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Immunohematology Journal of Blood Group Serology and Education

C e l e b r a ti n g

Y e ar s Volume 25, Number 2, 2009


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ImmunohematologyJournal of Blood Group Serology and Education

Volume 25, Number 2, 2009

ContentsInvited Review: Milestones Series

Milestones in laboratory procedures and techniquesM E !eid

Case Report nti!"p a #induced se$ere delayed hemolytic trans%usion reaction! "o#$y, B %atel, and J S &arri#on

Review&he '( blood group system re$isited) a re$ie* and updateJ ! Storry and M ' (l##on

Case Report

+linical e$aluation %or lymphoproli%erati$e disease prompted by %inding o% IgM *arm autoanti!I & in t*o cases! M 'eger, ) 'o*der, M + ungo, - +$en, & M Ma#on, and G Garratty

Original Report,outheast sian o$alocytosis is associated *ith increased e-pressiono% .u%%y antigen receptor %or chemo/ines . +2. J -oolley, % &utc$in#on, J + !eeder, J - "a/ura, and +ort1#

Review,ic/le cell disease) a re$ie* S !o#eff

Report+onsortium %or 'lood roup enes +' 2) 008 reportG enomme, + M -e#t$off, ' +a#til$o, and M E !eid for t$e +BGG

Special Dedication ohn udd I'M, MI'iol

Mallory

8 Letter from the Editors

83 A nnouncements

84 A dvertisements

88 Instructions for A uthors


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Editors in Chief ,andra :ance M, M& ,+;2,''

%$iladelp$ia, %enn#yl ania

+onnie M estho%% ;h. M& ,+;2,''%$iladelp$ia, %enn#yl ania

Senior Medical Editoreralyn M Meny M.

%$iladelp$ia, %enn#yl ania

Managing Editor +ynthialic/inger M& ,+;2,''%$iladelp$ia, %enn#yl ania

! ec hnical Editor +hristineder M. -a#$ington, i#trict of +olumbia

eorge arratty ;h. +;ath%omona, +alifornia

'renda rossman M.St 'oui#, Mi##ouri

ohn udd I'M, MI'iol nn rbor, Mic$igan

+hristine 902 -eb #ite? *** redcro## orgC20A@
http://www.redcross.org/immunohematologyhttp://www.redcross.org/immunohematologyhttp://www.redcross.org/immunohematology


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Invited Review: Milestones Series

IMMU NO HEMATO LOG Y, Volume !, Num"er , ##$ %

-

Milestones in la%orator$ procedures andtec hni&ues

M&E&Reid

$en . left England in 9 9, $emagglutination *a#done by #edimentation .n Ne* 3or4, . *a# introCduced to centrifugation a# a met$od to #peed t$e

proce## Bot$ approac$e# accompli#$ed #imilar goal#, butone *a# more time efficient #e of ot$er tec$ni6ue#, #uc$a# -e#tern immunoblotting, cloning gene#, andpolymera#e c$ain reaction, made it po##ible to gain muc$4no*ledge about blood group antigen#

Immunohematology " eginnings.n 9 5, Sandy Elli#or and . from +entral +alifornia

!egion of t$e merican !ed +ro## 7 !+8 and &elen GlidCden from !+ &ead6uarter# olunteered to coCedit t$efir#t American Red Cross Reference Laboratory

Newsletter ;$e purpo#e of t$i# ne*#letter, *$ic$ *a# fort$e tec$noloC gi#t# and by t$e tec$nologi#t#, *a# to #$aretec$ni6ue# and tec$nical tip#, educate, and mentor intec$nical *riting ;$e fir#t year 7 9 8, t$e ne*#letter *a#lo*Ctec$F it *a# #imply p$otocopied ;$at year, t$e !+!eference 'aboratory +ommittee ran a competition and bypopular ote t$e ne*#C letter *a# renamed t$e Red Cell

Free Press nd to impro e it# appearance it *a# printed;$i# informal ne*#letter *a# publi#$ed for D year#, until in

9D> it e ol ed into Immuno- hematology under t$e ableeditor#$ip of elore# MalloryB

uring t$e 25Cyear life of Immunohematology , tec$ni6ue#e ol ed t$at allo*ed t$e gat$ering of an ama/ing amountof 4no*ledge about blood group# and t$e membrane comCponent# on *$ic$ t$ey are carried e#pite t$i# e olution,to t$i# day *e #till mainly rely on $emagglutination 7directand indirect8 for detection and identification of antibodie#to blood group antigen# and for te#ting for incompatibility;$i# ama/ing tec$ni6ue i# $ard to beat in term# of#en#iti iC ty and #pecificity t$at are appropriate for #afetran#fu#ion#

Earl$ Immunohematolog$ ! esting # ractices.n t$e era before t$e ARC Newsletter , it *a# commonC

place to perform e:ce##i e te#ting 7e g , te#ting at roomtemperature, u#e of en/ymeCtreated !B+# at temperature# belo* A +, ab#orbing eluate# from autoimmune $emoClytic anemia ca#e#, and performing minor cro##matc$e#8on a #ingle blood #ample )ortunately, Eloi#e Giblett in t$eearly 9 0# ad ocated #topping unnece##ary te#tingF #$e belie ed te#ting #$ould be done a# clo#e to p$y#iologic conCdition# a# po##ible, i e , te#ting at A + u#ing pla#maC#u#Cpended !B+# &er rea#oning *a# #c$olarly and logical andc$anged t$e *ay te#ting *a# 7and i#8 done GiblettH# laboraC

tory u#ed pla#maC#u#pended !B+#, *$ic$ neutrali/ed mantibodie# to 'e*i# and +$

l#o in t$e late 9 0#, an e:traordinary numbercro##matc$e# *ere performed .ndeed, t$e number *a# ce##i e ;$e concept# of a Itype and #creen2 and a Ima:mum #urgical blood order #c$eduleA *ere introduce;$e#e approac$e# *ere 6uic4ly adopted, and t$ey reducnot only t$e number of cro##matc$e# but al#o t$e numof !B+ component# re#er ed for a particular patient Safter, t$e #ugge#tion to drop t$e antiglobulin cro##mafor patient# *$o $ad a negati e antibody #creen *a# ulea#$ed >K e#pite concern# t$at antibodie# to antigenot e:pre##ed on #creening !B+# 7e g , antiC-ra8 *ou be mi##ed, t$i# practice i# no* commonplace .ndeed,p$y#ical immediateC#pin cro##matc$ i# no* fre6uentlyplaced by a computer cro##matc$E

'se of Enhancement Reagents and (onserologic! ec hni&ues

(ld #tandby tec$ni6ue# #uc$ a# #aline and albumin from fa or and *ere largely replaced by lo*CionicC#tre#olution 7'.SS8 met$od# in t$e midC 9 0#D and by '.SSCaditi e #olution# #$ortly t$ereafter '.SS rapidly gaipopuC larity becau#e it #imultaneou#ly reduced incubatime and increa#ed #en#iti ity .n 9D>, t$e #ame yea

t$e fir#t olC ume of Immunohematology appeared, a #olp$a#e ad$erC ence a##ay for detection of antibodyCanreaction# *a# introduced )or a re ie* of t$i# tec$nolo#ee Bec4 et al9Sub#e6uently, ot$er tec$ni6ue# *ere reported and 6uic4 became popularF t*o e:ample# are t$e u#e of polyet$ylglycol 7%EG8 a# a potentiator of antibodyCantigen reacin 9D 0 and t$e column agglutination tec$nology, u#ia gel a# t$e #upport medium, in 990 utomated a##a ba#ed on $emagglutination and manual or automated #olp$a#e ad$erence a##ay# are no* in u#e, but t$ey $a e replaced $emagglutination te#t# in tube# in many #etting


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Many reagent# became commercially a ailable, and a#compliance re6uirement# became more #tringent, laboraCtorie# reduced t$e number of reagent# t$ey prepared inC$ou#e Safety concern# prompted many c$ange# )a oritemet$od# fell from grace, #uc$ a# t$e u#e of et$erLa# a reC#ult of concern# about it# lo* fla#$ point l#o, teratogenic,

carcinogenic, and neuroto:ic c$emical# became le## readCily a ailable *arene## of t$e potential $a/ard# of *or4Cing *it$ certain c$emical# and *it$ blood #ample# t$atmay contain ariou# pat$ogen# led to t$e #trictre6uirement to *ear per#onal protecti e e6uipment #uc$a# glo e#, laboraC tory coat#, eye protection, and clo#edCtoed #$oe# ;$e longC #tanding practice of drin4ing, eating,and #mo4ing in t$e laboratory *a# aboli#$ed

;$e alue of proteolytic en/yme#, notably ficin, for enC$ancing t$e reacti ity of #ome antibodyCantigen reaction# *$ile *ea4ening or ablating ot$er# $a# been appreciatedfor many year# 2 (t$er red cell modification# #uc$ a# diCt$iot$reitol 7 ;;8, tryp#in, and ' Cc$ymotryp#inA *ere inC

troduced &o*e er, it too4 #ome time before t$e full po*erof u#ing t$e combination 7i e , te#ting !B+# treated *it$ficin or papain, tryp#in, ' Cc$ymotryp#in, or ;;8 of t$e#emet$od# to aid in antibody identification *a# appreciated lt$oug$ cla##ic antibody identification approac$e# 7andappropriate control#8 are #till nece##ary to name an antiC body #pecificity po#iti ely, a #y#tem of parallel te#ting oft$e #ame !B+# untreated and treated *it$ differentreagent# pro ide# a aluable tool in $elping to guide u# int$e rig$t diC rection, *it$out re6uiring a a#t library of rarereagent# B>,B5 -$en u#ing en/yme# for t$i# purpo#e, it i# importantto include a negati e 7or auto8 control, a# a proportion of$uman #era contain antibodie# t$at attac$ to !B+# treated *it$ a proteolytic en/yme

'se of Monoclonal Reagents)or many year#, *e *ere dependent on polyclonal antiC

bodie# from $uman or rabbit #era or from plant lectin##uc$ a# icia graminea , !lex euro"eaus , and #olichosbiflorus for blood grouping reagent# .n 9 5, " $ler andMil#tein de#cribed a tec$ni6ue to fu#e murine myelomacell# *it$ antibodyC#ecreting B cell# to produce monoclonalantibodC ie# ;$i# tec$ni6ue *a# embraced, andmonoclonal anC tibodie# *ere produced to $ig$lyimmunogenic antigen# #uc$ a# to carbo$ydrate $uman blood group antigen# 7 and B, 'e*i#, and % 8 and $ig$copy number glycoprotein# 7M, N8 .t too4 #e eral year# before $uman B cell# *ere u#ed in place of mou#e cell# -it$ t$i# ad ancement came t$e production ofmonoclonal antiC in 9DA9 MonocloC nal antibodie# *it$ ot$er #pecificitie# $a e been made in t$e la#t 25 year# 9 ;$ey are no* t$e predominant #ource of typingreagent#, and t$ree international *or4#$op# $a e been$eld to #tudy reaction c$aracteri#tic# of numerou#monoclonal antibodie# Monoclonal antibodie# $a e $ada ma or impact on our ability to define ariant !B+#, e#peCcially partial antigen#, and to optimi/e tec$ni6ue# #uc$a# flo* cytometry and -e#tern immunoblotting Molecular

biology tec$ni6ue# $a e made it po##ible to con ert mur.gG monoclonal antibodie# to $uman .gG or directly aggltinating .gM 20

! ec hni&ues to #redict Clinical Significance of A nti%odies

&emagglutination detect# antibodie#, but in it#elf donot predict t$eir clinical #ignificance +riteria #uc$ a# tip$a#e of reacti ity, .g cla##, .gG #ubcla##, and #pecif7and t$e $i#toric 4no*ledge of t$e clinical #ignificancean antibody in ot$er patient#8 are u#eful indicator# but anot une6ui ocally good predictor# of clinical #ignifican;$e monocyte monolayer a##ay 7MM 8 i# a# clo#econdition# in i o a# i# po##ible to e#tabli#$ in itropro ide# inC #ig$t into t$e potential clinical #ignificancan antibody .t $a# been applied to predicting t$e clinicrele ance of antibodie# in tran#fu#ion2 and $emolytidi#ea#e of t$e ne*born,22K2> but i# a $ig$ly #peciali/ed antec$nically difC ficult te#t t$at belong# in a #mall numof laboratorie# not$er tec$ni6ue, flo* cytometry, $ been u#ed to detect minor !B+ population# in a fetamaternal $emorr$age and to follo* t$e #ur i al tran#fu#ed !B+#,25,2 to determine t$e do#age of a bloogroup antigen on !B+#,2 and 6uantiC tation of !B+Cboun.gG 2D

