)31:10<2942::AID-IMMU2942>3.0.CO;2-M","journal-title":"Eur J Immunol"},{"issue":"3","key":"719_CR14","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4049\/jimmunol.155.3.1151","volume":"155","author":"S Sakaguchi","year":"1995","unstructured":"Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M: Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995, 155 (3): 1151-1164.","journal-title":"J Immunol"},{"key":"719_CR15","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1034\/j.1600-065X.2001.1820102.x","volume":"182","author":"S Sakaguchi","year":"2001","unstructured":"Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T: Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001, 182: 18-32. 10.1034\/j.1600-065X.2001.1820102.x","journal-title":"Immunol Rev"},{"issue":"2","key":"719_CR16","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1084\/jem.188.2.287","volume":"188","author":"AM Thornton","year":"1998","unstructured":"Thornton AM, Shevach EM: CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998, 188 (2): 287-296. 10.1084\/jem.188.2.287","journal-title":"J Exp Med"},{"issue":"1","key":"719_CR17","doi-asserted-by":"publisher","first-page":"183","DOI":"10.4049\/jimmunol.164.1.183","volume":"164","author":"AM Thornton","year":"2000","unstructured":"Thornton AM, Shevach EM: Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000, 164 (1): 183-190.","journal-title":"J Immunol"},{"key":"719_CR18","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1034\/j.1600-065X.2001.1820104.x","volume":"182","author":"EM Shevach","year":"2001","unstructured":"Shevach EM, McHugh RS, Piccirillo CA, Thornton AM: Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol Rev. 2001, 182: 58-67. 10.1034\/j.1600-065X.2001.1820104.x","journal-title":"Immunol Rev"},{"key":"719_CR19","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/j.0105-2896.2006.00427.x","volume":"212","author":"S Sakaguchi","year":"2006","unstructured":"Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, Shimizu J, Takahashi T, Nomura T: Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006, 212: 8-27. 10.1111\/j.0105-2896.2006.00427.x","journal-title":"Immunol Rev"},{"issue":"4","key":"719_CR20","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/ni1179","volume":"6","author":"JD Fontenot","year":"2005","unstructured":"Fontenot JD, Rudensky AY: A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol. 2005, 6 (4): 331-337. 10.1038\/ni1179","journal-title":"Nat Immunol"},{"key":"719_CR21","doi-asserted-by":"publisher","first-page":"89017","DOI":"10.1155\/2007\/89017","volume":"2007","author":"HJ van der Vliet","year":"2007","unstructured":"van der Vliet HJ, Nieuwenhuis EE: IPEX as a result of mutations in FOXP3. Clin Dev Immunol. 2007, 2007: 89017-","journal-title":"Clin Dev Immunol"},{"issue":"1-3","key":"719_CR22","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1007\/s12026-007-0022-2","volume":"38","author":"HD Ochs","year":"2007","unstructured":"Ochs HD, Gambineri E, Torgerson TR: IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol Res. 2007, 38 (1-3): 112-121. 10.1007\/s12026-007-0022-2","journal-title":"Immunol Res"},{"issue":"7","key":"719_CR23","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1084\/jem.20031579","volume":"199","author":"V Viglietta","year":"2004","unstructured":"Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA: Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. JExpMed. 2004, 199 (7): 971-979.","journal-title":"JExpMed"},{"issue":"2","key":"719_CR24","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1002\/eji.200737271","volume":"38","author":"I Martinez-Forero","year":"2008","unstructured":"Martinez-Forero I, Garcia-Munoz R, Martinez-Pasamar S, Inoges S, Lopez-Diaz de Cerio A, Palacios R, Sepulcre J, Moreno B, Gonzalez Z, Fernandez-Diez B, et al.: IL-10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis. Eur J Immunol. 2008, 38 (2): 576-586. 10.1002\/eji.200737271","journal-title":"Eur J Immunol"},{"issue":"1","key":"719_CR25","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1172\/JCI0213605","volume":"109","author":"A Kukreja","year":"2002","unstructured":"Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K, Ten S, Sanz M, Exley M, Wilson B, et al.: Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest. 2002, 109 (1): 131-140.","journal-title":"J Clin Invest"},{"issue":"14","key":"719_CR26","doi-asserted-by":"publisher","first-page":"8372","DOI":"10.1073\/pnas.1533209100","volume":"100","author":"GQ Phan","year":"2003","unstructured":"Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Haworth LR, Seipp CA, Freezer LJ, et al.: Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA. 2003, 100 (14): 8372-8377. 10.1073\/pnas.1533209100","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"719_CR27","doi-asserted-by":"publisher","first-page":"192","DOI":"10.4049\/jimmunol.177.1.192","volume":"177","author":"AR Almeida","year":"2006","unstructured":"Almeida AR, Zaragoza B, Freitas AA: Indexation as a novel mechanism of lymphocyte homeostasis: the number of CD4+CD25+ regulatory T cells is indexed to the number of IL-2-producing cells. J Immunol. 2006, 177 (1): 192-200.","journal-title":"J Immunol"},{"issue":"5880","key":"719_CR28","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1126\/science.1155209","volume":"320","author":"JM Lund","year":"2008","unstructured":"Lund JM, Hsing L, Pham TT, Rudensky AY: Coordination of early protective immunity to viral infection by regulatory T cells. Science. 2008, 320 (5880): 1220-1224. 10.1126\/science.1155209","journal-title":"Science"},{"key":"719_CR29","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1111\/j.1600-065X.2007.00487.x","volume":"216","author":"J Carneiro","year":"2007","unstructured":"Carneiro J, Leon K, Caramalho I, van den Dool C, Gardner R, Oliveira V, Bergman ML, Sepulveda N, Paixao T, Faro J, et al.: When three is not a crowd: a Crossregulation Model of the dynamics and repertoire selection of regulatory CD4(+) T cells. Immunol Rev. 2007, 216: 48-68.","journal-title":"Immunol Rev"},{"issue":"5528","key":"719_CR30","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1126\/science.1062946","volume":"293","author":"RN Germain","year":"2001","unstructured":"Germain RN: The art of the probable: system control in the adaptive immune system. Science. 2001, 293 (5528): 240-245. 10.1126\/science.1062946","journal-title":"Science"},{"issue":"2","key":"719_CR31","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.4049\/jimmunol.178.2.1208","volume":"178","author":"E Kekalainen","year":"2007","unstructured":"Kekalainen E, Tuovinen H, Joensuu J, Gylling M, Franssila R, Pontynen N, Talvensaari K, Perheentupa J, Miettinen A, Arstila TP: A defect of regulatory T cells in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Immunol. 2007, 178 (2): 1208-1215.","journal-title":"J Immunol"},{"issue":"4","key":"719_CR32","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/ni1181","volume":"6","author":"Y Belkaid","year":"2005","unstructured":"Belkaid Y, Rouse BT: Natural regulatory T cells in infectious disease. Nat Immunol. 2005, 6 (4): 353-360.","journal-title":"Nat Immunol"},{"issue":"6","key":"719_CR33","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/ni.1736","volume":"10","author":"W O'Connor Jr","year":"2009","unstructured":"O'Connor W, Kamanaka M, Booth CJ, Town T, Nakae S, Iwakura Y, Kolls JK, Flavell RA: A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol. 2009, 10 (6): 603-609. 10.1038\/ni.1736","journal-title":"Nat Immunol"},{"key":"719_CR34","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1111\/j.1749-6632.1987.tb48723.x","volume":"504","author":"MC Mackey","year":"1987","unstructured":"Mackey MC, Milton JG: Dynamical diseases. Ann N Y Acad Sci. 1987, 504: 16-32. 10.1111\/j.1749-6632.1987.tb48723.x","journal-title":"Ann N Y Acad Sci"},{"issue":"2","key":"719_CR35","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1002\/ana.21634","volume":"65","author":"P Villoslada","year":"2009","unstructured":"Villoslada P, Steinman L, Baranzini SE: Systems biology and its application to the understanding of neurological diseases. Ann Neurol. 2009, 65 (2): 124-139. 10.1002\/ana.21634","journal-title":"Ann Neurol"},{"key":"719_CR36","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1038\/nri2192","volume":"7","author":"MG von Herrath","year":"2007","unstructured":"von Herrath MG, Sanda S, Herold K: Type 1 diabetes as a relapsing-remitting disease?. Nat Rev Immunol. 2007, 7: 988-994. 10.1038\/nri2192","journal-title":"Nat Rev Immunol"},{"issue":"7042","key":"719_CR37","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/nature03724","volume":"435","author":"CC Goodnow","year":"2005","unstructured":"Goodnow CC, Sprent J, Fazekas de St Groth B, Vinuesa CG: Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature. 2005, 435 (7042): 590-597. 10.1038\/nature03724","journal-title":"Nature"},{"issue":"1","key":"719_CR38","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.jaut.2003.10.002","volume":"22","author":"K Leon","year":"2004","unstructured":"Leon K, Faro J, Lage A, Carneiro J: Inverse correlation between the incidences of autoimmune disease and infection predicted by a model of T cell mediated tolerance. J Autoimmun. 2004, 22 (1): 31-42. 