Afrikaanse slaapziekte: nieuwe aspecten aan het licht gebracht
- KiavashMovahedi
AFRIKAANSE SLAAPZIEKTE: NIEUWE ASPECTEN AAN HET LICHT GEBRACHT
Slaapziekte eist jaarlijks het leven van duizenden Afrikanen.
Slaapziekte komt voor in grote delen van sub-Sahara Afrika. De ziekte wordt veroorzaakt door een parasiet, de trypanosoom, die op de mens wordt overgedragen door de tseetseevlieg. Bij infectie ervaren patiënten initieel milde symptomen zoals hoofdpijn en koorts, maar in een later stadium wordt de ziekte gekenmerkt door ernstigere problemen. Patiënten ondervinden dan onder meer neurologische symptomen zoals stoornissen in slaapritme –vandaar de naam slaapziekte. Indien de ziekte niet tijdig wordt behandeld, wordt ze fataal. Zo eist slaapziekte jaarlijks het leven van duizenden Afrikanen.
Uit onderzoek in diermodellen blijkt dat sterfte geen rechtstreeks gevolg is van de parasitaire infectie, maar dat de patiënt eerder bezwijkt onder de schade aangericht door zijn eigen immuunsysteem (immunopathologie). Het immuunsysteem is namelijk een defensiemechanisme van het lichaam dat ons in eerste instantie beschermt tegen ziekteverwekkers zoals trypanosomen, maar tegelijkertijd worden daarbij ook onze lichaamseigen weefsels onder vuur genomen. In het algemeen wordt de doodsoorzaak van slaapziekte toegeschreven aan extensieve leverschade, anemie (tekort aan rode bloedcellen) en meervoudig orgaanfalen.
Nieuw aandachtspunt in slaapziekte: de hersenen.
Gezien een laat stadium van infectie gepaard gaat met neurologische problemen, vermoedden wij dat –naast bovengenoemde algemeen veronderstelde doodsoorzaken– ook immunopathologie in de hersenen potentieel een belangrijke rol speelt.
De hersenen worden begrensd door drie barrières: de bloed-hersenbarrière, de bloed-hersenvliesbarrière en de bloed-cerebrospinale vloeistof (CSF)-barrière. Samen zorgen ze ervoor dat de infiltratie van onder meer immuuncellen (cellen van het immuunsysteem) vanuit de bloedsomloop naar de hersenen wordt geblokkeerd. Dit suggereert dat er geen immuuncellen in de hersenen aanwezig zijn. Daar is echter één belangrijke uitzondering op: de microglia. De microglia zijn hersen-residente immuuncellen die reeds sinds de geboorte in de hersenen aanwezig zijn en de hersenomgeving aftasten op zoek naar gevaar. In normale omstandigheden zijn dat dus de enige immuuncellen die in de hersenen aanwezig zijn. Wanneer de hersenomgeving wordt verstoord, daarentegen, bijvoorbeeld bij infectie, kunnen de hersenbarrières hun integriteit verliezen waardoor immuuncellen uit de bloedsomloop de hersenen toch kunnen infiltreren. In dat geval zijn zowel hersen-residente microglia als bloed-gerekruteerde immuuncellen in de hersenen aanwezig.
Over de betrokkenheid van de hersenen in slaapziekte is nog maar weinig geweten en met dit onderzoek beoogden wij daar een substantiële bijdrage aan te leveren. Als model werden de hersenen van trypanosoom-geïnfecteerde muizen bestudeerd.
Ons onderzoek: innovatief en baanbrekend.
Allereerst illustreerde ons onderzoek dat herseninfiltratie niet uitsluitend optreedt in een geavanceerd stadium van infectie, zoals algemeen wordt aangenomen, maar reeds vroeg in de infectie. Zowel parasieten als bloed-gerekruteerde immuuncellen (waaronder macrofagen) konden reeds vanaf dag 7 na infectie in de hersenen worden gedetecteerd en in de loop van de infectie bleven hun aantallen toenemen. Gepaard gaande met die progressieve herseninfiltratie, werden de hersen-residente immuuncellen, de microglia, gradueel geactiveerd en vermenigvuldigden zich ter plaatse.
Vervolgens wensten we na te gaan welke infiltratieroute de parasieten en bloed-gerekruteerde immuuncellen gebruikten om de hersenen te infiltreren –m.a.w. welke van de drie hersenbarrières hun integriteit hadden verloren– en of er een ruimtelijk verband was tussen beide. Drie complementaire experimentele analyses identificeerden bloed-CSF-barrièreverstoring als het primaire mechanisme. In een laat stadium van infectie waren namelijk zowel trypanosomen als immuuncellen via het CSF (het vocht waarin de hersenen baden) de hersenen binnengedrongen.
Tot slot werd er gezocht naar een eerste indicatie over de functies van hersen-residente microglia en bloed-gerekruteerde macrofagen –de overheersende immuuncelpopulaties in de hersenen van laat stadium geïnfecteerde muizen. Beide immuuncelpopulaties vertoonden een pro-inflammatoir karakter: ze bevorderden de aantrekking van additionele immuuncellen naar de hersenen. CCR2-knockout muizen[1], die na trypanosoominfectie significant hogere overlevingskansen hebben dan wild type muizen, vertoonden een reductie in het aantal immuuncellen in de hersenen, terwijl het aantal parasieten in de hersenen van beide muismodellen vergelijkbaar was. Bijgevolg lijkt het aannemelijk te veronderstellen dat het pro-inflammatoir karakter van residente microglia en bloed-gerekruteerde macrofagen rechtstreeks bijdraagt tot fatale immunopathologie.
Ter conclusie biedt dit onderzoek dus een nieuwe kijk op het ziekteverloop tijdens trypanosoominfecties. Tot enkele jaren geleden werd in de literatuur namelijk algemeen beschreven dat trypanosomen er pas in een laat stadium van infectie in slagen om via de bloed-hersenbarrière de hersenen te infiltreren. Onze resultaten leveren echter sterk experimenteel bewijs dat dit dogma over het tijdstip waarop en de route waarlangs trypanosomen de hersenen bereiken herzien moet worden. Wij hebben namelijk aangetoond dat herseninvasie reeds tijdens een vroeg stadium van infectie optreedt en dat parasitaire en cellulaire infiltratie via de bloed-CSF-barrière (en niet de bloed-hersenbarrière) aan de basis ligt van de herseninfectie. Bovendien suggereren onze data eveneens dat immunopathologie in de hersenen potentieel dé fatale gebeurtenis vormt, wat ook het huidige paradigma rond de doodsoorzaak van slaapziekte in vraag stelt.
