attique article

8/9/2019 Attique Article

1/12

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


2/12

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)


3/12

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


4/12


5/12

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)$


6/12


7/12

+eferences :

1. Afshar R, Medo BD, Luster AD. Allergic asthma: a tale of many T cells.Clinical and e!erimental allergy : "ournal of the British #ociety for Allergy andClinical $mmunology. %&&'()'*1%+:1'-/-.%. 0ing M, 2anania 3A. Asthma in the elderly: current 4no5ledge and futuredirections. Current o!inion in !ulmonary medicine. %&1&(16*1+://7.). 2ans8ro 9M, 0ai4o ;, eltreatments for asthma? British "ournal of !harmacology. %&11(16)*1+:'17/.. #canlon #T, Mc0en@ie A3. Ty!e % innate lym!hoid cells: ne5 !layers inasthma and allergy. Current o!inion in immunology. %&1%(%*6+:-&-1%.

/. 2eier $, Malmstrom 0, 9el4onen A#, Malm8erg L9, 0a"osaari M, Tur!einenM, et al. Bronchial res!onse !attern of antigen !resenting cells and regulatory Tcells in children less than % years of age. Thora. %&&'(6)*'+:-&)7.6. 0lein olterin4 R, 2endri4s R. Ty!e % innate lym!hocytes in allergicair5ay inammation. Current allergy and asthma re!orts. %&1)(1)*)+:%-1'&.-. hou , McLane M, Le>itt RC. Th% cyto4ines and asthma. $nterleu4in7 as athera!eutic target for asthma. Res!iratory research. %&&1(%*%+:'&.'. 0a5aguchi M, 0o4u8u


8/12

1/. Louten , Boniface 0, de aal Malefyt R. De>elo!ment and function ofT21- cells in health and disease. The ournal of allergy and clinical immunology.%&&7(1%)*/+:1&&11.16. 9u4elsheim 0, #toeger T, 0utsch4e D, anguly 0, "st M. Cyto4ine !roJlesin asthma families de!end on age and !henoty!e. 9lo# one. %&1&(/*1%+:e1%77.1-. 9oon A2, ;idelman D2, Martin , La!rise C, 2amid F. 9athogenesis ofse>ere asthma. Clinical and e!erimental allergy : "ournal of the British #ocietyfor Allergy and Clinical $mmunology. %&1%(%*/+:6%/)-.1'. #erge"e>a #, Linden A. $m!act of $L1- on cells of the monocyte lineage inhealth and disease. ;ndocrine, meta8olic E immune disorders drug targets.%&&7(7*%+:1-''6.17. 9ur5ar R, Cam!8ell , Mur!hy , Richards , Clar4 RA, 0u!!er T#.Resident memory T cells *T*RM++ are a8undant in human lung: di>ersity, function,and antigen s!eciJcity. 9lo# one. %&11(6*1+:e16%/.%&. 2i@a5a 3, 0a5aguchi M, 2uang #0, 3ishimura M. Role of interleu4in1-< inchronic inammatory and allergic lung disease. Clinical and e!erimentalallergy : "ournal of the British #ociety for Allergy and Clinical $mmunology.

%&&6()6*7+:11&71.%1. #un C, hou FT, ao . #!utum interleu4in1- is increased andassociated 5ith air5ay neutro!hilia in !atients 5ith se>ere asthma. Chinesemedical "ournal. %&&/(11'*11+:7/)6.%%. Bullens DM, Truyen ;, Coteur L, Dilissen ;, 2ellings 9, Du!ont L, et al. $L1- mR3A in s!utum of asthmatic !atients: lin4ing T cell dri>en inammation andgranulocytic inu? Res!iratory research. %&&6(-:1)/.%). #u@u4a5a M, Morita 2, 3am8u A, Arae 0, #himura ;, #hi8ui A, et al.;!ithelial cellderi>ed $L%/, 8ut not Th1- cellderi>ed $L1- or $L1-


9/12

)1. 2am@aoui A, Maalmi 2, Berraies A, A8id 2, Ammar , 2am@aoui 0.Transcri!tional characteristics of CD T cells in young asthmatic children: RGRCand es #L, Donnelly L;. Th1- cells in air5ay diseases. Current molecularmedicine. %&&'('*/+:16%6.)). Matsunaga 0. The utility of ehaled 8reath condensate analysis forasthma management. Rinsho 8yori The a!anese "ournal of clinical !athology.%&&-(//*+:)-/'&.). hou FT, #un C, ao . Characteristics of the air5ay inammation andthe relationshi! to interleu4in1- in se>ere asthma. honghua "ie he he hu i @a@hi N honghua "iehe he hui @a@hi N Chinese "ournal of tu8erculosis andres!iratory diseases. %&&/(%'*7+:6)&.)/. Besnard A, Tog8e D, Couillin $, Tan , heng #, ;rard e #, La"oie0adoch #, Audusseau #, Rothen8erg M;, e immunity. 3ature immunology. %&1&(11*-+:/--'./. Mishra A, ao P, Le>ine #. ere asthma. Disease models E mechanisms.%&1)(6*+:'--''.6. 2olgate #T. A loo4 at the !athogenesis of asthma: the need for a change indirection. Disco>ery medicine. %&1&(7*'+:)7-.


10/12

Figure no 1: "he many pathways to asthma)//,


11/12

Figure no &: "he +ole of "h& Immune 4athway 2odulation in the "reatment of @e!ere

Asthma and Its 4henotypes)/',


12/12

Figure $: "he pathogenesis of Asthma)/9,

Figure /:

attique article

Documents