Leukemia & Lymphoma
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Autoantibody Activity and V Gene Usage by B-Cell Malignancies Guillaume Dtghiero To cite this article: Guillaume Dtghiero (1992) Autoantibody Activity and V Gene Usage by BCell Malignancies, Leukemia & Lymphoma, 8:4-5, 345-351, DOI: 10.3109/10428199209051013 To link to this article: http://dx.doi.org/10.3109/10428199209051013
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Leukemia and Lymphoma, Vol. 8, pp. 345-351 Reprints available directly from the publisher Photocopying permitted by license only
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Autoantibody Activity and V Gene Usage by B-Cell Malignancies GUILLAUME DTGHIERO Downloaded by [NUS National University of Singapore] at 14:39 05 November 2015
Immunohematologie et Immunopathologie, lnstitut Pasteur, 75724 Paris Cedex 15, France (Received 21 April 1992)
Autoreactive B cells account for a substantial part of the B-cell repertoire. They frequently secrete polyspecific natural autoantibodies, which probably bind with low affinity to the different antigens they recognize and which express germinal genes. The role of this pre-immune repertoire still remains to be defined but it has been suggested that it participates in the elimination of cell breakdown products, serves as a first barrier of defense or acts as a template upon which antigen driven selection and somatic recombinations could induce the emergence of high affinity induced antibodies. The present study, reviews the evidence favouring the idea that this autoreactive B-cell repertoire, which expresses a restricted set of V genes, frequently undergoes malignant transformation. This evidence arises from the study of the autoantibody activity and V gene usage in three different models of B-cell malignancies namely monoclonal immunoglobulins; chronic lymphocytic leukemia; and follicular non-Hodgkin's lymphomas. KEY WORDS:
Auto antibodies
V gene
B-cell malignancies
system have not been described. Therefore, clonal deletion mechanisms cannot, at the present time, be During the past few years, we have been particularly completely excluded for such particular cases. In interested in the study of the origins and significance addition, results from transgenic mice led some of natural autoantibodies. With Guilbert and authors to conclude that clones specific for self Avrameas' at Pasteur Institute, we demonstrated the antigens associated to cellular membranes are deleted constant presence of natural autoantibodies directed in the bone-marrow, whereas clones specific for against a broad variety of ,autoantigens in normal soluble self antigens are anergized in peripheral human serum. These results led us to extrapolate them lymphoid organs2. The presence of natural autoantibodies in normal in order to formulate the hypothesis that natural autoantibodies reacting with a wide variety of serum implies the existence of normal autoreactive autoantigens will be found in normal human serum B-cell clones under physiological conditions. To and will constitute a substantial part of normal substantiate this further, we established natural circulating Igs. Taken together with those reported autoantibody secreting hybridomas from the spleens from other groups, these results challenge the clonal of adult3 and new-born4 normal unimmunized deletion theory as a general and unique explanation BALB/c mice. As is the case for natural autofor self-tolerance. However, autoantibodies against antibodies observed in human serum, these hybridovery specific antigens defining the polymorphism (e.g. mas secreted monoclonal antibodies frequently the A and B antigens in the case of subjects belonging displaying a polyspecific binding activity. The respectively to the A or B group) or against frequency of this precursor B cell repertoire was polymorphic antigens of the major histocompatibility impressively high, specially in new-born mice. These
INTRODUCTION
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autoreactive B cells secrete the so called “NAAB” characterized by their broad and puzzling reactivity, which is mainly directed against very well conserved public epitopes. They fulfil the definition of an autoantibody since they are self-reactive, but they are not ~elf-specific~. In 19833, while reporting our results with murine hybridomas displaying NAAB activity derived from BALB/c mice, we postulated: “If correct, this hypothesis would imply that these B cells carry a polyspecific receptor capable of fixing several different antigens. During active immunization, the binding of a given antigen to this receptor would then induce the corresponding B cell by a series of divisions and mutations, which, under the selective pressure of the antigen, would lead to the production of highly specific antibodies for a given epitope of these antigens. In that case, these B cells and their receptors would then be encoded by the germ-line, and the natural polyspecific antibodies would constitute the synthesized products secreted by these cells”. This provocative hypothesis assumed that NAAB were the product of the germ-line repertoire and that they constituted a template upon which Ag driven selection and somatic mutation could operate to derive highly specific immune antibodies. The germ-line origin was substantiated during the following years, since: polyreactive NAAB appear to predominate early during ontogeny4 even in germantigen free animals6; NAAB express recurrent idiotypes7- l 5 and appear to be highly interconnected16; furthermore structural studies have demonstrated their germinal origin 17-’0 and the fact that these autoantibodies are encoded by structural genetic elements similar to those employed by non-autoimmune autoantibodies’ ’*”. The template hypothesis is still awaiting an experimental verification. Only indirect evidence has been obtained as yet. In 1986 Naparstek rt reported their studies on a set of antibodies that use the VHIdCR gene, employed for the anti-arsonate system. They found that germ-line-encoded antibodies of this system do not bind arsonate, but display a polyreactive pattern of binding by reacting with DNA and cytoskeleton proteins. Upon immunization with arsonate, the VHIdCR gene undergoes somatic mutations allowing it to become a high affinity anti-arsonate antibody. This process is accompanied by loss of NAAB activity. Guilbert et aLZ4studied hybridomas derived from mice previously immunized with several different antigens and reported that, besides hybrids binding to specific immunizing
antigen, they could obtain hybrids binding not only to specific antigen but also to self antigen, suggesting that the latter could be in an intermediate stage between the preimmune and specifically immune repertoire. In our laboratory, Matthes rt u I . ~ ’ have , recently compared the epitopes recognized on tubulin by natural polyspecific autoantibodies and by induced antibodies, They found that whereas NAAB recognized the same or overlapping epitopes in the central part of both a and fl subunits of tubulin, induced antibodies recognized very different epitopes located either in amino-terminal or carboxyl-terminal parts of the tubulin sub-units. Whether these results indicate a different genetic origin for NAAB and induced antibodies, or extensive somatic mutations occurring in induced antibodies, is an unsolved issue. An alternative hypothesis to the template theory is that these NAAB constitute a phylogenetically very well conserved system which may act as a first ring of defense. In that sense, these probably low affinity widely reacting antibodies could allow some degree of protection. In primitive animals with no possibility of further diversification of the immune system, they could constitute the unique defense system. This primitive system could be conserved during evolution, since it allows some protection; meanwhile, the immune system develops more specific antibodies. Whatever the case, verification of these hypotheses requires careful experimentation at the clonal level5. Considerable evidence has accumulated indicating that this autoreactive B cell repertoire frequently undergoes malignant transformation. This evidence arose from the study of monoclonal immunoglobulins (MIg), chronic lymphocytic leukemia (CLL) and follicular non-Hodgkin lymphomas (FNHL).
1 ANTIBODY ACTIVITY OF MIg
MIg correspond to normal synthetic products whose counterpart can be found in the heterogenous normal Ig compartment. The antibody-like activity of MIg has been described against a large number of antigens, e.g. bacterial antigens, plasma proteins, tissue antigens and non-biological haptens”. However, an impressive and unexpected frequency of activities has been reported against: the Fc fraction of IgG (rheumatoid factor (RF)); the I blood group antigen (cold agglutinins, [CAI); and cytoskeleton proteins and DNA (polyreactive autoantibodies); and anti-myelin associated glycoproteins (MAG).
AUTOAB, V GENES AND B-CELL MALIGNANCIES
a
MIg with R F activity
with light and heavy chains have been described. The vast majority of CA employ a VKIII gene and a VH4 gene33.34.The amino acid sequence of light chains revealed striking similarities. Interestingly, some CA used the same Hum Kv-325 germinal gene employed by Wa + RF paraproteins, indicating that antigenic specificity against IgG or anti-I was supplied by heavy chains3 Nucleotidic sequence has been recently established for 2 clones secreting cold agglutinins, which were derived from 2 different patients suffering from cold agglutinin disease. Both clones were shown to use a common VH4 germ-line gene (VH4-21,33). Interestingly, a single base substitution at the CDRl region of both clones resulted in the replacement of an aspartic acid by a g l y ~ i n e ~suggesting ~, that aminoacid substitutions in the CDRs could be responsible for the acquisition of cold agglutinin specificity.
Since the first report by Kritzman et al.”, of a monoclonal IgMK paraprotein with anti-IgG activity, an increasing number of cases have been reported, and the frequency of this specificity has been estimated at more than 10% of total IgM, paraproteins”. Most monoclonal components with reported R F activity, were found to form a cryoprecipitate. Almost all cases corresponded to IgMK MIg, but rare cases of human monoclonal IgG and IgA with RF activity and cryoprecipitation have been described. Pioneer work from Kunkel’s laboratory demonstrated the presence of cross-reactive idiotypic (CRI) specificities among these MIgZ9.Sixty per cent of these MIg displaying RF activity were found to share a major CRI called Wa; 20% belonged to a less common CRI designated Po, and a few expressed a more rare CRI, named Bla. During recent years, considerable work, largely enamating from the group of Dennis Carson3’, has contributed important information concerning this type of MIg, by precisely defining genetic origins in c MIg with polyreactive activity serological and structural terms. These studies were Prompted by our results in normal human serum in mainly focused on MIg sharing the Wa CRI. It was the early 1980’s, we screened 612 MIg for the presence found that: of antibody activity directed against cytoskeleton Almost all Wa + RF share the 17109 CRI related proteins and DNA. Our results indicated that about to light chains and the G6 idiotype related 6% of all MIg and 10% of IgM paraproteins bound to heavy chains; they constantly express the minor to these antigens, and that most of them displayed a subgroup VKIIIb light chain; the VK light chain is polyreactive pattern of binding comparable to that derived from a single germinal gene (Hum Kv 325), found in normal human serum, indicating that MIg since most Wa + paraproteins display an identical or frequently correspond to expansion of a clone nearly identical light chain sequence, as stated by 13 normally producing a NAAB35*36.Delaggi et aL3’ complete light chain sequences; there is strong also reported the presence of IgM paraproteins sequence homology among p chains expressing the binding to intermediate filaments, and Shoenfeld et Wa idiotype. Most of them use the VH1 family (SOYO) found that more than 10% MIg shared the 16-6 and the minority use VH2 and VH3 families. CRI derived from a monoclonal Ig with anti-DNA Although information derived from Po + RF MIg activity. However, only 25% of these MIg were is less extensive, they appear to constantly use a VK demonstrated to possess anti-DNA activity. Another germinal gene (Hum Kv 328) and to use a conserved anti-idiotypic reagent (F4) was found to be present in VH3 seq~ence~’.~’. More recently, it has been 12% of MIg and was found to be strongly associated demonstrated that the idiotype Bla is encoded by a with IgG isotype and anti-DNA activity39. gene of the VH4 gene family3’. The presence of shared CRI within these polyreactive Mlg, favors their germinal rigi in'^*^^. Yet we do not presently have complete structural information on these paraproteins although, studies of monoclonal b MIg with CA activity NAAB derived from normal and autoimmune mice CA paraproteins are almost constantly IgMk and humans suggest a germinal origin. The use of paraproteins, which usually react with a set of multiple VH and VL genes has been reported for antigenic determinants directed against the Ii system, monoclonal NAAB34. However, the frequent expresor compound antigens including Ii (AI, HI, etc.). Their sion of MIg with anti-DNA activity of the 16-6 activity is increased by cold, but thermal amplitude is idiotype suggests the frequent usage of the VH3 V26 variable. As for RF cryoglobulins, CRI associated gene.
’.
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We have also studied VH expression in 40 CD5 + B-CLL and found that VH1 was utilised in A peripheral neuropathy is observed in about 5% of 17%, VH2 in 8%, VH3 in 36%, VH4 in 17%, VH5 Waldenstrom’s macroglobulinemia patients and stuin 8% and VH6 in 14%50.Although, our study failed demonstrated dies by Saito et aL4’ and Brouet et to find the same incidence of the small VH4, VH5 and that in the majority of these cases MIg displayed VH6 families; it showed a clear over-representation of antibody activity against a myelin associated glyco- these families. protein (MAG). The epitope recognized corresponds These results confirm that CD5 + B-CLL lymphoto a glycuronyl sulfate group. However, the cytes are frequently committed to the production of pathogenic role of the MIg has as yet not been natural autoantibodies. The results from Kipps el definitively established. Brouet et aL41, reported a ul.47348indicating the use of a restricted set of genes, recurrent idiotype among 9 MIg with anti-MAG by the CLL B-lymphocyte are confirmed by the high activity. Six of these 7 MIgs for which studies could frequency of natural autoantibody activity among be performed expressed VH3 and the rest VH2. B-CLL lymphocytes encountered in our studies. Interestingly the rare VKIV family was found in 3 cases, VK1 in 2 and VKII in 1 and the remaining 3 ANTIBODY ACTIVITY OF THE CD5-B patient expressed lambda light chain4’. LYMPHOCYTE FROM FOLLICULAR 2 ANTIBODY ACTIVITY OF THE CD5+ CLL NON-HODGKIN LYMPHOMAS (FNHL) B-LYMPHOCYTES Our results with CLL supported the hypothesis that In our laboratory, we recently examined the antibody CD5 + B cells mostly secrete autoantibodies. Howactivity of B lymphocytes proliferating in this disease, by fusing B lymphocytes with the non-secreting ever, in a recent work, based upon detection of mRNA murine myeloma X-63 cell. We were able to transcript of Lyl gene amoung 40 murine hybridomas demonstrate that a high percentage of B CLL displaying natural autoantibody activity, we were able lymphocytes are committed to the production of to demonstrate that both L y l + and Lyl - B natural aut~antibodies~’.Similar results have been lymphocyte subsets were involved in the production aut~antibodies~l. In order to gain better ~ , by Sthoeger et ~ 1 . ~of ~natural . reported by Broker et u I . ~and insight into this problem, we have recently studied 3 1 As for gene expression, Humphries et ~ 1reported . ~ ~ hybridomas obtained from CD5 negative B-cell that 30% of CLL patients were expressing VH251, R. A. Miller and follicular NHL in the laboratories of which is one of the two germinal members of the VH5 R. Levy. Our results indicated that 8 of the 31 family. Logtenberg et a/.46 found that B CLL hybridomas displayed rheumatoid factor activity and lymphocytes express VH4 in 50% of cases, VH5 in 2 of these displayed a multispecific activity5*. These 20% and VH6 in 15%. In recent studies Kipps et results obtained with Igs derived from CD5 negative u1.47-48found that a high proportion of B-CLL cells expressing K at the membrane reacted with a murine B-cell tumors strongly support the idea that CD5 anti-idiotypic antibody raised against a monoclonal negative B-cells are also involved in the production of IgM RF, expressing the Wa idiotype. Analysis of natural autoantibodies. Cleary et reported that in distinction to CLL Kappa light chain variable region genes expressed by and acute lymphoblastic leukemia, where a bias in leukemic cells sharing idiotype Wa, enabled these expression of VH4, VH5 and VH6 families has been authors to demonstrate that they were employing the B cells proliferating in demonstrated, CD5 negative germinal unmutated Hum K v 325 germinal gene. to employ VH gene families in a more NHL appear Similar restriction was found for the VH genes, since stochastic way, by employing the multigenic VH3 the germinal VHl 51P1 gene, was found to be family. In addition, there is an active somatic expressed in 20% of CLL cases4*. Spatz et u I . ~ ~ mutational process in B-cell follicular NHL, that is recently reported the nucleotide sequence of a clone rarely observed in B-CLL. derived from a CLL patient, which was found to bind
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d MIg with anti-MAG activity
MAG and denaturated DNA. This was found to express a VKIIIa gene with 96% of homology with the germinal counterpart and a VH3 gene whose germinal counterpart could correspond to the VH3-26 gene.
