title: Measles immune suppression: lessons from the macaque model.
abstract: Measles remains a significant childhood disease, and is associated with a transient immune suppression. Paradoxically, measles virus (MV) infection also induces robust MV-specific immune responses. Current hypotheses for the mechanism underlying measles immune suppression focus on functional impairment of lymphocytes or antigen-presenting cells, caused by infection with or exposure to MV. We have generated stable recombinant MVs that express enhanced green fluorescent protein, and remain virulent in non-human primates. By performing a comprehensive study of virological, immunological, hematological and histopathological observations made in animals euthanized at different time points after MV infection, we developed a model explaining measles immune suppression which fits with the "measles paradox". Here we show that MV preferentially infects CD45RA(-) memory T-lymphocytes and follicular B-lymphocytes, resulting in high infection levels in these populations. After the peak of viremia MV-infected lymphocytes were cleared within days, followed by immune activation and lymph node enlargement. During this period tuberculin-specific T-lymphocyte responses disappeared, whilst strong MV-specific T-lymphocyte responses emerged. Histopathological analysis of lymphoid tissues showed lymphocyte depletion in the B- and T-cell areas in the absence of apoptotic cells, paralleled by infiltration of T-lymphocytes into B-cell follicles and reappearance of proliferating cells. Our findings indicate an immune-mediated clearance of MV-infected CD45RA(-) memory T-lymphocytes and follicular B-lymphocytes, which causes temporary immunological amnesia. The rapid oligoclonal expansion of MV-specific lymphocytes and bystander cells masks this depletion, explaining the short duration of measles lymphopenia yet long duration of immune suppression.
authors.affiliation: Viroscience Lab, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Rory D
authors.initials: RD
authors.lastname: de Vries
authors.forename: Stephen
authors.initials: S
authors.lastname: McQuaid
authors.forename: Geert
authors.initials: G
authors.lastname: van Amerongen
authors.forename: Selma
authors.initials: S
authors.lastname: Yüksel
authors.forename: R Joyce
authors.initials: RJ
authors.lastname: Verburgh
authors.forename: Albert D M E
authors.initials: AD
authors.lastname: Osterhaus
authors.forename: W Paul
authors.initials: WP
authors.lastname: Duprex
authors.forename: Rik L
authors.initials: RL
authors.lastname: de Swart
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000821:virology; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D004195:Disease Models, Animal; D005260:Female; D005456:Fluorescent Dyes; D049452:Green Fluorescent Proteins; D006801:Humans; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D017493:Leukocyte Common Antigens / Q000276:immunology; D007970:Leukopenia / Q000276:immunology / Q000821:virology; D008212:Lymphocyte Depletion; D008221:Lymphoid Tissue / Q000276:immunology / Q000821:virology; D008251:Macaca; D008297:Male; D008457:Measles / Q000276:immunology* / Q000821:virology; D008459:Measles virus / Q000276:immunology* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D014766:Viremia / Q000276:immunology / Q000821:virology
chemical_list: D005456:Fluorescent Dyes; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D017493:Leukocyte Common Antigens