Goulmy, E.A.J.M.

Leeuwen, A. van

Rood, J.J. van

Leiden University Scholary Publications

Recognition by Human Β Cells of Foreign Antigenin the Context of the MHC: a Review[ GOUIMY Α VAN LiruwtN and J J VAN ROOIJDepartment of Immunohaematology and Bloodbank, University Hospital of leidenRijnsbuigerweg 10 2333 AA Leiden 1 he NetheilandsIhe expenmental evidence foi the existence of human Β cells that recognize foieignantigen in the conlexl of the MHC is very restnrted not lo say limited to only oneexample (Van Leeuwen et al 1979) at least with legatd to the known nature of theMHC allele and the antigen mvolved On the other hand in exenmental animalmodeis, the number of antigen specific MHC restricted antibodies leported (see thedetailed descnptions by different authois in this volume) greatly exceeds onethough it does not reach overwhelming levels Nevertheless, the independentobservations strongly support the notion that MHC lestncted antibodies do existalthough with Special regard to the human studies moie data aie needed tostrengthen the evidence for the existence of such antibodies in manThe assumption that some Β cells aie capable of geneiatmg MHC restricted antigen specific antibodies is based on oui earlier observation Moie than one decadehas now elapsed smee participation ot the HLA molecules in the lecognition of foieign antigen by cytotoxic T-lymphocytes (Cils) was leported (Gouimy et al 1976)Although such recognition is chaiactenstic foi Γ colls a caieful analysis of the seiumof the female patient whose lymphocytes were able to demonstrate HLA A2restricted H Υ specific cytotoxic activity levealed Β cell mediated activity comparable with the cytotoxic Τ cell responses (Van leeuwen et al 1979) It became appaient that lympholytic antibodies weie piesent in the serum which reacted with somemononuclear cells labend with anti Ig Ihe antibody activity was found in the IgMfraction The scrum was tested agamst a panel of iymphocytes of healthy male andfemale donors either positive οι negative for the lestncting molecule (i e Hl Α Α2)Ihe lesults demonstratec, that all Hl Α A2 positive male donois weie rea ting witnthis antiserum whe eas the lymphocytes ol III Α Α2 negative male οι female donorswere negative in the complemcnt dependent cylotoxicity assay Nevertheless of theH1A A2 positive female donois two gave a boideihne positive reaction It shouldbe noted that ihe lymphocytes of onp of Ihe latter females weie also boideilmolysed by the hl Α A2 lestnctod anti 11 Υ C ILs in the CV1I assay Comparalive analysisbetween thr outcome of the CM1 assav and the icactions obtained with the antiseium showed striking similanty (lable I) Because of the almost peifect correlationbetween the reactivity patterns of the CIIs and the anlibody it is ifasonableto assume that the HLA A2 testiicted antibody tecogni/es the same epitopeson the III Λ Α2 and on the 11 \ anligen as do ihe III Λ Α2 lestucted CIIs obtainedfiom the same individual Since vanants exist both at the level ol the anligenc ηAnti1 Λb ΟdeilinevalΓtuicof(Gobewhcthepattsaml0g!far \is ηlessstattantifere(SimItepitfunccamdonof IinfrcanaldemwithIIusinsho\MHC +X Rpcognilion by Human Antibody V:>\ I eiden,'p forcignonly onejrc o i theal animald (see the>eds one,ependentdo exist,eeded tof ted anti-e decadeon of for-al 1976)ihe serum> H1A-A2compara-mo appat\ith someη the IgMnale andIII Α Α2Ι(tmg withile donorsoss o i theIt shouldboiflerlinpν c analvsisι (he undonolationeasonabloepitopes- obtaincdi<> antigenTabie 1. Corrolation bctween the lysis patterns by the C TLs and by tho antiserum, bothdenved from the same individual tested against several healthy male and fomale individualsCytotoxir act/vityas exhibited byPanel ceüs tested by CTI s and antibodyA2+ males"in =20)A2+ females(n=7)A2— females,A2— males(n=16)20201 