patterson's allergic diseases (6ed, 2002)(509s)

8/18/2019 Patterson's Allergic Diseases (6ed, 2002)(509s)

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EditorsLesl ie C . Grammer M.D .Pro fessor o f Med ic ineDepar tment o f Med ic ine ; V ice Ch ie f , D iv i s ion o f A l le rgy - Immuno logy ; D i rec to r , Ernes t S.Baz ley As thma and A l le rg ic D iseases Center , Nor thwes te rn Un ivers i t y Med ica l Schoo l ;

A t t end ing Phys ic ian , Nor thwes te rn Memor ia l Hospi ta l , Ch icago, I l l i no is

Paul A . Greenberger M.D .Pro fessor o f Med ic ineDepar tment o f Med ic ine ; Assoc ia te Ch ie f , Educa t ion and C l in i ca l A f fa i rs , D iv i s ion o f A l le rgy -

Immuno logy , Nor thwes te rn Un ivers i t y Med ica l Schoo l ; A t tend ing Phys ic ian , Nor thwes te rnMemor ia l Hosp i ta l , Ch icago, I l l i no is

Contributing AuthorsHoward L . A l t M.D .

Ass is tan t Pro fe sso r of C l in i ca l Med ic ineDepar tment o f Psych ia t ry , Nor thwes te rn Un ivers i t y Med ica l Schoo l , Ch icago, I l l i no is

Andrea J . Apter M.D . , M.Sc.Chie f ; Assoc ia te Pro fessorDepar tment o f A l le rgy and Immuno logy , D iv i s ion o f Pu lmonary , A l le rgy , and Cr i t i ca l Care ,Hosp i ta l o f the Un ivers i t y o f Pennsy lvan ia , Un ivers i t y o f Pennsy lvan ia Schoo l o f Med ic ine ,Ph i lade lph ia , Pennsy lvan ia

Banani Baner jee Ph.D .Ins t ruc to r o f Ped ia t r i cs (A l le rgy / Immuno logy ) and Med ic ineMedica l Co l lege o f Wiscons in , M i lwaukee, Wiscons in

Melv in Berger M.D . Ph.D .

Pro fessorDepar tments o f Ped ia t r i cs and Patho logy , Case Wes tern Reserve Un ivers i t y ; Ch ie f ,Depar tment o f Ped ia t r i cs , Ra inbow, Bab ies and Ch i ld ren 's Hosp i ta l , Un ivers i t y Hosp i ta l sHea l th Sys tem, C leve land , Oh io

David I . Bernste in M.D .Pro fessor o f Med ic ineDepar tment o f Immuno logy , Un ivers i t y o f C inc inna t i Co l lege o f Med ic ine , C inc inna t i , Oh io

Jonathan A . Bernste in M.D . Asso cia te ProfessorDepar tment o f In te rna l Med ic ine , Un ivers i t y o f C inc inna t i , C inc inna t i , Oh io

Michael S. B la iss M.D .Cl in i ca l Pro fessorDepar tments o f Ped ia t r i cs and Med ic ine , Un ivers i t y o f Tennessee, Memph is , Depar tment o fPed ia t r i cs , Le Bonheur Ch i ld ren 's Med ica l Center , Memph is , Tennessee

Bernard H . Booth I I I M.D .Cl in i ca l Pro fessor

Depar tment o f Med ic ine , Un ivers i t y o f M iss iss ipp i Med ica l Center , Jackson, M iss iss ipp i

G. Danie l Brooks M.D .Depar tment o f Med ic ine , Un ivers i t y o f Wiscons in , Depar tment o f Med ic ine , Un ivers i t y o fWiscons in Hosp i ta l s and C l in i cs , Mad ison , Wiscons in

Robert K . Bush M.D .Pro fessorDepar tment o f Med ic ine , Un ivers i t y o f Wiscons in -Mad ison ; Ch ie f , Depar tment o f A l le rgy ,Wi l l i am. S. M idd le ton V.A. Hosp i ta l , Mad ison , Wiscons in

Rakesh K . Chandra M.D .Chie f Res iden tDepar tment o f O to la ryngo logy Head & Neck Surgery , Nor thwes te rn Memor ia l Hosp i ta l ,Nor thwes te rn Un ivers i t y , Ch icago, I l l i no is

David B . Conley M.D . Ass is tan t Pro fessorDepar tment o f O to la ryngo logy Head & Neck Surgery , Nor thwes te rn Un ivers i t y Med ica lSchoo l , Ch icago, I l l i no is

Thomas Corbr idge M.D . , F .C .C .P. Asso cia te ProfessorDepar tment o f Med ic ine , Nor thwes te rn Un ivers i t y Med ica l Schoo l ; D i rec to r , Med ica l In tens iveCare Un i t , Nor thwes te rn Memor ia l Hosp i ta l , Ch icago, I l l i no is

Anne M. D i t to M.D . Ass is tan t Pro fessorDepar tment o f Med ic ine , D iv i s ion o f A l le rgy - Immuno logy , Nor thwes te rn Un ivers i t y Med ica lSchoo l , Ch icago, I l l i no is

Jordan N . F ink M.D .Pro fessor and Ch ie fDepar tment o f Med ic ine , D iv i s ion o f A l le rgy - Immuno logy , M i lwaukee County Med ica lComplex , M i lwaukee, Wiscons in

Lesl ie C . Grammer M.D .Pro fessor o f Med ic ineDepar tment o f Med ic ine ; V ice Ch ie f , D iv i s ion o f A l le rgy - Immuno logy ; D i rec to r , Ernes t S.

Baz ley As thma and A l le rg ic D iseases Center , Nor thwes te rn Un ivers i t y Med ica l Schoo l ,Ch icago, I l l i no is

Thomas H . Grant D .O. Asso cia te Professor


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Depar tment o f Rad io logy , Nor thwes te rn Memor ia l Hosp i ta l , Nor thwes te rn Un ivers i t y Med ica lSchoo l , Ch icago, I l l i no is

Paul A . Greenberger M.D .Pro fessor o f Med ic ineDepar tment o f Med ic ine ; Assoc ia te Ch ie f , Educa t ion and C l in i ca l A f fa i rs , D iv i s ion o f A l le rgy -Immuno logy , Nor thwes te rn Un ivers i t y Med ica l Schoo l , Ch icago, I l l i no is

Kathleen E. Harr is B .S.Sen io r L i fe Sc iences ResearcherDepar tment o f Med ic ine , D iv i s ion o f A l le rgy - Immuno logy , Nor thwes te rn Un ivers i t y Med ica l

Schoo l , Ch icago, I l l i no isMary Beth Hogan M.D .

Ass is tan t Pro fessorDepar tment o f Ped ia t r i cs , Wes t V i rg in ia Un ivers i t y Schoo l o f Med ic ine , Morgantown, Wes tV i rg in ia

Carla I rani M.D .Sec t ion o f A l le rgy and Immuno logy , D iv i s ion o f Pu lmonary , A l le rgy , C r i t i ca l Care Med ic ine ,Un ivers i t y o f Pennsy lvan ia Schoo l o f Med ic ine , Ph i lade lph ia , Pennsy lvan ia

Kevin J . Kel ly M.D .Pro fessor and Ch ie fDepar tment o f A l le rgy / Immuno logy , Med ica l Co l lege o f Wiscons in ; Ch ie f , Depar tment o fMed ic ine , D iv i s ion o f A l le rgy / Immuno logy , Ch i ld ren 's Hosp i ta l o f Wiscons in , M i lwaukee,Wiscons in

Robert C . Kern M.D . , M.S. , F .A .C .S.Cha i rmanDiv is ion o f O to la ryngo logy , Cook County Hosp i ta l ; Assoc ia te Pro fessor , Depar tment o f

Oto la ryngo logy -Head & Neck Surgery , Nor thwes te rn Un ivers i t y Med ica l Schoo l , Ch icago,I l l i no is

Theodore M. Lee M.D .Peacht ree A l le rgy and As thma C l in i c , PC, At lan ta , Georg ia

Donald Y M Leung M.D . , Ph.D .Pro fessorDepar tment o f Ped ia t r i cs , Un ivers i t y o f Co lo rado Hea l th Sc iences Center ; Head, Depar tmento f Ped ia t r i c A l le rgy - Immuno logy , Nat iona l Jew ish Med ica l and Research Center , Denver ,Co lo rado

Phi l L ieberman M.D .Cl in i ca l Pro fessorDepar tment o f In te rna l Med ic ine and Ped ia t r i cs , Un ivers i t y o f Tennessee Co l lege o f Med ic ine, Cordova , Tennessee

Kris G. McGrath M.D . Asso cia te ProfessorDepar tment o f Med ic ine , Nor thwes te rn Un ivers i t y Med ica l Schoo l ; Ch ie f , Depar tment o f

A l le rgy- Immuno logy , Sain t Joseph Hosp i ta l , Ch icago, I l l ino is

Roger W. Melvold Ph.D .Pro fessor and Depar tment Cha i rDepar tment o f M ic rob io logy & Immuno logy , Schoo l o f Med ic ine and Hea l th Sc iences ,Un ivers i t y o f Nor th Dakota , Grand Forks , Nor th Dakota

W. James Metzger M.D .Pro fessor and Sec t ion HeadDepar tment o f A l le rgy , As thma and Immuno logy , Eas t Caro l ina Un ivers i t y Schoo l o f Med ic ine ,Greenv i l l e , Nor th Caro l ina

Babak Mokhles i M.D . Ass is tan t Pro fessorDepar tment o f Med ic ine , D iv i s ion o f Pu lmonary and Cr i t i ca l Care , Rush Med ica l Co l lege /CookCounty Hosp i ta l , Ch icago, I l l i no is

Michel le J . Naid ich M.D .Depar tment o f Rad io logy , Nor thwes te rn Memor ia l Hosp i ta l , Nor thwes te rn Un ivers i t y Med ica lSchoo l , Ch icago, I l l i no is

Sai R . N immagadda M.D . Ass is tan t Pro fessorDepar tment o f Ped ia t r i cs , Nor thwes te rn Un ivers i t y Med ica l Schoo l , Depar tment o fPed ia t r i cs /A l le rgy , Ch i ld ren 's Memor ia l Hosp i ta l , Ch icago, I l l i no is

Peck Y. Ong M.D .Fe l lowDepar tment o f Ped ia t r i cs , D iv i s ion o f A l le rgy and Immuno logy , Nat iona l Jew ish Med ica l andResearch Center , Denver , Co lo rado

Roy Pat terson M.D .Ernes t S. Baz ley Pro fessor o f Med ic ineDepar tment o f Med ic ine ; Ch ie f , D iv i s ion o f A l le rgy - Immuno logy , Nor thwes te rn Un ivers i t yMed ica l Schoo l , Ch icago, I l l i no is

Nei l l T . Peters M.D .Cl in i ca l Ins t ruc to rDepar tment o f Dermato logy , Mercy Hosp i ta l and Med ica l Center , Ch icago, I l l i no is

Jacquel ine A . Pongracic M.D . Ass is tan t Pro fessorDepar tment o f Ped ia t r i cs and Med ic ine , Nor thwes te rn Un ivers i t y Med ica l Schoo l ; Ac t ingD iv is ion Head, Depar tment o f A l le rgy , Ch i ld ren 's Memor ia l Hosp i ta l , Ch icago, I l l i no is

Jacob J . Pruzansky Ph.D .