De weg naar het uitroeien van Afrikaanse slaapziekte ligt open…
Het voortzetten van ons onderzoek is essentieel in het verder ontrafelen van de tot op heden ondermaats belichte aspecten in slaapziekte, wat potentieel cruciaal is in de zoektocht naar efficiëntere interventiestrategieën. Het uitroeien van slaapziekte zou de gezondheidsproblematiek en de socio-economische toestand op het Afrikaanse continent drastisch verbeteren. Echter, gezien de Westerse wereld quasi zuiver winst-gericht te werkt gaat, gaan algemeen weinig middelen uit naar onderzoek voor Afrikaanse ziektes. Tegenwoordig begint men echter in te zien dat door de huidige handels-, migratie- en reismentaliteit in onze maatschappij, Afrikaanse ziektes snel kunnen overwaaien naar andere werelddelen. Daarom zijn wij hoopvol dat farmaceutische bedrijven en/of overheden in de (nabije) toekomst steeds meer zullen willen investeren in dergelijk onderzoek.
[1] CCR2-knockout muizen zijn genetisch gemodificeerde muizen die veel minder monocyten in hun bloedsomloop hebben dan wild type (‘normale’) muizen; ze vertonen dus logischerwijs minder (monocytafgeleide) macrofaagrekrutering naar de hersenen.
Bibliografie
ADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY Abbas, A.K. & Janeway, C.A. (2000). Immunology: improving on nature in the twenty-first century. Cell 100, 129–138.
Aderem, A. & Ulevitch, R.J. (2000). Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787.
Ajami, B., Bennett, J.L., Krieger, C., McNagny, K.M. & Rossi, F.M.V. (2011). Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nature Neuroscience 14, 1142–1149.
Ajami, B., Bennett, J.L., Krieger, C., Tetzlaff, W. & Rossi, F.M.V. (2007). Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nature Neuroscience 10, 1538–1543.
Akira, S., Uematsu, S. & Takeuchi, O. (2006). Pathogen recognition and innate immunity. Cell 124, 783–801.
Alliot, F., Godin, I. & Pessac, B. (1999). Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Developmental Brain Research 117, 145–152.
Amrouni, D., Gautier-Sauvigné, S., Meiller, A., Vincendeau, P., Bouteille, B., Buguet, A. & Cespuglio, R. (2010). Cerebral and peripheral changes occurring in nitric oxide (NO) synthesis in a rat model of sleeping sickness: identification of brain iNOS expressing cells. PLoS One 5, e9211.
Andersen, M.H., Schrama, D., thor Straten, P. & Becker, J.C. (2006). Cytotoxic T cells. Journal of Investigative Dermatology 126, 32–41.
Banchereau, J. & Steinman, R.M. (1998). Dendritic cells and the control of immunity. Nature 392, 245–252.
Baruch, K., Kertser, A., Porat, Z. & Schwartz, M. (2015). Cerebral nitric oxide represses choroid plexus NFκB-dependent gateway activity for leukocyte trafficking. The EMBO Journal 34, 1816–1828.
Bassing, C.H., Swat, W. & Alt, F.W. (2002). The mechanism and regulation of chromosomal V(D)J recombination. Cell 109, S45–S55.
Bechmann, I., Galea, I. & Perry, V.H. (2007). What is the blood-brain barrier (not)? Trends in Immunology 28, 5–11.
Beck, G. & Habicht, G.S. (1996). Immunity and the invertebrates. Scientific American 275, 60–66.
Beers, D.R., Henkel, J.S., Xiao, Q., Zhao, W., Wang, J., Yen, A.A., Siklos, L., McKercher, S.R. & Appel, S.H. (2006). Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. PNAS 103, 16021–16026.
Belkaid, Y., Blank, R.B. & Suffia, I. (2006). Natural regulatory T cells and parasites: a common quest for host homeostasis. Immunological Review 212, 287–300.
Biswas, S.K. & Mantovani, A. (2010). Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nature Immunology 11, 889–896.
Blum, J., Schmid, C. & Burri, C. (2006). Clinical aspects of 2541 patients with second stage human African trypanosomiasis. Acta Tropica 97, 55–64.
Boltjes, A. & van Wijk, F. (2014). Human dendritic cell functional specialization in steady-state and inflammation. Frontiers in Immunology 5, 131.
Bonilla, F.A. & Oettgen, H.C. (2010). Adaptive immunity. Journal of Allergy and Clinical Immunology 125, S33–S40.
Borst, P. & Rudenko, G. (1994). Antigenic variation in African trypanosomes. Science 264, 1872–1873.
Bosschaerts, T., Guilliams, M., Stijlemans, B., Morias, Y., Engel, D., Tacke, F., Hérin, M., De Baetselier, P. & Beschin, A. (2010). Tip-DC development during parasitic infection is regulated by IL-10 and requires CCL2/CCR2, IFN-γ and MyD88 signaling. PLoS Pathogens 6, e1001045.
Brestoff, J.R. & Artis, D. (2013). Commensal bacteria at the interface of host metabolism and the immune system. Nature Immunology 14, 676–684.
Brinkmann, V., Reichard, U., Goosmann, C., Fauler, B., Uhlemann, Y., Weiss, D.S., Weinrauch, Y. & Zychlinsky, A. (2004). Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535.
Brun, R., Blum, J., Chappuis, F. & Burri, C. (2010). Human African trypanosomiasis. The Lancet 375, 148–159.
Buguet, A., Bourdon, L., Bisser, S., Chapotot, F., Radomski, M.W. & Dumas, M. (2001). La maladie du sommeil: trouble majeur des rythmes circadiens. Médecine Tropical 61, 328–339.
Capewell, P., Veitch, N.J., Turner, C.M.R., Raper, J., Berriman, M., Hajduk, S.L. & MacLeod, A. (2011). Differences between Trypanosoma brucei gambiense groups 1 and 2 in their resistance to killing by trypanolytic factor 1. PLoS Neglected Tropical Diseases 5, e1287.
Carayannopoulos, L.N. & Yokoyama, W.M. (2004). Recognition of infected cells by natural killer cells. Current Opinion in Immunology 16, 26–33.
Carlin, L.M., Stamatiades, E.G., Auffray, C., Hanna, R.N., Glover, L., Vizcay-Barrena, G., Hedrick, C.C., Cook, H.T., Diebold, S. & Geissmann, F. (2013). Nr4a1-dependent Ly6C-low monocytes monitor endothelial cells and orchestrate their disposal. Cell 153, 362–375.
