attique article
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Asthma and IL-17
Introduction: For the last two decades there has been great interest in cytokines specifically IL-17 in
the pathogenesis of Asthma. It has been the subect of possible therapeutic inter!ention. "hough most
of the research has been conducted in murine and mice models# the potential for inter!ention in
humans is unbound. "his re!iew takes into account the work done till now and the proections into the
future.
Discussion
Asthma affects nearly $%% million people and one of e!ery &'% deaths is attributed to this disease
worldwide. "he cost of asthma hospitali(ations# emergency room !isits# lost school# and workdays is
significant. Asthma is a common airway disorder that is characteri(ed by chronic airway
inflammation# mucus production# and airway hyper responsi!eness )A*+, with airway
remodelling)1,. umerous triggers can induce bronchoconstriction# including allergic responses#
respiratory infections# eercise# irritants# and non-steroidal anti-inflammatory drugs in select
patients)&,.Accumulating e!idence indicates that antigen-specific "h& cells and their cytokines such
as IL-/# IL-'# IL-1$ and IL-17-producing 0/
" cells )"h17 cells, and IL-&$# an IL-1&-related
cytokine that is essential for sur!i!al and functional maturation of "h17 cells# are in!ol!ed in antigen-
induced airway inflammation)$,.
New Paradigm
"he " helper 1 )"h1, cell and "h& cell paradigm# first proposed by 2osmann and 0offman# has been
used to eplain how hosts elicit different adapti!e immune responses to eradicate the e!asion of
!arious pathogens)/,. 3pon first encounter of foreign antigens presented by antigen-presenting cells
)A40s,# na56!e0/ " cells can differentiate into either interferon-g )IF-g,-producing"h1 cells or
IL-/-producing "h& cells# and this differentiation is largely controlled by !arious en!ironmental
factors# especially by signals coming directly from A40s)',. 3ncontrolled and persistent effector "
cell responses# howe!er# can dri!e the onset of autoimmunity# allergy# or atopy. 8!idence from clinical
obser!ations and from studies on eperimental animals supports the idea that uncontrolled "h& cell
responses# as well downstream cytokines IL-/# IL-'# and IL-1$# are underlying the de!elopment of
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atopic diseases# such as asthma)9# 7,. n allergen sensiti(ation# "h17 cells home to the lung and
enhance not only neutrophilic airway inflammation but also "h& cell-mediated eosinophilic airway
inflammation in mouse models of asthma);,. "hese obser!ations ha!e indicated that in!estigation of
the differentiation# effector function# and regulation of "h17 cells may offer a new way to control
asthma)
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inflammation)1',.
Interleukin 17 up regulates a di!erse set of cytokines# chemokines# adhesion
molecules# and growth factors.It has also been shown that IL-17A is epressed in the airways of
asthmatic patients and its epression is correlated with the se!erity of asthma) 19,. IL-17A has also
been shown to stimulate bronchial fibroblasts# epithelial cells# and smooth muscle cells and induce the
epression of a !ariety of cytokines and chemokines# which are important for granulopoiesis and
neutrophil recruitment )1;,. "he IL-/?IL-1$ signalling pathway accounts for the symptoms
eperienced by a subset of se!ere asthmatics with allergen-associated symptoms and high serum
immunoglobulin 8 )Ig8, le!els# and these patients are generally responsi!e to anti-Ig8 treatment. "he
IL-'?IL-$$ signalling pathway is likely to play a key role in the disease pathogenesis of those who are
resistant to high doses of inhaled corticosteroid but responsi!e to systemic corticosteroids and anti-
IL' therapy)17,.
Neutrophil Migration
"he ability of IL-17A to e!oke migration of neutrophils makes it likely that IL-17A is in!ol!ed in
se!ere asthma# of which neutrophil infiltration is one of the hallmarks. IL-17 appears to be an
important mediator of inflammation# especially in neutrophil-dominated responses to bacterial
challenge)1;,. "his connection is intriguing gi!en that epression of IL-17 is restricted to memory "
cells# which are associated with an adapti!e immune response# while neutrophils are !iewed primarily
as mediators of innate immunity)1uently induces chemokines and granulopoietic factors# memory " cells may enhance faster and
more effecti!e recruitment of neutrophils. In this respect IL-17 may ser!e as a modulator of early
immune responses to pathogens# and as such may be an important element of host defence. n the
other hand# the o!erproduction of IL-17 may aggra!ate inflammatory reactions and contribute to
tissue inury)&%,. @omewhat surprisingly# the IL-17 m+A le!els correlate positi!ely with the IL-'
m+A le!els in sputum from asthmatic patients)&1#&&,.=oth in plasma and in acti!ated peripheral
blood mononuclear cells from allergic asthmatics# the increase in IL-17 concentration is accompanied
by the enhanced concentration of IL-&$# which is a critical regulator of IL-17. In addition# an increase
in transcription factor ++t le!el is found in allergic asthmatics. "hese findings indicate that
increased epression of IL-&$ and ++t may contribute to the increase in IL-17 epression in
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effect on neutrophil recruitment# IL-17 can eert an indirect stimulatory effect on neutrophil acti!ity
in the airways. It is likely that IL-17 acti!ates airway neutrophils through the induced release of
neutrophil-acti!ating cytokines# such as IL-9 and IL-;# which are known to be released from the
bronchial epithelium and fibroblasts by IL-17)$/,. Interestingly# IL-1b# another cytokine that is
increased in obstructi!e airways disease does potentiate the stimulatory effect of IL-17 on neutrophil
acti!ation)$',. It can be speculated that IL-17 stimulates the release of IL-1b from airway
macrophages and that this IL-1b potentiates the IL-17-induced release of IL-9 and IL; in bronchial
epithelial cells. In short "he IL-17 signaling pathway is thought to contribute to Eneutrophilic
asthmaE)17,.
IL-17 and osinophils
"hese results ha!e suggested that IL-17 has a dual role in the regulation of eosinophilic airway
inflammation in asthma. "hus# IL-17 promotes eosinophilic airway inflammation by mounting "h&
responses during antigen sensiti(ation while inhibiting eosinophilic airway inflammation by acting as
a down-regulator of the dendritic cell-deri!ed "h& chemoattractant "A+0 during the effector phase
)$9, . *owe!er# more recent studies ha!e reported that administration of anti-IL-17 Ab to A-
inhaled mice in the challenge phase reduces antigen- induced airway infiltration of eosinophil
and "h& cytokine le!els in =AL fluids by using different sensiti(ation and challenge protocols)$7, .
In addition# an enhancing effect of IL-17 on 00L11 m+A epression and protein release in
human airway smooth muscle cells has been reported . 2oreo!er# IL-17 acti!ates F-G= pathway
that can subse>uently induce 00L11 and "A+0 epression# suspecting the presence of an indirect
regulatory pathway )$;,. "hese obser!ations suggest that IL-17 is associated with "h& cell-mediated
eosinophilic inflammation in asthma. IL-17 seems to contribute to neutrophilic inflammation as well
as "h& cell-mediated and eosinophilic inflammation in asthma)$
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Figure no 1: "he many pathways to asthma)//,
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Figure no &: "he +ole of "h& Immune 4athway 2odulation in the "reatment of @e!ere
Asthma and Its 4henotypes)/',
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Figure $: "he pathogenesis of Asthma)/9,
Figure /: