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For personal use only. 1994 84: 986-987 Inter-VH-gene-family shared idiotype on acquired immunodeficiency syndrome-associated lymphomas [letter] M Hurt, B Herndier, V Ng and MS McGrath Updated information and services can be found at: http://www.bloodjournal.org/content/84/3/986.citation.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved. From www.bloodjournal.org by guest on October 15, 2014. For personal use only. CORRESPONDENCE 986 Inter-VH-GeneFamily Shared ldiotype on Aquired Immunodeficiency Syndrome-Associated Lymphomas To the Editor: Lymphomas occurring in individuals infected with the human immunodeficiency virus type 1 (HIV-l),are predominantly of Bcell origin. Tumors of B-cell origin not occurring in HIV- 1-infected individuals have been shown to express shared idiotypes; in particular, one anti-idiotype, S2.33, reacted with the leukemic cells of 8 of 105 (7.6%) cases of chronic lymphocytic leukemias (CLL) and 11 of 178 (6.2%) cases of non-acquired immunodeficiency syndrome (AIDS) B-cell lymphomas.' We were interested in determining if B-cell lymphomas occurring in HIV-l-infected individuals similarly expressed shared idiotypes. We immunohistochemically stained 25 separate AIDS-associated B-cell lymphomas with a panel of antiidiotypes (generous gift of Rich Miller, IDEC Pharmaceuticals, Mountain View, CA); the S2.33 idiotype reacted with 7 (28%) (ie, 1 of 7 Burkitt's lymphomas, 4 of 16 immunoblastic lymphomas, A loc9 -19 -18 -17 -16 -15 -14 -13 -12 -10 -9 -8 -7 4 -5 -4 -3 -2 -1 AT0 WIG TI? GGG C I G AGC NNN NNN NTC CTT GTT GCT A l l ATA A44 GGT GTC CAG TGT -..A . A CAC C l - TG- TT- TTN NNC C - - - - G . - G . - A GC- CCC - G - 1 - G - - - -1- -CC BR loc9 1 2 3 4 5 6 7 8 10 9 171615 l 1141312 18 19 20 CAG GTG CAG CTG GTG GAG TCT GGG GGA Mjc TTG GTC AAG CC1 GGA GGG TCC CTG AGA CTC ...... ..A ..A CAA C.. ..C .C. .-A C.. 1 . G ...... TCG .A. A.. ... TCC ... BR loc9 COR1 21 22 23 24 M m 27 28 m 30 32 31 33 34 35 ~b 37 UI 39 U ) TCC TGT GCA GCC TCT GGA TTC ACC TTC ACT GAC TAC TAC ATG AGC TOG ATC CGC CAG GCT A n ..C -1. .A. 1.. ...... .GT ...... TG. .C. ............ C . C -20 BR 1oc9 CDR2 41 42 43 44 45 46 41 U ) 49 50 51 52 52a 53 54 55 56 51 58 CCA GGG AAG GGG CTG GAG TOG GTT TCA TAC ATT AGT AGT AGT GGT AGT ACC ATA TAC ............ 1.. ...... A.. m G . A ..C .A. CA. A.. G.A GA. .CC A.. BR GCA GAC TCT GTG AAG lOC9 MC CCG ..C BR loco Bo 81 82 820 82b 82c 03 M 85 86 81 89 88 90 91 92 93 94 CTG CM ATG M C AG2 CTG AGA GCC GAG GAC ACG GCC GTG TAT TAC TGT GCG A w 1 TCT GGG ... A.G ... ..T TCT G.. .CC ... .C. ...... ..T ..C . . . . . . . . . . . . . . . = . C C BR lK9 CDR3 k I b d e f h i m nl01102 9 7 9 8 9 9 1 M ) a c i g GTC AGG GAT UK: TAC AAT TTA GV ATG ATA GGG GAG TAC TAC TAC TAC TAC GGT ATG GAC .U: .G. .A. ..l C.C ... TA. BR €4 63 82 61 64 65 Mjc ... A - T ..C 66 67 68 73 72 71 70 69 CGA TTC ACC ATC TCC .A. G.. ... ..A ..A GTA M;G 59 TAC ..l 74 16 75 17 79 78 GAC AAC GCC AAG AAC TCA CTG TAT ... .CG T.. ...... C A G T - C -CC m - leader IIIIIIIIIIIIIIIIITi w?GLswLLvAIIIccvpc -20 BR -KWLWPXXL---APRW-LS 1oc9 1 11 9 iI I I liml.rn?tlrtai5 BR 1oc9 SGRDGYNLWIGDYXYYYGMDV GANUD-HP -Y - - l:JJ 6 Fig 1. Compllriron of the nucl.otid. (A) and prodicted amino wid 8 o q u . n ~(B) of tho BR and lOW V. fpnn. (A) Complomantaritydotsfmining rogiona (CDR.)and codon numbering a n asdrlinod by Kabat et al? N (io,at codons -14, -13, and -12) ropmsonb nucleotides whou identitywarenotdetermined with certainty bocauso of proximity to the digonucleotido primm. The loc8 V. gene i.du an amino acid at codon 52.; thir a b u n a is r o p m o d by a blank rp.a.The c " regionof BR h excrptionalty long, andcodons 100 "m" end "n" haw beon .dd.d to be consiatant with the boginning of the framework 4 region at codon 101, as M n e dby Kabat et ai.' (B) Amino add comparison is 8hown &ing to the style of Chothie et al' with numhing dopictd at 5 amino d d intwds. Amlno acid8 markmi with an asterisk ( 9 in the lOW aoquona mpraeent predicted aminoacid raplament mut.tion8 e8 comparedwith ita putative germlinecount.rp.rt, V. 4.21.3 From www.bloodjournal.org by guest on October 15, 2014. For personal use only. CORRESPONDENCE and of 2 low-grade lymphomas [ l CLL and 1 follicular lymphoma]), and reacted with 20% to 60% of lymphocytes present in 4 of 6 lymph nodes obtained from HIV-l-infected individuals and exhibiting follicular hyperplasia. Analysis of shared idiotypes on human B-cell tumors with wellcharacterized monoclonal antibodies (MoAbs) that recognize specific Ig heavy- or light-chain determinants (eg, MoAb 17.109 recognition of the K chain variable gene humkv325, MoAb 6B6.6 recognition of VKIIIa, MoAb G6 recognition of