CONCLUSION As a whole, these results indicate that the autoreactive B cell repertoire frequently undergoes malignant
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AUTOAB, V GENES AND B-CELL MALIGNANCIES
transformation. The activation of this repertoire through continuous challenge by self antigens may create appropriate conditions for mutations and chromosomal translocation to occur. However, this does not explain the results observed with MIgs and in CLL, where the repeated usage of a small selected number of genes has been observed. The binding specificities of antibody molecules is the consequence of the assembly of V, D and J genes for heavy chains and of V and J genes for light chains. These combination of events generate a large diversity of antigen binding specifities, which in adult lymphoid tissue appears to be random. However, Ab specificities are developmentally regulated and there is increasing evidence indicating that the fetal preimmune repertoire employs a limited set of V genes, which frequently encode a u t ~ a n t i b o d i e s5 ~6 . ~As these genes are recurrently expressed during B-cell malignancies, it could alternatively be postulated, that this developmentally regulated autoreactive Ej-cell repertoire has a selective advantage to undergo malignant transformation. The reasons accounting for overexpression of these recurrent genes are not clear as yet. The role of selective environmental influences such as the continuous challenge by autoantigens or idiotype-antiidiotype interactions needs to be more precisely defined. The study of the expression of these recurrent V genes in pre-B cell malignancies which do not express functional surface Igs, should allow one to conclude this matter. In the case that stimulation through an antigen receptor could be excluded, the possibility that overexpression of these developmentally regulated recurrent V genes, could be accounted for by the existence of putative transcriptional enhancers located upstream of these genes, needs to be further explored57.
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almost exclusively on IgG antibodies. J . lmmunol., 143, 1 7 4 180. Saito, T., Sherman, W. and Latov, N. (1983). Specificity and idiotype of M-proteins that react with MAG in patients with neuropathy. J. Immunol., 130, 24962502. Brouet, J. C., Dellagi, K., Gendron, M. C., Chevalier, A., Schmitt, C. and Mihaesco, E. (1989). Expression of a public idiotype by human monoclonal IgM directed to myelinassociated glycoprotein and characterization of the variability subgroup of their heavy and light chains. J. Exp. Med., 170, 1551-1 558. Borche, L., Lim, A,, Binet, J. L. and Dighiero, G. (1990). Evidence that chronic lymphocytic leukemia B lymphocytes are frequently committed to productions of natural autoantibodies. Blood, 76, 562-569. Broker, B. M., Klajman, A,, Youinou, P., Jouquan, J., Worman, C. P., Murphy, J., Mackenzie, L., Quartey-Papafio, R., Blaschek, M., Collins, P., Lal, S. and Lydyard, P. M. (1988). Chronic Lymphocytic Leukemia (CLL) cells secrete multispecific autoantibodies. J. oj‘Autoimmunity, I, 469-476. Sthoeger, 2. M., Wakai, M., Tse, D. B., Vinciguerra, V. P., Allen, S. L., Budman, D. R., Lichtman, S. M., Schulman, P., Weiselberg, L. R. and Chiorazzi, N. (1989). Production of autoantibodies by CD5-expressing B lymphocytes from patients with chroniclymphocytic leukemia. J. Exp. Med., 169, 255-268. Humphries, C. G., Shen, A,, Kuziel, W. A,, Capra, J. D., Blattner, F. R. and Tucker, P. W. (1988). A new human immunoglobulin VH family preferentially rearranged in immature B-cell tumors. Nature, 331, 4 4 t 4 4 9 . Logtenberg, T., Young, F. M., Van Es, J. H., Gmelig-Meyling, F. H. and Ah, F. W. (1989). Autoantibodiesencoded by the most JH proximal human immunoglobulin heavy chain variable region gene. J. Exp. Med., 170, 1347-1355. Kipps, T. J., Tomhave, E., Chen, P. P., and Carson, D. A. (1988). Autoantibody associated K light chain variable region gene expressed in chronic lymphocytic leukemia with little or no somatic mutation, implications for etiology and immunotherapy. J . E . Y ~Med., . 167, 840-852. Kipps, T. J., Tomhave, E., Pratt, L. F., Duffy, S . , Chen, P. P. and Carson, D. A. (1989). Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia. Proc. N ~ t n . Arcid. Sci. USA., 86, 591 3-5919. Spatz, L. A., Wong, K. K., Williams, M., Desai, R., Golier, J., Berman, J. E., Alt, F. W. and Latov, N. (1990). Cloning and sequence analysis of the VH and VL regions of antimyelin/DNA antibody from a patient with peripheral neuropathy and chronic lymphocytic leukemia. J. Irnmunol.. 144, 2821-2828. Mayer, R., Logtenberg, T., Strauchen, J., Dimitriu-Bona, A,, Mayer, L. and Mechanic, S . Chiorazzi, N., Borche, L., Dighiero, G., Mannheimer-Loryh, A., Diamond. B., Alt, F. W. and Bona, C. (1990).CD5 and immunoglobulin V gene expression in B-cell lymphomas and Chronic Lymphocytic Leukemia. Blood. 75, 15 18-1 525. Kaushik. A., Mayer, R., Fidanza, V., Zaghouani, H., Lim, A,, Bona, C. and Dighiero, G. (1990). Lyl and V-gene expression among hybridomas secreting natural autoantibody. Journtrl qf Aufoimmunity, 3, 687-700. Dighiero, G., Hart, S., Lim. A., Borche, L., Levy, R. and Miller, R. A. (1991). Autoantibody activity of immunoglobulins isolated from B-cell follicular lymphomas. Blood. 78, 581-586. Cleary, M. L.. Meeker, T. C., Levy, S., Lee, E., Trela, M.. Sklar, J. and Levy, R. (1986). Clustering of extensive somatic mutations in the variable region of an immunoglohulin heavy chain gene from a human B-cell. CM, 44, 97TlO4. Yancopoulos, G. D., Desiderio, S . V., Paskind, M., Kearney, J .