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Emer i tus Pro fessor o f M ic rob io logyDepar tment o f Med ic ine , D iv i s ion o f A l le rgy - Immuno logy , Nor thwes te rn Un ivers i t y Med ica lSchoo l , Ch icago, I l l i no is

Robert E. Reisman M.D .Cl in i ca l Pro fessorDepar tments o f Med ic ine and Ped ia t r i cs , S ta te Un ivers i t y o f New York a t Bu f fa lo , Depar tmento f Med ic ine (A l le rgy / Immuno logy ) , Bu f fa lo Genera l Hosp i ta l , Bu f fa lo , New York

Anthony J . R icket t i M.D . Associa te Professor o f Med ic ine

Seton Ha l l Un ivers i t y , Graduate Schoo l o f Med ic ine , Cha i rman, Depar tment o f Med ic ine , St .Franc is Med ica l Center , T ren ton , New Jersey

Eric J . Russel l M.D . , F .A .C .R .Pro fessorDepar tments o f Rad io logy , Neurosurgery , and Oto la ryngo logy , Nor thwes te rn Un ivers i t y , Ch ie fo f Neurorad io logy , Depar tment o f Rad io logy , Nor thwes te rn Memor ia l Hosp i ta l , Ch icago,I l l i no is

Carol A . Sa l toun M.D .Cl in i ca l Ins t ruc to rDepar tment o f Med ic ine , D iv i s ion o f A l le rgy - Immuno logy , Nor thwes te rn Un ivers i t y Med ica lSchoo l , Ch icago, I l l i no is

Andrew Scheman M.D . Associa te Prof essor o f C l in i ca l Dermato logy and De par tment o f Dermato logyNor thwes te rn Un ivers i t y Med ica l Center , Ch icago, I l l i no is

Wil l iam R. Solomon M.D .Pro fessor Emer i tus

Depar tment o f In te rna l Med ic ine (A l le rgy ) , Un ivers i t y o f M ich igan Med ica l Schoo l and ,Un ivers i t y o f M ich igan Med ica l Center , Ann Arbor , M ich igan

Abba I . Terr M.D . Asso cia te ProfessorDepar tment o f Med ic ine , Un ivers i t y o f Ca l i fo rn ia -San Franc isco , Schoo l o f Med ic ine , SanFranc isco , Ca l i fo rn ia

Anju Tr ipath i M.D . Ass is tan t Pro fessorDepar tments o f Med ic ine and A l le rgy , Nor thwes te rn Un ivers i t y Med ica l Schoo l , Ch icago,I l l i no is

Stephen I . Wasserman M.D .The He len M. Ranney Pro fessorDepar tment o f Med ic ine , Un ivers i t y o f Ca l i fo rn ia -San D iego , La Jo l la , Ca l i fo rn ia ; Pro fessorand Ch ie f o f A l le rg ic D iseases , Depar tment o f Med ic ine , Un ivers i t y o f Ca l i fo rn ia -San D iegoMed ica l Center , San D iego , Ca l i fo rn ia

Carol Ann Wiggins M.D .

Depar tment o f A l le rgy and Immuno logy , Emory Un ivers i t y Schoo l o f Med ic ine , Depar tment o f A l le rgy and Immuno logy, P iedmont Hosp i ta l , A t la nta , Georg ia

Nevin W. Wi lson M.D . Asso cia te ProfessorDepar tment o f Ped ia t r i cs , Wes t V i rg in ia Un ivers i t y , Schoo l o f Med ic ine , Morgantown, Wes tV i rg in ia

Lisa F . Wol fe M.D . Ass is tan t Pro fessor of Med ic ineCl in i ca l Ins t ruc to r , D iv i s ion o f Pu lmonary & Cr i t i ca l Care Med ic ine and the Center fo r S leepand C i rcad ian B io logy , Nor thwes te rn Un ivers i t y Med ica l Schoo l , Ch icago, I l l i no is

Michael C . Zachar isen M.D . Ass is tan t Pro fessorDepar tments o f Ped ia t r i cs and Med ic ine , Med ica l Co l lege o f Wiscons in , Ch i ld ren 's Hosp i ta lo f Wiscons in , M i lwaukee, Wiscons in

C. Raymond Zeiss M.D .Emer i tus Pro fessor o f Med ic ineDepar tment o f Med ic ine , D iv i s ion o f A l le rgy - Immuno logy , Nor thwes te rn Un ivers i t y Med ica lSchoo l , VA Ch icago Hea l th Care Sys tem–Lakes ide D iv i s ion , Ch icago, I l l i no is

In MemoriamIn Memoriam Jacob J. Pruzansky, Ph.D. June 20, 1921–April 5,2001Jack Pruzansky served as an au thor in f i ve ed i t i ons o f A l l e rg ic D iseases . He spent manyhours mentor ing fe l l ows in the A l le rgy - Immuno logy D iv i s ion dur ing h is 35-year tenure a tNor thwes te rn Un ivers i t y . A f te r h i s re t i rement , he s t i l l func t ioned as a consu l tan t and

p rov ided sc ien t i f ic exper t ise to the d iv is ion . Jack wa s an exper t on in v i t ro basophi lh i s tamine re lease and d iscovered how d i lu te hydroch lo r i c ac id wou ld a l l ow fo r remova l o f IgEf rom basoph i l s . Th is d i scovery a l l owed h im to s tudy pass ive t rans fe r exper imenta l l y and ledto s tud ies o f h i s tamine re leas ing fac to rs . H is in te l l ec t and adv ice he lped fe l l ows and facu l tys tay ou t o f “dark a l l eys ” as he wou ld say . He w i l l be missed .

In Memoriam Martha A. Shaughnessy, B.S. December 3, 1943–September 9, 1997Mar tha Shaughnessy was a chapte r au thor in the las t two ed i t i ons o f A l l e rg ic D iseases . Shehad a te r r i f i c sense o f humor and qu ick w i t . Her con t r ibu t ions to the d iv i s ion inc luded


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per fo rming immuno log ic research, wr i t i ng research papers and gran ts , teach ing fe l l ows , andadmin is t ra t ion o f the A l le rgy - Immuno logy D iv i s ion . She coauthored 71 peer - rev iewed papers ,66 o f wh ich were in co l labora t ion w i th o ther members o f the A l le rgy - Immuno logy D iv i s ion .She a lso coauthored ten book chapte rs , p r imar i l y i n a reas o f a l l e rgen immunotherapy andoccupat iona l immuno log ic lung d isease , her two ma jo r research in te res ts . She was admi redand respec ted by her co- inves t iga to rs and a l l who worked w i th her . We, her co l leagues andf r iends , now honor her .

In Memory of Ernest S. BazleyThe Ernes t S. Baz ley Gran t to Nor thwes te rn Memor ia l Hosp i ta l and Nor thwes te rn Un ivers i t yhas p rov ided con t inu ing research suppor t tha t has been inva luab le to the A l le rgy - Immuno logyD iv is ion o f Nor thwes te rn Un ivers i t y .

In Memoriam W. James Metzger, Jr., M.D. October 30, 1945–November 17, 2000J im was a fe l l ow a t Nor thwes te rn Un ivers i t y f rom 1974 to 1976 and spent h i s career inacademic med ic ine a t the Un ivers i t y o f Iowa and Eas t Caro l ina Med ica l Schoo l where he wasD iv is ion Ch ie f o f A l le rgy As thma and Immuno logy and V ice-Cha i r o f the Depar tment o fMed ic ine . He moved to Denver to the Nat iona l Jew ish Hosp i ta l i n the months be fo re hebecame i l l . He was an au thor in th ree ed i t i ons o f A l l e rg ic D iseases .J im had many accompl i shments in A l le rgy - Immuno logy inc lud ing the ear l y d i scovery tha ta l le rgen vacc ine therapy inh ib i ted some o f the la te a i rway response to a l l e rgen . J im was l i ked by everyone and i s deep ly m issed . I t was s ta ted , “As in so many th ings , J imwas the ca ta lys t tha t a l te red and en la rged an exper ience , wh i le manag ing to s tay a lmos tinv is ib le h imse l f . ”

ForewordA Major HonorI was in fo rmed by the pub l i sher tha t the name Roy Pa t te rson wou ld be on a l l fu tu re ed i t i onso f Al le rg ic Diseases : D iagnos is and Ma nagement . I cons ider th i s a g rea t honor and a t th i st ime I wou ld l i ke to acknowledge severa l co l leagues fo r the i r con t r ibu t ions to my persona lach ievements .

As of th i s wr i t i ng , I am 75 years o ld (as o f 4 /26/ 01) and am the Ernest S. Baz ley Pro fessor o fMed ic ine o f Nor thwes te rn Un ivers i t y Med ica l Schoo l and the Ch ie f o f the A l le rgy - Immuno logyDiv i s ion o f the Depar tment o f Med ic ine .I owe a deb t o f g ra t i tude to the fo l l owing fo r a l l the i r suppor t dur ing my academic career . Iw ish to thank :The Ernest S. Baz ley Trustees: Ca ther ine Ryan o f the Bank o f Amer ica , I l l i no is , the la teErnes t S. Baz ley , J r . , and the la te Gunnard Swanson. A ma jo r e f fo r t o f the Nor thwes te rn

A l le rgy- I mmuno logy p rogram has been the d iagnos is and management o f a l l forms of as thma.Research fund ing f rom the Baz ley Trus t has made many o f our accompl i shments in the a reaposs ib le .The Nat ional Inst i tute of A l lergy and Infect ious D iseases: R ichard Krause , M.D. , An thonyFauc i , M.D. , She ldon Cohen, M.D. , and Doro thy Sogn, M.D.Ful l t ime facul ty : pa r t i cu la r l y the la te Jacob J . Pruzansky , Ph .D.Voluntary facul ty : pa r t i cu la r l y R ichard S. DeSwar te , M.D.Technica l and support s ta f f : Mary Rober ts , R.N. , Ka th leen E. Har r i s , B .S. , Margare t A .Mate ja -Wiecker t , and the la te Mar tha A. Shaughnessy , B .S.F ina l l y , the Graduates of the A l lergy- Immunology t ra in ing program.

Roy Pa t te rson M.D.

