Neuroinvasion by a Creutzfeldt-Jakob disease agent in the absence of B cells and follicular dendritic cells

被引:35
作者
Shlomchik, MJ [1 ]
Radebold, K [1 ]
Duclos, N [1 ]
Manuelidis, L [1 ]
机构
[1] Yale Univ, Sch Med, Dept Surg, Sect Neuropathol, New Haven, CT 06510 USA
关键词
prion; amyloid; peripheral spread; immunoglobulin; myeloid cells;
D O I
10.1073/pnas.161055198
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
With the potential spread of bovine spongiform encephalopathy to people as a variant Creutzfeldt-Jakob disease (CJD), it becomes critical to identify cells in the periphery that carry infection. Initial work with scrapie agents suggested that B cells were central vectors for neuroinvasion. Subsequent studies indicated that B cells played an indirect role by promoting the development of follicular dendritic cells (FDCs) that accumulate abnormal prion protein (PrP). The mechanism for the role of FDCs, however, has not been clear. To further dissect potential B cell functions that contribute to neuroinvasion, we inoculated a CJD agent into mutant mice that (i) lacked B cells, (ii) had B cells unable to secrete Ig, or (iii) could secrete only IgM. Remarkably, all these mice developed disease with practically indistinguishable incubation times. The demonstration that neither immune complexes nor B cells were required for neuroinvasion from the periphery mandates a reanalysis of the accepted view of the essential role of B cells and FDC in these infections. Moreover, immune complexes were not required for the accumulation of pathologic PrP on the surface of FDCs, suggesting that PrP can bind to FDCs autonomously or by means of another factor. Wild-type mice had incubation times approximate to 50 days less than all mutant mice at the same peripheral doses, indicating that an intact immune system may increase agent uptake and delivery, but this condition is not essential. Specifically, the evidence to date suggests that IgG may enhance pivotal agent interactions with migratory myeloid cells.
引用
收藏
页码:9289 / 9294
页数:6
相关论文
共 32 条
[1]   Microglial activation varies in different models of Creutzfeldt-Jakob disease [J].
Baker, CA ;
Lu, ZY ;
Zaitsev, I ;
Manuelidis, L .
JOURNAL OF VIROLOGY, 1999, 73 (06) :5089-5097
[2]   Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells [J].
Brown, KL ;
Stewart, K ;
Ritchie, DL ;
Mabbott, NA ;
Williams, A ;
Fraser, H ;
Morrison, WI ;
Bruce, ME .
NATURE MEDICINE, 1999, 5 (11) :1308-1312
[3]   Follicular dendritic cells in TSE pathogenesis [J].
Bruce, ME ;
Brown, KL ;
Mabbott, NA ;
Farquhar, CF ;
Jeffrey, M .
IMMUNOLOGY TODAY, 2000, 21 (09) :442-446
[4]   A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus [J].
Chan, OTM ;
Hannum, LG ;
Haberman, AM ;
Madaio, MP ;
Shlomchik, MJ .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 189 (10) :1639-1647
[5]   IMMUNOGLOBULIN GENE REARRANGEMENT IN B-CELL DEFICIENT MICE GENERATED BY TARGETED DELETION OF THE J(H) LOCUS [J].
CHEN, JZ ;
TROUNSTINE, M ;
ALT, FW ;
YOUNG, F ;
KURAHARA, C ;
LORING, JF ;
HUSZAR, D .
INTERNATIONAL IMMUNOLOGY, 1993, 5 (06) :647-656
[6]   CHEMOPROPHYLAXIS OF SCRAPIE IN MICE [J].
DIRINGER, H ;
EHLERS, B .
JOURNAL OF GENERAL VIROLOGY, 1991, 72 :457-460
[7]   SUSTAINED VIREMIA IN EXPERIMENTAL HAMSTER SCRAPIE [J].
DIRINGER, H .
ARCHIVES OF VIROLOGY, 1984, 82 (1-2) :105-109
[8]   PATHOGENESIS OF SCRAPIE VIRUS INFECTION IN MOUSE [J].
EKLUND, CM ;
KENNEDY, RC ;
HADLOW, WJ .
JOURNAL OF INFECTIOUS DISEASES, 1967, 117 (01) :15-&
[9]   Scrapie pathogenesis in subclinically infected B-Cell-deficient mice [J].
Frigg, R ;
Klein, MA ;
Hegyi, I ;
Zinkernagel, RM ;
Aguzzi, A .
JOURNAL OF VIROLOGY, 1999, 73 (11) :9584-9588
[10]   Organogenic role of B lymphocytes in mucosal immunity [J].
Golovkina, TV ;
Shlomchik, M ;
Hannum, L ;
Chervonsky, A .
SCIENCE, 1999, 286 (5446) :1965-1968