Numerou# tec$ni6ue# $a e been u#ed to identify loantibodie# underlying autoantibodie#29KA2 ll are timecon#uming, a# are met$od# to #eparate patient !B+# frot$o#e of tran#fu#ed donor !B+# #o t$at t$e patientH# !Bcan be p$enotyped AA -a#$ing perip$eral blood !B+# fromtran#fu#ed patient# *it$ #ic4le cell di#ea#e *it$ a $ypotoic #olution i# a #imple and cle er tec$ni6ue to obtain tpatientH# !B+# for typing by $emagglutinationA> lt$ougt$e#e tec$ni6ue# $a e alue, t$ey al#o $a e limitation#

Molecular ! esting lt$oug$ $emagglutination remain# t$e predominan

te#t for detecting antibodyCantigen interaction#, unrelattec$ni6ue# $a e pro ided in#ig$t into !B+ component$at carry blood group antigen# .n t$e decade befo

Immunohematology fir#t appeared, t$e -e#tern immunoC blotting met$od *a# u#ed e:ten#i ely to #tudy c$aractertic# of component# carrying blood group# ;$i# approatoget$er *it$ cloning and #e6uencing of t$e geneencoding blood group antigen#,A5 $a# re ealed #e6uen$omology to 4no*n protein# in ot$er cell type# anpro ided in#ig$t# into t$e #tructure and function of t!B+ membrane comC ponent# carrying blood grou7;able 8A

;$e cloning and #e6uencing of gene# laid t$e ground *or4 for analy#i# of many allele# encoding ariant blogroup antigen# and p$enotype# and, t$u#, our ability te#t N by t$e polymera#e c$ain reaction 7%+!8 predict a blood group Sub#e6uent manufacturing mac$ine# to automatically perform %+! amplificatiomade it po##ible to perform t$i# tec$ni6ue in a cliniclaboratory #etting %+!Cba#ed te#t# on N to predi


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blood type $a e #e eral application# t$at pro ide a#ub#titute for p$enotypingA ;$e


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Milestones in l("or(tor) *ro+edures (nd te+ ni-ues

IMMU NO HEMATO LOG Y, Volume !, Num"er , ##$ .

) unction Car%oh$drate Single pass Multi pass * #I lin+ ed A dsor%ed

Gl)+o+(l)0 A1 O2

H IG LO1

M NS LE

Stru+tur(l GE 3IRH45

Tr(ns*ort 6O3I

GIL75 RH

R HAG45

Ad esion8re+e*tor

INLU

L9M NSO5S64G

YRA2H

7MH

En;)me 5E L 3OYT

6om*lementre


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ReferencesMallory Mile#tone# in .mmuno$ematology 9D>C

2009, .mmuno$ematology 2009F25? KD2 Boral '., &enry JB ;$e type and #creen? a #afe alterC

nati e and #upplement in #elected #urgical procedure#;ran#fu#ion 9 F ? AKD

A )riedman B , (berman & , +$ad*ic4 !, "ingdon". ;$e ma:imum #urgical blood order #c$edule and

D

9

+ra*ford &, Barlo* MJ, &arri#on J), -inger ',&ue$n# E! %roduction of $uman monoclonal ant body to r$e#u# antigen 'ancet 9DAF ?AD KD n#tee J, %ar#on# S), Mallin#on G, Spring )Jud#on % , Smyt$e J +$aracteri/ation of monoclonantibodC ie# again#t eryt$rocyte #ialoglycoprotein#

#erological analy#i#, immunoblotting and flocytometry !e )r ;ran#fu# .mmuno$ematol9DDFA ?A KA2

#urgical blood u#e in t$e nited State# ;ran#fu#ion9 F ?AD0K

> (berman & , Barne# B , )riedman B ;$e ri#4 of abC bre iating t$e ma or cro##matc$ in urgent or ma##i e

20 &uang ;J, !eid ME, &al er#on G!, 3a/danba4$#$ "%roduction of recombinant murineC$uman c$imer.gM and .gG antiCJ# b for u#e in t$e clinical laboratory;ran#fu#ion 200AF>A? 5DK >

tran#fu#ion ;ran#fu#ion 9 DF D? A K>5 Garratty G ;$e role of compatibility te#t# 7!eport of

a meeting #pon#ored by t$e Bureau of Biologic# for

2 Nance SJ, rndt %, Garratty G %redicting t$e cli#ignificance of red cell alloantibodie# u#ing a monocymonolayer a##ay ;ran#fu#ion 9D F2 ?>>9K52

t$e Blood %roduct# d i#ory +ommittee8 ;ran#fu#ion9D2F22? 9K 2

Garratty G bbre iated pretran#fu#ion te#ting 7editoCrial8 ;ran#fu#ion 9D F2 ?2 K 9Butc$ S&, Judd -J, Steiner E , Stoe M, (berman &Electronic 2erification of donorCrecipient compatibility?t$e computer cro##matc$ ;ran#fu#ion 99>FA>? 05K9

D Moore &+, Molli#on %' #e of a lo*CionicC#trengt$medium in manual te#t# for antibody detection ;ran#Cfu#ion 9 F ?29 K

9 Bec4 M', %lapp )V, Sinor ';, !ac$el JM SolidCp$a#etec$ni6ue# in blood tran#fu#ion #erology 7re ie*8 +rit!e +lin 'ab Sci 9D F22?A K>2

22 Nance SJ, Nel#on JM, &oren#tein J, rndt % , %' , Garratty G Monocyte monolayer a##ay? an efcient nonin a#i e tec$ni6ue for predicting t$e #e eriof $emolytic di#ea#e of t$e ne*born m J +lin %at$9D9F92?D9K92

2A 'uca# G), &adley G, Nance SJ, Garratty G %redic$emolytic di#ea#e of t$e ne*born? a compari#on of t$monocyte monolayer a##ay and t$c$emilumine#cence te#t ;ran#fu#ion 99AFAA?>D>

2> &unt JS, Bec4 M', -ood G- MonocyteCmediatederyt$rocyte de#truction? a comparati e #tudy of curremet$od# ;ran#fu#ion 9D F2 ? A5KD

25 Nance SJ, Nel#on JM, rndt % , 'am &+, Garratt0 Nance SJ, Garratty G ne* potentiator of red blood

cell antigenCantibody reaction# m J +lin %at$ol9D FD ? AAK5

G Ouantitation of fetalCmaternal $emorr$age by flocytometry? a #imple and accurate met$od m J +l%at$ol 9D9F9 ?2DDK92

2

A

>

5

'apierre 3, !igal , dam J, et al ;$e gel te#t? a ne* *ay to detect red cell antigenCantibody reaction#;ran#fu#ion 990FA0? 09K AMorton J , %ic4le# MM ;$e proteolytic en/yme te#tfor detecting incomplete antibodie# J +lin %at$ol

95 F>? D9K99Jud#on % , n#tee J +omparati e effect of tryp#inand c$ymotryp#in on blood group antigen# Med 'abSci 9 FA>? K

aniel# G Effect of en/yme# on and c$emicalmodificaC tion# of $ig$Cfre6uency red cell antigen#.mmuno$eC matology 992FD?5AK!eid ME, 'oma#C)ranci# + Blood group antigen# andantibodie#? a guide to clinical rele ance and tec$nicaltip# Ne* 3or4? Star Brig$t Boo4#, 200

2 Nance SJ, Garratty G pplication of flo* cytometryimmuno$ematology J .mmunol Met$ 9D F 0 ?A

2 (ien ', Nance S, rndt %, Garratty G etermination /ygo#ity u#ing flo* cytometric analy#i# of red cell angen #trengt$ ;ran#fu#ion 9DDF2D?5> K>

2D Garratty G, Nance SJ +orrelation bet*een in $emoly#i# and t$e amount of red cellCbound .gG me#ured by flo* cytometry ;ran#fu#ion 990FA0? K

29 !eid ME, Elli#or SS b#orption of *arm autoantiboie# u#ing glutaralde$ydeCtreated $uman red cell# mMed ;ec$nol 9D2F>D? 9KD>

A0 Branc$ !, %et/ ' ne* reagent 7PP %8 $amultiple application# in immuno$ematology m +lin %at$ol 9D2F D? K

"o$ler G, Mil#tein + +ontinuou# culture# of fu#ed cell##ecreting antibody of predefined #pecificity Nature

9 5F25 ?>95KBarn#table +J, Bodmer -), Bro*n G, et al %roduction

A !eid ME, ;oy %;+3 #e of pre#er ed autologou# blood cell# to ab#orb *arm autoantibodie# from t$#erum of patient# recei ing blood tran#fu#ion t$erap Vo: Sang 9D>F> ?A55K9

of monoclonal antibodie# to group eryt$rocyte#, &' and ot$er $uman cell #urface antigen#? ne* tool# forgenetic analy#i# +ell 9 DF >?9K20

A2 'eger !M, Garratty G E aluation of met$od# for dtecting alloantibodie# underlying *arm autoantibodCie# ;ran#fu#ion 999FA9? K


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AA !eid ME, ;oy %;+3 Simplified met$od for reco eryof autologou# red blood cell# from tran#fu#ed patient# m J +lin %at$ol 9DAF 9?A >K

A> Bro*n J rapid met$od for $ar e#ting autologou#red cell# from patient# *it$ $emoglobin S di#ea#e;ran#fu#ion 9DDF2D?2 KA

A5 ' gdberg ', !eid ME, 'amont !E, Pelin#4i ; &uman blood group gene# 200>? c$romo#omal location# andcloning #trategie# ;ran#f Med !e 2005F 9?>5K5

A !eid ME, Mo$anda# N !ed blood cell blood groupantigen#? #tructure and function Semin &ematol200>F> ?9AK

A !eid ME pplication# of N Cba#ed a##ay# in bloodgroup antigen and antibody identification ;ran#fu#ion200AF>A? >DK5

AD 'inden JV, %aul B, re##ler "% report of 0>tran#fu#ion error# in Ne* 3or4 State ;ran#fu#ion

992FA2? 0 KA9 S$ulman . , "ent nit placement error#? a

potential ri#4 factor for B( and !$ incompatible blood tran#fuC #ion# 'ab Med 99 F22? 9>K>0 -illiam#on 'M, 'o*e S, 'o e EM, et al Seriou# $a/C

ard# of tran#fu#ion 7S&(;8 initiati e? analy#i# of t$efir#t t*o annual report# BMJ 999FA 9? K 9

Marion E !eid, %$ , ).BMSEditorial Board

Immunohematology

> Sa/ama " !eport# of A55 tran#fu#ionCa##ociated deat$#?9 t$roug$ 9D5 ;ran#fu#ion 990FA0?5DAK90

(otice to Readers Immunohematology$ %ournal of &lood 'rou" (erology and )ducation$ i# printed on acidCfreepaper

Attention: State "lood "an+ Meeting Organi/ers

.f you are planning a #tate meeting and *ould li4e copCie# of Immunohematology for di#tribution, plea#e #endre6ue#t , > mont$# in ad ance, toimmunoQu#a redcro## org
mailto:immuno@usamailto:immuno@usa


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6(se Re*ort

"

Anti 0p a 1induced severe dela$ed hemol$tictransfusion reactionR&5 os ) , 1& 2(tel, (nd 7&S&H(rrison

