A molecular mimicry

occurs between platelets/endothelial cells and dengue virus antigens. Platelets and
endothelial cells are
bound by the cross-reactive anti-dengue virus antibodies such as anti-NS1 or anti-prM
antibodies
It is characteried by
biphasic !ever" myalgia" headache" pain in various parts
o! the body" rash" lymphadenopathy" and leucopenia
Not all #$%/#SS cases are secondary in!ections.
Although most o! the #$%/#SS in children are
secondary in!ection" but the #$%/#SS in in!ants are
primary in!ection. &omplement activation may be the
result o! severe disease" not the cause o! #$%/#SS.
#$% develops rapidly" usually over a period o! hours"
and resolves within 1 to ' days in patients who receive
appropriate (uid resuscitation.
Pato)siologi
#engue virus in!ection causes aberrant immune
responses. *hese aberrant immune responses not only
impair the immune response to clear the virus" result in
overproduction o! cyto+ines" as well as abnormal
production o! autoantibodies. *he aberrant generation
o! anti-NS1 antibodies that cross-react with platelet or
endothelial cells initiates the subse,uent development
o! dengue disease. Anti-platelet or anti-endothelial cell
autoantibodies must be involved in the clinical
mani!estation o! thrombocytopenia and endothelial cell
dys!unction. #engue virus in!ection-caused endothelial
damage and bleeding also contribute to the hemorrhage"
and the imbalance between coagulation and )brinolysis
activation increases the li+elihood o! severe
hemorrhage in #$%/#SS. $emostasis is maintained
unless the dysregulation o! coagulation and )brinolysis
persists.
Immunopathogenesis
Immunopathogenesis in dengue hemorrhagic !ever
has been proposed-1."1/0. Serotype cross-reactive
antibodies !rom the previous in!ection bind to virions
without neutraliation and enhance the entry o! virus
into monocytes. *he number o! virus-in!ected
monocytes increases. As a result" the level o! dengue
virus-speci)c * cell activation is mar+edly enhanced.
*he * cells" especially the cross-reactive * cells"
produce cyto+ines such as I%N-g" I1-' and *N%a and
lyse dengue virus-in!ected monocytes. *N%a is also
produced by activated monocytes. *he complement
cascade is activated by a virus-antibody comple2 as
well as by several cyto+ines to release &3a and &.a
which also have direct e4ects on vascular permeability.
*he synergistic e4ects o! I%N-g" *N%a and activated
complement proteins trigger plasma lea+age o!
endothelial cells in secondary dengue virus in!ection.
#engue !ever
is an acute !ebrile illness
with headache" retro-orbital pain" myalgia" arthralgia"
rash" leu+openia and mild thrombocytopenia. 5iphasic
!ever 6!ever then no !ever !or !ew days then again !ever7
and rash are the most characteristic !eatures o!
classic dengue !ever. Symptoms resolve a!ter ' to
8 days.
#engue hemorrhagic !ever
is an acute vascular
permeability syndrome accompanied by abnormalities
in hemostasis. *he clinical !eatures include plasma
lea+age" bleeding tendency" and liver involvement-1"'0.
&apillary lea+age develops rapidly over a period o!
hours" near or at the end o! the !ebrile period when the
symptoms o! classic #% resolve. Pleural e4usion"
ascites" and hemoconcentration are indicative o!
intravascular volume loss. It can ,uic+ly progress to
shoc+ i! patients do not receive intravascular (uid
resuscitation. *he hemorrhagic mani!estations range !rom a positive tourni,uet test to
spontaneous bleeding
!rom the nose or the gastrointestinal tract.
$emoconcentration and mar+ed thrombocytopenia are
two ma9or characteristic !eatures o! #$%/#SS. 1iver
involvement is common in dengue virus in!ection
with mild elevation o! serum transaminases.
Ample
studies demonstrate that dengue virus can in!ect a
variety o! human primary cells including
monocytes/macrophages" dendritic cells" 5 cells"
hepatocytes" :up4er cells and cell lines o! endothelial
and epithelial origin. $owever" these in vitro in!ections
are modulated by the cell type and viral strain-1;0.
*here!ore" damage or dys!unction o! these cells or
organs induced by dengue virus in!ection" either
directly or indirectly is responsible !or the progressive
development o! #$%/#SS.
anti-platelet and antiendothelial
cell IgM or Ig<
%urther studies showed that the
platelet or endothelial cell binding activities were
inhibited by pretreatment with dengue virus
nonstructural protein 1 6NS17.
A molecular mimicry
between the dengue virus and endogenous sel!-proteins
was proposed to be one o! the mechanisms !or the
induction o! autoimmunity during dengue virus
in!ection.
Dengue virus-induced vasculopathy:
*he most
characteristic !eature o! #$%/#SS and the best
indicator o! disease severity is plasma lea+age. Plasma
lea+age is caused by a di4use increase in capillary
permeability and mani!ests as any combination o!
hemoconcentration" pleural e4usion" or ascites. It
usually becomes evident on days 3-8 o! illness" during
which time dengue !ever resolve-1"'0. Plasma lea+age
occurs systemically" progressing ,uic+ly" but will
resolve within 1 to ' days in patients who receive
appropriate (uid resuscitation
No subse,uent tissue or
organ dys!unction is observed. Although perivascular
edema is obvious" no obvious destruction o! vascular
endothelial cells has been reported. It was previously
thought that plasma lea+age was due to altered vascular
permeability rather than to structural destruction o!
endothelial cells. *he !unctional alteration o!
endothelial cells is probably caused via by-standard
e4ects o! cyto+ine or mediator release in dengue
in!ection.=================== 6I1-/" I1-; and
>AN*?S
1. @e have reported that the anti-NS1 antibodies can
cross-react with non-in!ected endothelial cells and
induce these cells to undergo apoptosis7
'. #engue virus-in!ected endothelial cells are capable
o! activating complement and inducing the e2pression
o! adhesion molecules such as I&AM-1-AA0. *he
e2pression o! I&AM-1 together with the production o!
chemo+ines I1-; and >AN*?S increases the adherence
o! polymorphonuclear cells and mononuclear cells"
respectively" and results in increased vasopermeability
and thrombomodulin 6is an integral membrane protein expressed on the
surface of endothelial cells -- induced activation of protein C in the
anticoagulant pathway by forming a 1:1 stoichiometric complex with
thrombin. 7 release" a mar+er o! endothelial
cell damage.
It seems that both direct viral cytopathic
e4ects and immune mediated damage by leu+ocyte
recruitment can cause structural in9ury to in!ected
endothelial cells
*his vascular lea+age can be induced
either directly or indirectly during dengue virus
in!ection.
Moreover" although the endothelial cell
sur!ace molecules that are recognied by these
autoreactive antibodies need to be identi)ed" a crossreactivity
e2ists between endothelial cells and dengue
virus antigens due to the molecular mimicry.
*he
endothelial cells do not need to be in!ected by dengue
virus to be targeted. *he cross-reactive anti-dengue
antibody such as anti-NS1 or anti-prM can bind to the
un-in!ected endothelial cells to cause its damage.
5ecause endothelium plays a crucial role in maintaining
hemostasis" damage o! endothelial cells during dengue
virus in!ection may s+ew the procoagulant/
anticoagulant balance o! endothelium and increase the
bleeding tendency.
*he se,uestration o! platelets by
activated endothelial cells might also contribute to the
development o! thrombocytopenia.
&oagulopathy
#uring acute dengue virus in!ection" coagulation
parameters such as platelet counts" activated partial
thromboplastin time 6AP**7 as well as )brinolytic
parameters o! tPA and PAI-1 are altered. AP** is
prolonged while tPA increases. 5oth coagulation and
)brinolysis are activated" and this activation is much
more severe in #$%/#SS than in #% patients. A!ter
convalescence" rises in the PAI-1 level and platelet
counts are concomitant with the decline in the tPA level
and a return to normal o! AP**. *he tPA/PAI-1 ratio is
higher in #$%/#SS than in #% patients. AP**
prolongation and tPA/PAI-1 ratio increase in the acute
stage o! dengue virus in!ection correlate with disease
severity and can be used as early indicators o!
#$%/#SS-A8
AP**
prolongation and tPA/PAI-1 ratio increase in the acute
stage o! dengue virus in!ection correlate with disease
severity and can be used as early indicators o!
#$%/#SS-A80