10.1016\/j.jaut.2003.10.002","journal-title":"J Autoimmun"},{"issue":"3","key":"719_CR39","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/0092-8674(94)90419-7","volume":"78","author":"JJ Lafaille","year":"1994","unstructured":"Lafaille JJ, Nagashima K, Katsuki M, Tonegawa S: High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell. 1994, 78 (3): 399-408. 10.1016\/0092-8674(94)90419-7","journal-title":"Cell"},{"issue":"1","key":"719_CR40","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.jtbi.2005.11.010","volume":"241","author":"NJ Burroughs","year":"2006","unstructured":"Burroughs NJ, Miguel Paz Mendes de Oliveira B, Adrego Pinto A: Regulatory T cell adjustment of quorum growth thresholds and the control of local immune responses. J Theor Biol. 2006, 241 (1): 134-141. 10.1016\/j.jtbi.2005.11.010","journal-title":"J Theor Biol"},{"issue":"4 Pt 1","key":"719_CR41","doi-asserted-by":"publisher","first-page":"041911","DOI":"10.1103\/PhysRevE.77.041911","volume":"77","author":"Y Wu","year":"2008","unstructured":"Wu Y, Zhu WQ: Stochastic analysis of a pulse-type prey-predator model. Phys Rev E Stat Nonlin Soft Matter Phys. 2008, 77 (4 Pt 1): 041911-","journal-title":"Phys Rev E Stat Nonlin Soft Matter Phys"},{"issue":"3","key":"719_CR42","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.4049\/jimmunol.161.3.1087","volume":"161","author":"JA Borghans","year":"1998","unstructured":"Borghans JA, De Boer RJ, Sercarz E, Kumar V: T cell vaccination in experimental autoimmune encephalomyelitis: a mathematical model. J Immunol. 1998, 161 (3): 1087-1093.","journal-title":"J Immunol"},{"issue":"1355","key":"719_CR43","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1098\/rspb.1995.0025","volume":"259","author":"JA Borghans","year":"1995","unstructured":"Borghans JA, De Boer RJ: A minimal model for T-cell vaccination. Proc Biol Sci. 1995, 259 (1355): 173-178. 10.1098\/rspb.1995.0025","journal-title":"Proc Biol Sci"},{"issue":"3","key":"719_CR44","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/nrd2195","volume":"6","author":"H Kitano","year":"2007","unstructured":"Kitano H: A robustness-based approach to systems-oriented drug design. Nat Rev Drug Discov. 2007, 6 (3): 202-210. 10.1038\/nrd2195","journal-title":"Nat Rev Drug Discov"},{"issue":"11","key":"719_CR45","doi-asserted-by":"publisher","first-page":"e1222","DOI":"10.1371\/journal.pone.0001222","volume":"2","author":"R Palacios","year":"2007","unstructured":"Palacios R, Goni J, Martinez-Forero I, Iranzo J, Sepulcre J, Melero I, Villoslada P: A network analysis of the human T-cell activation gene network identifies JAGGED1 as a therapeutic target for autoimmune diseases. PLoS ONE. 2007, 2 (11): e1222- 10.1371\/journal.pone.0001222","journal-title":"PLoS ONE"},{"issue":"Suppl 1","key":"719_CR46","doi-asserted-by":"publisher","first-page":"2538","DOI":"10.1073\/pnas.012582499","volume":"99","author":"JM Carlson","year":"2002","unstructured":"Carlson JM, Doyle J: Complexity and robustness. Proc Natl Acad Sci USA. 2002, 99 (Suppl 1): 2538-2545.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"8","key":"719_CR47","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1172\/JCI200114235","volume":"108","author":"KW Wucherpfennig","year":"2001","unstructured":"Wucherpfennig KW: Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest. 2001, 108 (8): 1097-1104.","journal-title":"J Clin Invest"},{"issue":"7","key":"719_CR48","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1038\/nrg2395","volume":"9","author":"JR Oksenberg","year":"2008","unstructured":"Oksenberg JR, Baranzini SE, Sawcer S, Hauser SL: The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet. 2008, 9 (7): 516-526. 10.1038\/nrg2395","journal-title":"Nat Rev Genet"},{"issue":"Pt 8","key":"719_CR49","doi-asserted-by":"publisher","first-page":"1782","DOI":"10.1093\/brain\/awg182","volume":"126","author":"F Bagnato","year":"2003","unstructured":"Bagnato F, Jeffries N, Richert ND, Stone RD, Ohayon JM, McFarland HF, Frank JA: Evolution of T1 black holes in patients with multiple sclerosis imaged monthly for 4 years. Brain. 2003, 126 (Pt 8): 1782-1789.","journal-title":"Brain"},{"issue":"12","key":"719_CR50","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1038\/ni1536","volume":"8","author":"P Pandiyan","year":"2007","unstructured":"Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ: CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol. 2007, 8 (12): 1353-1362. 10.1038\/ni1536","journal-title":"Nat Immunol"},{"issue":"9","key":"719_CR51","doi-asserted-by":"publisher","first-page":"5332","DOI":"10.4049\/jimmunol.174.9.5332","volume":"174","author":"CW Lawrence","year":"2005","unstructured":"Lawrence CW, Ream RM, Braciale TJ: Frequency, specificity, and sites of expansion of CD8+ T cells during primary pulmonary influenza virus infection. J Immunol. 