"p a i# a lo*Cfre6uency antigen occurring in le## t$an 2 percentof t$e +auca#ian population Mild to moderate delayed $emolytictran#fu#ion reaction# 7 &;!8 and $emolytic di#ea#e of t$e fetu#and ne*born attributable to antiC"p a $a e been reported Se ereo ert &;! $a# not been reported *it$ antiC"pa ca#e of a #eC ere &;! attributed to antiC"p a after multiple !B+ tran#fu#ion#i# being reported 52CyearCold +auca#ian *oman recei ed mulCtiple unit# of !B+# for a lo*er ga#trointe#tinal bleed S$e *a# reCferred to our in#titution for $epatic and renal failure, *$ic$ *a##upported by laboratory finding# of pea4 ' &, bilirubin, B N,and creatinine ele ation# &emoglobin $ad dropped on ay 0after tran#fu#ion ;$e ; and antibody #creen 7 BS8 *ere negaCti e .nitial *or4up and #ub#e6uent BS *ere negati e ntiC"pa *a# identified *$en an additional !B+ panel *a# te#ted (ne oft$e !B+ unit# tran#fu#ed *a# incompatible by anti$uman globuClin 7 &G8 cro##matc$ *it$ t$e patientH# pla#ma and typedpo#iti e for "pa &;! *a# confirmed after e:ten#i e *or4up;$e patient re#ponded to #upporti e t$erapy and e:perienced anune entful reco ery &;! may not be con#idered *$en ;and BS are negati e &o*e er, correlation of recent tran#fu#ion *it$ #ign# and #ymptom# #$ould alert t$e clinician to entertainand in e#tiC gate a &;! t$at #$ould include t$e &Gcro##matc$ of all impliC cated !B+ unit# ;$e #e erity of t$ereaction al#o rai#e# concern# a# to *$en and *$at antigen#pecificity #$ould be con#idered for inclu#ion in t$e antibody#creening cell#

Immunohematology 009? 5)44#47

pa 7"E' A, %enney8 i# one of A antigen# in t$e "ell7.SB; #ymbol, "E'8 blood group #y#tem ;$e "ellantigen#, encoded by *)L , located on c$romo#ome

6AA, appear to be eryt$roid #pecific and are found in t$efetal li er and in bone marro* cell# "p a i# a lo*Cincidenceantigen found in le## t$an 2 percent of +auca#ian# ,2 ;$eantigen i# re#i#tant to t$e effect# of en/yme treatment buti# #en#iti e to treatment *it$ dit$iot$reitol and acid Mildto moderate delayed $emolytic tran#fu#ion reaction7 &;!8 and mild to moderate $emolytic di#ea#e of t$efetu# or ne*born 7& )N8 $a e been reported a# *ell a# aca#e of $ydrop# fetali# attributed to antiC"pa A ;$e antibodyi# an .gG>K Suppre##ion of eryt$ropoie#i# by antiC"pa $a# been reported a# t$e cau#e of decrea#ed $emoglobin in& )N E!eport# of an o ert &;! attributable to #e eralantibodie# mi##ed in t$e antibody #creen and immediateC#pin cro##C matc$ mention antiC"pa a# one of t$eantibodie# D &o*e er, t$ere $a e been no reported ca#e# of#e ere o ert &;! a# a re#ult of antiC"pa a# per ME '.NE#earc$

Case Report

52CyearCold +auca#ian *oman pre#ented to t$e gency room complaining of being lig$tC$eaded and $a


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Anti>5* ( Dindu+ed 3HTRrectal bleeding, nau#ea, *ea4ne##, and di//ine## !ectale:C amination confirmed t$e rectal fi##ure# and bleeding;$ere *ere no ot$er remar4able finding# noted onp$y#ical e:amC ination E+G #$o*ed #inu# tac$ycardia at

0 beat#


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! a%le ,- L("or(tor) d(t( =rom t e re=errin< os*it (l! ests (ormal range #atient results

Admission 3() 3() 3() /# 3() // 3() /

Hemo


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0 DR, *ere u#ed for re er#e typing, and antibody #creen *a#done by .gG gel card, 0 DR Surgi#creen 7Jo$n#on Jo$n#on, Ne* Brun#*ic4, NJ8 ntibody panel *a#performed u#ing0 DR !e#ol e %anel 7(rt$oC+linical iagno#tic#, .nc 8 and%anocell , by .mmucor, .nc 7Norcro##, G 8 ;$e ; *a#performed u#ing antiC.gGC+Ad *it$ c$ec4 cell#, antiC.gGand c$ec4 cell#, and antiC+Ab


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R& 5os ) et (l&

Results;$e &;! in e#tigation on t$e day of admi##ion at t$e

referral $o#pital re ealed a negati e antibody #creen *it$t$e t$reeCcell antibody #creen ;$e ; *a# negati e 7inCcluding a 5Cminute incubation8 *it$ poly#pecific, .gG, and+Ab


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peptide# .t al#o cataly/e# t$e formation of cytoto:ic lipidpero:ide ia lipid pero:idation and damage# N t$roug$o:idati e #tre## &eme, being a lipop$ilic molecule, interCcalate# in t$e membrane and impair# lipid bilayer# and orCganelle#, #uc$ a# mitoc$ondria and nuclei, and de#tabili/e#t$e cyto#4eleton .t al#o cau#e# endot$elial cell in ury, leadC

ing to a#cular inflammation, and #timulate# t$ee:pre##ion of intracellular ad$e#ion molecule# # aproinflammatory molecule, $eme induce# inflammationt$at re#ult# in to:ic effect# on t$e 4idney, li er, centralner ou# #y#tem, and carC diac ti##ue0 ;$e #e ere $emeto:icity may al#o be attributC able to t$e mar4edlycompromi#ed renal condition o*ing to t$e #e ere #teno#i#of t$e rig$t renal artery

;$e #e erity of t$e &;! in t$i# ca#e may *arrantconC #ideration for inclu#ion of clinically #ignificant lo*Cfre6uency antigen# t$at may be mi##ed by current#creening cell# for detection of clinically #ignificant !B+antibodie# &o*C e er, t$e ri#4 of o ert &;!# to lo*Cincidence antigen# i# e#timated at per 50,000cro##matc$e#5 ;$e calculation *a# ba#ed on report ofprobability of acute o ert $emolytic tran#fu#ion reaction at

per 2 0,000 *it$ immediateC#pin cro##matc$e# of Amillion negati e antibody #creen#D # t$e ri#4 of o ert

&;! i# e:tremely #mall, t$e co#t benefit #$ould becon#idered for inclu#ion of lo*Cfre6uency anC tigen# #uc$a# -r a, + * , and "p a in t$e antibody #creening cell#5 -econcur *it$ t$e pre iou# ob#er ation &G p$a#ecro##matc$ mu#t be included in t$e in e#tigation of any#u#pected &;! irre#pecti e of a negati e ; or negaCti e antibody #creen ppropriate and timely patient careto a ert furt$er patient $arm depend# on a t$oroug$in e#tiC gation

References!obac4, J , ed ;ec$nical Manual t$ ed Bet$e#da,

M ? merican ##ociation of Blood Ban4#, 200D2 llen )& Jr, 'e*i# SJ "pa 7%enney8, a ne* antigen in

t$e "ell blood group #y#tem Vo: Sang 95 F2?D K

A Smoleniec J, nder#on N, %oole G &ydrop# fcau#ed by a blood group antibody u#ually undetectein routine #creening rc$ i# +$ild )etal Neonatal E

99>F ?)2 K> %in4erton %&, +oo adia S, Gold#tein J )re6uenc

delayed $emolytic tran#fu#ion reaction# follo*ing antibody #creening and immediateC#pin cro##matc$in;ran#fu#ion 992FA2?D >K

5 Garratty G &o* concerned #$ould *e be about miing antibodie# to lo* incidence antigen#U ;ran#fu#ion200AF>A?D>>K>

!eid ME, 'oma#C)ranci# + ;$e blood group antigefact#boo4 San iego, + ? cademic %re##, 99 ?>

;u#on M, "oyal ", e#ai !, et al %robable #uppre##of fetal eryt$ropoie#i# by antiC"p 7ab#tract8 ;ran##ion 200 F> 7A Suppl8?

D S$ulman . ;$e ri#4 of an o ert $emolytic tran#fu#reaction follo*ing t$e u#e of an immediate #pin cro##matc$ rc$ %at$ol 'ab Med 990F >?> 2K >

9 'ee S, Pamba# E , Mar#$ -', !edman +M Molecularcloning and primary #tructure of "ell blood group protein %roc Natl cad Sci S 99 FDD? A5AK

0 "umar S, Bandyopad$yay )ree $eme to:icity anit# deto:ification #y#tem# in $uman ;o:icol 'ett2005F 5 ? 5KDD

Ranie *oshy$ M# +corres"onding author,$ #irector$ &lood &an and .ransfusion (er/ices$ and &hishma Patel$ (&&$ &lood &an and .ransfusion (afety 0fficer$ #e"artmentof Pathology and Laboratory Medicine$ N%M(1!M#N%$C232$ !ni/ersity 4os"ital$ Newar $ N% 352367 and %ona-than (8 4arrison$ M#$ #e"artment of Medicine$ 4ema-tology$ Robert 9ood %ohnson Medical (chool:Pisc1New &runswic $ New &runswic $ N%8


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Review

B

el

;

2

2

int

%

0

m

end

)

/

B

A/

A

A

Ael

!he A"O %lood group s$stem revisited: areview and update

7&R& Storr) (ndM&L&Olsson

;$e antigen# of t$e B( #y#tem *ere t$e fir#t to be recogni/ed a# blood group# and actually t$e fir#t $uman genetic mar4er#4no*n

Variation in antigen e:pre##ion *a# al#o recogni/e ery early in t$e t*entiet$ century 7re ie*ed in !ace and

;$eir pre#ence and t$e reali/ation of naturally occurring antibodCie# to t$o#e antigen# lac4ing from t$e cell# made #en#e of t$e

Sanger 08, and t$e blood group *a# di ided into , (t$er de#cription# of *ea4ened antigen

and

erratic failure of blood tran#fu#ion $it$erto and opened up t$e 2 e:pre##ionpo##ibility of a #afe treatment practice in lifeCt$reatening bloodlo## lt$oug$ initially apparently #imple, t$e B( #y#tem $a#come to gro* in comple:ity o er t$e year# ;$e ma## of 4no*lCedge relating to carbo$ydrate c$emi#try, en/ymology, moleculargenetic#, and #tructural and e olutionary biology i# no*enormou# t$an4# to more t$an a century of re#earc$ u#ing B(a# a principal model ;$i# $a# pro ided u# *it$ data to form a#olid platform of e idenceCba#ed tran#fu#ion and tran#plantationmedicine u#ed e ery day in laboratorie# and clinic# around t$eglobe ;$i# re ie* aim# to #ummari/e 4ey finding# and recentprogre## made to*ard furt$er under#tanding of t$i##urpri#ingly polymorp$ic #y#tem Immunohematology

009? 5)48#59

0e$ 4ords: B(, blood group, antigen, allele, genotype

$ere $a e been many re ie*# of t$e B( blood

group#y#tem *ritten t$roug$out t$e year#, co ering difC

follo*ed, and t$e blood group *a# #ubdi ided furt$e ba#ed on c$aracteri#tic reacti ity *it$ $uman polyclonanti#era, i e , #trengt$ of reacti ity and pre#ence of mfield agglutinationF pre#ence of antiC F and *$et$er & blood group #ub#tance *a# pre#ent in t$e #ali a#ecretor #ub ect# 7;able 8 -ea4 form# of B antigen *al#o found but are typically more difficult to defi#erologically into #pecific categorie# alt$oug$ #o#ubgroup# 7e g , B 8 are elanalogou# to t$eir counterpart# 7 8

;$e fre6uency of t$e common B( p$enotype# 7 , B, B, B, and (8 arie# greatly among different popution# 2, A%opulation# *it$ a $ig$ fre6uency of p$enotyare found mainly in Nort$ern and +entral Europe, and t$e

!a%le ,- Su" and moleculargenetic#5, (ur intention i# not to reproduce t$em but tofollo* t$e guideline# of t$i# ne* #erie# of blood group #y#Ctematic re ie*# in Immunohematology to pro ide a brief

NNNN NNNN NNNN # A, H No

A NNNN NNNN # NNNN A, H Some>times

A NNNN NNNN NN@NA NNN A, H Nointroduction to t$i# ama/ingly comple: blood group #y#tem A NN@NAm= NN@NAm= # NNNN A, H Some>

times

7istor$;$e di#co ery of t$e B( blood group #y#tem range#

from myt$ and fol4 legend all t$e *ay to t$e Nobel %ri/e"arl 'and#teiner, a Vienne#e pat$ologi#t, made t$eob#er ation t$at *$en $i# #erum and t$at of fi e colleague# *ere mi:ed

