Proinflammatory cytokines and chemokines in humans with Japanese encephalitis.
BACKGROUND
Japanese encephalitis virus (JEV), the mosquito-borne flavivirus, annually causes an estimated 35,000-50,000 encephalitis cases and 10,000-15,000 deaths in Asia, and there is no antiviral treatment. The role played by the immune response in determining the outcome of human infection with JEV is poorly understood, although, in animal models of flavivirus encephalitis, unregulated proinflammatory cytokine responses can be detrimental.


METHODS
We studied the innate, cellular, and humoral immune responses in 118 patients infected with JEV, of whom 13 (11%) died.


RESULTS
Levels of interferon (IFN)- alpha , the proinflammatory cytokine interleukin (IL)-6, and the chemokine IL-8 were all higher in the cerebrospinal fluid (CSF) of the nonsurvivors than of the survivors (P=.04, P=.006, and P=.04, respectively), as were both the IL-6 : IL-4 ratio in CSF (a marker of the balance of pro- and anti-inflammatory cytokines) and the level of the chemokine RANTES (regulated on activation, normally T cell expressed and secreted) in plasma (P=.03). In contrast, levels of immunoglobulin (Ig) M and IgG in CSF and of IgM in plasma were higher in the survivors (P=.035, P=.003, and P=.009, respectively). Levels of IFN- gamma and nitric oxide did not vary with outcome.


CONCLUSIONS
During JEV infection, elevated levels of proinflammatory cytokines and chemokines are associated with a poor outcome, but whether they are simply a correlate of severe disease or contribute to pathogenesis remains to be determined.
Department of Neurological Science, University of Liverpool, United Kingdom.
Peter M
PM
Winter
Nguyen Minh
NM
Dung
Ha Thi
HT
Loan
Rachel
R
Kneen
Bridget
B
Wills
Le Thi
le T
Thu
Deborah
D
House
Nicholas J
NJ
White
Jeremy J
JJ
Farrar
C Anthony
CA
Hart
Tom
T
Solomon
D000293:Adolescent; D000328:Adult; D000368:Aged; D018946:Chemokine CCL5 / Q000097:blood / Q000134:cerebrospinal fluid; D018925:Chemokines / Q000032:analysis* / Q000097:blood / Q000134:cerebrospinal fluid; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000032:analysis* / Q000097:blood / Q000134:cerebrospinal fluid; D004672:Encephalitis, Japanese / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000134:cerebrospinal fluid; D007075:Immunoglobulin M / Q000097:blood / Q000134:cerebrospinal fluid; D007223:Infant; D016898:Interferon-alpha / Q000097:blood / Q000134:cerebrospinal fluid; D007371:Interferon-gamma / Q000097:blood / Q000134:cerebrospinal fluid; D007378:Interleukins / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood / Q000134:cerebrospinal fluid; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid; D014744:Vietnam
D018946:Chemokine CCL5; D018925:Chemokines; D016207:Cytokines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016898:Interferon-alpha; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma