{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:45:32Z","timestamp":1787507132496,"version":"build-2736575974"},"reference-count":59,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,3]],"date-time":"2020-06-03T00:00:00Z","timestamp":1591142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system. It represents one of the main causes of neurological disability in young people. In MS, the autoimmune response is directed against myelin antigens but other possible bio-molecular markers are investigated. The aim of this work was, through an in silico study, the evaluation of the transcriptional modifications between healthy subjects and MS patients in six brain areas (corpus callosum, hippocampus, internal capsule, optic chiasm, frontal and parietal cortex) in order to identify genes representative of the disease. Our results show the upregulation of the Heat Shock Proteins (HSPs) HSPA1A, HSPA1B, HSPA7, HSPA6, HSPH1 and HSPA4L of the HSP70 family, among which HSPA1A and HSPA1B are upregulated in all the brain areas. HSP70s are molecular chaperones indispensable for protein folding, recently associated with immune system maintenance. The little overexpression of the HSPs protects the cells from stress but extreme upregulation can contribute to the MS pathogenesis. We also investigated the genes involved in the immune system that result in overall upregulation in the corpus callosum, hippocampus, internal capsule, optic chiasm and are absent in the cortex. Interestingly, the genes of the immune system and the HSP70s have comparable levels of expression.<\/jats:p>","DOI":"10.3390\/genes11060615","type":"journal-article","created":{"date-parts":[[2020,6,4]],"date-time":"2020-06-04T04:36:09Z","timestamp":1591245369000},"page":"615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Could the Heat Shock Proteins 70 Family Members Exacerbate the Immune Response in Multiple Sclerosis? An in Silico Study"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0358-7348","authenticated-orcid":false,"given":"Luigi","family":"Chiricosta","sequence":"first","affiliation":[{"name":"IRCCS Centro Neurolesi Bonino Pulejo, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnese","family":"Gugliandolo","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi Bonino Pulejo, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Placido","family":"Bramanti","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi Bonino Pulejo, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Mazzon","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi Bonino Pulejo, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/s41572-018-0041-4","article-title":"Multiple sclerosis","volume":"4","author":"Filippi","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s40263-019-00691-7","article-title":"Efficacy and safety of oral therapies for relapsing-remitting multiple sclerosis","volume":"34","author":"Paolicelli","year":"2020","journal-title":"CNS Drugs"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.neuron.2018.01.021","article-title":"Multiple sclerosis: Mechanisms and immunotherapy","volume":"97","author":"Kaskow","year":"2018","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"618127","DOI":"10.1155\/2011\/618127","article-title":"Hsp70 and its molecular role in nervous system diseases","volume":"2011","author":"Turturici","year":"2011","journal-title":"Biochem. Res. Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"243","DOI":"10.5507\/bp.2005.033","article-title":"Heat shock proteins in autoimmune diseases","volume":"149","author":"Raska","year":"2005","journal-title":"Biomed. Pap. Med. Fac. Univ. Palacky, Olomouc, Czechoslov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/978-3-319-47861-6_3","article-title":"Heat shock proteins in multiple sclerosis","volume":"958","author":"Pinar","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1097\/NEN.0000000000000136","article-title":"Positive or negative involvement of heat shock proteins in multiple sclerosis pathogenesis: An overview","volume":"73","author":"Turturici","year":"2014","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"D991","DOI":"10.1093\/nar\/gks1193","article-title":"Ncbi geo: Archive for functional genomics data sets--update","volume":"41","author":"Barrett","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"D8","DOI":"10.1093\/nar\/gkx1095","article-title":"Database resources of the national center for biotechnology information","volume":"46","author":"Coordinators","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10130","DOI":"10.1073\/pnas.1821306116","article-title":"Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis","volume":"116","author":"Voskuhl","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"D19","DOI":"10.1093\/nar\/gkq1019","article-title":"The sequence read archive","volume":"39","author":"Leinonen","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_13","unstructured":"(2019, June 01). University of California Santa Cruz (Ucsc). Available online: http:\/\/labshare.cshl.edu\/shares\/gingeraslab\/www-data\/dobin\/STAR\/STARgenomes\/Old\/ENSEMBL\/homo_sapiens\/ENSEMBL.homo_sapiens.release-75\/."