a V, 1 gene, and MoAb (9G4 recognition of V,4.21) has suggested that the observation of shared idiotypes might in fact be a phenotypic marker for expression of specific V genes? The molecular nature of the S2.33 shared idiotype is not known; the observation that S2.33 reactive lymphomas expressed either K or X light chains suggested to us that the S2.33 idiotope might be unique to the coexpressed V, gene. An autoreactive IgM K produced by one previously described well-Characterized cell line, lOC9, derived from an AIDS-associated Burkitt’s lymphoma, was S2.33 reactive and used a VH4 gene 95% related to the V,4.21 gene.3 Preferential use of the V, 4.21 gene has been shown with antibodies associated with autoimmune disease4; the relatively high frequency of S2.33 binding to human Bcell lymphomas suggested that the S2.33 anti-idiotype might be a marker for use of the V, 4.21 gene. To pursue this hypothesis, we determined the V, gene used by the leukemic cells of an S2.33reactive AIDS-associated CLL (BR). The VH gene was amplified using the polymerase chain reaction (PCR) from DNA extracted from paraffin-embedded tissue’ and previously described methods.’ A single PCR product was observed with a 5‘ V, 3 leader sequence/ 3’ consensus JH primer pair. Nucleotide sequence showed the PCR product to be 100% homologous to a previously described germline V, 3 gene, 22-2B.6 The VL gene used by BR was not determined. When the two nucleotide sequences (Fig 1A) or predicted amino acid sequences (Fig 1B) of the 1OC9 and BR VHgenes were aligned, there were no obvious regions of homology to serve as candidates for a shared idiotope. An idiotope could theoretically be as small as 5 amino acids; the only linear stretches of the 2 VHgenes to satisfy that requirement were between codons 43 through 47 and 86 through 94, the sequences of which were identical to that of another IgM produced by an AIDS lymphoma cell line, 2F7,’ which failed to react with S2.33. The possibility that the VHantigen binding hypervariable region (ie, H1 and H2 canonical structures that are adjacent to and slightly overlap the complementarity determining regions’) constituted the idiotope was considered when BR and 1OC9 were observed to have the same type 1 H1 canonical structure; however, this possibility was eliminated when the 2F7 IgM was also noted to have the same type 1 H1 canonical structure. In contrast to other studies that have used well-characterized MoAbs to show “shared idiotypes,” we present preliminary evi- 987 dence that the S2.33 anti-idiotype recognizes a shared idiotype encoded by at least two different V, gene families (ie, V, 3 and V” 4). The molecular nature of the idiotope remains unknown, but may be an as-yet-unidentified secondary or tertiary structure common to both VH genes, or a structural determinant contributed by both the V, and VL genes. Mark Hurt Brian Hemdier Valerie Ng Michael S . McGrath Departments of Laboratory Medicine, Pathology, and Medicine University of California School of Medicine and San Francisco General Hospital San Francisco, CA REFERENCES 1. Swisher EM, Shawler DL, Collins HA, Bustria A, Hart S , Bloomfield C, Miller RA, Royston I: Expression of shared idiotypes in chronic lymphocytic leukemia and small lymphocytic lymphoma. Blood 77:1977, 1991 2. Kipps TJ, Robbins BA, Kuster P, Carson DA: Autoantibodyassociated cross-reactive idiotypes expressed at high frequency in chronic lymphocytic leukemia relative to B-cell lymphomas of follicular center cell origin. Blood 72:422, 1988 3. Ng V L , Hurt MH, Fein CL, Khayam-Bashi F, Marsh J, Nunes W M , McPhaul LW, Feigal E, Nelson P, Hemdier BG, Shiramizu B, Reyes GR, Fry KE, McGrath MS: IgMs produced by two acquired immune deficiency syndrome lymphoma cell lines: Ig binding specificityand VH- gene putative somatic mutation analysis. Blood 83:1067, 1994 4. Pascual V, Capra JD: V&-21,Ahuman VH gene segment overrepresented in the autoimmune repertoire. Arthritis Rheum 35:11, 1992 5. Samoszuk M, Nguyen V, Shadan FF, Ramzi E: Incidence of Epstein-Barr Virus in AIDS-related lymphoma specimens. J Acquir Immune Defic Syndr 6:913, 1993 6 . Berman JE, Mellis SJ, Pollock R, Smith CL, Suh H, Heinke B, Kowal C, Surti U, Chess L, Cantor CR. Alt F W : Content and organization of the human IgV, locus: Definition of three new VH families and linkage to the Ig C, locus. EMBO J 7:727, 1988 7. Chothia C, Lesk AM, Gherardi E, Tomlinson IM, Walter G, Marks JD, Llewelyn MB, Winter G: Structural repertoire ofthe human V, segments. J Mol Biol 227:799, 1992 8. Kabat EA, Wu TT, Perry HM, Gottesman KS, Foeller C: Sequences of Proteins of Immunological Interest (ed 5 ) . Washington, D C , US Department of Health and Human Services, 1991