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F., Baltimore, D. and Ah, F. (1984). Preferential utilization of the most JH-proximal VH gene segments in pre-B cell lines. Nature, 311, 727-730. 55. Schroeder, H. W., Hilson, J. L. and Perlmutter, R. M. (1987). Early restriction of the human antibody repertoire. Science, 238, 791-793. 56. Dighiero, G., Lim, A,, Lembezat, M. P., Kaushik, A,, Andrade, L. and Freitas, A. (1989). Comparative usage of VH gene family
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usage by newborn Xid and non Xid mice, newborn NZB and adult NZB and by splenic and peritoneal cavity B cell compartments. Eur. J. Immunol., 18, 1979-1983. 57. Chen, P. P., Olsen, N. J., Yang, P. M., Soto-Gil, R. W., Olee, T., Siminovitch, K. A. and Carson, D. A. (1990). From human autoantibodies to the fetal antibody repertoire to B cell malignancy: It’s a small world after all. Inter. Rev. Immunol., 5, 239-251.
ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Autoantibody Activity and V Gene Usage by B-Cell Malignancies Guillaume Dtghiero To cite this article: Guillaume Dtghiero (1992) Autoantibody Activity and V Gene Usage by BCell Malignancies, Leukemia & Lymphoma, 8:4-5, 345-351, DOI: 10.3109/10428199209051013 To link to this article: http://dx.doi.org/10.3109/10428199209051013
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Autoantibody Activity and V Gene Usage by B-Cell Malignancies GUILLAUME DTGHIERO Downloaded by [NUS National University of Singapore] at 14:39 05 November 2015
Immunohematologie et Immunopathologie, lnstitut Pasteur, 75724 Paris Cedex 15, France (Received 21 April 1992)
Autoreactive B cells account for a substantial part of the B-cell repertoire. They frequently secrete polyspecific natural autoantibodies, which probably bind with low affinity to the different antigens they recognize and which express germinal genes. The role of this pre-immune repertoire still remains to be defined but it has been suggested that it participates in the elimination of cell breakdown products, serves as a first barrier of defense or acts as a template upon which antigen driven selection and somatic recombinations could induce the emergence of high affinity induced antibodies. The present study, reviews the evidence favouring the idea that this autoreactive B-cell repertoire, which expresses a restricted set of V genes, frequently undergoes malignant transformation. This evidence arises from the study of the autoantibody activity and V gene usage in three different models of B-cell malignancies namely monoclonal immunoglobulins; chronic lymphocytic leukemia; and follicular non-Hodgkin's lymphomas. KEY WORDS:
Auto antibodies
V gene
B-cell malignancies
system have not been described. Therefore, clonal deletion mechanisms cannot, at the present time, be During the past few years, we have been particularly completely excluded for such particular cases. In interested in the study of the origins and significance addition, results from transgenic mice led some of natural autoantibodies. With Guilbert and authors to conclude that clones specific for self Avrameas' at Pasteur Institute, we demonstrated the antigens associated to cellular membranes are deleted constant presence of natural autoantibodies directed in the bone-marrow, whereas clones specific for against a broad variety of ,autoantigens in normal soluble self antigens are anergized in peripheral human serum. These results led us to extrapolate them lymphoid organs2. The presence of natural autoantibodies in normal in order to formulate the hypothesis that natural autoantibodies reacting with a wide variety of serum implies the existence of normal autoreactive autoantigens will be found in normal human serum B-cell clones under physiological conditions. To and will constitute a substantial part of normal substantiate this further, we established natural circulating Igs. Taken together with those reported autoantibody secreting hybridomas from the spleens from other groups, these results challenge the clonal of adult3 and new-born4 normal unimmunized deletion theory as a general and unique explanation BALB/c mice. As is the case for natural autofor self-tolerance. However, autoantibodies against antibodies observed in human serum, these hybridovery specific antigens defining the polymorphism (e.g. mas secreted monoclonal antibodies frequently the A and B antigens in the case of subjects belonging displaying a polyspecific binding activity. The respectively to the A or B group) or against frequency of this precursor B cell repertoire was polymorphic antigens of the major histocompatibility impressively high, specially in new-born mice. These
INTRODUCTION
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autoreactive B cells secrete the so called “NAAB” characterized by their broad and puzzling reactivity, which is mainly directed against very well conserved public epitopes. They fulfil the definition of an autoantibody since they are self-reactive, but they are not ~elf-specific~. In 19833, while reporting our results with murine hybridomas displaying NAAB activity derived from BALB/c mice, we postulated: “If correct, this hypothesis would imply that these B cells carry a polyspecific receptor capable of fixing several different antigens. During active immunization, the binding of a given antigen to this receptor would then induce the corresponding B cell by a series of divisions and mutations, which, under the selective pressure of the antigen, would lead to the production of highly specific antibodies for a given epitope of these antigens. In that case, these B cells and their receptors would then be encoded by the germ-line, and the natural polyspecific antibodies would constitute the synthesized products secreted by these cells”. This provocative hypothesis assumed that NAAB were the product of the germ-line repertoire and that they constituted a template upon which Ag driven selection and somatic mutation could operate to derive highly specific immune antibodies. The germ-line origin was substantiated during the following years, since: polyreactive NAAB appear to predominate early during ontogeny4 even in germantigen free animals6; NAAB express recurrent idiotypes7- l 5 and appear to be highly interconnected16; furthermore structural studies have demonstrated their germinal origin 17-’0 and the fact that these autoantibodies are encoded by structural genetic elements similar to those employed by non-autoimmune autoantibodies’ ’*”. The template hypothesis is still awaiting an experimental verification. Only indirect evidence has been obtained as yet. In 1986 Naparstek rt reported their studies on a set of antibodies that use the VHIdCR gene, employed for the anti-arsonate system. They found that germ-line-encoded antibodies of this system do not bind arsonate, but display a polyreactive pattern of binding by reacting with DNA and cytoskeleton proteins. Upon immunization with arsonate, the VHIdCR gene undergoes somatic mutations allowing it to become a high affinity anti-arsonate antibody. This process is accompanied by loss of NAAB activity. Guilbert et aLZ4studied hybridomas derived from mice previously immunized with several different antigens and reported that, besides hybrids binding to specific immunizing
antigen, they could obtain hybrids binding not only to specific antigen but also to self antigen, suggesting that the latter could be in an intermediate stage between the preimmune and specifically immune repertoire. In our laboratory, Matthes rt u I . ~ ’ have , recently compared the epitopes recognized on tubulin by natural polyspecific autoantibodies and by induced antibodies, They found that whereas NAAB recognized the same or overlapping epitopes in the central part of both a and fl subunits of tubulin, induced antibodies recognized very different epitopes located either in amino-terminal or carboxyl-terminal parts of the tubulin sub-units. Whether these results indicate a different genetic origin for NAAB and induced antibodies, or extensive somatic mutations occurring in induced antibodies, is an unsolved issue. An alternative hypothesis to the template theory is that these NAAB constitute a phylogenetically very well conserved system which may act as a first ring of defense. In that sense, these probably low affinity widely reacting antibodies could allow some degree of protection. In primitive animals with no possibility of further diversification of the immune system, they could constitute the unique defense system. This primitive system could be conserved during evolution, since it allows some protection; meanwhile, the immune system develops more specific antibodies. Whatever the case, verification of these hypotheses requires careful experimentation at the clonal level5. Considerable evidence has accumulated indicating that this autoreactive B cell repertoire frequently undergoes malignant transformation. This evidence arose from the study of monoclonal immunoglobulins (MIg), chronic lymphocytic leukemia (CLL) and follicular non-Hodgkin lymphomas (FNHL).
