{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:56:37Z","timestamp":1790502997070,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2005,4,30]],"date-time":"2005-04-30T00:00:00Z","timestamp":1114819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Although the role of systemic proinflammatory cytokines, IL-1\u03b2 and TNF-\u03b1, and their up-regulation of adhesion molecules, ICAM-1, VCAM-1 and E-Selectin, in the pathogenesis of cerebral malaria (CM) is well established, the role of local cytokine release remain unclear. Immunohistochemistry (IHC) was used to compare the expression of ICAM-1, VCAM-1, E-Selectin, IL-1\u03b2, TNF-\u03b1 and TGF- \u03b2 at light microscopic level in cerebral, cerebellar and brainstem postmortem cryostat sections from 10 CM, 5 severe malarial anemia (SMA), 1 purulent bacterial meningitis (PBM), 2 non-central nervous system infections (NCNSI) and 3 non-infections (NI) deaths in Ghanaian children. Fatal malaria and Salmonella sepsis showed significantly higher vascular expression of all 3 adhesion molecules, with highly significant co-localization with sequestration in the malaria cases. However, there was negligible difference between CM and SMA. TGF-\u03b2 showed intravascular and perivascular distribution in all cases, but expression was most intense in the PBM case and CM group. TNF-\u03b1 and IL-1\u03b2 showed prominent brain parenchymal staining, in addition to intravascular and perivascular staining, in only the PBM case and CM group. The maximal expression of all 6 antigens studied was in the cerebellar sections of the malaria cases. Endothelial activation is a feature of fatal malaria and Salmonella sepsis, with adhesion molecule expression being highly correlated with sequestration. IL-1\u03b2 and TNF-\u03b1 are upregulated in only cases with neurodegenerative lesions, whilst TGF-\u03b2 is present in all cases. Both cytokines and adhesion molecules were maximally upregulated in the cerebellar sections of the malaria cases.<\/jats:p>","DOI":"10.3390\/ijerph2005010123","type":"journal-article","created":{"date-parts":[[2008,10,25]],"date-time":"2008-10-25T13:52:15Z","timestamp":1224942735000},"page":"123-131","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Cytokines and Adhesion Molecules Expression in the Brain in Human Cerebral Malaria"],"prefix":"10.3390","volume":"2","author":[{"given":"Henry","family":"Armah","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Ghana Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin Kwame","family":"Wiredu","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Ghana Medical School"},{"name":"Department of Medical Laboratory Sciences, School of Allied Health Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred Kofi","family":"Dodoo","sequence":"additional","affiliation":[{"name":"Histology & Electron Microscopy Unit, Noguchi Memorial Institute for Medical Research, University of Ghana College of Health Sciences, Accra, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew Anthony","family":"Adjei","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Ghana Medical School"},{"name":"Department of Medical Laboratory Sciences, School of Allied Health Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Tettey","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Ghana Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Gyasi","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Ghana Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2005,4,30]]},"reference":[{"key":"ref_1","unstructured":"(1998). Tropical Research, 7th Program Report, UNDPA World Bank\/WHO."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/0140-6736(90)92827-5","article-title":"TNF concentration in fatal cerebral, non-fatal cerebral and uncomplicated Plasmodium falciparum malaria","volume":"336","author":"Kwiatkowski","year":"1990","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0163-7258(98)00008-4","article-title":"Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment","volume":"79","author":"Newton","year":"1998","journal-title":"Pharmacol Ther"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1046\/j.1365-2249.2003.02174.x","article-title":"The war between the malaria parasite and the immune system: immunity, immunoregulation and immuno-pathology","volume":"133","author":"Tongren","year":"2003","journal-title":"Clin Exp Immunol"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1086\/315078","article-title":"Cytokine Expression in the Brain in Human Cerebral Malaria","volume":"180","author":"Brown","year":"1999","journal-title":"J Infect Dis"},{"key":"ref_6","first-page":"249","article-title":"Immunogenetics and cerebral malaria","volume":"92","author":"Mazier","year":"1999","journal-title":"Bull Soc. Pathol Exot"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"461","DOI":"10.4269\/ajtmh.1999.61.467","article-title":"Cytoadherence