A #8 NN@NA # NNNN H O=ten

A N N # NNNN H Some>times

A #8 #8 # NNNN A, H No

A N N # NNNN H Yes

=inn

indi idually *it$ t$eir #alineC#u#pended !B+#, agglutinaCtion *a# ob#er ed *it$ #ome mi:ture# but not *it$ ot$er#&e reported t$i# a# a footnote to a paper publi#$ed in

900E

"(ntu

/(e

@ @ # NNNN H Yes

# # BB NNNN H YesBBB

follo*ed by a more compre$en#i e paper in 90D ;ran#laC A # # # NNNN A, H Notion# of bot$ paper# can be found in t$e re ie* by +ampand Elli# .n t$e#e early #tudie#, $e #$o*ed t$at t*o eac$of t$e #i: #era di#criminated among t$ree blood group#? ,B, and + 7later renamed ( from t$e German ohne , meaning

# # # NNNN H Some>times

BAne


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A1O "lood


19/72


20/72

official but often u#ed terminology i# found at t$e BloodGroup ntigen Gene Mutation ataba#e, al#o 4no*n a# t$e

C H 3 O

H O

O O H

O H

O H

H d iis a c c h a rr ii d e


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7&R& Storr) (ndM&L&Olsson

)ig- 2 Or A / +onsensus @nonsense & Verti+(l "(rs indi+(te nu+leotide"0 "&

@nt *ositions @leles t (t en+ode (


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:

A

pre#ence of A or A2 allele# unle## #pecifically de#ignedto detect rare 0 allele#, *$ic$ *ill re#ult in t$e potentiallycata#trop$ic prediction of group in a group ( per#onSecond, t$e p$enotype actually con eyed by in$eritance ofone of t$e#e #oCcalled0 allele# i# not al*ay# ( but often *ea4 or (Cli4e but *it$out antiC pre#ent in pla#ma ;$erea#on for t$i# i# currently unclear, but t$ere $a# recently been a #erie# of paper# in e#tigating t$e #erologic patternand mec$ani#m# be$ind t$i# intere#ting p$enomenonADK>2;$ere i# currently no 0 allele de#cribed t$at i# ba#ed on a e6uence, but *e predict t$at *$en #uc$ an allele i# found,it *ill #$o* t$e oppo#ite #erology, i e , eit$er *ea4 Be:pre#C #ion or (Cli4e *it$out antiCB in pla#ma

.t i# t$e molecular genetic# t$at ma4e t$i# #y#tem #ofa#C cinating becau#e mutation# ranging from #inglenucleotide c$ange# to more comple: $ybrid geneformation# can alter t$e #pecificity of t$e en/yme, t$eefficacy of t$e en/yme, or bot$F c$ange# t$at, at t$ep$enotypic le el, are manife#ted #imply by altered antigen

e:pre##ion Good e:ample# are

cal p$enotype# can $a e more t$an one molecular gene bac4ground

;$e regulatory mec$ani#m of t$e A&0 gene $a# bein e#tigated e:ten#i ely n en$ancer element locatedpro:imately > 4bp up#tream of e:on 50 *a# found to cotain four >ACbp repeat# in all allele# e:cept A A232W

t$e infre6uent 02

036 W, *$ic$ $a e only one copy5

;$imay play a role in e:pre##ion52 ;$e en$ancer regiocontain# a +B),55 ;$iappear# to #pea4 again#t a critical role for +B) repeat#eryt$roid A&0 regulation, but more *or4 i# re6uire;$ere i# al#o an Sp Cbinding #ite in t$e pro:imal promot$at may be important for eryt$roid A&0 regulaC tion5

t$e ariou# molecular ba#e# of t$e p$enotype, *$ic$ can lt$oug$ muc$ i# under#tood regarding t$e cau#eit$er re#ult from a #ingle mi##en#e mutation in e:on ofan A A232W allele or be ba#ed on different $ybrid#, for inC#tance bet*een t$e 5Q end of & and t$e AQ end of 0allele#>A,>>

*ea4 5 .n adC dition to altered #pecificityor en/ymatic efficacy, aberrant intracellular traffic4ing of

B( tran#fera#e may cau#e *ea4 #ubgroup p$enotype#>

# alluded to pre iou#ly, t$i# added layer ofcomple:ity, in *$ic$ mutation# affect en/yme acti ity andnot t$e antiC gen directly, pro ide# difficultie# in de#igninggenotyping a##ay# t$at *ill detect rare ariant#, *$ic$ ifmi#interpreted can $a e #eriou# con#e6uence# in B(group determinaC tion>E

;$ere are problem# a##ociated *it$ all t$e more t$anA0 A&0 genotype #creening met$od# publi#$ed orcommerC cially a ailable #o far 7re ie*ed in (l##on and+$e#ter>D8 ;$e a#t ma ority i# only de#igned to determine bet*een t$ree and #i: of t$e common allele#, alt$oug$additional allele# can often #urface if t$eir polymorp$i#m#interfere *it$ t$e detection #y#tem &o*e er, irtually allmet$od# *ill fail to predict t$e p$enotype of a #ample int$e pre#C ence of mo#t 98 *e recently de eloped and implemented an impro ed A&0genotype #creening met$od t$at addre##e# t$e#e problem#and can be u#ed in a clinical laboratory #etting> .n#ummary, t$e comple: genetC ic# of B( i# a ma orc$allenge for A&0 genotyping effort#, not lea#t becau#e oft$e di#turbing fact t$at a certain allele can lead to more

t$an one p$enotype and #eemingly identiC


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matologic malignancy, e#pecially in t$e myeloidlineage 5E,5D Very recently it *a# #ugge#ted t$at met$ylation of t$e A&0pro:imal promoter i# t$e rea#on for #uc$ leu4emiaCa##ociated do*nregulation 59 !educed and B antigene:pre##ion in bladder and oral carcinoma# i# partiallyattributable to lo## of $etero/ygo#ity or$ypermet$ylation 0, )urt$ermore, urot$elial tumorti##ue contain# decrea#ed amount# of > but t$e rea#on for t$i# i# #till un4no*n

"ioc hemistr$;$e bioc$emi#try of t$e and B antigen# *a# elucidatC

ed by t$e a#toni#$ingly early and brilliant *or4 from t$egroup# of Morgan and -at4in#, and "abat 7re ie*ed by -at4in# 2 and "abat A8 ;$e , B, and & determinant# *ere$ypot$e#i/ed to re#ide on *aterC#oluble glycoprotein# ableto in$ibit agglutination of !B+# by antibodie# or lectin#

precur#or #ub#tance, &, *a# $ypot$e#i/ed a# a building#tructure for and B, and t$e term#0- 7or 4- 8 substanceand anti-4 *ere introduced in 9>D >

(*ing to difficultie# in obtaining #ufficient 6uantitie#of blood group acti e material after e:traction from !B+#,mo#t of t$e early #tudie# *ere performed on o arian cy#t oranimal mucin, ric$ in #ecreted blood group #ub#tance#Before i#olaC tion and c$emical identification of t$e#e#ub#tance#, in$ibiC tion *it$ #imple #ugar# indicated N CacetylCd Cgalacto#amine 7GalN c8,d Cgalacto#e 7Gal8, andl Cfuco#e 7)uc8 a# t$e definC ing #ugar# in blood group# , B,and (, re#pecti ely 5,

.ndependent of t$e blood group of t$e indi idual

in e#tigated, a #urpri#ingly #imilar compo#ition of carboC


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UUUUUU (((((( )))))) ********

++++ (((( )))) **** ,,,,

++ aa ll>>

22 rr ee ++ uu rr

HHHHHH (( nn

UUUUUUUU (((((((( ))))))))

AAAAAA ((((((nnnnnn tttttt iiiiii 8 carC bo$ydrate precur#or# found!B+# D ;$e clo#ely related F!.; gene encode# a e#imilar 2C' Cfuco#yltran#fera#e 7' 2)uc;28 t$at i# e:pre##edin epit$elial cell# and #ynt$eC #i/e# & antigen mainlytype and type A c$ain# ;$e ma or precur#or typepre#ent in different ti##ue# and

G32 > u+ G 32

+ G aa (l llVV>>R > -

U32 > G(I NA+ U32

A tr(ns=er(seA (nti-

' ' 2

#ecretion# are #$o*n in ;able A!a%le 2- 2eri* er(l +ore stru+tures (nd t eir *rin+i*(l tissue

%

G(l > R H Ht r taa r ( nn ns s = e .e r ( rr sa e s e

' 2'

,u uc+

H (nti

-

distri"ution @modi=ied =rom 6l(usen (nd H(?omori

2re+ursor

U23 > G(l U32

''

, u ucc +

)ig- 9- S+ em(ti+ de*i+tion o= t e "ios)nt eti+ *(t w()s =or +on>version o= H determin(nts to A or 1 determin(nts& R re*resents t e+ore stru+ture& See te0t =or en;)me (""revi(tions&

lt$oug$ t$e compo#ition of t$e and B antigen# i#apparently #traig$tfor*ard, t$e bioc$emi#try be$ind t$e#$ared ,B antigen recogni/ed by many group ( pla#ma#$a# only recently been elucidated e:perimentally Bo inand $i# colleague# #ynt$e#i/ed a deacetylated tri#acc$aCride #tructure and bound it to t$e precur#or in #uc$ a *aya# to e:po#e *$at t$ey $ypot$e#i/ed *ould be t$e common ,B epitope ;$ey *ere able to demon#trate binding of bot$ monoclonal and polyclonal antiC ,B to t$e #ynt$etic#trucC ture

lt$oug$ it i# *ell 4no*n t$at t$ere are appro:imately

R C inner +ore stru+ture or lin?(


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protein# located in t$e Golgi compartment,9,D0alt$oug$ #oluble form# are found in pla#ma and ot$er body fluid# ;$e en/yme con#i#t# of a #$orttran#membrane domain, a #tem region, and a catalyticdomain t$at e:tend# into t$e Golgi lumen 7)ig 8 ;$ecry#tal #tructure elucidated by


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22

)ig- A: T e to*oloi;ed, mem"r(ne>"ound en;)me wit ( +)to*l(smi+ N >terminus (nd+(t(l)ti+ C >termin(l dom(in @modi=ied =rom 2(ulson (nd 6olle) $ &" and C : T e t ree>dimension(l sur=(+e model ;"< w(s +re(tedwit t e 3ee* View Swiss 2d" Viewer version %& , (nd t et ree>

dimension(l ri""on stru+ture ;C< w(s Y+

t$o#e *$o#e !B+# carry certain #ubgroup# 7;able 8 al#o produce antiC , generally reacti e at room tempture and belo* lt$oug$ B( antibodie# of .gG type ccro## t$e placenta, #e ere B(Crelated $emolytic di#of t$e ne*born i# not common ;$e mec$ani#m# be$t$i# are di#cu##ed in more detail in t$e #ection on clincon#e6uence#

#athogen InteractionsBacteria, iru#e#, and para#ite# $a e been propo#e

important dri ing force# for t$e geograp$ic di#tribution B( blood group p$enotype# becau#e different pat$ogedemon#trate blood groupKidentical or Kcro##Creacti eecule# on t$eir #urface# ;$e#e are t$e probable target#Iblood group antibodie#, and t$eir e:i#tence i# t$e leing $ypot$e#i# a# to *$y *e ma4e naturally occurring atibodie# again#t t$e carbo$ydrate blood group# *e lac4addition, many pat$ogen# #$o* #electi e binding to blgroup carbo$ydrate moietie# ia lectin# 7re ie*ed by Gratty D 8 More recent but per$ap# anecdotal e idencet$i# t$eory *a# pro ided after #e ere $emolytic tran#fureaction# in t*o group B patient# recei ing ap$ere#i# pllet# from t$e #ame group platelet donorDD;$e donor $adonated regularly for a period of 20 year#, during *$time no ad er#e effect# of tran#fu#ion $ad been ob#er but $ad recently begun to #upplement $i# diet *it$ $igdo#e probiotic# and $i# antiCB titer *a# #$o*n to be gret$an D000 .n$ibition #tudie# performed *it$ pla#ma frrandom group donor# and #olubili/ed probiotic tabledemon#trated a reduction in titer, $inting at a role for Bantibodie# in neutrali/ing pat$ogen# ;$i# line of t$in4i# #upported furt$er by data from #tudie# on iral glyclation in $o#t cell# &.V cultured in itro *it$ perip$ blood mononuclear cell# 7%BM+8 from donor# of diff