PrefaceThe s ix th ed i t i on covers a l l e rg ic and immuno log ic p rob lems tha t a re encounte red in theambu la to ry p rac t i ce o r i n hosp i ta l i zed pa t ien ts . The quan t i t y and complex i t y o f genera l andspec i f i c knowledge in the f i e ld o f A l le rgy - Immuno logy con t inues to expand a t an exc i t i ng bu tdaun t ing pace . Fur ther , the p rac t i ce o f A l le rgy - Immuno logy requ i res fami l i a r i t y w i th manyspec i f i c de ta i l s . The 42 chap te rs con ta in use fu l , app l i cab le , and up- to -da te in fo rmat ion onhow to d iagnose and manage near l y a l l o f the cond i t i ons in A l le rgy - Immuno logy . The h is to ry

o f Al le rg ic Diseases : D iagnos is and Management th rough s i x ed i t i ons inc ludes be ing a use fu ltex tbook where impor tan t , c ruc ia l i n fo rmat ion can be found and app l ied . Ed i t i on s i x has 15new chap te rs , and the c lass ic Drug A l le rgy chap te r o r ig ina ted by Richard DeSwar te has beend iv ided in to th ree par ts . The new chap te rs cover ing rad io log ic f i nd ings o f the s inuses andlungs , ro le o f rh inoscopy and surgery fo r ch ron ic s inus i t i s , and work -up fo r immunodef i c iencyre f lec t the b roadened base o f knowledge requ i red fo r the p rac t i ce o f A l le rgy - Immuno logy . Intha t as thma i s now recogn ized as o f one the mos t compl i ca ted d iso rders a phys ic ians mus tt rea t , f i ve new chap te rs were p repared to cover med ica t ions fo r as thma, inha le r dev ices andde l i ve ry sys tems, and nove l approaches to t rea tment .There a re shor tages o f spec ia l i s ts i n A l le rgy - Immuno logy in p rac t i ce and even more so inacademic med ica l cen te rs . We hope th i s tex tbook ass is ts phys ic ians to p rov ide be t te r ca refo r the i r pa t ien ts , i nsp i res med ica l s tuden ts and res iden ts to pursue t ra in ing in A l le rgy -Immuno logy , and ass is ts inves t iga to rs in advanc ing our knowledge . We wi l l a lways havemuch more to lea rn .We are g ra te fu l to the au thors fo r the i r superb chap te rs , each o f wh ich has been approved byus , shou ld there be any overs igh ts . We cou ld no t have comple ted th i s tex tbook wi thou t thelove and suppor t f rom our fami l i es who g ive us the t ime to con t inue in the Nor thwes te rn

Un ivers i t y A l le rgy - Immuno logy t rad i t i on tha t i s now over 40 years o ld !Spec ia l apprec ia t ion goes to our suppor t s ta f f , espec ia l l y Ka th leen E. Har r i s and Margare tMate ja Wiecker t , ou r t ra inees and g radua tes , and our pa t ien ts , f rom whom we can a lwayslearn .

Les l ie C. Grammer M.D.


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Pau l A. Greenberger M.D.

1

Review of ImmunologyRoger W. MelvoldDepar tment o f M ic rob io logy and Immuno logy , Schoo l o f Med ic ine and Hea l th Sc iences , Un ivers i t y o fNor th Dakota , Grand Forks , Nor th Dakota

Contents

• ANTIGENS • MOLECULES OF THE IMMUNE SYSTEM • MOLECULES FOR ADHESION, RECIRCULATION, AND HOMING • CELLS OF THE IMMUNE SYSTEM • PRIMARY ORGANS: BONE MARROW AND THYMUS • INTERACTIONS IN IMMUNE RESPONSES • THE IMMUNE SYSTEM: A DOUBLE-EDGED SWORD • TOLERANCE

A l thou gh immuno logy i s a r e la t i ve n ewcomer amon g the sc iences , i t s phenomena have long beenrecogn ized and man ipu la ted . Anc ien t peop les unders tood tha t su rv i vo rs o f par t i cu la r d i seases werepro tec ted f rom those d iseases fo r the rema inder o f the i r l i ves , and the anc ien t Ch inese and Egyp t ianseven p rac t i ced fo rms o f immun iza t ion . Surgeons have a lso long unders tood tha t t i ssues and o rganswou ld no t su rv i ve when exchanged be tween d i f fe ren t i nd iv idua ls (e .g . , f rom cadaver donors ) bu tcou ld succeed when t ransp lan ted f rom one s i te to ano ther wi th in the same ind iv idua l . However , on lydur ing the pas t cen tu ry have the mechan isms o f the immune sys tem been i l l umina ted , a t l eas t i n par t .Keep in m ind tha t the immune sys tem, as we usua l l y th ink o f i t , i s the body 's second l i ne o f de fense .The f i rs t l i ne o f de fense cons is ts o f a number o f bar r ie rs , i nc lud ing the sk in and mucous membranes ,the fa t t y ac ids o f the sk in , the h igh pH o f the s tomach, res iden t m ic rob ia l popu la t ions , and ce l l s tha tac t nonspec i f i ca l l y aga ins t i n fec t ious o rgan isms (1 ) .L i ke the nervous and endocr ine sys tems, the immune sys tem is adap t i ve , spec i f i c , andcommunica t i ve . I t recogn izes and responds to changes in the env i ronment , and i t d i sp lays memory byadapt ing o r a l te r ing i t s response to s t imu l i tha t i t has encounte red p rev ious ly . I t can de tec t the

presence o f m i l l i ons o f d i f fe ren t subs tances (an t igens ) and has an exqu is i te ab i l i t y to d i sc r im ina teamong c lose ly re la ted mo lecu les . Communica t ion and in te rac t ion , i nvo lv ing bo th d i rec t con tac t andso lub le med ia to rs , mus t occur among a var ie ty o f l ympho id and o ther ce l l s fo r op t ima l func t ion .The complex i t y o f the immune sys tem is ex tended by gene t i c d i f fe rences among ind iv idua ls . Th is i sbecause the “ reper to i re ” o f immune responses var ies among unre la ted ind iv idua ls in an ou tb red ,gene t i ca l l y he te rogeneous spec ies such as our own. Fur thermore , each o f us , i n a sense , i s“ immuno log ica l l y i ncomple te ” because none o f us i s ab le to recogn ize and respond to a l l o f theposs ib le an t igens tha t ex is t . Severa l fac to rs con t r ibu te to th i s : (a ) gene t i c o r env i ronmenta l l y i nducedcond i t i ons tha t nonspec i f i ca l l y d im in ish immune func t ions , (b ) va r ia t ion among ind iv idua ls in thegenes encod ing the an t igen recep to rs o f l ymphocy tes , (c ) gene t i ca l l y encoded d i f fe rences amongind iv idua ls (o f ten de te rmined by the h igh ly po lymorph ic genes o f the human leukocy te an t igen [HLA]complex ) tha t d i c ta te whether and how the ind iv idua l w i l l respond to spec i f i c an t igens , and (d ) thefac t tha t each ind iv idua l ' s immune sys tem mus t d i f fe ren t ia te be tween se l f ( those subs tances tha t a rea norma l par t o f the body) and fo re ign , o r nonse l f , i n o rder to avo id au to immun i ty . However , becausese l f d i f fe rs f rom one ind iv idua l to the nex t , wha t i s fo re ign a lso d i f fe rs among ind iv idua ls .

ANTIGENSPar t o f "1 - Rev iew o f Immuno logy "

An t ige ns were in i t i a l l y de f ined as subs tances iden t i f i ed and bo und by an t ibodies ( immun og- lobu l ins)p roduced by B l ymphocy tes . However , because the spec i f i c an t igen recep to rs o fP.2

T l ymphocy tes a re no t immunog lobu l ins , the de f in i t i on mus t be b roadened to inc lude subs tances tha tcan be spec i f i ca l l y recogn ized by the recep to rs o f T o r B l ymphocy tes o r bo th . I t i s es t imated tha t theimmune sys tem can spec i f i ca l l y recogn ize a t l eas t 10 6 to 10 7 d i f fe ren t an t igens . These inc lude bo thsubs tances tha t a re fo re ign to the body (nonse l f ) and subs tances tha t a re norma l cons t i tuen ts o f thebody (se l f ) .The immune sys tem mus t d i s t i ngu ish be tween nonse l f and se l f an t igens so tha t , under norma lcond i t i ons , i t can a t tack the fo rmer bu t no t the la t te r . Thus , the immune sys tem shou ld be to le ran t o fse l f bu t i n to le ran t o f nonse l f . Au to immune d iseases a r i se when such d is t inc t ions a re los t and theimmune sys tem a t tacks se l f an t igens , a phenomenon o r ig ina l l y desc r ibed by Pau l Er l i ch as hor ro rau to tox icus . We l l -known examples inc lude rheumato id a r th r i t i s , psor ias is , sys temic lupus

ery thematosus , and some fo rms o f d iabe tes . An t ige ns can be d iv ided in to th ree genera l t ypes—immunogens , haptens , and to lerogens—depend in gon the way in wh ich they s t imu la te and in te rac t w i th the immune sys tem ( 2 ,3 and 4) . An immunogencan, by i t se l f , bo th s t imu la te an immune response and subsequent l y se rve as a ta rge t o f tha tresponse . The te rms immunogen and ant igen a re o f ten , bu t i nappropr ia te l y , used in te rchangeab ly . A


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hapten cannot , by i t se l f , s t imu la te an immune response . However , i f a hap ten i s a t tached to a la rgerimmunogen ic mo lecu le (a “ca r r ie r ” ) , responses can be s t imu la ted aga ins t bo th the car r ie r and thehapten , and the hap ten i t se l f can subsequent l y se rve as the ta rge t o f a response so invoked . Ato le rogen i s a subs tance tha t , a f te r an in i t i a l exposure to the immune sys tem, inh ib i t s fu tu reresponses aga ins t i t se l f .Because o f the gene t i c d i ve rs i t y among ind iv idua ls , a subs tance tha t i s an immunogen fo r one personmay be a to le rogen fo r ano ther and may be ignored comple te ly by the immune sys tem o f s t i l l o thers .

A lso , a subs tance tha t ac ts as a n immunog en when admin is te red b y one rou te (e .g . , i n t ramuscu la r l y)may ac t as a to le rogen when app l ied by a d i f fe ren t rou te (e .g . , i n t ragas t r i ca l l y ) .

An t igens a re usua l l y p ro te in o r ca rbohydrat e in na ture and may be found as f ree s ing le mo lecu les o r

as par ts o f l a rger s t ruc tu res (e .g . , expressed on the sur face o f an in fec t ious agen t ) . A l though someant igens a re very sma l l and s imp le , o thers a re la rge and complex , con ta in ing many d i f fe ren t s i testha t can be ind iv idua l l y i den t i f i ed by l ymphocy te recep to rs o r f ree immunog lobu l ins . Each suchind iv idua l par t o f an an t igen tha t can be d is t i nc t l y i den t i f i ed by the immune sys tem is ca l led anep i tope or determinant ( i .e . , the sma l les t i den t i f i ab le an t igen ic un i t ) . Thus , a s ing le la rge an t igenmay con ta in many d i f fe ren t ep i topes . In genera l , the more complex the mo lecu le and the g rea te r thenumber o f ep i topes i t d i sp lays , the more po ten t i t i s as an immunogen.

Ad juvan ts a re substances tha t , wh en admin is t ered toge ther wi th an immunogen (o r a hap ten coup ledto an immunogen) , enhance the response aga ins t i t ( 5 ) . For example , immunogens may be suspendedin m ix tu res (e .g . , co l l o ida l suspens ions o f mycobac te r ia l p ro te ins and o i l ) tha t i nduce loca l i zedin f lammat ions and a id in a rousa l o f the immune sys tem.

MOLECULES OF THE IMMUNE SYSTEMPar t o f "1 - Rev iew o f Immuno logy "

ImmunoglobulinB lymphocy tes syn thes ize recep to rs ( immunog- lobu l ins ) ab le to recogn ize and b ind spec i f i cs t ruc tu res (an t igens , de te rminan ts , ep i topes) . A l l immunog lobu l ins p roduced by a s ing le B ce l l , o r bya c lona l l y der i ved se t o f B ce l l s , have the same spec i f i c i t y and a re ab le to recogn ize and b ind on ly as ing le an t igen o r ep i tope (2 ,3 and 4) . Immunog lobu l in ex is ts e i ther as a sur face membrane-boundmolecu le o r i n a sec re ted fo rm by B ce l l s tha t have been appropr ia te l y s t imu la ted and matured .The immunog lobu l in mo lecu le i s a g l ycopro te in composed o f two iden t i ca l l i gh t cha ins and twoiden t i ca l heavy cha ins (F ig . 1 .1 ) l i nked by d isu l f i de bonds ( 6 ) . Enzymat i c c leavage o f theimmunog lobu l in mo lecu le c rea tes de f ined f ragments . Papa in p roduces two an t igen-b ind ing f ragments(Fab) and one c rys ta l l i zab le f ragment (Fc ) . Peps in p roduces on ly a d i va len t an t igen-b ind ing f ragmentte rmed F(ab ′ ) 2 , and the rema inder o f the mo lecu le tends to be degraded and los t .