Cella, M., Engering, A., Pinet, V., Pieters, J. & Lanzavecchia, A. (1997). Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 388, 782–787.
Chaplin, D.D. (2010). Overview of the immune response. Journal of Allergy and Clinical Immunology 125, S3–S23.
Chatila, T.A. (2005). Role of regulatory T cells in human diseases. Journal of Allergy and Clinical Immunology 116, 949–959.
Chen, L. (2004). Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nature Reviews Immunology 4, 336–347.
Clark, R. & Kupper, T. (2005). Old meets new: the interaction between innate and adaptive immunity. Journal of Investigative Dermatology 125, 629–637.
Corti, S., Locatelli, F., Donadoni, C., Strazzer, S., Salani, S., Del Bo, R., Caccialanza, M., Bresolin, N., Scarlato, G. & Comi, G.P. (2002). Neuroectodermal and microglial differentiation of bone marrow cells in the mouse spinal cord and sensory ganglia. Journal of Neuroscience Research 70, 721–733.
Cottle, L.E., Peters, J.R., Hall, A., Bailey, W.J., Noyes, H.A., Rimington, J.E., Beeching, N.J., Squire, B.S. & Beadsworth, M.B.J. (2012). Multiorgan dysfunction caused by travel-associated African trypanosomiasis. Emerging Infectious Diseases 18, 287–289.
Courtin, D., Berthier, D., Thevenon, S., Dayo, G.K., Garcia, A. & Bucheton, B. (2008). Host genetics in African trypanosomiasis. Infection, Genetics and Evolution 8, 229–238.
Craner, M.J., Damarjian, T.G., Liu, S., Hains, B.C., Lo, A.C., Black, J.A., Newcombe, J., Cuzner, M.L. & Waxman, S.G. (2005). Sodium channels contribute to microglia/macrophage activation and function in EAE and MS. Glia 49, 220–229.
Danilova, N. (2012). The evolution of adaptive immuninty. In: Self and Nonself (Lópes-Larrea, C., Ed). Springer Science & Business Media, New York, USA, pp. 218–235.
De Baetselier, P., Namangala, B., Noël, W., Brys, L., Pays, E. & Beschin, A. (2001). Alternative versus classical macrophage activation during experimental African trypanosomosis. International Journal for Parasitology 31, 575–587.
De Greef, C., Chimfwembe, E., Kihang’a Wabacha, J., Bajyana Songa, E. & Hamers, R. (1992). Only the serum-resistant bloodstream forms of Trypanosoma brucei rhodesiense express the serum resistance associated (SRA) protein. Annales de la Société Belge de Médicine Tropical 72, 13–21.
de Haas, A.H., Boddeke, H.W.G.M. & Biber, K. (2008). Region-specific expression of immunoregulatory proteins on microglia in the healthy CNS. Glia 56, 888–894.
Dempsey, P.W., Vaidya, S.A. & Cheng, G. (2003). The art of war: innate and adaptive immune responses. Cellular and Molecular Life Sciences 60, 2604–2621.
de Sousa, K.P., Atouguia, J. & Silva, M.S. (2010). Partial biochemical characterization of a metalloproteinase from the bloodstream forms of Trypanosoma brucei brucei parasites. Protein Journal 29, 283–289.
Djukic, M., Mildner, A., Schmidt, H., Czesnik, D., Brück, W., Priller, J., Nau, R. & Prinz, M. (2006). Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice. Brain 129, 2394–2403.
Eglitis, M.A. & Mezey, É. (1997). Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. PNAS 94, 4080–4085.
Engelhardt, B. & Ransohoff, R.M. (2005). The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends in Immunology 26, 485–495.
Epelman, S., Lavine, K.J. & Randolph, G.J. (2014). Origin and functions of tissue macrophages. Immunity 41, 21–35.
Faust, N., Varas, F., Kelly, L.M., Heck, S. & Graf, T. (2000). Insertion of enhanced green fluorescent protein into the lysozyme gene creates mice with green fluorescent granulocytes and macrophages. Blood 96, 719–726.
Fife, B.T., Huffnagle, G.B., Kuziel, W.A. & Karpus, W.J. (2000). CC chemokine receptor 2 is critical for induction of experimental autoimmune encephalomyelitis. Journal of Experimental Medicine 192, 899–905.
Finlay, B.B. & McFadden, G. (2006). Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell 124, 767–782.
Flügel, A., Bradl, M., Kreutzberg, G.W. & Graeber, M.B. (2001). Transformation of donor-derived bone marrow precursors into host microglia during autoimmune CNS inflammation and during the retrograde response to axotomy. Journal of Neuroscience Research 66, 74–82.
Franco, J.R., Simarro, P.P., Diarra, A. & Jannin, J.G. (2014). Epidemiology of human African trypanosomiasis. Clinical Epidemiology 6, 257–275.
Frevert, U., Movila, A., Nikolskaia, O.V., Raper, J., Mackey, Z.B., Abdulla, M., McKerrow, J. & Grab, D.J. (2012). Early invasion of brain parenchyma by African trypanosomes. PLoS One 7, e43913.
Geissmann, F., Jung, S. & Littman, D.R. (2003). Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82.
Geissmann, F., Manz, M.G., Jung, S., Sieweke, M.H., Merad, M. & Ley, K. (2010). Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661.
Gerdes, J., Lemke, H., Baisch, H., Wacker, H.H., Schwab, U. & Stein, H. (1984). Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. The Journal of Immunology 133, 1710–1715.
Getts, D.R., Terry, R.L., Getts, M.T., Müller, M., Rana, S., Shrestha, B., Radford, J., van Rooijen, N., Campbell, I.L. & King, N.J.C. (2008). Ly6c+ “inflammatory monocytes” are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis. Jounal of Experimental Medicine 205, 2319–2337.
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M.F., Conway, S.J., Ng, L.G., Stanley, E.R., Samokhvalov, I.M. & Merad, M. (2010). Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845.
Ginhoux, F. & Jung, S. (2014). Monocytes and macrophages: developmental pathways and tissue homeostasis. Nature Reviews Immunology 14, 392–404.
Ginhoux, F., Lim, S., Hoeffel, G., Low, D. & Huber, T. (2013). Origin and differentiation of microglia. Frontiers in Cellular Neuroscience 7, 45.