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"Star: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"Htseq--a python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with deseq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"Kegg: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/j.1399-0039.1995.tb02492.x","article-title":"Heat shock protein 70 gene polymorphisms and multiple sclerosis","volume":"46","author":"Ramachandran","year":"1995","journal-title":"Tissue Antigens"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.jneuroim.2016.07.011","article-title":"Heat shock protein 70-hom gene polymorphism and protein expression in multiple sclerosis","volume":"298","author":"Boiocchi","year":"2016","journal-title":"J. Neuroimmunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jneuroim.2014.01.004","article-title":"Are hsp70 protein expression and genetic polymorphism implicated in multiple sclerosis inflammation?","volume":"268","author":"Boiocchi","year":"2014","journal-title":"J. Neuroimmunol."},{"key":"ref_21","first-page":"599","article-title":"Heat shock protein 70 and the risk of multiple sclerosis in the iranian population","volume":"20","author":"Tarzjani","year":"2019","journal-title":"Cell J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1034\/j.1399-0039.2001.580205.x","article-title":"Heat shock protein 70 gene polymorphism in japanese patients with multiple sclerosis","volume":"58","author":"Niino","year":"2001","journal-title":"Tissue Antigens"},{"key":"ref_23","first-page":"2055217318767192","article-title":"Serum heat shock protein 70 levels as a biomarker for inflammatory processes in multiple sclerosis","volume":"4","author":"Lechner","year":"2018","journal-title":"Mult. Scler. J.-Exp. Transl. Clin."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3109\/08916934.2013.866104","article-title":"Up-regulation of inducible heat shock protein-70 expression in multiple sclerosis patients","volume":"47","author":"Mansilla","year":"2014","journal-title":"Autoimmunity"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s40478-019-0705-7","article-title":"Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis","volume":"7","author":"Melief","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1242\/jcs.01284","article-title":"\u201cThe stress of dying\u201d: The role of heat shock proteins in the regulation of apoptosis","volume":"117","author":"Beere","year":"2004","journal-title":"J. Cell Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Mansilla, M.J., Costa, C., Eixarch, H., Tepavcevic, V., Castillo, M., Martin, R., Lubetzki, C., Aigrot, M.S., Montalban, X., and Espejo, C. (2014). Hsp70 regulates immune response in experimental autoimmune encephalomyelitis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105737"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.2119\/molmed.2012.00119","article-title":"Heat shock protein 70: Roles in multiple sclerosis","volume":"18","author":"Mansilla","year":"2012","journal-title":"Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S0167-4781(00)00203-7","article-title":"The human hsp70b gene at the hspa7 locus of chromosome 1 is transcribed but non-functional","volume":"1494","author":"Parsian","year":"2000","journal-title":"Biochim. Et Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Brocchieri, L., de Macario, E.C., and Macario, A.J. (2008). Hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions. BMC Evol. Biol., 8.","DOI":"10.1186\/1471-2148-8-19"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1007\/s11064-016-2084-9","article-title":"Targeting of heat shock protein hspa6 (hsp70b\u2019) to the periphery of nuclear speckles is disrupted by a transcription inhibitor following thermal stress in human neuronal cells","volume":"42","author":"Becirovic","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1007\/s12192-016-0724-2","article-title":"Dynamics of the association of heat shock protein hspa6 (hsp70b\u2019) and hspa1a (hsp70-1) with stress-sensitive cytoplasmic and nuclear structures in differentiated human neuronal cells","volume":"21","author":"Shorbagi","year":"2016","journal-title":"Cell Stress Chaperones"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1038\/sj.emboj.7601138","article-title":"Molecular chaperones of the hsp110 family act as nucleotide exchange factors of hsp70s","volume":"25","author":"Dragovic","year":"2006","journal-title":"EMBO J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.3233\/JAD-180536","article-title":"Intracellular targeting of heat shock proteins in differentiated human neuronal cells following proteotoxic stress","volume":"66","author":"Deane","year":"2018","journal-title":"J. Alzheimer\u2019s Dis. Jad"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"41727","DOI":"10.1074\/jbc.M407947200","article-title":"Hsp105alpha suppresses hsc70 chaperone activity by inhibiting hsc70 atpase activity","volume":"279","author":"Yamagishi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1042\/BJ20130579","article-title":"Nogo-a couples with apg-1 through interaction and co-ordinate expression under hypoxic and oxidative stress","volume":"455","author":"Kern","year":"2013","journal-title":"Biochem. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s00418-011-0791-5","article-title":"Differential expression of hspa1 and hspa2 proteins in human tissues; tissue microarray-based immunohistochemical study","volume":"135","author":"Scieglinska","year":"2011","journal-title":"Histochem. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s11010-013-1844-y","article-title":"Association of heat-shock proteins in various neurodegenerative disorders: Is it a master key to open the therapeutic door?","volume":"386","author":"Paul","year":"2014","journal-title":"Mol. Cell Biochem"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"202","DOI":"10.4049\/jimmunol.172.1.202","article-title":"Inducible heat shock protein 70 promotes myelin autoantigen presentation by the hla class ii","volume":"172","author":"Mycko","year":"2004","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.jaut.2011.05.001","article-title":"Role of hla class ii genes in susceptibility and resistance to multiple sclerosis: Studies using hla transgenic mice","volume":"37","author":"Luckey","year":"2011","journal-title":"J. Autoimmun."