FIG. 1 .1 . The immunog lobu l in mo lecu le .

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Each cha in (heavy and l i gh t ) con ta ins one o r more cons tan t reg ions (C H o r C L ) and a var iab le reg ion(V H or V L ) . Toge ther , the var iab le reg ions o f the l i gh t and heavy cha ins con t r ibu te to the an t igen-b ind ing s i tes (Fab) o f the immunog lobu l in mo lecu le . The cons tan t reg ions o f the heavy cha in

(par t i cu la r l y i n the Fc por t i on ) de te rmine what subsequent i n te rac t ions may occur be tween the boundimmunog lobu l in and o ther ce l l s o r mo lecu les o f the immune sys tem. When the an t igen-b ind ing s i tesare f i l l ed , a s igna l i s t ransmi t ted th rough the immunog lobu l in mo lecu le , wh ich resu l ts i ncon fo rmat iona l changes in the Fc por t i on o f the heavy cha in . These con fo rmat iona l changes permi tthe Fc por t i on to then in te rac t w i th o ther mo lecu les and ce l l s . The con fo rmat iona l l y a l te red Fc may


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be recogn ized by recep to rs (Fc recep to rs [FcR] ) on macrophages and o ther ce l l s , wh ich a l l ow them tod is t ingu ish bound f rom unbound immunog lobu l in mo lecu les (7 ,8) , i nc reas ing the i r e f f i c iency o fphagocy tos is . O ther con fo rmat iona l changes in the Fc por t i on o f bound immunog lobu l in permi t theb ind ing o f complement component C1q to in i t i a te the c lass ic pa thway o f complement ac t i va t ion . TheFab and F(ab ′ ) 2 f ragments a re use fu l exper imenta l and therapeu t i c too ls tha t can b ind an t igenswi thou t the ensu ing consequences resu l t i ng f rom the p resence o f the Fc reg ion ( 9 ) .Immunog lobu l in l i gh t cha ins con ta in one o f two types o f cons tan t reg ions , κ o r λ . The cons tan treg ions o f the heavy cha ins ex is t i n f i ve ma jo r fo rms ( Tab le 1 .1 ) , each assoc ia ted wi th a par t i cu la rimmunog lobu l in i so type o r c lass : Cα ( immunog lobu l in A [ IgA] ) , Cδ ( IgD) , Cε ( IgE) , Cγ ( IgG) , and Cµ( IgM) . Some o f these can be subd iv ided in to subc lasses (e .g . , IgG1, IgG2, IgG3, and IgG4) . Each

norma l i nd iv idua l can genera te a l l o f the i so types . Wi th in a s ing le immunog lobu l in mo lecu le , bo thl i gh t cha ins a re iden t i ca l and o f the same type (bo th κ o r bo th λ ) , and the two heavy cha ins a rel i kewise iden t i ca l and o f the same i so type . IgD, IgG, and IgE ex is t on ly as monomer ic bas icimmunog lobu l in un i t s ( two heavy cha ins and two l i gh t cha ins ) , bu t se rum IgM ex is ts as a pen tamer o ff i ve bas ic un i t s un i ted by a J ( j o in ing) cha in . IgA can be found in a var ie ty o f fo rms (monomers ,d imers , t r imers , te t ramers ) bu t i s mos t commonly seen as a monomer ( in se rum) o r as a d imer ( i nex te rna l body f l u ids , such as mucus , tears , and sa l i va ) .P.4

The d imer i c fo rm con ta ins two bas ic un i t s , bound toge ther by a J cha in . In pass ing th roughspec ia l i zed ep i the l ia l ce l l s to ex te rna l f l u ids , i t a l so adds a “sec re to ry p iece , ” wh ich inc reases i t sres is tance to degrada t ion by ex te rna l enzymes ( 10) .


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TABLE 1 .1 . Immunog lobu l in i so types

In add i t i on to an t igen-b ind ing spec i f i c i t y , va r iab i l i t y among immunog lobu l in mo lecu les der i ves f romthree fu r ther sources : a l l o types , i so types , and id io types . A l lo types a re d ic ta ted by m inor amino ac idsequence d i f fe rences in the cons tan t reg ions o f heavy o r l i gh t cha ins , wh ich resu l t f rom s l i gh tpo lymorph isms in the genes encod ing these mo lecu les . A l lo typ ic d i f fe rences typ ica l l y do no t a f fec tthe func t ion o fP.5

the mo lecu le and segrega te wi th in fami l i es l i ke typ ica l mende l ian t ra i t s . I so types , as a l readyd iscussed , a re de te rmined by more subs tan t ia l d i f fe rences in the heavy cha in cons tan t reg ionsa f fec t ing the func t iona l p roper t ies o f the immunog lobu l ins ( 11) (Tab le 1 .1 ) . F ina l l y , many an t igen icde te rminan ts may be bound in more than one way , and thus there may be mu l t i p le , s t ruc tu ra l l yd is t i nc t , immunog lobu l ins wi th the same an t igen ic spec i f i c i t y . These d i f fe rences wi th in the an t igen-b ind ing domains o f immunog lobu l ins tha t b ind the same an t igen ic de te rminan ts a re te rmed i d io types .

Generation of Antigen Binding Diversity among ImmunoglobulinsEach immunog lobu l in cha in , l i gh t and heavy , i s encoded no t by a s ing le gene bu t by a ser ies o fgenes occur r ing in c lus te rs a long the chromosome ( 11) . In humans , the ser ies o f genes encod ing κ l i gh t cha ins , the ser ies encod ing λ l i gh t cha ins , and the ser ies encod ing heavy cha ins a re a l l l oca tedon separa te chromosomes . Wi th in each ser ies , the genes a re found in c lus te rs , each con ta in ing a se t


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of s im i la r , bu t no t i den t i ca l , genes . A l l o f the genes a re p resen t i n embryon ic and germ ce l l s and ince l l s o ther than B l ymphocy tes . When a ce l l becomes commi t ted to the B- l ymphocy te l i neage , i trear ranges the DNA encod ing i t s l i gh t and heavy cha ins ( 1 1,12) by c l i pp ing ou t and degrad ing someof the DNA sequences . Each d i f fe ren t ia t ing B ce l l chooses e i ther the κ se r ies o r the λ se r ies (bu t no tbo th ) . In add i t i on , a l though bo th the materna l l y and pa te rna l l y der i ved chromosomes car ry these se tso f genes , each B ce l l uses on ly one o f them ( e i ther pa te rna l or mate rna l ) to p roduce a func t iona lcha in , a phenomenon te rmed a l le l i c exc lus ion .For the l i gh t cha ins , the re a re th ree d is t i nc t c lus te rs o f genes tha t con t r ibu te to the syn thes is o f theen t i re po lypep t ide : va r iab le genes (V L ) , j o in ing genes (J L ) , and cons tan t genes (C L ) (F ig . 1 .2 ) . Inadd i t i on , each V gene i s p receded by a leader sequence encod ing a por t i on o f the po lypep t ide tha t i s

impor tan t dur ing the syn the t i c p rocess bu t i s removed when the mo lecu le becomes func t iona l . The V L and D L genes a re used to p roduce the var iab le domain o f the l i gh t cha in . Th is i s accompl i shed by therandom se lec t ion o f a s ing le V L gene and a s ing le J L gene to be un i ted (V L –J L ) by sp l i c ing ou t andd iscard ing the in te rven ing DNA. Hence fo r th , tha t ce l l and a l l o f i t s c lona l descendants a re commi t tedto tha t par t i cu la r V L –J L combina t ion . Messenger RNA fo r the l i gh t cha in i s t ransc r ibed to inc lude theV L –J L genes , the C L gene o r genes , and the in te rven ing DNA be tween them. Be fo re t rans la t ion , themessenger RNA (mRNA) i s sp l i ced to un i te the V L –J L genes wi th a C L gene so tha t a s ing lecon t inuous po lypep t ide can be p roduced f rom th ree genes tha t were o r ig ina l l y separa ted on thechromosome.

FIG. 1 .2 . Syn thes is o f immunog lobu l in l i gh t cha ins .

For heavy cha ins , the re a re four d i s t i nc t c lus te rs o f genes invo lved ( F ig . 1 .3 ) : va r iab le genes (V H ) ,d i ve rs i t y genes (DH ) , j o in ing genes (J H ) , and a ser ies o f d i s t i nc t cons tan t genes (C µ , C δ , C γ , C ε , and

Cα ) . As wi th the l i gh t cha in genes , each V gene i s p receded by a leader sequence (L ) tha t p lays aro le dur ing syn thes is bu t i s subsequent l y l os t . One V H gene , one DH gene , and one J H gene a rerandomly se lec ted , and the in te rven ing DNA segments a re exc ised and d iscarded to b r ing thesegenes toge ther (V H –DH –J H ) . Messenger RNA is then t ransc r ibed to inc lude bo th the V H –DH –J H andcons tan t genes , bu t un l i ke fo r the l i gh t cha ins , the p rocesses invo lv ing cons tan t genes a re d is t i nc t l yd i f fe ren t i n s t imu la ted and uns t imu la ted B l ymphocy tes .


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FIG. 1 .3 . Syn thes is o f immunog lobu l in heavy cha ins .

Uns t imu la ted B ce l l s t ransc r ibe heavy cha in mRNA f rom V H –DH –J H th rough the C µ and C δ genes . Th ist ransc r ip t does no t con ta in the in fo rmat ion f rom the C γ , C ε , o r C α genes . The mRNA is then sp l i ced tobr ing V H –D H –J H ad jacen t to e i ther C µ o r C δ , wh ich permi ts the t rans la t ion o f a s ing le con t inuouspo lypep t ide wi th a var iab le domain ( f rom V H –DH –J H ) and a cons tan t domain ( f rom e i ther C µ o r C δ ) .Thus , the sur face immunog lobu l in o f na ïve uns t imu la ted B ce l l s i nc ludes on ly the IgM and IgDiso types .

Af t er an t igen ic s t imu la t ion , B ce l ls can undergo an iso type swi tch in wh ich sp l ic ing o f DNA, r at herthan RNA, b r ings the un i ted V H –DH –J H genes ad jacen t to a cons tan t reg ion gene ( 13 ,14) . Th ist rans i t i on i s con t ro l l ed by cy tok ines sec re ted by T l ymphocy tes . Depend ing on the amount o f DNAexc ised , the V H –DH –J H genesP.6

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may be jo ined to any o f the d i f fe ren t C H genes (F ig . 1 .4 ) . As a resu l t o f the i so type swi tch , B-ce l l“subc lones” a re genera ted tha t p roduce an a r ray o f immunog lobu l ins tha t have iden t i ca l an t igen-b ind ing spec i f i c i t y bu t d i f fe ren t i so types .


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FIG. 1 .4 . The i so type swi tch .