2005, 174 (9): 5332-5340.","journal-title":"J Immunol"},{"issue":"2","key":"719_CR52","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1093\/intimm\/dxh029","volume":"16","author":"X Zhang","year":"2004","unstructured":"Zhang X, Koldzic DN, Izikson L, Reddy J, Nazareno RF, Sakaguchi S, Kuchroo VK, Weiner HL: IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells. Int Immunol. 2004, 16 (2): 249-256. 10.1093\/intimm\/dxh029","journal-title":"Int Immunol"},{"issue":"1-2","key":"719_CR53","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/S0022-1759(00)00181-2","volume":"239","author":"J Walker","year":"2000","unstructured":"Walker J, Rigley K: Gene expression profiling in human peripheral blood mononuclear cells using high-density filter-based cDNA microarrays. J Immunol Methods. 2000, 239 (1-2): 167-179. 10.1016\/S0022-1759(00)00181-2","journal-title":"J Immunol Methods"},{"issue":"2","key":"719_CR54","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1084\/jem.20030315","volume":"198","author":"LS Walker","year":"2003","unstructured":"Walker LS, Chodos A, Eggena M, Dooms H, Abbas AK: Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J Exp Med. 2003, 198 (2): 249-258. 10.1084\/jem.20030315","journal-title":"J Exp Med"},{"issue":"9","key":"719_CR55","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/ni0901-816","volume":"2","author":"KJ Maloy","year":"2001","unstructured":"Maloy KJ, Powrie F: Regulatory T cells in the control of immune pathology. Nat Immunol. 2001, 2 (9): 816-822. 10.1038\/ni0901-816","journal-title":"Nat Immunol"},{"issue":"5","key":"719_CR56","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1084\/jem.20041982","volume":"201","author":"R Setoguchi","year":"2005","unstructured":"Setoguchi R, Hori S, Takahashi T, Sakaguchi S: Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med. 2005, 201 (5): 723-735. 10.1084\/jem.20041982","journal-title":"J Exp Med"},{"issue":"3","key":"719_CR57","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/ni0308-229","volume":"9","author":"AS Shaw","year":"2008","unstructured":"Shaw AS: How T cells 'find' the right dendritic cell. Nat Immunol. 2008, 9 (3): 229-230. 10.1038\/ni0308-229","journal-title":"Nat Immunol"},{"issue":"5 Pt 1","key":"719_CR58","doi-asserted-by":"publisher","first-page":"051914","DOI":"10.1103\/PhysRevE.75.051914","volume":"75","author":"R Abta","year":"2007","unstructured":"Abta R, Shnerb NM: Angular velocity variations and stability of spatially explicit prey-predator systems. Phys Rev E Stat Nonlin Soft Matter Phys. 2007, 75 (5 Pt 1): 051914-","journal-title":"Phys Rev E Stat Nonlin Soft Matter Phys"},{"issue":"5 Pt 1","key":"719_CR59","doi-asserted-by":"publisher","first-page":"051907","DOI":"10.1103\/PhysRevE.74.051907","volume":"74","author":"T Reichenbach","year":"2006","unstructured":"Reichenbach T, Mobilia M, Frey E: Coexistence versus extinction in the stochastic cyclic Lotka-Volterra model. Phys Rev E Stat Nonlin Soft Matter Phys. 2006, 74 (5 Pt 1): 051907-","journal-title":"Phys Rev E Stat Nonlin Soft Matter Phys"},{"issue":"6 Pt 1","key":"719_CR60","doi-asserted-by":"publisher","first-page":"061907","DOI":"10.1103\/PhysRevE.63.061907","volume":"63","author":"AF Rozenfeld","year":"2001","unstructured":"Rozenfeld AF, Albano EV: Critical and oscillatory behavior of a system of smart preys and predators. Phys Rev E Stat Nonlin Soft Matter Phys. 2001, 63 (6 Pt 1): 061907-","journal-title":"Phys Rev E Stat Nonlin Soft Matter Phys"},{"key":"719_CR61","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1146\/annurev.immunol.23.021704.115601","volume":"24","author":"B Kyewski","year":"2006","unstructured":"Kyewski B, Klein L: A central role for central tolerance. Annu Rev Immunol. 2006, 24: 571-606. 10.1146\/annurev.immunol.23.021704.115601","journal-title":"Annu Rev Immunol"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-5-114.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T04:32:31Z","timestamp":1686198751000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-5-114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,7,15]]},"references-count":61,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["719"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-5-114","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,7,15]]},"assertion":[{"value":"13 December 2010","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2011","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2011","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"114"}}