Download Can helper T-17 cells play a role in dengue haemorrhagic

Indian J Med Res 130, July 2009, pp 5-8
Editorial
Can helper T-17 cells play a role in dengue
haemorrhagic fever?
Dengue virus (DV) infection produces epidemics
of a mild acute febrile illness, dengue fever (DF)
that may progress to a life threatening severe illness,
dengue haemorrhagic fever (DHF). DHF is the most
important arbovirus disease in man and the frequency
of dengue epidemics has markedly increased with
expansion to newer geographical areas. Understanding
the factors that are involved in the pathogenesis of
DHF continues to be one of the most active area of
dengue research. It has been established that DHF is
caused by a “Cytokine Tsunami” but despite extensive
studies for over four decades, its genesis is still not
fully understood. Any time a possibility appears in the
horizon, attempt is made to fit it in the scheme of events
in DHF somewhat akin to the Indian anecdote of twelve
blind persons trying to figure out an elephant. The
mechanisms that have been considered to cause DHF
include, antibody-dependent enhancement (ADE) of
infection, dengue virus NS1-antibodies cross-reacting
with vascular endothelium (a type of autoimmune
phenomenon), immune complex disease, complement
and its products, memory T cells, various soluble
mediators including cytokines resulting in “Cytokine
Tsunami”, selection of virulent strains and virus
virulence, etc.1-5. A new entity that is knocking at the
door of DHF research is helper T cell-17 (Th17 cells)
that deserves serious consideration and investigation
both, in man and mouse infection with DV. We have
discussed here why it may be worthwhile to direct
attention of the dengue virologists/immunologists to
the Th17 cells.
secrete interferon-gamma (IFN-α), interleukin-2 (IL2) and tumour necrosis factor-beta (TNF-β) and are
responsible for cell-mediated inflammatory reactions,
delayed type hypersensitivity and tissue injury in
infections and autoimmune diseases. The Th-2 cells
secrete IL-4, IL-5, IL-6, IL-10, and IL-13 and are
associated with help for B cell antibody production.
Infections with a dominant humoral immune response
induce a higher expression of Th2-related cytokines and
those characterized by delayed type hypersensitivity
response show a higher expression of Th1 cytokines.
Th1 cells eradicate pathogens, but may also cause
immunopathology. This adverse effect is minimized by anti-inflammatory cytokine IL-10 which suppresses the
production of proinflammatory cytokines by dendritic
cells and macrophages, including IL-12, thereby
inhibiting the ability of antigen- presenting cells to induce differentiation of Th1 cells. IL-10 was originally
isolated from Th2 cells, it is now known to be produced
by many cell types, e.g., monocytes, macrophages,
dendritic cells, B cells, CD8+T cells, regulatory T
cells, Th1 cells and Th17 cells. The main role of IL10 appears to contain and suppress inflammatory
responses, thus to downregulate effector adaptive
immune responses and minimize tissue damage in
response to microbial infection3,7,8. In a number of viral
infections such as dengue, human immunodeficiency,
herpes simplex and influenza viruses, a Th1 response
is linked to recovery from infection while a Th2-type
response leads to severe pathology and exacerbation
of the disease6. The Th1-Th2 paradigm was a simple
classification that served well in a number of situations
so far but left a number of aspects unexplained.