Two add i t i ona l sources o f d i ve rs i t y i n the var iab le (an t igen-b ind ing) reg ions o f l i gh t and heavyimmunog lobu l in cha ins occur . F i rs t , j unc t iona l d i ve rs i t y may resu l t f rom imprec is ion in the p rec isep lacement o f the cu t t i ng and sp l i c ing tha t b r ing V, D, and J genes toge ther ; second , somat i cmuta t ions may occur and accumula te in success ive genera t ions o f c lona l l y der i ved B l ymphocy tes

when they undergo res t imu la t ion th rough la te r exposures to the same an t igen ic ep i topes ( 15 ,16) .

T-cell ReceptorT l ymphocy tes (T ce l l s ) do no t use immunog lobu l ins as an t igen recep to rs bu t ra ther use a d is t i nc t se to f genes encod ing four po lypep t ide cha ins ( α , β , γ , and δ ) , each wi th var iab le and cons tan t domains ,used to fo rm T-ce l l recep to rs (TCRs) ( 17 ,18 and 19) . The TCR is a he te rod imer , e i ther an α β o r a γ δ cha in combina t ion , wh ich recogn izes and b inds an t igen ( F ig . 1 .5 ) . Th is he te rod imer , wh ich i s no tcova len t l y l i nked toge ther , i s complexed wi th severa l o ther mo lecu les (e .g . , CD3, CD4, and CD8) ,tha t p rov ide s tab i l i t y and aux i l i a ry func t ions fo r the recep to r ( 20 ,21 and 22) . Un l i ke immunog lobu l in ,wh ich can b ind to f ree an t igen a lone , TCRs b ind on ly to spec i f i c combina t ions o f an t igen and cer ta inse l f ce l l su r face mo lecu les . They a re there fo re res t r i c ted to recogn i t i on and b ind ing o f an t igen on ce l lsu r faces and a re unab le to b ind f ree an t igen . In humans , the se l f mo lecu les a re encoded by thepo lymorph ic genes o f the HLA complex ( 23) : c lass I (encoded by the HLA-A, -B, and -C loc i ) andc lass I I (encoded by the -DP, -DQ, and -DR loc i w i th in the D/DR reg ion) . TCRs o f T ce l l s i n wh ichCD8 i s par t o f the TCR complex can recogn ize and b ind an t igenP.8

on ly when tha t an t igen i s assoc ia ted wi th (o r p resen ted by ) c lass I mo lecu les , whereas those T ce l l sin wh ich CD4 i s par t o f the TCR complex can recogn ize and b ind an t igen on ly when the an t igen i sp resen ted by c lass I I mo lecu les .


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FIG. 1 .5 . The T-ce l l recep to r .

L i ke immunog lobu l in , the TCR cha ins con ta in var iab le and cons tan t domains . The var iab le domainsare encoded by a ser ies o f V , J , and somet imes D (β and δ cha ins on ly ) gene c lus te rs tha t undergoDNA rear rangement , and the cons tan t reg ions a re encoded by cons tan t genes . TCRs do no t undergoany changes equ iva len t to the i so type swi tch . Junc t iona l d i ve rs i t y p rov ides an add i t i ona l source o fvar ia t ion fo r the var iab le domains o f α and β cha ins bu t no t fo r the γ and δ cha ins . Somat i c muta t ion ,so impor tan t i n the d ive rs i t y o f immunog lobu l ins , does no t occur in TCRs and i s apparen t l y“ fo rb idden . ”

Cell Determinant MoleculesSevera l ce l l su r face mo lecu les , the ce l l de te rminan t (CD) mo lecu les , i nd ica te the func t iona lcapac i t i es o f l ymphocy tes and o ther ce l l s ( 24) . The mos t commonly used a re those d is t ingu ish ing T-l ymphocy te subse ts .

• CD3 i s a complex o f severa l mo lecu les assoc ia ted wi th the T-ce l l an t igen recep to r ( 21,22) . I tp rov ides suppor t fo r the TCR and i s i nvo lved in t ransmembrane s igna l ing when the TCR isf i l l ed . I t i s found on a l l T ce l l s .

• CD4 i s found on T l ymphocy tes o f the he lper T-ce l l (T H ) and de layed hypersens i t i v i t y (T d h )subse ts (25 ,26 and 27 ) . CD4 mo lecu les a re found in assoc ia t ion wi th the TCR and recogn izec lass I I ma jo r h i s tocompat ib i l i t y complex (MHC) mo lecu les on an t igen-p resen t ing ce l l s(APCs) . The TCR o f CD4 + ce l l s a re thus res t r i c ted to recogn iz ing combina t ions o f an t igenand c lass I I MHC.

• CD8 i s found on T ce l l s o f the cy to tox ic T- l ymphocy te (CTL) and suppressor T-ce l l (T s )subse ts (25 ,27) . CD8 mo lecu les a re found in assoc ia t ion wi th the TCR and recogn ize c lass IMHC molecu les on APCs. The TCR o f CD8 + ce l l s a re thus res t r i c ted to recogn iz ingcombina t ions o f an t igen and c lass I MHC.

A l l αβ T ce l l s express e i ther CD4 or CD8 (and , dur ing an ear l y deve lopmenta l s tage , bo th ) . The γδ Tce l l s , on the o ther hand , o f ten express ne i ther CD4 nor CD8 ( 19) .

Human Leukocyte Antigen MoleculesThe HLA i s the MHC o f humans ( 23) . I t i s a sma l l reg ion o f ch romosome 6 con ta in ing severa l (10 to20) ind iv idua l genes encod ing p ro te ins o f th ree

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d i f fe ren t t ypes , ca l led c lass I , I I , and I I I MHC molecu les ( F ig . 1 .6A) .


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FIG. 1 .6 . A : The HLA complex . B : The D/DR reg ion .

• Class I mo lecu les a re membrane-bound g lycopro te ins found on a l l nuc lea ted ce l l s (28) . Theyare a s ing le la rge po lypep t ide (abou t 350 amino ac ids ) assoc ia ted wi th a sma l le r mo lecu le(β 2 -m ic rog lobu l in ) . The HLA complex inc ludes th ree d is t i nc t c lass I l oc i (HLA-A, -B, and -C) ,each hav ing scores o f a l l e les .

• Class I I mo lecu les a re he te rod imers ( F ig . 1 .6B) cons is t ing o f two membrane-bound,noncova len t l y l i nked cha ins (α and β ) and show a much more l im i ted ce l lu la r d i s t r i bu t ionthan c lass I mo lecu les ( 29) . They a re encoded by the DR, DP, and DQ reg ions o f the HLAcomplex . They a re expressed cons t i tu t i ve ly on B l ymphocy tes , macrophages , monocy tes , ands im i la r ce l l s i n va r ious t i ssues (Kup f fe r ce l l s , as t rocy tes , Langerhans ce l l s o f the sk in ) .Some o ther ce l l s (e .g . , vascu la r ep i the l ium) a re ab le to express c lass I I mo lecu lest rans ien t l y under par t i cu la r cond i t i ons .

• Class I I I mo lecu les a re those complement mo lecu les (e .g . , C2 , C4 , Bf ) encoded wi th in theHLA complex (30) .

Cytokines and LigandsCytok ines a re shor t - range ac t ing , so lub le p roduc ts tha t a re impor tan t i n the ce l lu la r communica t ionnecessary fo r the genera t ion o f immune responses ( 31 ,32 ,33 ,34 ,35 ,36 and 37) . Those p roducedpredominan t l y by l ymphocy tes o r monocy tes a re o f ten re fe r red to as l ymphok ines or monok ines , bu tbecause so many a re p roduced by mu l t i p le ce l l t ypes , the te rm cy tok ine has ga ined favor . A la rgenumber o f cy tok ines have been iden t i f i ed , a l though the ro les o f many o f them are no t ye t we l lunders tood . Many o f the cy tok ines a re c ruc ia l i n regu la t ing l ymphocy te deve lopment and the types o fimmune responses evoked by spec i f i c responses ( 37 ,3 8,39 and 40) . Those mos t bas ica l l y i nvo lved incommon immune responses a re l i s ted in Tab le 1 .2 .


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TABLE 1 .2 . Cytok ines

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L igands a re ce l l su r face mo lecu les tha t b ind mo lecu les on the sur face o f o ther ce l l s i n o rder tot ransmi t o r rece ive s igna ls c r i t i ca l to deve lopment o r ac t i va t ion . Among those impor tan t fo r immunefunc t ion a re B7 /CD28 and CD40/CD40 l i gand . B7 on APCs b inds CD28 o r CTLA-4 (o r bo th ) on Tlymphocy tes to p rov ide s igna ls fo r ac t i va t ion and inh ib i t i on , respec t i ve ly ( 41) . CD40 l i gand (CD40L)on ac t i va ted T l ymphocy tes b inds CD40 on B l ymphocy tes and macrophages to p rov ide ac t i va t ions igna ls to those ce l l s (42 ,43) .

ComplementComplement i s the compos i te te rm fo r a number o f se rum pro te ins (complement components ) tha t canin te rac t w i th one ano ther , as we l l as wi thP.11

an t ibod ies under some c i rcumstances , to p roduce severa l d i f fe ren t chemica l s igna ls and des t ruc t i veresponses (44) . The complement components (C1 th rough C9 p lus B, D, and P) ac t on one ano thersequent ia l l y ( the complement “cascade” ) (F ig . 1 .7 ) . The cascade beg ins wi th the b ind ing o f e i thercomponent C1 to an an t igen–ant ibody complex o r o f component C3 to a bac te r ia l o r o ther membrane

sur face (wi thou t the ass is tance o f an t ibody ) . The b ind ing o f C1 in i t i a tes what i s te rmed the c lass ic pa thway ( i nvo lv ing the subsequent b ind ing o f components C4, C2 , and C3) , whereas the d i rec tb ind ing o f C3 in i t i a tes the a l te rna t i ve pa thway ( i nvo lv ing the add i t i ona l b ind ing o f components D, B,and P) . A th i rd pa thway fo r complement ac t i va t ion , the l ec t in pa thway , beg ins wi th the b ind ing o fmannose-b ind ing p ro te in (MBP) to mannose on bac te r ia l ce l l su r faces . A l l th ree pa thways even tua l l y


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l ead to the ac t i va t ion and b ind ing o f component C5 , fo l l owed by components C6, C7 , C8 , and C9. Thecomple t ion o f th i s combina t ion o f C5 th rough C9 i s te rmed the membrane a t tack complex and resu l tsin the rup tu re o f the ce l l su r face to wh ich i t i s a t tached (45) .

FIG. 1 .7 . The complement cascade.

As complement co mpo nents in te rac t w i th one ano ther , each i s c leaved int o f ragments . Some becomeenzymat i ca l l y ac t i ve to con t inue the cascade. The sma l le r f ragments ga in hormone- l i ke func t ions andare impor tan t i n s t imu la t ing var ious in f lammatory reac t ions ( 46) . C5a (a f ragment o f C5) a t t rac tsneu t roph i l s and macrophages to the s i te o f i n te res t . C3a (a f ragment o f C3) causes smooth musc lecon t rac t ion and s t imu la tes basoph i l s , mas t ce l l s , and p la te le ts to re lease h is tamine and o therchemica ls con t r ibu t ing to in f l ammat ion . C3b (ano ther f ragment o f C3) s t imu la tes the inges t ion(opson iza t ion) o f the ce l l s on to wh ich the C3b i s bound by monocy tes and o ther phagocy t i c ce l l s . C4a( f ragment o f C4) has ac t i v i t y s im i la r to C5a, a l though less e f fec t i ve .