characteristics of Plasmodium falciparum-infected erythrocytes from Malawian children with severe and uncomplicated malaria","volume":"61","author":"Rogerson","year":"1999","journal-title":"Am J. Trop. Med. Hyg"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/S0002-9440(10)65136-X","article-title":"A quantitative analysis of the microvascular sequestration of malaria parasites in the Human Brain","volume":"755","author":"Silamut","year":"1999","journal-title":"Am J. Pathol"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/infdis\/164.1.163","article-title":"Molecular basis of sequestration in severe and uncomplicated Plasmodium falciparum malaria: differential adhesion of infected erythrocytes to CD36 and ICAM-1","volume":"164","author":"Ockenhouse","year":"1991","journal-title":"J Infect Dis"},{"key":"ref_10","first-page":"1057","article-title":"An immunohistochemical study of the pathology of fatal Malaria: evidence for systemic endothelial activation","volume":"145","author":"Turner","year":"1994","journal-title":"Am J. Pathol"},{"key":"ref_11","first-page":"1477","article-title":"Systemic endothelial activation in both mild and severe malaria: correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity","volume":"152","author":"Turner","year":"1998","journal-title":"Am J. Pathol"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1084\/jem.176.4.1183","article-title":"Human vascular endothelial cell adhesion receptors for Plasmodium falciparum infected erythrocytes: roles for endothelial leukocytes adhesion molecule-1 and vascular cell adhesion molecule-1","volume":"176","author":"Ockenhouse","year":"1992","journal-title":"J. Exp Med"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"391","DOI":"10.4269\/ajtmh.1992.46.391","article-title":"A primate model for human cerebral malaria: Plasmodium coatneyi- infected rhesus monkeys","volume":"46","author":"Aikawa","year":"1992","journal-title":"Am J. Trop. Med. Hyg"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"445","DOI":"10.4049\/jimmunol.155.1.445","article-title":"hihibitors of protein tyrosine kinase suppress TNF-stimulated induction of endothelial cell adhesion molecules","volume":"755","author":"Weber","year":"1995","journal-title":"J. Immunol"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"501","DOI":"10.4269\/ajtmh.1997.57.501","article-title":"Involvement of cytokines in the histopathology of Malaria","volume":"57","author":"Udomsangpetch","year":"1997","journal-title":"Am J. Trop. Med. Hyg"},{"key":"ref_16","first-page":"142","article-title":"Immunopathological changes in Human Cerebral Malaria","volume":"12","author":"Porta","year":"1993","journal-title":"Clin Neuropathol"},{"key":"ref_17","first-page":"1473","article-title":"TNF-\u03b1expression in the brain during fatal murine cerebral malaria: evidence for production by microglia and astrocytes","volume":"750","author":"Medana","year":"1997","journal-title":"Am J. Pathol"},{"key":"ref_18","first-page":"277","article-title":"Histochemistry of cerebral lesions in mice infected with","volume":"39","author":"Polder","year":"1988","journal-title":"Plasmodium berghei. Trop. Med. Parasitol"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Polder, T. W., Eling, W. M., Jerusalem, C. R., and Wijers-Rouw, M. (1991a). J Neural Sci, 707, 24\u201334.","DOI":"10.1016\/0022-510X(91)90015-Y"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/0022-510X(91)90016-Z","article-title":"Morphological characteristics of intracerebral arterioles in clinical (Plasmodium falciparum) and experimental (Plasmodium berghei) cerebral malaria","volume":"707","author":"Polder","year":"1991b","journal-title":"J Neurol Sci"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0301-0082(97)00066-X","article-title":"Transforming growth factor-betas in neurodegenerative disease","volume":"54","author":"Flanders","year":"1998","journal-title":"Prog Neurobiol"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/S0046-8177(96)90392-5","article-title":"Distribution of transforming growth factor-beta isoforms in HIV-1 encephalitis","volume":"27","author":"Johnson","year":"1996","journal-title":"Hum Pathol"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1084\/jem.188.1.39","article-title":"Transforming growth factor beta production is inversely correlated with severity of murine malaria infection","volume":"188","author":"Omer","year":"1998","journal-title":"J. Exp. Med"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0304-3940(97)00830-6","article-title":"Central nervous system TNF-alpha mRNA expression during rabbit experimental pneumococcal meningitis","volume":"237","author":"Bitsch","year":"1997","journal-title":"Neurosci. Lett"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1159\/000097283","article-title":"Neuronal expression of tumour necrosis factor alpha in the murine