},{"key":"ref_41","first-page":"1","article-title":"The role of hla in ms susceptibility and phenotype","volume":"26","author":"Greer","year":"2015","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jneuroim.2013.02.004","article-title":"Genome wide differences of gene expression associated with hla-drb1 genotype in multiple sclerosis: A pilot study","volume":"257","author":"Apperson","year":"2013","journal-title":"J. Neuroimmunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/0022-510X(95)00039-5","article-title":"Increased cathepsin b activity in multiple sclerosis brain","volume":"131","author":"Bever","year":"1995","journal-title":"J. Neurol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.cyto.2014.09.011","article-title":"T cell subsets and their signature cytokines in autoimmune and inflammatory diseases","volume":"74","author":"Raphael","year":"2015","journal-title":"Cytokine"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Richter, K., Rufer, A.C., Muller, M., Burger, D., Casagrande, F., Grossenbacher, T., Huber, S., Hug, M.N., Koldewey, P., and D\u2019Osualdo, A. (2020). Small molecule ax-024 reduces t cell proliferation independently of cd3&epsilon;-nck1 interaction, which is governed by a domain-swap in the nck1-sh3.1 domain. J. Biol. Chem.","DOI":"10.1074\/jbc.RA120.012788"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.cyto.2017.10.022","article-title":"Stat5a and stat6 gene expression levels in multiple sclerosis patients","volume":"106","author":"Hatami","year":"2018","journal-title":"Cytokine"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"274","DOI":"10.3109\/1547691X.2015.1089343","article-title":"Il-21 and il-21 receptor in the immunopathogenesis of multiple sclerosis","volume":"13","author":"Ghalamfarsa","year":"2016","journal-title":"J. Immunotoxicol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"35","DOI":"10.4161\/self.2.1.15639","article-title":"A role of il-1r1 signaling in the differentiation of th17 cells and the development of autoimmune diseases","volume":"2","author":"Sha","year":"2011","journal-title":"Self\/Nonself"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"543","DOI":"10.3389\/fimmu.2016.00543","article-title":"Activated il-1ri signaling pathway induces th17 cell differentiation via interferon regulatory factor 4 signaling in patients with relapsing-remitting multiple sclerosis","volume":"7","author":"Sha","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.autrev.2012.08.011","article-title":"Targeting irf4 in autoimmune diseases","volume":"11","author":"Xu","year":"2012","journal-title":"Autoimmun. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.4049\/jimmunol.1302672","article-title":"Anti-cd79 antibody induces b cell anergy that protects against autoimmunity","volume":"192","author":"Hardy","year":"2014","journal-title":"J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1084\/jem.20011571","article-title":"Vav3 modulates b cell receptor responses by regulating phosphoinositide 3-kinase activation","volume":"195","author":"Inabe","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.3389\/fimmu.2018.01539","article-title":"Bcl10 - bridging cards to immune activation","volume":"9","author":"Gehring","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.ajhg.2013.04.019","article-title":"Network-based multiple sclerosis pathway analysis with gwas data from 15,000 cases and 30,000 controls","volume":"92","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.1365-2567.2009.03097.x","article-title":"Regulation of t-cell immunity by leucocyte immunoglobulin-like receptors: Innate immune receptors for self on antigen-presenting cells","volume":"127","author":"Anderson","year":"2009","journal-title":"Immunology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.it.2005.12.002","article-title":"Ifngammar2 trafficking tunes ifngamma-stat1 signaling in t lymphocytes","volume":"27","author":"Regis","year":"2006","journal-title":"Trends Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1084\/jem.20011508","article-title":"C-jun nh(2)-terminal kinase (jnk)1 and jnk2 have distinct roles in cd8(+) t cell activation","volume":"195","author":"Conze","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1080\/09168451.2016.1165601","article-title":"Generating hescs with reduced immunogenicity by disrupting tap1 or tapbp","volume":"80","author":"Cui","year":"2016","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_59","first-page":"677","article-title":"Review of the novelties presented at the 27th congress of the european committee for treatment and research in multiple sclerosis (ectrims) (i)","volume":"54","author":"Fernandez","year":"2012","journal-title":"Rev. De Neurol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/6\/615\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:35:17Z","timestamp":1760175317000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/6\/615"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,3]]},"references-count":59,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["genes11060615"],"URL":"https:\/\/doi.org\/10.3390\/genes11060615","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,3]]}}}