Girard, M., Ayed, Z., Preux, P.M., Bouteille, B., Preud’homme, J.L., Dumas, M. & Jauberteau, M.O. (2000). In vitro induction of nitric oxide synthase in astrocytes and microglia by Trypanosoma brucei brucei. Parasite Immunology 22, 7–12.
Girard, M., Bisser, S., Courtioux, B., Vermot-Desroches, C., Bouteille, B., Wijdenes, J., Preud’homme, J.L. & Jauberteau, M.O. (2003). In vitro induction of microglial and endothelial cell apoptosis by cerebrospinal fluids from patients with human African trypanosomiasis. International Journal for Parasitology 33, 713–720.
Girard, M., Giraud, S., Courtioux, B., Jauberteau-Marchan, M.O. & Bouteille, B. (2005). Endothelial cell activation in the presence of African trypanosomes. Molecular & Biochemical Parasitology 139, 41–49.
Goldmann, T., Wieghofer, P., Costa Jordão, M.J., Prutek, F., Hagemeyer, N., Frenzel, K., Amann, L., Staszewski, O., Kierdorf, K., Krueger, M., Locatelli, G., Hochgerner, H., Zeiser, R., Epelman, S., Geissmann, F., Priller, J., Rossi, F.M.V., Bechmann, I., Kerschensteiner, M., Linnarsson, S., Jung, S. & Prinz, M. (2016). Origin, fate and dynamics of macrophages at central nervous system interfaces. Nature Immunology
Grab, D.J., Garcia-Garcia, J.C., Nikolskaia, O.V., Kim, Y.V., Brown, A., Pardo, C.A., Zhang, Y., Becker, K.G., Wilson, B.A., de A. Lima, A.P.C., Scharfstein, J. & Dumler, J.S. (2009). Protease activated receptor signaling is required for African trypanosome traversal of human brain microvascular endothelial cells. PLoS Neglected Tropical Diseases 3, e479.
Grab, D.J. & Kennedy, P.G.E. (2008). Traversal of human and animal trypanosomes across the blood-brain barrier. Journal of NeuroVirology 14, 344–351.
Griciuc, A., Serrano-Pozo, A., Parrado, A.R., Lesinski, A.N., Asselin, C.N., Mullin, K., Hooli, B., Choi, S.H., Hyman, B.T. & Tanzi, R.E. (2013). Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 22, 631–643.
Guilliams, M., Movahedi, K., Bosschaerts, T., VandenDriessche, T., Khim Chuah, M., Hérin, M., Acosta-Sanchez, A., Ma, L., Muriel, M., Van Ginderachter, J.A., Brys, L., De Baetselier, P. & Beschin, A. (2009). IL-10 dampens TNF/inducible nitric oxide synthase-producing dendritic cell-mediated pathogenicity during parasitic infection. The Journal of Immunology 182, 1107–1118.
Gutknecht, M.F. & Bouton, A.H. (2014). Functional significance of mononuclear phagocyte populations generated through adult hematopoiesis. Journal of Leukocyte Biology 96, 969–980.
Hailer, N.P., Grampp, A. & Nitsch, R. (1999). Proliferation of microglia and astrocytes in the dentate gyrus following entorhinal cortex lesion: a quantitative bromodeoxyuridine-labelling study. European Journal of Neuroscience 11, 3359–3364.
Haniffa, M., Bigley, V. & Collin, M. (2015). Human mononuclear phagocyte system reunited. Seminars in Cell and Developmental Biology 41, 59–69.
Hashimoto, D., Chow, A., Noizat, C., Teo, P., Beasley, M.B., Leboeuf, M., Becker, C.D., See, P., Price, J., Lucas, D., Greter, M., Mortha, A., Boyer, S.W., Forsberg, E.C., Tanaka, M., van Rooijen, N., García-Sastre, A., Stanley, E.R., Ginhoux, F., Frenette, P.S. & Merad, M. (2013). Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804.
Hendriks, E., van Deursen, F.J., Wilson, J., Sarkar, M., Timms, M. & Matthews, K.R. (2000). Life-cycle differentiation in Trypanosoma brucei: molecules and mutants. Biochemical Society Transactions 28, 531–536.
Heppner, F.L., Greter, M., Marino, D., Falsig, J., Raivich, G., Hövelmeyer, N., Waisman, A., Rülicke, T., Prinz, M., Priller, J., Becher, B. & Aguzzi, A. (2005). Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nature Medicine 11, 146–152.
Hess, D.C., Abe, T., Hill, W.D., Studdard, A.M., Carothers, J., Masuya, M., Fleming, P.A., Drake, C.J. & Ogawa, M. (2004). Hematopoietic origin of microglial and perivascular cells in brain. Experimental Neurology 186, 134–144.
Hickey, M.J. & Kubes, P. (2009). Intravascular immunity: the host-pathogen encounter in blood vessels. Nature Reviews Immunology 9, 364–375.
Hoeffel, G. & Ginhoux, F. (2015). Ontogeny of tissue-resident macrophages. Frontiers in Immunology 6, 486.
Horn, D. (2014). Antigenic variation in African trypanosomes. Molecular and Biochemical Parasitology 195, 123–129.
Hu, X., Li, P., Guo, Y., Wang, H., Leak, R.K., Chen, S., Gao, Y. & Chen, J. (2012). Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43, 3063–3070.
Huitinga, I., van Rooijen, N., de Groot, C.J.A., Uitdehaag, B.M.J. & Dijkstra, C.D. (1990). Suppression of experimental allergic encephalomyelitis in lewis rats after elimination of macrophages. Journal of Experimental Medicine 172, 1025–1033.
Iwasaki, A. & Medzhitov, R. (2015). Control of adaptive immunity by the innate immune system. Nature Immunology 16, 343–353.
Izikson, L., Klein, R.S., Charo, I.F., Weiner, H.L. & Luster, A.D. (2000). Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. Journal of Experimental Medicine 192, 1075–1080.
Janeway, C.A., Travers, P., Walport, M. & Shlomchik, M.J. (2001). Antigen recognition by B-cell and T-cell receptors. In: Immunobiology: the immune system in health and disease, 5th edition (Janeway, C.A., Travers, P., Walport, M. & Shlomchik, M., Eds). Garland Science, New York, USA, pp. 110-111.
Janssen, E.M., Lemmens, E.E., Wolfe, T., Christen, U., von Herrath, M.G. & Schoenberger, S.P. (2003). CD4+ T cells are required for secondary expansion and memory CD8+ T lymphocytes. Nature 421, 852–856.