Helper T cells
More than two decades back Mosmann et al6
classified the fully differentiated CD4+ helper T (Th)cells into two major subsets depending upon their
cytokine secretion pattern that correlated well with
the distinctive functions of these cells. The Th-1 cells
Th 17 cells
Recently, a third lineage of CD4+ helper T cells,
the Th17 cells have been described that secrete mainly
IL-17. The naïve CD4+ T cells differentiate into
INDIAN J MED RES, JULY 2009
distinct Th17 cell in response to combined signals
from transforming growth factor (TGF)-beta, IL-6, IL21, IL-1beta and IL-23. Further, IL-1alpha or IL-1beta
along with IL-23 can promote IL-17 secretion from
memory T cells. The induction/functions of Th17 cells
are regulated by cytokines secreted by the other major
subtypes of T cells, including IFN-gamma, IL-4, IL-10
and at high concentrations, TGF-beta. Fig. 1 shows the
differentiation of naïve T cell into the three different T
helper cell types i.e., Th1, Th2 and Th17, based on the
cytokine stimulus received. Th17 cells are a distinct
linage from Th1 or Th2 cells; the transcriptional factor
ROR-gt directs development of Th17 cells, while T-bet
and GATA3 induce the development of Th1 and Th2
cells, respectively, and inhibit differentiation of Th17
cells. The main function of IL-17-secreting T cells is
to mediate inflammation, by stimulating production
of inflammatory cytokines, such as TNF-alpha, IL1beta and IL-6, and inflammatory chemokines,
including CXCL-6, CXCL-7, CXCL-8, IL-8 and
monocyte chemoattractant protein-1 (MCP-1), and
metalloproteinases that promote the recruitment of
neutrophils and macrophages (recruited by Th1 cells)
resulting in inflammation and tissue pathology (Fig.
2). IL-17-producing T cells play a key role in the
pathogenesis of organ-specific autoimmune diseases,
and together with Th1 cells mediate protective
immunity to pathogens. Besides the Th17 cells, IL-17
is also secreted by CD8+T cells, χδ T cells and natural
killer T (NKT) cells7,9,10.
Th-17 cells play a role in bacterial and fungal
defense, acute inflammation, and autoimmunity6. There
is very little information on the role of Th17 cells in viral
infections. Role of Th17 cells in cornea of mice infected
with HSV-1 and infection with hepatitis C virus have
been suggested11,12. Both human immunodeficiency
virus type 1 (HIV1) and cytomegalovirus-specific IL17-producing CD4+ T cells have been detected in early
HIV-1 infection10. Pathogenic role of Th17 cells via IL17 has been suggested in persistent Theiler’s murine
encephalomyelitis virus infection and its associated
chronic inflammatory diseases13. The role of Th17
in other viral infections is not known. Here we have
examined the possibility of involvement of Th17 cells
in the pathogenesis of severe forms of dengue disease,
the DHF.
Possible role of Th17 cells in dengue disease
Th17 cells have an important role in host defence
against specific microbes and are potent inducers of
Fig. 1. Differentiation and functions of the subtypes of helper T
cells. Under the influence of different cytokines naive Th cells
differentiate into Th1, Th2 or Th17 cells. IL-12 enhances expression
of T-bet and STAT-4 and promotes development of Th1 cells.
IL-4 enhances expression of GATA-3 and STAT-6 and promotes
development of Th2 cells. TGF-beta with IL-6 or IL-21 enhances
expression of RORgt (their expansion is enhanced by IL-1 and
IL-23) and promote development of Th17 cells. IL-4 and IFN-γ
control the development of Th17 cells. STAT 6-signal transducer
and activator of transcription 6.
Fig. 2. Role of Th17 cells in inflammation and tissue damage. Th17
cells activate pro-inflammatory cytokine and chemokine production
by macrophages and epithelial cells which recruit macrophages
and neutrophils, resulting inflammation and tissue damage. MMPs,
metalloproteins; NO, nitric oxide.
autoimmunity and tissue inflammation. Implications
of autoimmunity in dengue pathogenesis have been
suggested. Antibodies against DV nonstructural protein
1 cross-react with human platelets and endothelial
cells, leading to platelet and endothelial cell damage
and inflammatory activation14. A number of cytokines
are significantly increased in patients with DHF. The
findings presented in the Table summarize the cytokines
that are raised in DHF and are also induced by the
Th17 cells. IL-17 has been shown to cause increased
GUPTA & CHATURVEDI: CAN HELPER T-17 CELLS PLAY A ROLE IN DENGUE HAEMORRHAGIC FEVER ?