b2Antibody3 A2 + = I ILA A2 positive A2 - = Hl A-A2 negativeb Only one of the two HLA-A2+ female cells tested by both CTI s and antibody gave a borderline positive icaction with the I l-Y spetific C FLsΗ Υ and at the level of the restncting molecule Hl A-A2, our hypothesis could beevaluatedTo approach the question of whether CTls and antibody recogm/e similar struc-tures on the H-Y molecule, we studied the chromosomes and the reaction patternsof a small senes of individuals with abnormal sex chromosome constitutions(Coulmy e+ Μ 1983) It should be emphasized that the number of cases which rouldbe studied was limited since the reagents are applicable only to those mdividualswho carry the appropnate MHC restncting moiecule The picture that arose fromthe latter study confnmed the earher observed correlation between the reactivitypatterns of CTLs and antibody Moreover, the combmed analysis (each showmg thesame discnminatory patterns) levealed a correlation with the presence of the cyto-logically detectable Y-chromosome matenal but nol with the presence of festes Sofar we have assumed that the antigen recogni/ed by both the Β cells and the Γ cellsis most probably identical with the classical transplantation antigen H-Y Neverthe-less, we have not yel reached the point at which we would be justified in makingStatements concerning tho nature of the H-Y antigen as recognized by CTI s andantibody Current exammation oi sex reversed humans by combmed analyses of different sets of Y-DNA probes and l l-Y specific C f ls will hopefully resolve this issuc(Simpson et al 1987)lo elaborate on the assumption that IILA-A2 restncted Β cells use the same MHCepitopes as I I[A A2 restncted I cells for the recognition of the "MHC + X" complex,functional analyses of an established MHC class I "vanant" IIIA-A2 molecule werecarned out foi this purpose sorological HLA-A2 positive lymphocytes from a maledonor designated M7 were used Biddison et al (1980a) demonstrated, by the useof Hl Α Α2 restncted influen/a virus immune Γ cells, a lack of recognition of virusinfected III Α A2 positive lymphocytes from donor M7 Additionally, biochemicalanalysis by means of isoeleclnc focusing of the Hl Α A2 molecule fiom donor M7demonstrated a differenre in the III Α Α2 heavy polypeptide chain when comparedwith the HIA-A2 molecules of other donois (Biddison et al 1980b)I h e lymphocytes from donor M7 were subsequenlly analy/ed in oui laboratoiyusing both the HIA-A2 restncted H-Y antigen specific C f ls and antibody lable 2shows that HIA A2 restncted anti H-Y C l l s failed to lyse the lymphocytes from1 . '. * v.36 Ε Goulmy et alTable 2 Differential recognition of Hl Α A2 vanant cells (M7) by HLA A2 restricted Η Υ antigen specific CTLs and antibodyTarget Cells HLA A2 restncted anti Η ΥCTLs AntibodyHLA A2+ male cellsHLA A2+ male cellsHLA A 2 + male M7 cellsHLA A2+ female cells64d671345 a41Γ36]°/( cytotoxicitydonor M7 This reaction pattern is comparable to the absence of recognition usmgHLA A2 restncted mfluenza virus specific CTLs (Biddison et al 1980a) However theHLA A2 restncted anti Η Υ antiserum did react with the M7 cells to an extent comparable to that in other HLA A2 positive male donors it is clear from these observations not only that alloimmune HLA A2 specific antisera and alloimmune HLA A2specific CTLs might use different epitope(s) on the same HIAA2 molecule forallorecognition (Horai et al 1982) but also that monospecific anti II Υ antiserumand "monospecific anti-H Υ CTLs (both denved from the same mdividual) apparently use different epitopes on the HLA A2 molecule for associative recognition ofthe foreign antigen Thus the Η Υ specific antibody recognizes seif determinants onthe HLA A2 molecule that are distinct from those that are seen by Η Υ specific