Jung, S., Aliberti, J., Graemmel, P., Sunshine, M.J., Kreutzberg, G.W., Sher, A. & Littman, D.R. (2000). Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Molecular and Cellular Biology 20, 4106–4114.
Kalla, R., Liu, Z., Xu, S., Koppius, A., Imai, Y., Kloss, C.U.A., Kohsaka, S., Gschwendtner, A., Möller, J.C., Werner, A. & Raivich, G. (2001). Microglia and the early phase of immune surveillance in the axotomized facial motor nucleus: impaired microglial activation and lymphocyte recruitment but no effect on neuronal survival or axonal regeneration in macrophage-colony stimulating factor-deficient mice. The Journal of Comparative Neurology 436, 182–201.
Kamanaka, M., Kim, S.T., Wan, Y.Y., Sutterwala, F.S., Lara-Tejero, M., Galán, J.E., Harhaj, E. & Flavell, R.A. (2006). Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 25, 941–952.
Kawai, T. & Akira, S. (2010). The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunology 11, 373–384.
Kawamoto, H. & Katsura, Y. (2009). A new paradigm for hematopoietic cell lineages: revision of the classical concept of the myeloid-lymphoid dichotomy. Trends in Immunology 30, 193–200.
Keita, M., Vincendeau, P., Buguet, A., Cespuglio, R., Vallat, J.M., Dumas, M. & Bouteille, B. (2000). Inducible nitric oxide synthase and nitrotyrosine in the central nervous system of mice chronically infected with Trypanosoma brucei brucei. Experimental Parasitology 95, 19–27.
Kennedy, P.G.E. (2004). Human African trypanosomiasis of the CNS: current issues and challenges. The Journal of Clinical Investigation 113, 496–504.
Kennedy, P.G.E. (2013). Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness). The Lancet Neurology 12, 186–194.
Kettenmann, H., Hanisch, U.K., Noda, M. & Verkhratsky, A. (2011). Physiology of microglia. Physiological Reviews 91, 461–553.
Kierdorf, K., Erny, D., Goldmann, T., Sander, V., Schulz, C., Gomez Perdiguero, E., Wieghofer, P., Heinrich, A., Riemke, P., Hölscher, C., Müller, D.N., Luckow, B., Brocker, T., Debowski, K., Fritz, G., Opdenakker, G., Diefenbach, A., Biber, K., Heikenwalder, M., Geissmann, F., Rosenbauer, F. & Prinz, M. (2013). Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nature Neuroscience 16, 273–280.
Kigerl, K.A., Gensel, J.C., Ankeny, D.P., Alexander, J.K., Donnelly, D.J. & Popovich, P.G. (2009). Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. The Journal of Neuroscience 29, 13435–13444.
Kim, J.V, Kang, S.S., Dustin, M.L. & McGavern, D.B. (2009). Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457, 191–195.
King, I.L., Dickendesher, T.L. & Segal, B.M. (2009). Circulating Ly6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 113, 3190–3197.
Klein, M.A., Möller, J.C., Jones, L.L., Bluethmann, H., Kreutzberg, G.W. & Raivich, G. (1997). Impaired neuroglial activation in interleukin-6 deficient mice. Glia 19, 227–233.
Kloss, C.U.A., Kreutzberg, G.W. & Raivich, G. (1997). Proliferation of ramified microgila on an astrocyte monolayer: characterization of stimulatory and inhibitory cytokines. Journal of Neuroscience Research 49, 248–254.
König, R. (2002). Interactions between MHC molecules and co-receptors of the TCR. Current Opinion in Immunology 14, 75–83.
Kristensson, K., Nygard, M., Bertini, G. & Bentivoglio, M. (2010). African trypanosome infections of the nervous system: parasite entry and effects on sleep and synaptic functions. Progress in Neurobiology 91, 152–171.
Kurihara, T., Warr, G., Loy, J. & Bravo, R. (1997). Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor. Jounal of Experimental Medicine 186, 1757–1762.
Langousis, G. & Hill, K.L. (2014). Motility and more: the flagellum of Trypanosoma brucei. Nature Reviews Microbiology 12, 505–518.
Lemos, K.R., Marques, L.C., Aquino, L.P.C.T., Alessi, A.C. & Zacarias Zacarias, R. (2008). Astrocytic and microglial response and histopathological changes in the brain of horses with experimental chronic Trypanosoma evansi infection. Revista do Instituto de Medicina Tropical de São Paulo 50, 243–249.
Lim, T.S., Goh, J.K.H., Mortellaro, A., Lim, C.T., Hämmerling, G.J. & Ricciardi-Castagnoli, P. (2012). CD80 and CD86 differentially regulate mechanical interactions of T-cells with antigen-presenting dendritic cells and B-cells. PLoS One 7, e45185.
Liu, K., Victora, G.D., Schwickert, T.A., Guermonprez, P., Meredith, M.M., Yao, K., Chu, F.F., Randolph, G.J., Rudensky, A.Y. & Nussenzweig, M. (2009). In vivo analysis of dendritic cell development and homeostasis. Science 324, 392–397.
London, A., Benhar, I., Mattapallil, M.J., Mack, M., Caspi, R.R. & Schwartz, M. (2013a). Functional macrophage heterogeneity in a mouse model of autoimmune CNS pathology. The Journal of Immunology 190, 3570–3578.
London, A., Cohen, M. & Schwartz, M. (2013b). Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Frontiers in Cellular Neuroscience 7, 34.
Macey, M.G. (2007). Flow Cytometry. Human Press Incorporated, Totowa, New Jersey, VSA, 290 pp.
MacLean, L., Myburgh, E., Rodgers, J. & Price, H.P. (2013). Imaging African trypanosomes. Parasite Immunology 35, 283–294.
Magez, S., Schwegmann, A., Atkinson, R., Claes, F., Drennan, M., De Baetselier, P. & Brombacher, F. (2008). The role of B-cells and IgM antibodies in parasitemia, anemia, and VSG switching in Trypanosoma brucei-infected mice. PLoS Pathogens 4, e1000122.
Magez, S., Stijlemans, B., Radwanska, M., Pays, E., Ferguson, M.A.J. & De Baetselier, P. (1998). The glycosyl-inositol-phosphate and dimyristoylglycerol moieties of the glycosylphosphatidylinositol anchor of the trypanosome variant-specific surface glycoprotein are distinct macrophage-activating factors. The Journal of Immunology 160, 1949–1956.
Malvy, D. & Chappuis, F. (2011). Sleeping sickness. Clinical Microbiology and Infection 17, 986–995.