Antigen–Antibody ComplexesBind ing o f an t igen wi th an t ibody i s noncova len t and revers ib le . The s t reng th o f the in te rac t ion i ste rmed af f in i t y and de te rmines the re la t i ve concen t ra t ions o f bound versus f ree an t igen and an t ibody .The fo rmat ion o f an t igen–ant ibody complexes resu l ts i n to la t t i ce - l i ke aggrega tes o f so lub le an t igenand an t ibody , and the e f f i c iency o f such b ind ing i s a f fec ted by the re la t i ve concen t ra t ions o f an t igenand an t ibody (2 ,3 and 4 ,47) . Th is i s bes t i l l us t ra ted by the quan t i ta t i ve p rec ip i t i n reac t ion ( F ig . 1 .8 ) .When there i s an excess o f e i ther an t ibody o r an t igen , the an t igen–ant ibody complexes tend toremain sma l l and in so lu t ion . The op t ima l b ind ing , p roduc ing la rge aggrega tesP.12

tha t fa l l ou t o f so lu t ion , occurs when the concen t ra t ions o f an t ibody and an t igen a re in equ iva lence .The quan t i ta t i ve p rec ip i t i n cu rve p rov ides the bas is o f l abora to ry methods fo r de te rmin ing the amounto f an t igen o r an t ibody in , fo r example , a pa t ien t ' s se rum.


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FIG. 1 .8 . The p rec ip i t i n reac t ions .

MOLECULES FOR ADHESION, RECIRCULATION, AND

HOMINGPar t o f "1 - Rev iew o f Immuno logy "

A number o f su r face mo lecu les (adhes ins , i n tegr ins, se lect ins ) a re used by var ious e lements of theimmune sys tem to s tab i l i ze b ind ing be tween ce l l s to fac i l i t a te b ind ing o f an t igen-spec i f i c recep to rs ,to fac i l i t a te a t tachment o f l eukocy tes to endo the l ia l su r faces in o rder to leave the b lood vesse ls andente r i n to the sur round ing t i ssues , to iden t i f y and accumula te a t s i tes o f i n f l ammat ion , and to iden t i f yo rgan- o r t i ssue-spec i f i c s i tes (e .g . , l ymph nodes , i n tes t ina l mucosa) in to wh ich they mus t en te r i no rder to undergo deve lopmenta l p rocesses o r ca r ry ou t o ther immuno log ic func t ions ( 48 ,49 and 50 ).

CELLS OF THE IMMUNE SYSTEMPar t o f "1 - Rev iew o f Immuno logy "

Lymphocytes (General)The ab i l i t y o f the immune sys tem to recogn ize spec i f i ca l l y a d i ve rse range o f an t igens res ides wi ththe l ymphocy tes (2 ,3 and 4) . The l ymphocy t i c l i neage , der i ved f rom s tem ce l l s res id ing wi th in the

bone mar row, inc ludes the B l ymphocy tes , T l ymphocy tes , and nu l l ce l l s . B l ymphocy tes mature in thebone mar row, and those des t ined to become T l ymphocy tes m ig ra te to the thymus , where theymature . The bone mar row and thymus thus cons t i tu te the p r imary l ympho id o rgans o f the immunesys tem, as opposed to the secondary o rgans (e .g . , sp leen , l ymph nodes , Peyer pa tches) , where ce l l sla te r per iod ica l l y congrega te as they c i rcu la te th roughout the body .The ab i l i t y o f the immune sys tem to iden t i f y so many d i f fe ren t an t igens i s based on a d iv i s ion o flabor—each l ymphocy te (o r c lone o f l ymphocy tes ) i s ab le t o iden t i f y on ly one ep i tope o r de te rminan t .Dur ing i t s deve lopment and d i f fe ren t ia t ion , each ce l l tha t i s commi t ted to becoming a B o r Tlymphocy te rear ranges the DNA encod ing i t s recep to rs (as p rev ious ly desc r ibed) to cons t ruc t aun ique an t igen recep to r . Therea f te r , tha t ce l l and a l l o f i t s c lona l descendants express recep to rs wi ththe same an t igen ic spec i f i c i t y . O ther su r face mo lecu les and sec re ted p roduc ts serve to de f inefunc t iona l subse ts o f l ymphocy tes ( Tab le 1 .3 ) . The spec i f i c i t y o f an immune response l i es in the fac ttha t the en t ry o f a fo re ign an t igen in to the body s t imu la tes on ly those l ymphocy tes whose recep to rsrecogn ize and b ind the de te rminan ts expressed on the an t igen . As a resu l t o f th i s spec i f i c b ind ingand subsequent i n te rce l lu la r communica t ion , a response i s i n i t i a ted tha t i nc ludes the fo l l owingd is t inc t phases :


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TABLE 1 .3 . Cel l s o f the human immune sys tem: markers and func t ions

• Recogn i t i on o f an t igen by b ind ing to the recep to rs o f l ympho id ce l l s—of ten man i fes ted byc lona l p ro l i fe ra t ion o f the s t imu la ted ce l l s

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• Di f fe ren t ia t ion and matura t ion o f the s t imu la ted ce l l s to matu re func t iona l capac i ty• Response aga ins t the an t igen , ce l l , o r o rgan ism by any o f severa l methods• Estab l i shment o f immuno log ic memory

Memory res ides in a por t i on o f the s t imu la ted l ymphocy tes tha t do no t ca r ry ou t e f fec to r func t ions(51 ,52) . Ins tead , they rema in qu iescen t i n the sys tem, p rov id ing an en la rged poo l o f ac t i va ted ce l l sspec i f i c fo r the o r ig ina l s t imu la t ing ep i tope . As a resu l t , subsequent exposures to tha t same ep i tope

can p roduce fas te r and h igher (secondary o r anamnes t i c ) responses than were seen in the in i t i a l(p r imary ) response . Memory can pers is t fo r l ong per iods o f t ime and i s p r imar i l y ma in ta ined by Tlymphocy tes .

B Lymphocytes


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some types o f suppress ion , the mutua l nega t i ve regu la t ion o f T H1 and T H 2 ce l l s p rov id ingone such example .

A l though T l ymphocytes wi th αβ TCR a lso express e i ther the CD4 or C D8 markers , those wi th γδ TCRusua l l y express ne i ther . The on togeny , d i s t r i bu t ion , and func t iona l ro les o f γδ T l ymphocy tes a re s t i l lno t as we l l unders tood as those o f αβ T l ymphocy tes (65 ) . The TCRs o f a l i neage o f T ce l l s do no taccumula te muta t ions and , under a f f i n i t y , matu ra t ion , as do immunog lobu l ins .

Macrophages and Other Antigen-presenting CellsTCRs do no t usua l l y recogn ize an t igen a lone in i t s na tu ra l fo rm, bu t ra ther b ind to an t igen tha t has

been p rocessed and p resen ted on the sur face o f appropr ia te APCs ( 66 ,67 and 68) . APCs in te rna l i zean t igen , enzymat i ca l l y degrade i t i n to f ragments (p rocess ing) , and pu t the f ragments back on to the i rsu r face in assoc ia t ion wi th c lass I and I I MHC molecu les (p resen ta t ion ) ( 7 ) . APCs (Tab le 1 .3 ) i nc ludemonocy tes , macrophages , and o ther re la ted t i ssue-spec i f i c ce l l s tha t express c lass I I MHC molecu les(e .g . , as t rocy tes in the cen t ra l nervous sys tem, Langerhans ce l l s i n the sk in , Kup f fe r ce l l s i n thel i ve r , and so fo r th ) . In add i t i on , B l ymphocy tes (wh ich norma l l y express c lass I I ) can e f f i c ien t l yp rocess and p resen t an t igen ( 69 ,70) . There a re some o ther ce l l s tha t a re capab le o f t rans ien texpress ion o f c lass I I (e .g . , vascu la r endo the l ium) . In add i t i on , a var ie ty o f o ther mo lecu les on APCsand T ce l l s se rve to s tab i l i ze the con tac t be tween the TCR and combina t ion o f an t igen and MHCmolecu le .

Null CellsIn add i t i on to T and B ce l l s , the l ympho id l i neage inc ludes a subse t o f ce l l s l ack ing bo th o f thec lass ic l ympho id an t igen recep to rs ( immunog lobu l in and TCR) . Th is subse t i nc ludes k i l l e r (K) andnatu ra l k i l l e r (NK) ce l l s , and p robab ly o ther ce l l s , such as l ymphok ine-ac t i va ted k i l l e r ce l l s and la rgegranu la r l ymphocy tes , wh ich may represen t d i f fe ren t ia l l y ac t i va ted fo rms o f K and NK ce l l s ( 71 ,72) . Kce l l s bear recep to rs capab le o f recogn iz ing the Fc por t i on o f bound immunog lobu l ins . I f the an t igen i son the sur face o f a ce l l , the K ce l l uses the bound immunog lobu l in to make con tac t w i th tha t ce l l andlyse i t by d i rec t con tac t , a p rocess te rmed ant ibody-dependent ce l lu la r cy to tox ic i t y (ADCC) . The Kce l l has no spec i f i c i t y fo r the an t igen tha t i s bound to the an t ibody , on ly fo r the Fc por t i on o f thebound an t ibody . NK ce l l s appear to d i s t i ngu ish be tween a l te red (by ma l ignan t t rans fo rmat ion o r v i ra li n fec t ion ) ce l l s and comparab le norma l ce l l s and to b ind p re fe ren t ia l l y and l yse the fo rmer . Themeans by wh ich they make th i s d i s t i nc t ion i s unknown, bu t the i r ac t i v i t y i s he igh tened by IFN- γ andIL -2 . NK ce l l s a re ab le to recogn ize dec reases in the leve ls o f c lass I MHC molecu les o r o thermo lecu les on the sur face o f i n fec ted o r ma l ignan t ce l l s ( 71 ,7 2) . Recen t ev idence sugges ts tha t Kce l l s may be a subse t o f NK ce l l s and tha t the d is t i nc t ion be tween them may s imp ly re f lec tP.16

d is t inc t s tages o f d i f fe ren t ia t ion , o r even s imp ly the use o f d i f fe ren t assay sys tems.

Mast Cells and Granulocytes A var ie ty o f o ther ce l ls a re invo lved in some immune responses , par t i cu la r l y those invo lv ingin f lammat ion (Tab le 1 .3 ) . Mas t ce l l s and basoph i l s bear recep to rs (Fc εRI) fo r the Fc por t i on o funbound IgE, permi t t i ng them to use IgE on the i r own sur face as an an t igen de tec to r ( 73 ) . Whenant igen b inds s imu l taneous ly to two o r more such IgE mo lecu les on the same mas t ce l l (ca l l ed

br idg ing ) , a s igna l i s t ransmi t ted in to the ce l l , l ead ing to degranu la t ion and re lease o f a var ie ty o fmed ia to rs , i nc lud ing h is tamine , resu l t i ng in immed ia te hypersens i t i v i t y (a l l e rg ic ) responses ( 74) .Neut roph i l s a re d rawn to s i tes o f i n f l ammat ion by cy tok ines , where the i r phagocy t i c ac t i v i t y andproduc t ion o f enzymes and o ther so lub le med ia to rs con t r ibu te to the in f lammat ion . Eos inoph i l s(75 ,76) a re invo lved in immune responses aga ins t l a rge paras i tes , such as roundworms, and a reapparen t l y capab le o f k i l l i ng them by d i rec t con tac t .