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B( group# demon#trated #pecific neutrali/ation *it$antiC of t$o#e i#olate# gro*n in group %BM+# but nott$o#e cultured *it$ group B or group ( cell# D9 Mea#le# iCru#, *$en cocultured in a #y#tem e:pre##ing B& glyco#ylCtran#fera#e# 7to mimic an in i o en ironment8, e:pre##ed or B epitope#, or not, according to t$e en/yme#

e:pre##ed Viral particle# could t$en be neutrali/ed bynormal polyC clonal antiC or antiCB #era in t$e pre#ence ofcomplement if t$e corre#ponding glycan# *ere pre#ent90+on er#ely, t$e and B 7and &8 antigen# are al#o u#ed a#receptor# for pat$ogen in a#ion by attac$ment to $o#t cell#a# mentioned pre iou#ly, #o t$e e6uilibrium bet*eenin a#ion and e aC #ion i# a fine balance on bot$ #ide#

)urt$ermore, gro*ing e idence for a leading role of Plasmodium falci"arum a# t$e ma or force #$aping t$e $uCman genome including t$e di#tribution of t$e blood group#$a# emerged 9 ,92 ;$e para#iteCinduced !B+ #urface proteinpfEM% i# 4no*n to bind to t$e antigen tri#acc$aride,9Aand it $a# been #$o*n t$at t$e #e erity, includingmortality, of malarial di#ea#e i# #ignificantly lo*er in group( c$ildren t$an in ot$er group#, mainly t$roug$ t$emec$ani#m of reC duced ro#etting9>,95 .t i# t$e focu# onpediatric di#ea#e t$at i# t$oug$t to ma4e t$i# pat$ogenparticularly effecti e in e:erting a #election pre##ure on ourgenome

;$e general t$eme $ere i# t$e concept of $erd immuCnity, i e , t$e fact t$at difference# in t$e population *ill4eep at lea#t a fraction of all indi idual# protected frommo#t if not all pat$ogen# for $umanity to #ur i e B(difference# a# part of our innate immunity appear to be oneof t$e betC ter e:ample# of t$i# idea9

Clinical Significance(f all antibodie# to !B+ blood group antigen#, antiC

and antiCB are arguably t$e mo#t clinically important (nt$e ot$er $and antiC and antiC& are ery #eldom foundto correlate *it$ $emolytic ad er#e e ent# but often #$o*lo*er t$ermal optima Before t$e di#co ery of B(, tran#Cfu#ion bet*een $uman# $ad been attempted *it$ mi:ed#ucce## .n #ome ca#e#, t$e patient #ur i ed and got betCter .n ot$er# t$e patient died rapidly, *$ic$ *e no* reCali/e *a# attributable to rapid intra a#cular $emoly#i# of B(Cincompatible !B+# 7re ie*ed by Molli#on et al9E8.t $a# been reported t$at tran#fu#ion of a# little a# A0 m'of B(Cmi#matc$ed blood can re#ult in a rapid fatal inCtra a#cular tran#fu#ion reaction 7re ie*ed in .##itt and n#tee9D8 ;oget$er *it$ tran#fu#ionCrelated acute lungin ury 7;! '.8 and bacterial contamination of blood comCponent#, B( incompatibility i# #till one of t$e main ri#4#for ma or morbidity and mortality a##ociated *it$ tran#fuC#ion#, after erroneou# tran#fu#ion#99, 00 ;$e late#t ) reCport on tran#fu#ionCa##ociated fatalitie# 7found at $ttp?


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lyco lyco Counteractin Counteractin en ymesen ymes

CellCell sur.acesur.ace receptorreceptor ariation ariation

An(l)ti+An(l)ti+

+enotypin+eno

5n ym5n ym iicc

,orward,orward typin typin

Adsorption/Adsorption/ elutionelution

-e erse-e erse typin typin6itration6itration

N(tur(lN(tur(l

Neutrali ationNeutrali atio n 4y4y

toget$er *it$ #tandard immuno#uppre##ion protocol#re#ult# in #ucce##ful and #table engraftment %rogre##continue# in t$i# field, dri en by a #$ortage of appropriateorgan# for tran#plant 3a/er and ;riul/i 09 conclude t$atimmune $emoly#i# remain# a ma or complication in B(Cmi#matc$ed tran#plantation of #olid organ# and to a le##ere:tent $ematopoietic progenitor cell# &o*e er, pa##engerlymp$ocyte #yndrome attributable to B( or ot$er bloodgroup antibodie# can no* often be ameliorated by monoCclonal antibody t$erapy, once clinician# reali/e t$e probClem

Summar$ and )uture # erspectivese#pite t$e relati e #implicity of t$e and B antigen#,

per$ap# e#pecially con#idering t$e minor bioc$emical difCference bet*een t$em, t$e B( blood group #y#temremain# one of t$e mo#t intere#ting, bot$ clinically and#cientifiC cally, di iding t$e *orldH# population includingpatient# and donor# into four group# irre#pecti e of originor creed )igure #ummari/e# t$e four principal le el# at *$ic$ t$e B( #y#tem can be con#idered and #$o*# $o*immuno$eC matologi#t# $a e been able to e:ploit t$e#teadily increa#ing 4no*ledge of t$i# #y#tem by de i#ingte#t# ta4ing ad anC tage of eac$ of t$e different le el# .tal#o #$o*# #ome of t$e natural con#e6uence# generatedand t$eir relation to t$e microbe# #urrounding u#

Anal$tic modalities (atural conse&uences

*e recently introduced t$e fir#t microarrayCba#ed typC ing #y#tem t$at ta4e# t$e fir#t #tep# to*ard t$i# on a $ig$er t$roug$put #y#tem 0Effort# to rene* met$odfor #erologic typing are al#o ongoing )or in#tance, young field of microfluidic# $old# promi#e for alterna blood grouping tec$nology being more rapid, u#ing #ma olC ume# of reactant#, and being applicable to brote#ting platform#BBB

;$e temptation to create B(Cuni er#al blood ftran#fu#ion purpo#e# $a# 4ept #cienti#t# bu#y #inceearly 9D0# *$en t$e fir#t #ucce##ful report of delibetran#fu#ion *it$ modified !B+# acro## t$e B( barri *a# publi#$ed 2 %rogre## from t$o#e early day#, u#ipoorly effecti e BCcon erting e:oglyco#ida#e from coffee bean#, $a# continued *it$ t$e aim# of eliminat B(C a##ociated $emolytic tran#fu#ion reaction# #implifyC ing blood logi#tic# and in entory managemNot only $a# t$e proce## ta4en important #tride# to* becoming a reality *it$ bot$ C and BCdegrading en/yrecombiC nantly a ailable and nece##ary clinical triaprogre## or being de#igned, but t$e pro ect $a# broug$t *it$ it t$e #cientifically e:citing di#co ery olarge ne* cla## of bacC terially deri ed e:oglyco#en/yme# un4no*n $it$erto and *it$out clear $omology ore#emblance to any ot$er group of molecule# A, > .t un4no*n at t$i# point *$y #o many different bacteri#pecie# $a e de eloped t$e#e blood groupKcon een/yme# Speculation include# t$at it *ould #imply bmean# of dige#ting potential nutrient

Genot)*in< +enetic le el(NA7 m-NA 1

5n yme le el

)olymorphic population

6ounter(+tin< en;)mes

#acc$aride#, but it al#o may be yet anot$er *ay formicrobe# to ma4e #ure t$ey are able to attac$ to t$e $o#t

cell #urface,e en if t$e $i#toCblood group of t$e current $o#t $appEn;)mi+ (+tivit)

orw(rd t)*in< Adsor*tion8elution

low +)tomer)S(liv( in i"ition

Reverse t)*in< Titr(tion

@rentl) e0*loited (t e(+ level (re listed t e ri< t side s ows some o=t e inn(te me+ (nisms used "etween ost (nd *(t o


29/72

A c +nowledgmentsSome of t$e content and figure# in t$i# re ie* $a e

been modified from t$e doctoral t$e#e# of M ' (7Molecular GeC netic Studie# of t$e Blood Group B('ocu# in ManF 'und ni er#ity, 99 8 and r Ba$ram&o##einiCMaaf 7Genetic +$aracteri#ation of &uman B(

Blood Group Variant# *it$ a )ocu# on Subgroup# and&ybrid llele#F 'und ni er#ity,200 8

References+amp )!, Elli# )! Selected contribution# to t$e literaC

ture of blood group# and immunology )ort "no:, "3?S rmy Medical !e#earc$ 'aboratory, 9

2 -at4in# -M Bioc$emi#try and genetic# of t$e B(,'e*i# and % blood group #y#tem# .n? &arri# &,

D

9

"orc$agina E3, %oc$ec$ue a ;V, (bu4$o a %)ormano #4y , .mberty , !ieben !, Bo in NV

e#ign of t$e blood group B glycotope Glycocon2005F22? 2 KAA+lau#en &, 'e ery SB, abel#teen E, &a4omori Blood group B& antigen#? a ne* #erie# of blood

group Ca##ociated #tructure# 7genetic regulation ati##ue di#tribution8 ;ran#plant %roc 9D F 9?>>0S en##on ', !ydberg ', de Matto# '+, &enry SMBlood group and re i#ited? an immunoc$emicalanaly#i# Vo: Sang 2009F9 ?5 K

aniel# G', )letc$er , Garratty G, et al Blood grouterminology 200>? from t$e .nternational Society Blood ;ran#fu#ion committee on terminology for recell #urface antigen# Vo: Sang 200>FD ?A0>K

&ir#c$$orn ", ed# d ance# in $uman genetic# Ne* 3or4? %lenum %re##, 9D0? K A

A +lau#en &, &a4omori S B& and related $i#toCbloodgroup antigen#F immunoc$emical difference# in carrier

20 Blumenfeld ((, %atnai4 S" llelic gene# of blogroup antigen#? a #ource of $uman mutation# and cN%# documented in t$e Blood Group ntigen GeMutation ataba#e &um Mutat 200>F2A?DKi#otype# and t$eir di#tribution Vo: Sang 9D9F5 ? K

202 Ep#tein , (ttenberg ! Simple met$od of performi

#erum reaction# %roc N 3 %at$ol Soc 90DFD?> 3a/er M&, %alcic MM ;$e importance of di#ordered

loop# in B( glyco#yltran#fera#e# ;ran#fu# Med !e 2005F 9?2 0K

5 3amamoto ) Molecular genetic# of B( Vo: Sang2000F D?9 K 0A

+$e#ter M , (l##on M' ;$e B( blood group gene?a locu# of con#iderable genetic di er#ity ;ran#fu# Med!e 200 F 5? K200'and#teiner " Pur "enntni# der antifermentati en,

lyti#c$en und agglutinierenden -ir4ungen de# Blut#eCrum# und der 'ymp$e Pbl Ba4t 900F2 ?A5 K 2

D 'and#teiner " Zber gglutination#er#c$einungen norCmalen Men#c$lic$en Blute# -ien "lin -oc$en#c$r

90 F >? A2K>9 eca#tello , Sturli eber die i#oagglutinine im geC

#under und 4ran4er men#c$en Munc$ Med -oc$enC#c$rift 902F>9? 090K5

0 !ace !!, Sanger ! Blood group# in man t$ ed (:Cford, "? Blac4*ell Scientific %ublication#, 9 5

22 on ungern E, &ir#/feld ' +oncerning $ereity of group #pecific #tructure# of blood ;ran#fu#

9 2F2? 0K22A Bern#tein ) Pu#ammenfa##ande betrac$tungen [

die erblic$en Blut#tru4turen de# Men#c$en P .ndu b#tamm u Vererb'e$re 925FA ?2A K 0

2> +ro* J) )eli: Bern#tein and t$e fir#t $uman mar4elocu# Genetic# 99AF AA?>K

25 )ergu#onCSmit$ M , it4en , ;urleau +, Grouc$y J 'ocali#ation of t$e $uman B(? NpC ? lin4age group by regional a##ignment of "C to 96&um Genet 9 FA>?A5K>A

2 3amamoto ), +lau#en &, -$ite ;, Mar4en J&a4omori S Molecular genetic ba#i# of t$e $i#toCbgroup B( #y#tem Nature 990FA>5?229KAA