Manaenko, A., Chen, H., Kammer, J., Zhang, J.H. & Tang, J. (2011). Comparison Evans Blue injection routes: intravenous versus intraperitoneal, for measurement of blood-brain barrier in a mice hemorrhage model. Journal of Neuroscience Methods 195, 206–210.
Mansfield, J.M. & Paulnock, D.M. (2005). Regulation of innate and acquired immunity in African trypanosomiasis. Parasite Immunology 27, 361–371.
Masocha, W. & Kristensson, K. (2012). Passage of parasites across the blood-brain barrier. Virulence 3, 202–212.
Masocha, W., Robertson, B., Rottenberg, M.E., Mhlanga, J., Sorokin, L. & Kristensson, K. (2004). Cerebral vessel laminins and IFN-γ define Trypanosoma brucei brucei penetration of the blood-brain barrier. The Journal of Clinical Investigation 114, 689–694.
Matthews, K.R. (2005). The develpmental cell biology of Trypanosoma brucei. Journal of Cell Science 118, 283–290.
McCluskey, L.P. & Lampson, L.A. (2000). Local neurochemicals and site-specific immune regulation in the CNS. Journal of Neuropathology and Experimental Neurology 59, 177–187.
McGavern, D.B. & Kang, S.S. (2011). Illuminating viral infections in the nervous system. Nature Reviews Immunology 11, 318–329.
Mellman, I. & Steinman, R.M. (2001). Dendritic cells: specialized and regulated antigen processing machines. Cell 106, 255–258.
Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. (2013). The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annual Review of Immunology 31, 563–604.
Mildner, A., Mack, M., Schmidt, H., Brück, W., Djukic, M., Zabel, M.D., Hille, A., Priller, J. & Prinz, M. (2009). CCR2+ Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132, 2487–2500.
Mildner, A., Schmidt, H., Nitsche, M., Merkler, D., Hanisch, U.K., Mack, M., Heikenwalder, M., Brück, W., Priller, J. & Prinz, M. (2007). Microglia in the adult brain arise from Ly-6C-hi CCR2+ monocytes only under defined host conditions. Nature Neuroscience 10, 1544–1553.
Miron, V.E., Boyd, A., Zhao, J.W., Yuen, T.J., Ruckh, J.M., Shadrach, J.L., van Wijngaarden, P., Wagers, A.J., Williams, A., Franklin, R.J.M. & Ffrench-Constant, C. (2013). M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nature Neuroscience 16, 1211–1218.
Mogk, S., Meiwes, A., Boßelmann, C.M., Wolburg, H. & Duszenko, M. (2014a). The lane to the brain: how African trypanosomes invade the CNS. Trends in Parasitology 30, 470–477.
Mogk, S., Meiwes, A., Shtopel, S., Schraermeyer, U., Lazarus, M., Kubata, B., Wolburg, H. & Duszenko, M. (2014b). Cyclical appearance of African trypanosomes in the cerebrospinal fluid: new insights in how trypanosomes enter the CNS. PLoS One 9, e91372.
Morioka, T., Kalehua, A.N. & Streit, W.J. (1991). The microglial reaction in the rat dorsal hippocampus following transient forebrain ischemia. Journal of Cerebral Blood Flow & Metabolism 11, 966–973.
Mosser, D.M. & Edwards, J.P. (2008). Exploring the full spectrum of macrophage activation. Nature Reviews Immunology 8, 958–969.
Movahedi, K., Laoui, D., Gysemans, C., Baeten, M., Stangé, G., Van de Bossche, J., Mack, M., Pipeleers, D., In’t Veld, P., De Baetselier, P. & Van Ginderachter, J.A. (2010). Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Research 70, 5728–5739.
Movahedi, K. & Van Ginderachter, J.A. (2016). The ontogeny and microenvironmental regulation of tumor-associated macrophages. Antioxidants and Redox Signaling.
Mulenga, C., Mhlanga, J.D.M., Kristensson, K. & Robertson, B. (2001). Trypanosoma brucei brucei crosses the blood-brain barrier while tight junction proteins are preserved in a rat chronic disease model. Neuropathology and Applied Neurobiology 27, 77–85.
Murphy, K.M. (2012). Janeway’s Immunobiology, 8th edition. Garland Science, New York, USA, 868 pp.
Naik, S.H., Perié, L., Swart, E., Gerlach, C., van Rooij, N., de Boer, R.J. & Schumacher, T.N. (2013). Diverse and heritable lineage imprinting of early haematopoietic progenitors. Nature 496, 229–232.
Namangala, B. (2011). How the African trypanosomes evade host immune killing. Parasite Immunology 33, 430–437.
Namangala, B., Noël, W., De Baetselier, P., Brys, L. & Beschin, A. (2001). Relative contribution of interferon-γ and interleukin-10 to resistance to murine African trypanosomosis. The Journal of Infectious Diseases 183, 1794–1800.
Nikolskaia, O.V., Kim, Y.V., Kovbasnjuk, O., Kim, K.J. & Grab, D.J. (2006). Entry of Trypanosoma brucei gambiense into microvascular endothelial cells of the human blood-brain barrier. International Journal for Parasitology 36, 513–519.
Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318.
Nishiyori, A., Minami, M., Ohtani, Y., Takami, S., Yamamoto, J., Kawaguchi, N., Kume, T., Akaike, A. & Satoh, M. (1998). Localization of fractalkine and CX3CR1 mRNAs in rat brain: does fractalkine play a role in signaling from neuron to microglia? FEBS 429, 167–172.
Noël, W., Hassanzadeh Ghassabeh, G., Raes, G., Namangala, B., Daems, I., Brys, L., Brombacher, F., De Baetselier, P. & Beschin, A. (2002). Infection stage-dependent modulation of macrophage activation in Trypanosoma congolense-resistant and -susceptible mice. Infection and Immunity 70, 6180–6187.
Noelle, R.J., Ledbetter, J.A. & Aruffo, A. (1992). CD40 and its ligand, an essential ligand-receptor pair for thymus-dependent B-cell activation. Immunology Today 13, 431–433.
Olivera, G.C., Ren, X., Vodnala, S.K., Lu, J., Coppo, L., Leepiyasakulchai, C., Holmgren, A., Kristensson, K. & Rottenberg, M.E. (2016). Nitric oxide protects against infection-induced neuroinflammation by preserving the stability of the blood-brain barrier. PLoS Pathogens 12, e1005442.
Onai, N. & Ohteki, T. (2014). Bipotent or oligopotent? A macrophage and DC progenitor revisited. Immunity 41, 5–7.