PRIMARY ORGANS: BONE MARROW AND THYMUSPar t o f "1 - Rev iew o f Immuno logy "The p r imord ia l s tem ce l l s tha t u l t imate ly p roduce the human immune sys tem (and o ther e lements o fthe hematopo ie t i c sys tem) o r ig ina te in the yo lk sac , abou t 60 days a f te r fe r t i l i za t ion . These ce l l smig ra te to the fe ta l l i ve r and then (beg inn ing abou t 80 days a f te r fe r t i l i za t ion ) to the bone mar row,where they rema in fo r l i f e . These p r imord ia l hematopo ie t i c s tem ce l l s g i ve r i se to more spec ia l i zeds tem ce l l s , wh ich lead to the e ry th rocy t i c , g ranu locy t i c , th rombocy t i c (p la te le t ) , mye locy t i c (e .g . ,macrophages and monocy tes ) , and l ymphocy t i c l i neages .

Pr imary l ympho id o rgans cons is t o f the bone mar row and thymus , where B and T l ymphocy tes ,respec t i ve ly , matu re . B ce l l s undergo the i r deve lopment , i nc lud ing genera t ion o f immunog lobu l inrecep to rs , wh i le in the bone mar row. Ce l l s o f the T- l ymphocy te l i neage , however , m ig ra te f rom thebone mar row to the thymus , where they undergo deve lopment and genera t ion o f TCRs ( 77 ,78) . Morethan 95% o f the ce l l s tha t m ig ra te in to the thymus per i sh there , fa i l i ng to surv i ve a r igo rous se lec t ionprocess to p romote the deve lopment o f those re levan t to the ind iv idua l ' s MHC genotype and toe l im ina te po ten t ia l l y se l f - reac t i ve ce l l s . I t i s i n the thymus , under the in f luence o f thymic s t roma,nurse ce l l s , and thymic APCs, tha t T ce l l s rece ive an in i t i a l “ thymic educa t ion” w i th regard to whatshou ld be recogn ized as se l f (79 ,80) .

Secondary Organs: Spleen and Lymph NodesThe secondary o rgans (e .g . , sp leen , l ymph nodes , Peyer pa tches) p rov ide s i tes where rec i rcu la t inglymphocy tes and APCs en te r a f te r passage th rough d ive rse par ts o f the body , “m ing le ” i n c loseprox im i ty fo r a per iod o f t ime, and then leave aga in to rec i rcu la te . Th is in t imate con tac t be tweenrec i rcu la t ing ce l l s fac i l i t a tes the c lose in te rac t ions needed to in i t i a te immune responses and genera teappropr ia te l y sens i t i zed ce l l s , whose ac t i v i t i es may then be expressed th roughout the body ( 2 ,3 and4) . Thus , mos t immune responses a re ac tua l l y i n i t i a ted in the secondary o rgans .

INTERACTIONS IN IMMUNE RESPONSESPar t o f "1 - Rev iew o f Immuno logy "


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Antibody ResponsesMore than 99% o f an t ibody responses a re aga ins t T -dependent an t igens , wh ich requ i re theinvo lvement o f T l ymphocy tes in genera t ion o f the responses . The re la t i ve ly few T- independent (T I )an t igens , wh ich can p rovoke an t ibody p roduc t ion in the absence o f T -ce l l i nvo lvement , fa l l i n to twogenera l ca tegor ies : T I -1 and T I -2 . T I -1 an t igens (e .g . , a va r ie ty o f l ec t ins ) a re m i togen ic , i nduc ingpro l i fe ra t ion and d i f fe ren t ia t ion th rough b ind ing o f B-ce l l su r face mo lecu les o ther thanimmunog lobu l ins , whereas T I -2 an t igens have regu la r repea t ing s t ruc tu res (e .g . , dex t ran , w i threpe t i t i ve carbohydra te mo ie t ies ) and a re capab le o f c ross - l i nk ing mu l t i p le immunog lobu l in mo lecu leson the sur face o f the same B ce l l .

An t ibody responses to mos t an t igen s a re T dependent and requi re in te rac t ions be tween APCsP.17

(e .g . , macrophages) , T l ymphocy tes , and B l ymphocy tes ( 53 ,81 ,82 ,83 and 8 4) , as i l l us t ra ted in F ig .1 .9 . B l ymphocy tes respond ing to T-dependent an t igens requ i re two s igna ls fo r p ro l i fe ra t ion andd i f fe ren t ia t ion : (a ) the b ind ing o f the i r su r face immunog lobu l in by appropr ia te spec i f i c an t igen , and(b) the b ind ing o f cy tok ines (e .g . , IL -4 and o ther he lper fac to rs ) p roduced by ac t i va ted he lper T ce l l s(85 ,86) . The he lp p rov ided by T ce l l s ac ts on ly over a shor t range ; thus , the T and B ce l l s mus t be infa i r l y i n t imate con tac t fo r these in te rac t ions to occur success fu l l y . The invo lvement o f APCs, such asmacrophages o r even B ce l l s themse lves , i s essen t ia l fo r the ac t i va t ion o f he lper T ce l l s and p rov idesa means o f b r ing ing T and B ce l l s i n to p rox im i ty .

FIG. 1 .9 . In te rac t ions in an t ibody p roduc t ion .

Cellular ResponsesThe mixed l ymphocy te response (MLR) i s an i n v i t ro measure o f T -ce l l p ro l i fe ra t ion (p r imar i l y o f CD4 + T ce l l s ) tha t i s o f ten used as a measure o f the in i t i a l phase ( recogn i t i on and p ro l i fe ra t ion ) o f thece l lu la r response . Sp len ic o r l ymph node T ce l l s (o r bo th ) f rom the ind iv idua l i n ques t ion ( responder )a re m ixed wi th l ymphocy tes f rom ano ther ind iv idua l (sens i t i ze r ) aga ins t whom the response i s to beeva lua ted . The sens i t i z ing ce l l s a re usua l l y t rea ted (e .g . , w i th m i tomyc in o r i r rad ia t ion ) to p reven tthem f rom pro l i fe ra t ing . The two ce l l popu la t ions a re incuba ted toge ther fo r 4 to 5 days , a f te r wh icht ime t r i t i a ted thymid ine i s added to the cu l tu re fo r a few hours . I f the responder ce l l s ac t i ve lyp ro l i fe ra te as a resu l t o f the recogn i t i on o f fo re ign an t igens on the sens i t i z ing ce l l s , s ign i f i can tinc reases o f thymid ine incorpora t ion (over con t ro l l eve ls ) can be measured . The s t ronges t MLRresponses typ ica l l y occur when the sens i t i z ing ce l l s bear d i f fe ren t c lass I I MHC molecu les than therespond ing ce l l s , a l though p r imary s ign i f i can t MLR responses can a lso o f ten be observed fo r c lass IMHC d i f fe rences on ly , and even fo r some non-MHC gene d i f fe rences , such as the Mls gene in themouse (87) . I f the responder was su f f i c ien t l y sens i t i zed i n v i vo be fo re the MLR, s ign i f i can t responsesto o ther non-MHC a l loan t igens can o f ten be seen as we l l . The MLR is a spec ia l subse t o f T -p ro l i fe ra t i ve assays , one tha t i s d i rec ted a t gene t i ca l l y encoded a l loan t igens be tween two popu la t ionso f l ymphocy tes . The same pr inc ip le can , however , be used to assess the p ro l i fe ra t ion o f T ce l l saga ins t an t igen in o ther fo rms , such as so lub le an t igen on the sur face o f APCs.Ce l l -med ia ted l ys i s i s the response func t ion o f cy to tox ic T l ymphocy tes . A f te r appropr ia te s t imu la t ion(by an t igen in con junc t ion wi th c lass IP .18

MHC molecu les on the sur face o f APC, toge ther wi th he lp f rom T H 1 ce l l s ) , CTLs p ro l i fe ra te andd i f fe ren t ia te to become capab le o f b ind ing and des t roy ing ta rge t ce l l s th rough d i rec t ce l l–ce l l con tac t(F ig . 1 .10) . C lona l l y der i ved CTLs can l yse on ly those ce l l s tha t bear the same combina t ion o fan t igen and c lass I MHC molecu les o r ig ina l l y recogn ized by the o r ig ina l l y s t imu la ted CTL f rom wh ichthe c lone was genera ted . Death o f the ta rge t ce l l can be induced th rough the ac t ion o f per fo r inssec re ted by the CTL o r th rough apop tos is induced by b ind ing o f ta rge t ce l l recep to rs by l i gands on

the sur face o f CTLS or by cy tok ines sec re ted by the CTL.


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FIG. 1 .10 . Cy to tox ic T l ymphocy tes .

DTH is an i n v i vo response by in f lammatory T H 1 (o r T d h ) ce l l s (F ig . 1 .11) . Ind iv idua ls p resens i t i zedaga ins t a par t i cu la r an t igen , then la te r cha l lenged in t raderma l l y w i th a sma l l amount o f the sameant igen , d i sp lay loca l i n f l ammatory responses 24 to 72 hours la te r a t the s i te o f cha l lenge . Perhapsthe bes t known example i s a pos i t i ve tubercu l in sk in tes t (Mantoux tes t ) . The response i s med ia tedby CD4 + T H1 ce l l s , p rev ious ly sens i t i zed aga ins t a par t i cu la r combina t ion o f an t igen and c lass I I MHCmolecu les . Upon subsequent exposure to the same combina t ion o f an t igen and c lass I I MHCmolecu les , the T H1 ce l l s respond by sec re t ing a ser ies o f cy tok ines ( Tab le 1 .2 ) tha t a t t rac tmacrophages to the s i te o f i n te res t and ac t i va te them. The ac t i va ted macrophages exh ib i t aninc reased s i ze and ac t i v i t y , enab l ing them to des t roy and phagocy t i ze the an t igen ic s t imu lus .However , because macrophages a re no t an t igen spec i f i c , they may a lso des t roy norma l ce l l s andt i ssues in the loca l a rea , re fe r red to as i nnocent bys tander des t ruc t ion .

FIG. 1 .11 . De layed- type hypersens i t i v i t y .