Table. Comparison of cytokines that are increased in patients with DHF and induced during Th-17 cell activity
Cytokines
Dengue haemorrhagic fever
Th-17 cells
Present
References
Present
IL-6
Yes
Yes
Chaturvedi et al4
IL-8
Yes
Yes
Raghupathy et al16
Monocyte chemoattractant protein-1
Yes
Yes
Lee et al17
(MCP-1)
(GM)-CSF
Yes
Yes
Bozza et al18
Prostaglandins
Yes
Yes
Chaturvedi et al21
TNF-alpha
Yes
Yes
Chaturvedi et al4
IL-1beta
Yes
Yes
Bozza et al18
GRO- alpha
Yes
Yes
Moreno-Altamirano et al24
GM-CSF, granulocyte macrophage colony stimulating factor; GRO-a, growth regulated oncogene-alpha
secretion of IL-6, IL-8, prostaglandin E (PGE), MCP-1
and GM-CSF from fibroblasts, keratinocytes, epithelial,
endothelial and stromal cells15. IL-6 and IL-8 are IL-17
induced proinflammatory cytokines and have been seen
to have a role in pathogenesis of DHF4,5,16. Extremely
high expression of MCP-1 has been found in DHF
patients which may reduce tight junctions of vascular
endothelial cells, leading to vascular leakage seen in
DHF17. GM-CSF (granulocyte macrophage colony
stimulating factor) is raised in severe dengue illness
as compared to the mild disease and increased levels
have been well correlated with hypotension in DHF
patients18,19. Prostaglandins (PGE) are synthesized at the
sites of inflammation and acts as a potent vasodilator,
synergistically with histamine and bradykinin increase
vascular permeability resulting in oedema and inhibit
platelet aggregation20. Elevated levels of PGE have
been reported in dengue virus infection21 and may
be involved in the pathogenesis of DHF. TNF-α
induced by IL-17 causes expression of proadhesive
molecules on the endothelium, which results in
leukocyte accumulation, adhesion and migration from
capillaries22. TNF-α is significantly increased in severe
dengue disease also4. IL-17 stimulates the production
and expression of proinflammatory cytokine, IL1β by human macrophages22. This cytokine is
significantly increased in patients with severe clinical
manifestations of dengue18 and has a potential role in
apoptosis23. Growth regulated oncogene-α (GRO-α) is
a proinflammatory cytokine contributing to neutrophil
recruitment at the site of inflammation.Transcripts of
GRO- α are raised during infection with any of the
four serotypes of dengue virus infection24 and is also
induced by IL-1725.
As discussed above and depicted in the Table,
Th17 cells through secretion of IL-17 seem to have a
very strong potential role in the pathogenesis of severe
dengue disease by inducing several cytokines (Cytokine
References
Fossiez et al15
Fossiez et al15
Fossiez et al15
Numasaki et al19
Fossiez et al15
Jovanovic et al22
Jovanovic et al22
Witowski et al25
Tsunami). It is very important to understand the exact role
of these cells in the pathogenesis of DHF to understand
the entire mechanism of the disease, mechanism
behind switch from Th1 to Th2 cytokine response and
development of DHF in some patients as compared to
simple dengue fever in the others. The first study that
described shift fromTh1 response in mild dengue fever
to Th2 response in severe DHF showed the about 30 per
cent of the patients were indeterminate and could not be
placed in either Th1 or Th2 response4,26. Similarly, there
are a number of findings, which could not be explained
on the basis of the two Th1, and Th2 subtypes6. The
discovery of Th17 cells has led to a shift in the Th1-Th2
paradigm and has helped to explain some anomalies in
the original model. DHF is a multifactorial syndrome of
capillary leakage due to ‘Cytokine Tsunami’. The results
of various studies are not mutually exclusive. There is
a need of unifying all the known factors. Attempt has
been made in this direction recently5. Still there are lots
of loose ends that need to be tied up. Future studies may
clarify our understanding.
Acknowledgment
Prof. UCC acknowledges the financial assistance by the
Indian National Science Academy, New Delhi, as INSA Honorary
Scientist.
Nivedita Gupta & U.C. Chaturvedi*
Division of Epidemiology & Communicable Diseases
Indian Council of Medical Research
Ansari Nagar, New Delhi
& *INSA Honorary Scientist
201-Annapurna Apartments
No.1, Bishop Rocky Street
Faizabad Road
Lucknow 226 007, India
*
For correspondence:
[email protected]
[email protected]
INDIAN J MED RES, JULY 2009
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