Parkhurst, C.N., Yang, G., Ninan, I., Savas, J.N., Yates III, J.R., Lafaille, J.J., Hempstead, B.L., Littman, D.R. & Gan, W.B. (2013). Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609.
Parkin, J. & Cohen, B. (2001). An overview of the immune system. The Lancet 357, 1777–1789.
Paul, W.E. (2011). Bridging innate and adaptive immunity. Cell 147, 1212–1215.
Pays, E. & Nolan, D.P. (1998). Expression and function of surface proteins in Trypanosoma brucei. Molecular and Biochemical Parasitology 91, 3–36.
Poltorak, M.P. & Schraml, B.U. (2015). Fate mapping of dendritic cells. Frontiers in Immunology 6, 199.
Prinz, M. & Priller, J. (2014). Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nature Reviews Neuroscience 15, 300–312.
Quan, N., Mhlanga, J.D.M., Whiteside, M.B., McCoy, A.N., Kristensson, K. & Herkenham, M. (1999). Chronic overexpression of proinflammatory cytokines and histopathology in the brains of rats infected with Trypanosoma brucei. The Journal of Comparative Neurology 414, 114–130.
Radbruch, A. (2000). Flow cytometry and cell sorting. Springer, Berlijn, Duitsland, 223 pp.
Rademakers, R., Baker, M., Nicholson, A.M., Rutherford, N.J., Finch, N., Soto-Ortolaza, A., Lash, J., Wider, C., Wojtas, A., DeJesus-Hernandez, M., Adamson, J., Kouri, N., Sundal, C., Shuster, E.A., Aasly, J., MacKenzie, J., Roeber, S., Kretzschmar, H.A., Boeve, B.F., Knopman, D.S., Petersen, R.C., Cairns, N.J., et al. (2012). Mutations in the colony stimulating factor 1 receptor (CSF1R) cause hereditary diffuse leukoencephalopathy with spheroids. Nature Genetics 44, 200–205.
Radwanska, M., Guirnalda, P., De Trez, C., Ryffel, B., Black, S. & Magez, S. (2008). Trypanosomiasis-induced B cell apoptosis results in loss of protective anti-parasite antibody responses and abolishment of vaccine-induced memory responses. PLoS Pathogens 4, e1000078.
Ransohoff, R.M. & Engelhardt, B. (2012). The anatomical and cellular basis of immune surveillance in the central nervous system. Nature Reviews Immunology 12, 623–635.
Raper, J., Nussenzweig, V. & Tomlinson, S. (1996). The main lytic factor of Trypanosoma brucei brucei in normal human serum is not high density lipoprotein. The Journal of Experimental Medicine 183, 1023–1029.
Reiner, S.L. (2007). Development in motion: helper T cells at work. Cell 129, 33–36.
Reinitz, D.M. & Mansfield, J.M. (1990). T-cell-independent and T-cell-dependent B-cell responses to exposed variant surface glycoprotein epitopes in Trypanosome-infected mice. Infection and Immunity 58, 2337–2342.
Remington, L.T., Babcock, A.A., Zehntner, S.P. & Owens, T. (2007). Microglial recruitment, activation, and proliferation in response to primary demyelination. The American Journal of Pathology 170, 1713–1724.
Reynolds, G. & Haniffa, M. (2015). Human and mouse mononuclear phagocyte networks: a tale of two species? Frontiers in Immunology 6, 330.
Rodgers, J. (2010). Trypanosomiasis and the brain. Parasitology 137, 1995–2006.
Roditi, I. & Liniger, M. (2002). Dressed for success: the surface coats of insect-borne protozoan parasites. Trends in Microbiology 10, 128–134.
Rodriguez, M., Alvarez-Erviti, L., Blesa, F.J., Rodríguez-Oroz, M.C., Arina, A., Melero, I., Ramos, L.I. & Obeso, J.A. (2007). Bone-marrow-derived cell differentiation into microglia: a study in a progressive mouse model of Parkinson’s disease. Neurobiology of Disease 28, 316–325.
Romo, M.R., Pérez-Martínez, D. & Ferrer, C.C. (2016). Innate immunity in vertebrates: an overview. Immunology 148, 125–139.
Rosas, M., Thomas, B., Stacey, M., Gordon, S. & Taylor, P.R. (2010). The myeloid 7/4-antigen defines recently generated inflammatory macrophages and is synonymous with Ly-6B. Journal of Leukocyte Biology 88, 169–180.
Rosin, D.L. & Okusa, M.D. (2011). Dangers within: DAMP responses to damage and cell death in kidney disease. Journal of the American Society of Nephrology 22, 416–425.
Schneider, A. (2001). Unique aspects of mitochondrial biogenesis in trypanosomatids. International Journal for Parasitology 31, 1403–1415.
Schultzberg, M., Ambatsis, M., Samuelsson, E.B., Kristensson, K. & van Meirvenne, N. (1988). Spread of Trypanosoma brucei to the nervous system: early attack on circumventricular organs and sensory ganglia. Journal of Neuroscience Research 21, 56–61.
Schulz, C., Perdiguero, E.G., Chorro, L., Szabo-Rogers, H., Cagnard, N., Kierdorf, K., Prinz, M., Wu, B., Jacobsen, S.E.W., Pollard, J.W., Frampton, J., Liu, K.J. & Geissmann, F. (2012). A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90.
Shechter, R., London, A. & Schwartz, M. (2013). Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nature Reviews Immunology 13, 206–218.
Shishido, S.N., Varahan, S., Yuan, K., Li, X. & Fleming, S.D. (2012). Humoral innate immune response and disease. Clinical Immunology 144, 142–158.
Simard, A.R. & Rivest, S. (2004). Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia. The FASEB Journal 18, 998–1000.
Simarro, P.P., Cecchi, G., Paone, M., Franco, J.R., Diarra, A., Ruiz, J.A., Fèvre, E.M., Courin, F., Mattioli, R.C. & Jannin, J.G. (2010). The atlas of human African trypanosomiasis: a contribution to global mapping of neglected tropical diseases. International Journal of Health Geographics 9, 57.
Skaper, S.D. (2011). Ion channels on microglia: therapeutic targets for neuroprotection. CNS & Neurological Disordorders - Drug Targets 10, 44–56.
Sternberg, J.M., Rodgers, J., Bradley, B., MacLean, L., Murray, M. & Kennedy, P.G.E. (2005). Meningoencephalitic African trypanosomiasis: brain IL-10 and IL-6 are associated with protection from neuro-inflammatory pathology. Journal of Neuroimmunology 167, 81–89.