THE IMMUNE SYSTEM: A DOUBLE-EDGED SWORDPar t o f "1 - Rev iew o f Immuno logy "


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The immune sys tem evo lved to p ro tec t the body f rom a var ie ty o f ex te rna l ( i n fec t ious agen ts o rharmfu l mo lecu les ) and in te rna l (ma l ignan t ce l l s ) th rea ts . In th i s regard , the immune sys tem prov idesthe body wi th a means fo r m in im iz ing o r p reven t ing d isease . Th is i s mos t c lear l y i l l us t ra ted byind iv idua ls who have de fec ts in immune func t ion ( immunodef i c iency d isease) resu l t i ng f rom genet i c ,deve lopmenta l , i n fec t i ve , o r therapeu t i c causes . Because o f i t s des t ruc t i ve po ten t ia l , however , theimmune sys tem is a l so capab le o f caus ing d isease when con f ron ted wi th inappropr ia te an t igen ics t imu la t ion o r l oss o f regu la to ry con t ro l ( 88) .P.19

TransplantationTransp lan ta t ion invo lves the ab i l i t y to rep lace damaged o r d i seased body par ts by t ransp lan t ingorgans f rom one ind iv idua l to ano ther . Un fo r tuna te ly , the immune sys tem is exqu is i te l y adep t a trecogn iz ing nonse l f and re jec t ing t ransp lan ted o rgans f rom donors d i f fe r ing gene t i ca l l y f rom therec ip ien t (89) . The gene t i ca l l y encoded mo lecu les tha t t r i gger the re jec t ion response a re te rmedh is tocompat ib i l i t y an t igens and a re d iv ided in to two p r imary ca tegor ies : ma jo r (encoded by c lass Iand I I MHC genes) and minor (scores , poss ib l y hundreds , o f an t igens encoded by wide ly d i ve rsegenes sca t te red ac ross the chromosomes) . Because a gene t i ca l l y per fec t match be tween hos t anddonor in humans ex is ts on ly be tween iden t i ca l tw ins , t ransp lan ta t ion surgeons a re fo rced to m in im izeor e l im ina te the rec ip ien t immune response aga ins t the t ransp lan ted o rgan . Some o f these responsescan be min im ized by us ing the c loses t poss ib le gene t i c match be tween donor and rec ip ien t by t i ssuetyp ing , bu t i n humans , th i s i s poss ib le on ly fo r the HLA sys tem. The a l te rna t i ve i s the use o f d rugs toreduce immune respons iveness . Idea l l y , on ly the ab i l i t y o f the immune sys tem to reac t to thean t igens on the t ransp lan ted o rgan wou ld be d im in ished ( i .e . , i nduc t ion o f an t igen-spec i f i cimmuno log ic to le rance) , l eav ing the res t o f the immune sys tem in tac t . However , we cur ren t l y mus tre ly on d rugs tha t depress the immune sys tem in a re la t i ve ly nonspec i f i c fash ion , thus leav ing thepa t ien t suscep t ib le to po ten t ia l l y fa ta l oppor tun is t i c i n fec t ions . Recen t l y , some agents ( i .e . ,

cyc lospor ine and FK506) have been found to d im in ish immune responses in a somewhat more spec i f i cfash ion , bu t the i r l ong- te rm use may have secondary adverse e f fec ts on o rgans .Bone mar row t ransp lan ta t ion represen ts a spec ia l case in wh ich the g ra f t i t se l f compr isesimmunocompeten t t i ssue and the hos t i s e i ther immunodef i c ien t o r immunosuppressed . Thus , there i sthe poss ib i l i t y o f the g ra f t mount ing an immune response aga ins t fo re ign hos t ce l l s and t i ssues ,lead ing to g ra f t -ve rsus -hos t d i sease ( 90,91)

Autoimmunity Au to immune d iseases invo lve the deve lopment o f an t ibody o r ce l l -med ia ted immune resp onsesd i rec ted aga ins t se l f an t igens ( 88 ,92) . In many au to immune d iseases , an ind iv idua l ' s r i sk i sP.20

a f fec ted by h is o r her HLA genes (2 ,3 and 4 ,93 ,94) . There a re severa l poss ib le scenar ios underwh ich such undes i rab le responses migh t be in i t i a ted .

Au to immune responses may a r i se when an t igens t ha t have been norma l l y seques te red f rom theimmune sys tem (e .g . , i n immuno log ica l l y p r i v i l eged s i tes ) a re exposed as a resu l t o f t rauma. Hav ingnever been de tec ted p rev ious ly by the immune sys tem as i t deve loped i t s sense o f se l f ve rsus

nonse l f , such an t igens a re now seen as fo re ign . Second, the in te rac t ion o f se l f mo lecu les wi th sma l lreac t i ve chemica ls (e .g . , hap tens ) o r w i th in fec t ious agen ts may p r oduce a l te ra t ions in se l f mo lecu les(a l te red an t igens o r neoant igens) , resu l t i ng in the i r de tec t ion as nonse l f . Th i rd , immune responsesaga ins t de te rminan ts on in fec t ious agen ts may genera te c lones o f l ymphocy tes wi th recep to rscapab le o f c ross - reac t ing wi th se l f an t igens (c ross - reac t i ve an t igens ) . A c lass ic example i s rheumat i cfever , wh ich resu l ts f rom immune responses aga ins t s t rep tococca l an t igens tha t a re c ross - reac t i vewi th mo lecu les found on card iac t i ssue . F ina l l y , some au to immune responses , espec ia l l y those tha ttend to deve lop in la te r l i f e , may resu l t f rom senescence o f i nh ib i to ry mechan isms, such assuppressor T l ymphocy tes , tha t keep au to immune responses under con t ro l . For example , the onse t o fsys temic lupus e ry thematosus i s assoc ia ted wi th age and an accompany ing dec l ine in suppressor T-ce l l func t ion .

Immune Complex DiseasesThe humora l immune response i s genera l l y e f f i c ien t i n e l im ina t ing an t igen–ant ibody complexesth rough the phagocy t i c ce l l s o f the re t i cu loendothe l ia l sys tem. There a re , however , s i tua t ions inwh ich an t igen–ant ibody complexes ( invo lv ing IgG and IgM an t ibod ies ) reach such h igh concen t ra t ionstha t they p rec ip i ta te ou t o f so lu t ion and accumula te in t i ssues , o f ten unre la ted to the source o f thean t igen . Th is may lead to sys temic o r l oca l i zed in f lammat ion as the complexes b ind and ac t i va te

serum complement components , a t t rac t phagocy t i c ce l l s , and induce the re lease o f p ro teo ly t i cenzymes and o ther med ia to rs o f i n f l ammat ion . A t tempts to c lear depos i t i ons o f an t igen–ant ibodycomplexes o f ten damage the t i ssues and o rgans invo lved . Such s i tua t ions mos t o f ten a r i se as asecondary e f fec t o f s i tua t ions in wh ich there i s a pers i s tence o f an t igen (e .g . , ch ron ic in fec t ion ,cancer , au to immun i ty , o r f requent repea ted admin is t ra t ion o f an ex te rna l reagent ) , l ead ing tocon t inua l s t imu la t ion o f the immune sys tem and p roduc t ion o f h igh leve ls o f an t ibod ies aga ins t thepers is t i ng an t igen . Among the mos t commonly damaged s i tes a re the k idneys , o f wh ich the f i l t ra t ionappara tus tends to accumula te depos i ted complexes (g lomeru lonephr i t i s ) ; the synov ia l j o in tmembranes ( rheumato id a r th r i t i s ) ; the sk in ( rashes) ; and the endo the l ia l wa l l s o f b lood vesse ls(a r te r i t i s ) .

Contact DermatitisContac t dermat i t i s i s an example o f a norma l l y p ro tec t i ve T-ce l l–med ia ted immune response tha tbecomes harmfu l under ce r ta in c i rcumstances . Contac t dermat i t i s i s a DTH r esponse , usua l l y causedby the p resence o f sma l l , chemica l l y reac t i ve an t igens (e .g . , heavy meta ls o r , as in the case o fpo ison i vy , p lan t l i p ids such as ca techo l ) tha t b ind to se l f p ro te ins (e .g . , c lass I I MHC molecu les ) onthe sk in and p roduce neoant igens .

Allergies and Anaphylaxis (Immediate Hypersensitivity) A l l e rg ies and anaphylax is represent ant igen-speci f ic immuno log ic reac t ions invo lv ing IgE an t ibod iesbound (by the i r Fc domain ) to the membranes o f mas t ce l l s and basoph i l s ( 95) . When an t igen i sbound, resu l t i ng in c ross - l i nk ing o f the IgE mo lecu les , the mas t ce l l s a re s t imu la ted to degranu la teand re lease h is tamine , se ro ton in , p la te le t -ac t i va t ing fac to rs , and o ther med ia to rs o f immed ia te


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hypersens i t i v i t y . The resu l t i s the rap id onse t o f an in f lammatory response . Immed ia tehypersens i t i v i t y may deve lop aga ins t a wide a r ray o f env i ronmenta l subs tances and may be loca l i zed(e .g . , i t ch ing , tear ing) o r sys temic (e .g . , i nvo lv ing the c i rcu la to ry sys tem) . The la t te r may be l i fe -th rea ten ing i f severe . T rea tmentP.21

invo lves the p rompt admin is t ra t ion o f pharmaceut i ca l agen ts (e .g . , ep inephr ine , an t ih i s tamines ) .

TOLERANCEPar t o f "1 - Rev iew o f Immuno logy "In many cases , i t i s des i rab le to d im in ish o r e l im ina te immune responses , thus induc ing to le rance tosome par t i cu la r an t igen . For example , au to immune responses , as thmat i c and a l l e rg ic responses , andthe hos t responses aga ins t t ransp lan ted t i ssues o r o rgans a l l represen t s i tua t ions in wh ich suchto le rance wou ld be des i rab le . There a re two approaches : nonspec i f i c and spec i f i c .Immunosuppress ion i s the e l im ina t ion o f a l l immune responses , regard less o f the spec i f i c i t y o f thoseresponses . Th is may occur na tu ra l l y , as in the case o f i nd iv idua ls who a re de f i c ien t i n immunefunc t ion fo r gene t i c reasons (e .g . , severe combined immunodef i c iency d isease) o r as the resu l t o fin fec t ion (e .g . , acqu i red immunodef i c iency syndrome) . A l te rna t i ve ly , i t may be in ten t iona l l y imposedby the app l i ca t ion o f rad ia t ion , d rugs , o r o ther therapeu t i c reagents (e .g . , an t i l ymphocy te sera ) . Suchprocedures , however , impose a new se t o f r i sks because the i r nonspec i f i c i t y l eaves the pa t ien t (o rexper imenta l an ima l ) open to in fec t ions by oppor tun is t i c pa thogens . At tempts to d im in ish theseconsequences invo lve the deve lopment o f reagents wi th nar rower e f fec ts , i nc lud ing d rugs such ascyc lospor ine and FK506, o r the app l i ca t ion o f an t ibod ies spec i f i c fo r on ly par t i cu la r subse ts o fl ymphocy tes (96) . Immuno log ic to le rance i s the spec i f i c acqu i red inab i l i t y o f i nd iv idua ls to respond toa spec i f i c immunogen ic de te rminan t toward wh ich they wou ld o therwise norma l l y respond. To le rance

is more des i rab le than immunosuppress ion because i t e l im ina tes o r i nac t i va tes on ly thoselymphocy tes invo lved in the responses o f concern , l eav ing the rema inder o f the immune sys tem in tac tto dea l w i th oppor tun is t i c i n fec t ions .The na tu ra l i nduc t ion o f to le rance dur ing the deve lopment o f the immune sys tem preven ts immuneresponses aga ins t se l f an t igens ( se l f to le rance ) , thus p reven t ing au to immun i ty ( 97 ,98 ).Exper imenta l l y , to le rance can be induced in immunocompeten t adu l t an ima ls by man ipu la t ing avar ie ty o f fac to rs , i nc lud ing age , the phys ica l na tu re and dose o f an t igen , and the rou te o fadmin is t ra t ion ( 99 ,100) . To le rance may be induced in bo th T and B l ymphocy tes , a l though to le ranceo f T ce l l s genera l l y requ i res lower doses o f an t igen and i s e f fec t i ve fo r a longer per iod o f t ime. Inadd i t i on , because B l ymphocy tes requ i re T-ce l l he lp , the induc t ion o f to le rance in T ce l l s o f ten a lsod im in ishes cor respond ing an t ibody responses .The means by wh ich spec i f i c to le rance i s i nduced and ma in ta ined invo lve th ree genera l mechan isms,a l l o f wh ich p robab ly occur in va r ious

patterson's allergic diseases (6ed, 2002)(509s)

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