1 ANTIBODY ACTIVITY OF MIg
MIg correspond to normal synthetic products whose counterpart can be found in the heterogenous normal Ig compartment. The antibody-like activity of MIg has been described against a large number of antigens, e.g. bacterial antigens, plasma proteins, tissue antigens and non-biological haptens”. However, an impressive and unexpected frequency of activities has been reported against: the Fc fraction of IgG (rheumatoid factor (RF)); the I blood group antigen (cold agglutinins, [CAI); and cytoskeleton proteins and DNA (polyreactive autoantibodies); and anti-myelin associated glycoproteins (MAG).
AUTOAB, V GENES AND B-CELL MALIGNANCIES
a
MIg with R F activity
with light and heavy chains have been described. The vast majority of CA employ a VKIII gene and a VH4 gene33.34.The amino acid sequence of light chains revealed striking similarities. Interestingly, some CA used the same Hum Kv-325 germinal gene employed by Wa + RF paraproteins, indicating that antigenic specificity against IgG or anti-I was supplied by heavy chains3 Nucleotidic sequence has been recently established for 2 clones secreting cold agglutinins, which were derived from 2 different patients suffering from cold agglutinin disease. Both clones were shown to use a common VH4 germ-line gene (VH4-21,33). Interestingly, a single base substitution at the CDRl region of both clones resulted in the replacement of an aspartic acid by a g l y ~ i n e ~suggesting ~, that aminoacid substitutions in the CDRs could be responsible for the acquisition of cold agglutinin specificity.
Since the first report by Kritzman et al.”, of a monoclonal IgMK paraprotein with anti-IgG activity, an increasing number of cases have been reported, and the frequency of this specificity has been estimated at more than 10% of total IgM, paraproteins”. Most monoclonal components with reported R F activity, were found to form a cryoprecipitate. Almost all cases corresponded to IgMK MIg, but rare cases of human monoclonal IgG and IgA with RF activity and cryoprecipitation have been described. Pioneer work from Kunkel’s laboratory demonstrated the presence of cross-reactive idiotypic (CRI) specificities among these MIgZ9.Sixty per cent of these MIg displaying RF activity were found to share a major CRI called Wa; 20% belonged to a less common CRI designated Po, and a few expressed a more rare CRI, named Bla. During recent years, considerable work, largely enamating from the group of Dennis Carson3’, has contributed important information concerning this type of MIg, by precisely defining genetic origins in c MIg with polyreactive activity serological and structural terms. These studies were Prompted by our results in normal human serum in mainly focused on MIg sharing the Wa CRI. It was the early 1980’s, we screened 612 MIg for the presence found that: of antibody activity directed against cytoskeleton Almost all Wa + RF share the 17109 CRI related proteins and DNA. Our results indicated that about to light chains and the G6 idiotype related 6% of all MIg and 10% of IgM paraproteins bound to heavy chains; they constantly express the minor to these antigens, and that most of them displayed a subgroup VKIIIb light chain; the VK light chain is polyreactive pattern of binding comparable to that derived from a single germinal gene (Hum Kv 325), found in normal human serum, indicating that MIg since most Wa + paraproteins display an identical or frequently correspond to expansion of a clone nearly identical light chain sequence, as stated by 13 normally producing a NAAB35*36.Delaggi et aL3’ complete light chain sequences; there is strong also reported the presence of IgM paraproteins sequence homology among p chains expressing the binding to intermediate filaments, and Shoenfeld et Wa idiotype. Most of them use the VH1 family (SOYO) found that more than 10% MIg shared the 16-6 and the minority use VH2 and VH3 families. CRI derived from a monoclonal Ig with anti-DNA Although information derived from Po + RF MIg activity. However, only 25% of these MIg were is less extensive, they appear to constantly use a VK demonstrated to possess anti-DNA activity. Another germinal gene (Hum Kv 328) and to use a conserved anti-idiotypic reagent (F4) was found to be present in VH3 seq~ence~’.~’. More recently, it has been 12% of MIg and was found to be strongly associated demonstrated that the idiotype Bla is encoded by a with IgG isotype and anti-DNA activity39. gene of the VH4 gene family3’. The presence of shared CRI within these polyreactive Mlg, favors their germinal rigi in'^*^^. Yet we do not presently have complete structural information on these paraproteins although, studies of monoclonal b MIg with CA activity NAAB derived from normal and autoimmune mice CA paraproteins are almost constantly IgMk and humans suggest a germinal origin. The use of paraproteins, which usually react with a set of multiple VH and VL genes has been reported for antigenic determinants directed against the Ii system, monoclonal NAAB34. However, the frequent expresor compound antigens including Ii (AI, HI, etc.). Their sion of MIg with anti-DNA activity of the 16-6 activity is increased by cold, but thermal amplitude is idiotype suggests the frequent usage of the VH3 V26 variable. As for RF cryoglobulins, CRI associated gene.
’.