Stijlemans, B., Guilliams, M., Raes, G., Beschin, A., Magez, S. & De Baetselier, P. (2007). African trypanosomosis: from immune escape and immunopathology to immune intervention. Veterinary Parasitology 148, 3–13.
Stijlemans, B., Leng, L., Brys, L., Sparkes, A., Vansintjan, L., Caljon, G., Raes, G., Van Den Abbeele, J., Van Ginderachter, J.A., Beschin, A., Bucala, R. & De Baetselier, P. (2014). MIF contributes to Trypanosoma brucei associated immunopathogenicity development. PLoS Pathogens 10, e1004414.
Stuart, K., Brun, R., Croft, S., Fairlamb, A., Gürtler, R.E., McKerrow, J., Reed, S. & Tarleton, R. (2008). Kinetoplastids: related protozoan pathogens, different diseases. The Journal of Clinical Investigation 118, 1301–1310.
Sunderkötter, C., Nikolic, T., Dillon, M.J., van Rooijen, N., Stehling, M., Drevets, D.A. & Leenen, P.J.M. (2004). Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. The Journal of Immunology 172, 4410–4417.
Tanaka, R., Komine-Kobayashi, M., Mochizuki, H., Yamada, M., Furuya, T., Migita, M., Shimada, T., Mizuno, Y. & Urabe, T. (2003). Migration of enhanced green fluorescent protein expressing bone marrow-derived microglia/macrophage into the mouse brain following permanent focal ischemia. Neuroscience 117, 531–539.
Taylor, J.E. & Rudenko, G. (2006). Switching trypanosome coats: what’s in the wardrobe? Trends in Genetics 22, 614–620.
Thiel, V.E. & Audus, K.L. (2001). Nitric oxide and blood–brain barrier integrity. Antioxidants & Redox Signaling 3, 273–278.
Torres-Platas, S.G., Comeau, S., Rachalski, A., Dal Bo, G., Cruceanu, C., Turecki, G., Giros, B. & Mechawar, N. (2014). Morphometric characterization of microglial phenotypes in human cerebral cortex. Journal of Neuroinflammation 11, 12.
Tremblay, M.È., Stevens, B., Sierra, A., Wake, H., Bessis, A. & Nimmerjahn, A. (2011). The role of microglia in the healthy brain. The Journal of Neuroscience 31, 16064–16069.
Trinchieri, G. (2007). Interleukin-10 production by effector T cells: Th1 cells show self control. Journal of Experimental Medicine 204, 239–243.
Turvey, S.E. & Broide, D.H. (2010). Innate immunity. Journal of Allergy and Clinical Immunology 125, S24–S32.
Ueno, N. & Lodoen, M.B. (2015). From the blood to the brain: avenues of eukaryotic pathogen dissemination to the central nervous system. Current Opinion in Microbiology 26, 53–59.
Untucht, C., Rasch, J., Fuchs, E., Rohde, M., Bergmann, S. & Steinert, M. (2011). An optimized in vitro blood-brain barrier model reveals bidirectional transmigration of African trypanosome strains. Microbiology 157, 2933–2941.
Urech, K., Neumayr, A. & Blum, J. (2011). Sleeping sickness in travelers - do they really sleep? PLoS Neglected Tropical Diseases 5, e1358.
Van Den Abbeele, J., Claes, Y., Van Bockstaele, D., Le Ray, D. & Coosemans, M. (1999). Trypanosoma brucei spp. development in tsetse fly: characterization of the post-mesocyclic stages in the foregut and proboscis. Parasitology 118, 469–478.
Van Ginderachter, J.A., Movahedi, K., Hassanzadeh Ghassabeh, G., Meerschaut, S., Beschin, A., Raes, G. & De Baetselier, P. (2006). Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. Immunobiology 211, 487–501.
Vanhamme, L. & Pays, E. (2004). The trypanosome lytic factor of human serum and the molecular basis of sleeping sickness. International Journal for Parasitology 34, 887–898.
Varol, C., Yona, S. & Jung, S. (2009). Origins and tissue-context-dependent fates of blood monocytes. Immunology and Cell Biology 87, 30–38.
Verdonk, F., Roux, P., Flamant, P., Fiette, L., Bozza, F.A., Simard, S., Lemaire, M., Plaud, B., Shorte, S.L., Sharshar, T., Chrétien, F. & Danckaert, A. (2016). Phenotypic clustering: a novel method for microglial morphology analysis. Journal of Neuroinflammation 13, 153.
Vincendeau, P. & Bouteille, B. (2006). Immunology and immunopathology of African trypanosomiasis. Anais da Academia Brasileira de Ciências 78, 645–665.
Vivier, E., Raulet, D.H., Moretta, A., Caligiuri, M.A., Zitvogel, L., Lanier, L.L., Yokoyama, W.M. & Ugolini, S. (2011). Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49.
Wang, G., Zhang, J., Hu, X., Zhang, L., Mao, L., Jiang, X., Liou, A.K.F., Leak, R.K., Gao, Y. & Chen, J. (2013). Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. Journal of Cerebral Blood Flow & Metabolism 33, 1864–1874.
Weinstein, J.S., Hernandez, S.G. & Craft, J. (2012). T cells that promote B-cell maturation in systemic autoimmunity. Immunological Reviews 247, 160–171.
Wilson, E.H., Weninger, W. & Hunter, C.A. (2010). Trafficking of immune cells in the central nervous system. The Journal of Clinical Investigation 120, 1368–1379.
Witko-Sarsat, V., Rieu, P., Descamps-Latscha, B., Lesavre, P. & Halbwachs-Mecarelli, L. (2000). Neutrophils: molecules, functions and pathophysiological aspects. Laboratory Investigation 80, 617–653.
Wolburg, H., Mogk, S., Acker, S., Frey, C., Meinert, M., Schönfeld, C., Lazarus, M., Urade, Y., Kubata, B.K. & Duszenko, M. (2012). Late stage infection in sleeping sickness. PLoS One 7, e34304.
Wraith, D.C. & Nicholson, L.B. (2012). The adaptive immune system in diseases of the central nervous system. The Journal of Clinical Investigation 122, 1172–1179.
Zhang, Y.Q., Van Neerven, R.J.J., Van Gool, S.W., Coorevits, L., De Boer, M. & Ceuppens, J.L. (1997). B7-CD28 interaction is a late acting co-stimulatory signal for human T cell responses. International Immunology 9, 1095–1102.