2 3amamoto ), Mar4en J, ;#u i ;, -$ite ;, +lau#en &,&a4omori S +loning and c$aracteri/ation of Ncomplementary to $uman %CGalN c?)ucCalp$a2Gal alp$a KAGalN c tran#fera#e 7$i#toCblood g

2

A

>

5

on ungern E, &ir/#feld ' ber die gruppen#Cpe/ifi#c$e #tru4turen de# blute# ... .mmun )or#c$2 9 FD?52 K 2Mourant E, "ope +, omanie*#4a " ;$e di#tribuCtion of $uman blood group# and ot$er polymorp$i#m#Ne* 3or4? (:ford ni er#ity %re##, 9!oyc$oud$uri ", Nei M &uman polymorp$ic gene# *orld di#tribution (:ford? (:ford ni er#ity %re##,

9DD'alue/aC)o: +, Gigli E, de la !a#illa M, )ortea J, !o#a# , Bertranpetit J, "rau#e J Genetic c$aracteri/ation oft$e B( blood group in Neandertal# BM+ E ol Biol200DFD?A>2+rainic ", urigon M, (riol ! B( ti##ue antigen# of Egyptian mummie# )oren#ic Sci .nt 9D9F>A? AK2>

tran#fera#e8 m!N J Biol +$em 990F2 5? >2D +lau#en &, -$ite ;, ;a4io ", et al .#olation to $omo

geneity and partial c$aracteri/ation of a $i#toCbloogroup defined )ucCalp$a K2Gal alp$a KAC N Cacetygalacto#aminyltran#fera#e from $uman lung ti##ueBiol +$em 990F2 5? A9K>5

29 3amamoto ), McNeill % , &a4omori S &uman $i blood group 2 tran#fera#e coded by 2 allele, onet$e #ubtype#, i# c$aracteri/ed by a #ingle badeletion in t$e coding #e6uence, *$ic$ re#ult# in aadditional domain at t$e carbo:yl terminal Bioc$eBiop$y# !e# +ommun 992F D ?A K >

A0 3amamoto ), McNeill % , &a4omori S Genomic ni/ation of $uman $i#toCblood group B( gene# Gcobiology 995F5?5 KD


30/72

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995F20 ?A DK25

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> Selt#am , Gruger , Ju#t B, et al berrant intracA2 "ominato 3, &ata 3, ;a4i/a*a &, et al lternati e

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AA &o##einiCMaaf B, Smart E, +$e#ter M , (l##on M';$e bantu p$enotype in t$e B( blood group #y#temi# due to a #pliceC#ite mutation in a $ybrid bet*een ane* 02 Cli4e allelic lineage and t$e A; allele Vo: Sang2005FDD?25 K >

A> +alafell ), !oubinet ), !amire/CSoriano , Saitou N,Bertranpetit J, Blanc$er E olutionary dynamic# oft$e $uman B( gene &um Genet 200DF 2>? 2AKA5

A5 !oubinet ), "ermarrec N, e#piau S, poil % , ugCou on JM, Blanc$er Molecular polymorp$i#m of (allele# in fi e population# of different et$nic origin#.mmunogenetic# 200 F5A?95K 0>

A (l##on M', Guerreiro J), Pago M , +$e#ter M MoClecular analy#i# of t$e ( allele# at t$e blood group B(locu# in population# of different et$nic origin re eal#no el cro##ingCo er e ent# and point mutation# BioCc$em Biop$y# !e# +ommun 99 F2A>? 9KD2

lar traffic4ing of a ariant B glyco#yltran#fera#e ;rfu#ion 200DF>D? D9DK905

> &o##einiCMaaf B, &ellberg , +$e#ter M , (l##o n e:ten#i e %+!C S% #trategy for clinical B( bgroup genotyping t$at a oid# potential error# cau by null, #ubgroup and $ybrid allele# ;ran#fu#200 F> ?2 0K25

>D (l##on M', +$e#ter M %olymorp$i#m and reconation e ent# at t$e B( locu#? a ma or c$allengegenomic B( blood grouping #trategie# ;ran#fu# M200 F ?295KA A

>9 %rocter J, +ra*ford J, Bunce M, -el#$ ". ramolecC ular met$od 7polymera#e c$ain reaction *#e6uenceC #pecific primer#8 to genotype for B( b

group and #ecretor #tatu# and it# potential for orgtran#plant# ;i##ue ntigen# 99 F50?>publi#$ed erratum appear# in ;i##ue ntig99DF5 ?A 9W

50 "ominato 3, ;#uc$iya ;, &ata N, ;a4i/a*a &, 3amamoto ) ;ran#cription of $uman B( $i#toCblogroup gene# i# dependent upon binding tran#cription facC tor +B)5? 0KD

A9 Selt#am , a# G+, -agner )), Bla#c/y4 ! NondeleCtional B(\( allele# e:pre## *ea4 blood group p$eCnotype# ;ran#fu#ion 2005F>5?A59K 5

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5A Selt#am , -agner )), Gr[ger , Gupta + , BadeCeding +, Bla#c/y4 ! -ea4 blood group B p$enotypmay be cau#ed by ariation# in t$e ++ ;Cbinding tor ?2AA0K5

> -agner )), Bla#c/y4 !, Selt#am Nondeletional B(\( allele# fre6uently cau#e blood donor typing

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5> ;*u 3+, ie$ +3, 3u '+ E:pre##ion of t$e $i# blood group B gene predominate# in BCgeno

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9A


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5 &ata 3, "ominato 3, 3amamoto )., ;a4i/a*a & +$arCacteri/ation of t$e $uman B( gene promoter ineryt$C roid cell lineage Vo: Sang 2002FD2?A9K>

5 Bianco ;, )armer BJ, Sage !E, obro ic 'o## of redcell , B, and & antigen# i# fre6uent in myeloid maligCnancie# Blood 200 F9 ?A AAK9


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99DF AA? 9 K59 BiancoCMiotto ;, &u##ey J, ay ;", (H"eefe S, oC

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0> !omano E', Soyano , Montano !), et al ;reatment o B( $emolytic di#ea#e *it$ #ynt$etic blood grotri#acC c$aride# Vo: Sang 99>F ? 9>K9

05 !ydberg ' B(Cincompatibility in #olid organ tran#ptation ;ran#fu# Med 200 F ?A25K>2

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9 +#erti +M, /i4 -& ;$e B( blood group #y#Ctem and Plasmodium falci"arum malaria Blood200 F 0?2250KD

200 FD ?A0 K0D ;obian , S$irey !S, Montgomery ! , ;i#c$ J, Ne

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blood group? i# t$ere any relation#$ipU %ara#itol !e#200 F 00? 59K 5

9A +$en O, &eddini , Barragan , )ernande/ V, %earceS), -a$lgren M ;$e #emicon#er ed $ead #tructure of Plasmodium falci"arum eryt$rocyte membrane proCtein mediate# binding to multiple independent $o#treceptor# J E:p Med 2000F 92? K 0

9> 'o#certale# M%, (*en# S, (H onnell J, Bunn J, Bo#c$C+apblanc$ @, Brabin BJ B( blood group p$enotype#and Plasmodium falci"arum malaria? unloc4ing a pi Cotal mec$ani#m d %ara#itol 200 F 5? K50

95 !o*e J , &andel .G, ;$era M , et al Blood group (protect# again#t #e ere Plasmodium falci"arum maClaria t$roug$ t$e mec$ani#m of reduced ro#etting%roc Natl cad Sci S 200 F 0>? > K

9 Gagneu: %, Var4i E olutionary con#ideration# in reClating oligo#acc$aride di er#ity to biological functionGlycobiology 999F9? > K559 Molli#on %', Engelfriet +%, +ontrera# M Blood tran#Cfu#ion in clinical medicine 0t$ ed 'ondon? Blac4*ellScientific, 99

9D .##itt % , n#tee J pplied blood group #erology >t$ed Miami? Montgomery Scientific %ublication#, 99D

99 Sa/ama " !eport# of A55 tran#fu#ionCa##ociateddeat$#?

9 t$roug$ 9D5 ;ran#fu#ion 990FA0?5DAK9000 Stain#by , Jone# &, #$er , et al Seriou# $a/ard# of

tran#C fu#ion? a decade of $emo igilance in t$e ";ran#fu# Med !e 200 F20?2 AKD2

0 'inden JV, -agner ", Voyto ic$ E, S$ee$an J;ran#C fu#ion error# in Ne* 3or4 State? an analy#i# of

0 year#H e:perience ;ran#fu#ion 2000F>0? 20 K A02 S$an*ell , nder##on ;M, !o#tgaard ", et al %o#tC

tran#C fu#ion mortality among recipient# of B(Ccompatible but nonCidentical pla#ma Vo: Sang2009F9 ?A K2A

0A Blumberg N, &eal JM, &ic4# G' Jr, !i#$er -& ##oCciation of B(Cmi#matc$ed platelet tran#fu#ion# *it$morbidity and mortality in cardiac #urgery ;ran#fu#ion200 F> ? 90KA

titer# to permit B(Cincompatible renal tran#plantatio;ran#fu#ion 2009 )eb Epub a$ead of printW

09 3a/er M&, ;riul/i J .mmune $emoly#i# follo* B(C mi#matc$ed #tem cell or #olid ortran#plantation +urr (pin &ematol 200 F >? >K

0 ent N , Martine/ , )legel - , et al ;$e BloodGpro ect? to*ard ma##C#cale compre$en#i e genotof blood donor# in t$e European nion and beyon;ran#fu#ion 200 F> 7Suppl8?>0SK S

"line ;!, !unyon M", %ot$ia*ala M, .#magilo ! B(, blood typing and #ubtyping u#ing plugCbamicrofluidic# nal +$em 200DFD0? 90K

2 Gold#tein J, Si iglia G, &ur#t !, 'enny ', !eic$Group B eryt$rocyte# en/ymatically con erted to gro( #ur i e normally in , B, and ( indi idual# Scie

9D2F2 5? DK 0A 'iu O%, Sul/enbac$er G, 3uan &, et al Bacterico#ida#e# for t$e production of uni er#al red bcell# Nat Biotec$nol 200 F25?>5>K >

> (l##on M', +lau#en & Modifying t$e red cell #uto*ard# an B(Cuni er#al blood #upply Br J &aem200DF >0?AK 2

5 'iu O%, 3uan &, Bennett E%, et al .dentificatioG& 0 #ubfamily of alp$a ,ACgalacto#ida#e#? n/yme# for remo al of t$e alp$a AGal :enotran#plantion antigen J Biol +$em 200DF2DA?D5>5K5>

%ill R8 (torry$ Ph#$ FI&M( +corres"onding author,$ Coor-dinator$ ("ecial (erology$ #e"artment of Clinical Immu-nology and .ransfusion Medicine$ !ni/ersity and

Regional Laboratories$ and Martin L8 0lsson$ M#$ Ph#$ #i/ision of 4aematology and .ransfusion Medicine$ #e"artment of Laboratory Medicine$ Lund !ni/ersity$ Lund$ (weden8


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6(se Re*ort

Clinical evaluation for l$mphoproliferativedisease prompted %$ finding of IgM warm

autoanti I!

in two casesR&M&Le


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-B+ ^ D _ 09Y+ *it$ group ( adult .,cord, and adult i !B+#, 0 and for +a#e , *it$ ;;Ctreatedautologou# !B+S ;$e te#t# at eac$ temperature *ere #etup #eparately 7i e , u#ing #epaC rate #et# of dilution#8 toeliminate potential carryo er of agglutination %atient#H#era *ere al#o te#ted by a pre iou#C ly de#cribed #erum#creen met$od 0 u#ed to c$aracteri/e antibodie# in .&Briefly, #erum *a# te#ted *it$ and *it$out

ResultsCase 1

;$e ; on ;;Ctreated !B+# *a# AT *it$ antiC.gGand antiC+AF t$e R albumin control *a# nonreacti einitial titer and t$ermal amplitude #tudie# #$o*ed a Aagglutinin t$at reacted to a $ig$er titer *it$ cord !B+

t$an *it$ adult . !B+# ;itration re#ult# *it$ adult ., cori, and adult i !B+# 7to determine #pecificity8 are #$o*n;able nomalou# re#ult# 7une:plained $ig$ titer8 *obtained *it$ ;;Ctreated autologou# !B+#? titer# of 5at A Y+,