brain","volume":"3","author":"Gahring","year":"1996","journal-title":"Neuroimmunomodulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/0736-5748(95)00018-C","article-title":"Cytokines in neurodegeneration and repair","volume":"13","author":"Rothwell","year":"1995","journal-title":"Int J Dev Neurosci"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"530","DOI":"10.4269\/ajtmh.2000.62.530","article-title":"Expression of proinflammatory cytokines in four regions of the brain in Macaque Mulatta ( rhesus) monkeys infected with Plasmodium coatneyi","volume":"62","author":"Tongren","year":"2000","journal-title":"Am J. Trop. Med. Hyg"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"379","DOI":"10.4269\/ajtmh.1996.55.379","article-title":"Multi-organ erythrocyte sequestration and ligand expression in rhesus monkeys infected with Plasmodium coatneyi malaria","volume":"55","author":"Smith","year":"1996","journal-title":"Am J. Trop. Med. Hyg"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"504","DOI":"10.4269\/ajtmh.1993.48.504","article-title":"Differential sequestration pattern of parasitized erythrocytes in the cerebrum and cerebellum in Human Cerebral Malaria","volume":"48","author":"Sein","year":"1993a","journal-title":"Am J Trop Med Hyg"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"513","DOI":"10.4269\/ajtmh.1993.49.513","article-title":"Sequestration pattern of parasitized erythrocytes in cerebrum, mid-brain and cerebellum of Plasmodium coatneyi-iniected rhesus monkeys (Macaca mulatto)","volume":"49","author":"Sein","year":"1993b","journal-title":"Am J Trop Med Hyg"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1084\/jem.20020128","article-title":"Locally up-regulated lymphotoxin alpha, not systemic tumour necrosis factor alpha is the principal mediator of murine cerebral malaria","volume":"195","author":"Engwerda","year":"2002","journal-title":"J. Exp Med"},{"key":"ref_32","first-page":"298","article-title":"Postmortem examination in cerebral malaria: a new simple method of demonstrating parasites in the capillaries of the brain","volume":"57","author":"Raja","year":"1922","journal-title":"Indian Med. Gazette"},{"key":"ref_33","unstructured":"(2000). Trans Roy Soc Trop Med Hyg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1086\/367960","article-title":"Platelet accumulation in brain microvessels in fatal paediatric cerebral malaria","volume":"187","author":"Grau","year":"2003","journal-title":"J. Infect Dis"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/j.1749-6632.2003.tb03135.x","article-title":"Pathophysiology of cerebral malaria: role of host cells in the modulation of cytoadhesion","volume":"992","author":"Wassmer","year":"2003a","journal-title":"Ann NY Acad Scl"},{"key":"ref_36","first-page":"254","article-title":"Pathogenesis of cerebral malaria: facts and hypotheses","volume":"63","author":"Wassmer","year":"2003b","journal-title":"Med Trop (Mars)"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1086\/380761","article-title":"Platelets reorient Plasmodium falciparum-infected erythrocyte cytoadhesion activated endothelial cells","volume":"189","author":"Wassmer","year":"2004","journal-title":"J. Infect Dis"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1179\/000349804225003271","article-title":"The cerebral-malaria-associated expression of RANTES, CCR3 and CCR5 in post mortem tissue samples","volume":"98","author":"Sarfo","year":"2004","journal-title":"Ann Trop Med. Parasitol"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4253","DOI":"10.1182\/blood-2002-05-1493","article-title":"CCR5 deficiency decreases susceptibility to experimental cerebral malaria","volume":"101","author":"Belnoue","year":"2003","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.4049\/jimmunol.170.4.2221","article-title":"Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis","volume":"170","author":"Nitcheu","year":"2003","journal-title":"J. Immunol"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/S0035-9203(99)90368-1","article-title":"Cognitive sequelae of severe malaria with impaired consciousness","volume":"93","author":"Holding","year":"1999","journal-title":"Trans Roy Soc Trop Med Hyg"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1001\/archneur.1991.00530230086029","article-title":"An emerging concept: The cerebellar contribution to higher functions","volume":"45","author":"Schmahmann","year":"1991","journal-title":"Arch. Neurol"}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/2\/1\/123\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T22:25:41Z","timestamp":1760221541000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/2\/1\/123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,4,30]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2005,5]]}},"alternative-id":["ijerph2005010123"],"URL":"https:\/\/doi.org\/10.3390\/ijerph2005010123","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,4,30]]}}}