CTLsLately addilional Information has become available on the more precise locationof the target structures for CTLs on the HLA A2 molecule Combined investigation(resultmg from a collaborative effort) of the HLA A2 vanant molecules at the molecular (Ezquerra et al 1986) and at the functional (Goulmy et al 1984) level demonstrated that ammo acid changes at position 43 and in the residues 145 157 (i ecellular defined subtypes HLA A2 2 and HIAA2 3) lead to the loss of epitope(s)necessary for associative recognition of the Η Υ antigen by HLA A2 restncted CTlsInterestingly enough a Single ammo acid change at position 9 in the heavy cham ofthe HLA A2 molecule (ι e cellular defined subtype LILA A2 4) does not affect thetecognition of Η Υ by HLA A2 restricted CTLsObviously it is of interest to examine the reactivity pattems of the cells of theindividuals expressmg the cellular defined HLA A2 i and HLA A2 4 subtypes (donoiM7 see Table 2 carnes fhe HLA Λ2 2 subtype) with oui Hl Α A2 restncted Η Υ specific antibody Unforturately the amounts of the Η Υ specific antibody at our disposal were small the Η Υ aitibody was only present in the patient s serum for 1 yeaiafter bone marrow transplantation and the activity declmed theieafterAt present attempts are being made at the in vitro production of the Η Υ antibody by Epstem Garr virus transformed Β cells denved from the original Ll Υ producing female patientAcknowledgrmnf; Ihe authors vvouid like to thank Eis Blokland and Jos Pool foi thtir tcchnical assistance and Ingrid Cunel for typmg the manuscnpt Τ his woik was supported in pari bygrants from the Dutch Foundation for Medical Health Reseaich (Medigon) which rs subsidν U VMHC + X Recognition by Human Antibody 37ized by the Dutch Organization for the Advancement of Pure Research (ZWO), and theJ.A.Cohen Institute for Radiopathology and Radiation Protection (IRS).ReferencesBiddison WE, Ward FE, Shearer GM, Shaw S (1980a) The seif determinants recognized byhuman virus immune Τ cells can be distinguished from the serologically defined HLA anti-gens. J Immunol 124: 548-552Biddison WE, Krangel MS, Strominger JL, Ward FE, Shearer GM, Shaw S (1980 b) Virus immunecytotoxic Τ cells recognized structural differences between serologically indistinguishableHLA-A2 Hum Immunol 1: 225-232Ezquerra A, Domenech N, van der Poel JJ, Strominger JL, Vega MA, Lopez de Castro JA (1986)Molecular analysis of an HLA-A2 functional variant C1a defined by cytolytic Τ lymphocytes.J Immunol 137· 1642-1649Goulmy E, Termijtelen A, Bradley BA, van Rood JJ (1976) Alloimmumty to human H-Y.Lancet 2:1206Goulmy E, van Leeuwen A, Blokland E, Sachs ES, Geraedts JPM (1983) Ehe recognition ofabnormal sex chromosome constitution by ElLA-restricted anti-H-Y cytotoxic Τ cells andantibody Immunogenetics 17. 523-531Goulmy E, van der Poel JJ, Giphart M, van Rood JJ (1984) Analysis of the functional epitopes ondifferent HLA-A2 molecules Immunogenetics 20. 13-21Horai S, van der Poel JJ, Goulmy Ε (1982) Differential recognition of the serologically definedE1LA-A2 antigen by allogeneic cytotoxic Τ cells. I. Population studies Immunogenelics 16:135-142Simpson E, Chandler P, Goulmy E, Disteche CM, Ferguson-Smith MA, Page D (1987) Separa-tion of the genetic loci for the H-Y antigen and for testis determmation on human Υ chro-mosome. Nature 326: 876-878Van Leeuwen A, Goulmy E, van Rood JJ (1979) Major histocompatibility complex-restrictedantibody reactivity rnainly, but not exclusively directed against cells from male individuals. JExp Med 150· 1075-1083anti-pro

Recognition by human B cells of foreign antigen in the context of MHC

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Recognition by human B cells of foreign antigen in the context of MHC

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