02> at A0Y+, 20>D at 22Y+, and D000 at >Y+ n aantiC. *a# detected at >Y+ 7adult . !B+ titer of 25 , c!B+ titer of >8 n acid eluate prepared from t$e patie!B+# reacted more #trongly *it$ cord !B+# t$an *itadult . !B+# at A Y+ fter treatment *it$ ;;, tpatientH# #eC rum and t$e eluate did not agglutinate !B+#, but reC acted T and >T, re#pecti ely, atantiglobulin te#t *it$ antiC.gG ;$e dilution control 7

t$e aboli#$ed agglutiC nation8 reacted A to >T *it$ #erum and T *it$ t$e eluate ;$u#, .gM plu# .gG an. ; *a# demon#trated in bot$ t$e #erum and t$e eluatet$e .& #erum #creen, agglutination *a# ob#er ed22Y+ and A Y+ #imilar to t$at in t$e titration and t$eamplitude #tudie#F a $emoly#in *a# al#o ob#er ed en/ymeCtreated !B+# at bot$ temC perature#, but *it$ouclear preference for eit$er temperC ature

Case 2;$e ; on ;;Ctreated !B+# *a# >T *it$ antiC.gG

and antiC+AF t$e R albumin control *a# nonreacti et$e initial titer and t$ermal amplitude #tudie#, an agglutinreC acted at A Y+ *it$ cord !B+#F adult . !B+# didreact atA Y+ or A0Y+ ;itration re#ult# *it$ adult ., cord iadult i !B+# are #$o*n in ;able Sufficient autolog!B+# *ere not a ailable ;; treatment of t$e patient#erum aboli#$ed agglutination *it$ cord !B+#F $o*edilution# of ;;C treated #erum te#ted again#t adult . ancord !B+# did not #$o* a difference in reaction #trengt$t$e .gG component ;$u#, an .gM antiC.; plu# a broadreacti e .gG antibody *a# demon#trated in t$e #erum eluate contained an .gG anC tibody #ugge#ti e of an7titer


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R&M&LeF >?22

+orrection note? ;ran#fu#ion 9 >F >? A0 W> Garratty G, &afleig$ B, al/iel J, %et/ ' n .gG

tiC.; detected in a +auca#ian merican ;ran#fu#io9 2F 2?A25K9

5 'e ine M, ;$ornton %, )orman SJ, et al %o#i+oomb# te#t in &odg4inH# di#ea#e? #ignificance anplication# Blood 9D0F55? 0 K

&afleig$ EB, -ell# !), Grumet )+ Non$emolytic .gantiC.; ;ran#fu#ion 9 DF D?592K

)reedman J, Ne*land# M, Jo$n#on + -arm .gMantiC.; cau#ing autoimmune $aemolytic anaemia VSang 9 FA2? A5K>2

D )reedman J, +$eng '), Murray , Myer# ! unu#ual autoimmune $emolytic anemia in a patien *it$ immuC nobla#tic #arcoma m J &ema

9DAF >? 5KD>9 'eger !M, Nguyen N, Garratty G, 'o*der ), )eldman

N n unu#ual .gM *arm T .gG autoantiC.; a##ociate *it$ lymp$oma, pancytopenia and $emolytic anemi7ab#tract8 ;ran#fu#ion 200AF>A? 00

0 %et/ ' , Garratty G .mmune $emolytic anemia#ed %$iladelp$ia? +$urc$ill 'i ing#tone, 200>

pur#ued after t$e initial increa#ed reacti ity *it$ cord!B+# *a# ob#er ed E:ample# of antiC.; $a e beenreported to be .gM cold agglutinin# or .gG antibodie#optimally reacti e at A Y+ -e are only a*are of onereported e:ample of .gM *arm antiC. ; , and t$at ca#e *a#not a##ociated *it$ &odgC 4inH# di#ea#e or lymp$oma.nmore t$an 20 year#, *e $a e encountered only t*o ot$ere:ample# of .gM *arm reacti e antiC.; F neit$er $ad an .gGcomponent, but bot$ *ere a#C #ociated *it$ a $i#tory oflymp$oma before t$e #erologic *or4up

etermining t$e #pecificity of autoantibodie# i# typicalC

2

A

!eid ME utoagglutination di#per#al utili/ing #ulp$dryl compound# ;ran#fu#ion 9 DF D?A5AK5'eger !M, rndt % , +ie#iel#4i J, Garratty G )al#po#iti e eluate reacti ity due to t$e lo*Cionic *a#$ lution u#ed *it$ commercial acidCelution 4it# ;ran##ion 99DFAD?5 5K 2 rndt % , 'eger !M, Garratty G Serologic findinin autoimmune $emolytic anemia a##ociated *it$ immunoglobulin M *arm autoantibodie# ;ran#fu#io2009F>9?2A5K>2

ly of academic intere#t only .n general, #erologic re#ult# donot nece##arily prompt a clinical e aluation for lymp$oma.n bot$ of t$e#e ca#e#, t$e unu#ual !B+ antibody and t$e$i#toric a##ociation of t$i# #pecificity *it$ lymp$oma, toCget$er *it$ t$e pre#enting finding# of .& , led to t$e lymCp$oma *or4up )or patient# *$o do not progre## to lymCp$oma, one mig$t #peculate t$at ritu:imab 7antiC+ 208gi en for t$e .& could $a e eradicated a malignantclone of B cell#

Regina M8 Leger$ M(?A$ M.+A(CP,(&&$ Research Associ- ate$ American Red Cross &lood (er/ices$ (outhernCalifor- nia$ 233 Red Cross Circle$ Pomona$ CA


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R&M&Le


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.

Ori9, MannC-$itney ! te#t8 increa#e in )y e:pre##ion onS ( !B+ compared *it$ !B+ from indi idual# *it$out t$i#polymorp$i#m? mean )y e:pre#C #ion 7mean fluore#cenceinten#ity M).W8 *a# 0 2 22 for S ( $etero/ygote# er#u# anM). of D 95 for indi idual# *it$out S ( )or reticulocyte#t$e M). alue# *ere 2 9 2 for S ( $etero/ygote# and

> A D for control# S ( i# a##ociated *it$ increa#ed and

not decrea#ed )y e:pre##ion #o t$at #u#ceptibility to P8 /i/axinfection i# unli4ely to be affected Immunohematology 009? 5)63#66

0e$ 4ords: uffy, Sout$ea#t #ian o alocyto#i#, antigen

!B+ morp$ology A S ( i# *ide#pread in #e eral popution# of %apua Ne* Guinea 7%NG8, *$ere it# pre acorrelate# *it$ malaria endemicity and altitude > .n t$e#population#, $omo/ygo#ity i# apparently incompatible *full de elopment of t$e fetu# ina#muc$ a# no per#on#mo/ygou# for t$e band A mutation $a e yet been de#crib but $etero/ygo#ity confer# #trong protection again#t ce bral malaria 5, lt$oug$ early #tudie# $ad #ugge#ted tt$e S ( trait may afford #ome protection again#t /i/ax

falci"arum "arasitemia , K9 ot$er #tudie# did not #uppot$i# $ypot$e#i# 0 ;$e mec$ani#m of protection againcerebral malaria i# not completely under#tood, , 2 but t$#pecific protection again#t cerebral malaria #ugge#t# t$may operate by mean# of alteration# in #e6ue#tration offected !B+ &o*e er, S ( confer# limited or no protectiagain#t placental malaria, *$ic$ i# al#o lin4ed to #e6ue#tion of infected !B+# BA,B>

.ndi idual# *$o#e !B+# are negati e for e:pre##ionuffy antigen# illu#trate $omo/ygote ad antage for i

malaria in t$at t$eir !B+# are completely refractory to i a#ion by Plasmodium /i/ax 5 &i#toric #erologic data #ge#t e:pre##ion of #ome antigen# on $uman !B+# *a# #pre##ed by t$e S ( trait, but e:pre##ion of uffy antigedid not appear #uppre##ed a# determined by t$e le## #e

e:pre##ion ti e #erologic in#trument# a ailable at t$at timeB .n t$o#

n 9>9 &aldane propo#ed t$at malaria $ad a dramaticinfluence on t$e $uman genome, by #electing for geCnetic polymorp$i#m# t$at *ere 4no*n or #u#pected to

protect again#t malaria lt$oug$ #ome of t$e#e polymorCp$i#m# can be detrimental *$en indi idual# are $omo/yC

gou#, e g , #ic4le cell anemia, t$eir apparent #election in

$uC man population# li ing in malariaCendemic area# i#e idence t$at t$ey offer #ome protection again#t deat$from malaria, an infectiou# di#ea#e t$at continue# to 4ill

more t$an milC lion per#on# annually2 +ritical to t$i#t$eory i# t$e concept of $etero/ygote ad antage ;$at i#,

carriage of t$e mutant gene on one member of ac$romo#omal pair i# beneficial *$erea# $omo/ygo#ity i#

deleteriou# n e:treme e:ample of $etero/ygotead antage in Melane#ian population# i# Sout$ea#t #iano alocyto#i# 7S (8, a $ereditary form of o alocyto#i# t$at

i# cau#ed by a 2 Cba#e pair deletion in t$e gene encodingt$e ma or integral !B+ membrane protein band A 7 E ,

S'+> 8, leading to a di#tincti e c$ange in

#tudie#, antibodie# of arying #pecificitie# *ere placetube# u#ing #erial dilution, and re#ult# *ere read mac#copically *it$ t$e aid of an eyepiece u#ing a #tandai/ed #coring #y#tem .n t$i# #tudy, *e u#ed molecularcytometric tec$ni6ue# to diagno#e S ( and to ree:amin *$et$er t$ere *a# a difference in e:pre##ion of uffy atigen receptor for c$emo4ine# 7 !+8 bet*een S ( ancontrol indi idual# in t$e conte:t of po##ible differen#u#ceptibility to infection *it$ different Plasmodium #pcie#

Materials and Method sBlood *a# collected by enipuncture in +% antico

ulant or by finger pric4 u#ing a B Microtainer 7Becic4in#on, San Jo#e, + 8 *it$ E ; anticoagulant fro

$ealt$y olunteer# from t*o illage#, Sempi and Bemon t$e nort$ coa#t of t$e Madang %ro ince, %NG (raformed con#ent *a# obtained after appro al for t$e #tu by t$e Medical !e#earc$ d i#ory +ommittee of t$e %


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I&7&9oolle) et (l&

H. IMMU NO HEMATO LOG Y, Volume !, Num"er , ##

Mini#try of &ealt$ fter collection, #ample# *ere 4ept onice or refrigerated at >Y+ -it$in *ee4, flo* cytometric#tudie# *ere underta4en *it$ antibody to )y 74indly proC ided by Jo$n Barn*ell, + +, tlanta, G 8 ;$i# i# amou#e monoclonal antibody t$at attac$e# to t$e fir#te:tracellular domain of t$e )y glycoprotein, in an area

t$oug$t to corC re#pond to t$e binding #ite of P8 /i/axmero/oite# , D;$e antibody *a# con ugated directly to ap$ycoeryt$rin 7%E8 label 7%ro/yme, San 'eandro, + 8according to t$e manuC facturerH# in#truction# 5C`'ali6uot of blood *a# *a#$ed t$ree time# in 50 `' of %BSand pelleted !B+# *ere incuC bated *it$ 50 `' of a in 50dilution of )y antibody for 5 minute# at A Y+ +ell# *eret$en *a#$ed t*ice in %BS and re#u#pended in t$ia/oleorange 7;(8 #olution according to t$e manufacturerH##pecification# 7Becton ic4in#on8 ;$e #ample# *ereanaly/ed on a flo* cytometer 7MoC)lo, aC 4o+ytomation,)ort +ollin#, +(8 e6uipped *it$ a 0Cm- airCcooled argonion la#er at >DD nm ;( fluore#cence *a# read *it$ a 525C

nm bandpa## optical filter and %E fluore#C cence *it$ a5 0Cnm bandpa## filter +ompen#ation *a# applied, andnegati e fluore#cence #ignal# *ere ad u#ted until t$ey *ereort$ogonal )or*ardC#catter, #ideC#catter, and fluore#cencedata *ere analy/ed count of 5000 ;(C po#iti e cell# *a#ta4en per #ample ;$i# *a# appro:imately

to 2 percent of t$e total number of cell# a##ayed for eac$indi idual Bead# of 4no*n immunofluore#cence 7.mmuCnoCBrite, +oulter, %uerto !ico8 *ere u#ed to #tandardi/ee:periment# underta4en at different time# etection oft$e S ( mutation *a# underta4en u#ing pre iou#lyde#cribed %+! met$od# 9 E:perienced micro#copi#t# fromt$e %NG .n#titute of Medical !e#earc$ performed lig$t

micro#copic in#pection of Giem#aC#tained blood film# formalaria paraC #ite# Stati#tical analy#i# *a# underta4en byu#ing S%SS 7Stat ie* > 5 , bacu# +oncept#, Ber4eley,+ 8 -e $a e u#ed nonparametric te#ting becau#e *e donot $a e e iC dence for normal di#tribution of !+abundance in t$e #urface of S ( eryt$rocyte#

ResultsSample# from 9 S ( $etero/ygote# and 20 nonCS (

donor# *ere e:amined Mean age of donor# did not difCfer #ignificantly bet*een t$e t*o group# 7mean age, 29 A2

A 0 year# for S ( $etero/ygote# er#u# 2 9 D0 year# for nonCS ( indi idual#8 )our indi idual# $ad maClaria infection ba#ed on in#pection of blood #mear# (neS ( and one nonCS ( indi idual $ad Plasmodiummalari- ae , and t*o nonCS ( donor# $ad Plasmodium falci"arum S ( !B+ #$o*ed increa#ed e:pre##ion of )yglycoprotein relati e to nonCS ( !B+ a# mea#ured by binding of t$e )y monoclonal antibody 7;able 8 ;$ele el of )y antigen *a# al#o $ig$er in S ( reticulocyte#compared *it$ control reticulocyte#, but t$e difference *a#not #tati#tically #igC nificant 7;able 8 Sub#e6uent analy#i#of t$e data did not #ugge#t t$e difference# *ere cau#ed by a#y#temic bia# atC tributable to #e:, illage of origin, ormet$od of obtaining blood 7data not #$o*n8

!a%le ,- Me(n =luores+en+e intensit) @ st(nd(rd devi(tion o= )(nti"od) "indin< to er)t ro+)tes (nd reti+ulo+)tes

All Su% ects;Reticuloc$tes98 in )y antie:pre##ion by S ( !B+# *$en compared *it$ !B+# fromnonCS ( indi idual# from t$e #ame area ;$i# differen *a# #ignificant *$en e:pre##ion by all !B+ population *a# e aluated but not *$en only S ( reticulocyte# *erecompared *it$ nonCS ( reticulocyte# 7alt$oug$ a #uggeti e trend e:i#ted8 # anticipated, reticulocyte e:pre##of )y antigen e:ceeded !B+ e:pre##ion 20 ;$e rea#on# fot$e increa#ed !B+ )y antigen e:pre##ion in S ( are unCclear at pre#ent, but it may reflect eit$er a decrea#ed rate lo## of )y antigen from t$e #urface of S ( !B+ relati e control !B+, per$ap# in relation to t$e increa#ed rigidity ot$e S ( cell *all, or difference# in t$e #urface area oo aloC cyte# er#u# nonCS ( !B+ Becau#e t$ere *a#a #mall increa#e in )y antigen e:pre##ion on S ( !B+and t$ere *a# no #tati#tically #ignificant increa#e in treticulocyte #ubpopulation, *$ic$ i# t$e on#ubpopulation #u#ceptible to infection by P8 /i/ax , it iunli4ely t$at t$i# alteration afC fect# #u#ceptibility to tpara#ite, alt$oug$ t$ere i# ot$er in itro e idence t$alteration# in number# of )y antigen# e:pre##ed may altt$at #u#ceptibility2 .t i# not #urpri#ing t$at t$e differencin )y le el# *a# not #$o*n in t$e paper of Boot$ et al becau#e t$ey *ere u#ing le## #en#iti e #eC rologic metor becau#e )y antigen i# more a ailable or moe:pre##ed in S ( o alocyto#i# o er t$e antigen# te#tedt$e pre iou# #tudy &o*e er, t$eir finding# *it$ re#pecot$er antigen#, including !$ polypeptide#, $a#ub#e6uently been confirmed by molecular tec$ni6ue#22

)y antigen negati ity cau#ed by $omo/ygo#ity forproC moter mutation t$at #ilence# tran#cription of t$e FBgene2A i# ob#er ed in many et$nic group# in #ubCSa$a frica, and pre#umably account# for t$e relati e lac4 i a: maC laria in t$i# part of t$e *orld ;$e apparenindependent emergence of $etero/ygo#ity for t$i# #ampromoter mutaC tion $a# al#o been de#cribed in t$e -o#earea of %NG, *$ere S ( i# rare or none:i#tent ;$ere i#need for furt$er e aluation of *$et$er ot$er common !B+polymorp$i#m# affect )y antigen e:pre##ion, e#peciat$o#e t$at are a#C #ociated *it$ c$ange# in !B+ #$ape a#urface area )or e:ample, ' Ct$ala##emia i# common%NG, and in many area#, including t$e Madang %ro inearly all indi idual# $a e t$e typical' Cglobin mutatio#een in Melane#ian#2> .t


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SAO (nd 3 AR

#eem# unli4ely t$at t$i# common polymorp$i#m *ould acta# a confounding factor in our #tudy on t$e ground# of bioClogic plau#ibility, lo* li4eli$ood of lin4age di#e6uilibrium,and ery $ig$ pre alence in t$e region 7a##uming t$ereforemore or le## e6ual di#tribution bet*een S ( and controlindi idual# *it$in t$e population #tudied8 )inally, it *ill

9 Ser eant#on S, Bry#on ", mato , Babona Mand $ereditary o alocyto#i# &um Genet 9 FA

0 )oo '+, !e4$ra V, +$iang G', Ma4 J- ( alocyto#protect# again#t #e ere malaria para#itemia in t$e Mlayan aborigine# m J ;rop Med &yg 992F> ?2

be important to determine *$et$er en ironmental ariCable# e:tant in malariaCendemic population# mig$t c$ange)y antigen e:pre##ion not$er e:ample *ould be irondefiC ciency, *$ic$ i# pre alent in %NG and many ot$ermalariaC endemic region# of t$e *orld

;$ere i# e idence t$at t$e S ( trait affect# #e eral#tep# of t$e biologic cycle of P8 falci"arum t$at may berele ant for t$e #electi e ad antage conferred by t$i# traitagain#t malaria .n particular, S ( !B+# are partlyre#i#tant to inC a#ion in culture by mero/oite# of

Plasmodium nowlesi and #e eral line# of P8 falci"arum ,25,2 and t$e S ( trait al#o re#ult# in alteredad$e#ion of infected !B+# to + A # *it$ B(,2 it i#

li4ely t$at t$e e olutionary pre##ure e:C erted by #ur i al *it$ S ( i# related to #ur i al of c$ildren from cerebralmalaria before reproducti e age lt$oug$ )y e:pre##ionprobably affect# P8 /i/ax infection,2D t$i# e oluC tionarypre##ure i# almo#t certainly cau#ed by P8 falci"arumt$roug$ it# relation#$ip to !B+ ad$e#ion

A c +nowledgment;$i# #tudy *a# funded in part by a +o ance )ello*#$ip

from t$e !oyal u#trala#ian +ollege of %$y#ician# 7. - 8

References&aldane JBS i#ea#e and e olution !ic Sci Suppl 9>9F 9? DK

2 Maitland ", Be on %, Ne*ton +! Malaria +urr (pin.nfect i# 200AF ?AD9K95

A Jarolim %, %ale4 J, mato , et al eletion in eryt$roCcyte band A gene in malariaCre#i#tant Sout$ea#t #iano alocyto#i# %roc Natl cad Sci S 99 FDD? 022K

> Mgone +S, "o4i G, %aniu MM, et al (ccurrence of t$eeryt$rocyte band A 7 A)2 8 gene deletion in relation tomalaria endemicity in %apua Ne* Guinea ;ran# ! Soc;rop Med &yg 99 F90?22DKA

5 Genton B, alC3aman ), Mgone +S, et al ( alocyto#i#

2

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+orte# , Benet , +oo4e BM, Barn*ell J-, !eeder J+ bility of Plasmodium falci"arum to in ade Sout$ea #ian o alocyte# arie# bet*een para#ite line# B200>F 0>?29 K+orte# , Mellombo M, Mgone +S, Bec4 &%, !eedeJ+, +oo4e BM d$e#ion of Plasmodium

falci"arum K infected red blood cell# to + A undeflo* i# en$anced by t$e cerebral malariaCprotecti etrait Sout$CEa#t #ian o alocyto#i# Mol Bioc$em%ara#itol 2005F >2?252K (H onnell , !ai4o +legg JB, -eat$erall J, llen SJ Sout$ea#t #iano alocyto#i# and pregnancy in a malariaCendemicregion of %apua Ne* Guinea m J ;rop Med &yg

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9D F ? KD5 -a#nio*4#a ", Blanc$ard , Jan ier , et al .dentifcation of t$e )y epitope recogni#ed by t*o monoclonantibodie# in t$e N Cterminal e:tracellular portion t$e uffy antigen receptor for c$emo4ine# Mol munol 99 FAA?9 K2AJarolim %, %ale4 J, mato , et al eletion in erytcyte band A gene in malariaCre#i#tant Sout$ea#t o alocyto#i# %roc Natl cad Sci S 99 FDD

and cerebral malaria Nature 995FA D?5 >K5 llen SJ, (H onnell , le:ander N , et al %re entionof cerebral malaria in c$ildren in %apua Ne* Guinea by Sout$ea#t #ian o alocyto#i# band A m J ;ropMed

20 -oolley .J, &otmire " , Sram4o#4i !M, Pimmerma% , "a/ura J- ifferential e:pre##ion of t$e ufantigen receptor for c$emo4ine# according to !B+ aand )3 genotype ;ran#fu#ion 2000F>0?9>9K5A

&yg 999F 0? 05 K 0)o*4e# )J, Mic$on %, %illing ', et al &o#t eryt$rocyte

polymorp$i#m# and e:po#ure to Plasmodium falci"ar-um in %apua Ne* Guinea Malar J 200DF ?

D +attani J , Gib#on ) , lper# M%, +rane GG &erediCtary o alocyto#i# and reduced #u#ceptibility to malarCia in %apua Ne* Guinea ;ran# ! Soc ;rop Med &yg

9D FD ? 05K9

2 Mic$on %, -oolley ., -ood EM, "a#ten# -, Pimmerman % , dam# J& uffyCnull promoter $etero/yty reduce# !+ e:pre##ion and abrogate# ad$e#iont$e P8 /i/ax ligand re6uired for bloodC#tage infect)EBS 'ett 200 F>95? K >


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22 Bec4mann !, Smyt$e JS, n#tee J, ;anner MJ +oe:Cpre##ion of band A mutant# and !$ polypeptide#? difCferential effect# of band A on t$e e:pre##ion of t$e !$comple: containing polypeptide and t$e !$ comple:containing +cEe polypeptide Blood 200 F9 ?2>9 K505

2A ;ournamille +, +olin 3, +artron J%, 'e Van "im + i#Cruption of a G ; motif in t$e uffy gene promoteraboli#$e# eryt$roid gene e:pre##ion in uffyCnegati eindi idual# Nat Genet 995F 0?22>KD

2> +oc4burn . , Mac4innon MJ, (H onnell , et al $uman complement receptor polymorp$i#m t$at reCduce# Plasmodium falci"arum ro#etting confer#protecC tion again#t #e ere malaria %roc Natl cadSci S 200>F 0 ?2 2K

25 "id#on +, 'amont G, Saul , Nur#e G; ( alocyticeryt$rocyte# from Melane#ian# are re#i#tant toin a#ion by malaria para#ite# in culture %roc Natl

cad Sci S 9D F D?5D29KA22 &adley ;, Saul , 'amont G, &ud#on E, Miller '&,"id#on + !e#i#tance of Melane#ian elliptocyte# 7o aloCcyte#8 to in a#ion by Plasmodium nowlesi and Plas-modium falci"arum malaria para#ite# in itro J +lin.n e#t 9DAF ? D0K2

2 +#erti +M, /i4 -& ;$

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