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G. DIGHIERO
We have also studied VH expression in 40 CD5 + B-CLL and found that VH1 was utilised in A peripheral neuropathy is observed in about 5% of 17%, VH2 in 8%, VH3 in 36%, VH4 in 17%, VH5 Waldenstrom’s macroglobulinemia patients and stuin 8% and VH6 in 14%50.Although, our study failed demonstrated dies by Saito et aL4’ and Brouet et to find the same incidence of the small VH4, VH5 and that in the majority of these cases MIg displayed VH6 families; it showed a clear over-representation of antibody activity against a myelin associated glyco- these families. protein (MAG). The epitope recognized corresponds These results confirm that CD5 + B-CLL lymphoto a glycuronyl sulfate group. However, the cytes are frequently committed to the production of pathogenic role of the MIg has as yet not been natural autoantibodies. The results from Kipps el definitively established. Brouet et aL41, reported a ul.47348indicating the use of a restricted set of genes, recurrent idiotype among 9 MIg with anti-MAG by the CLL B-lymphocyte are confirmed by the high activity. Six of these 7 MIgs for which studies could frequency of natural autoantibody activity among be performed expressed VH3 and the rest VH2. B-CLL lymphocytes encountered in our studies. Interestingly the rare VKIV family was found in 3 cases, VK1 in 2 and VKII in 1 and the remaining 3 ANTIBODY ACTIVITY OF THE CD5-B patient expressed lambda light chain4’. LYMPHOCYTE FROM FOLLICULAR 2 ANTIBODY ACTIVITY OF THE CD5+ CLL NON-HODGKIN LYMPHOMAS (FNHL) B-LYMPHOCYTES Our results with CLL supported the hypothesis that In our laboratory, we recently examined the antibody CD5 + B cells mostly secrete autoantibodies. Howactivity of B lymphocytes proliferating in this disease, by fusing B lymphocytes with the non-secreting ever, in a recent work, based upon detection of mRNA murine myeloma X-63 cell. We were able to transcript of Lyl gene amoung 40 murine hybridomas demonstrate that a high percentage of B CLL displaying natural autoantibody activity, we were able lymphocytes are committed to the production of to demonstrate that both L y l + and Lyl - B natural aut~antibodies~’.Similar results have been lymphocyte subsets were involved in the production aut~antibodies~l. In order to gain better ~ , by Sthoeger et ~ 1 . ~of ~natural . reported by Broker et u I . ~and insight into this problem, we have recently studied 3 1 As for gene expression, Humphries et ~ 1reported . ~ ~ hybridomas obtained from CD5 negative B-cell that 30% of CLL patients were expressing VH251, R. A. Miller and follicular NHL in the laboratories of which is one of the two germinal members of the VH5 R. Levy. Our results indicated that 8 of the 31 family. Logtenberg et a/.46 found that B CLL hybridomas displayed rheumatoid factor activity and lymphocytes express VH4 in 50% of cases, VH5 in 2 of these displayed a multispecific activity5*. These 20% and VH6 in 15%. In recent studies Kipps et results obtained with Igs derived from CD5 negative u1.47-48found that a high proportion of B-CLL cells expressing K at the membrane reacted with a murine B-cell tumors strongly support the idea that CD5 anti-idiotypic antibody raised against a monoclonal negative B-cells are also involved in the production of IgM RF, expressing the Wa idiotype. Analysis of natural autoantibodies. Cleary et reported that in distinction to CLL Kappa light chain variable region genes expressed by and acute lymphoblastic leukemia, where a bias in leukemic cells sharing idiotype Wa, enabled these expression of VH4, VH5 and VH6 families has been authors to demonstrate that they were employing the B cells proliferating in demonstrated, CD5 negative germinal unmutated Hum K v 325 germinal gene. to employ VH gene families in a more NHL appear Similar restriction was found for the VH genes, since stochastic way, by employing the multigenic VH3 the germinal VHl 51P1 gene, was found to be family. In addition, there is an active somatic expressed in 20% of CLL cases4*. Spatz et u I . ~ ~ mutational process in B-cell follicular NHL, that is recently reported the nucleotide sequence of a clone rarely observed in B-CLL. derived from a CLL patient, which was found to bind
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d MIg with anti-MAG activity
MAG and denaturated DNA. This was found to express a VKIIIa gene with 96% of homology with the germinal counterpart and a VH3 gene whose germinal counterpart could correspond to the VH3-26 gene.
CONCLUSION As a whole, these results indicate that the autoreactive B cell repertoire frequently undergoes malignant
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AUTOAB, V GENES AND B-CELL MALIGNANCIES
transformation. The activation of this repertoire through continuous challenge by self antigens may create appropriate conditions for mutations and chromosomal translocation to occur. However, this does not explain the results observed with MIgs and in CLL, where the repeated usage of a small selected number of genes has been observed. The binding specificities of antibody molecules is the consequence of the assembly of V, D and J genes for heavy chains and of V and J genes for light chains. These combination of events generate a large diversity of antigen binding specifities, which in adult lymphoid tissue appears to be random. However, Ab specificities are developmentally regulated and there is increasing evidence indicating that the fetal preimmune repertoire employs a limited set of V genes, which frequently encode a u t ~ a n t i b o d i e s5 ~6 . ~As these genes are recurrently expressed during B-cell malignancies, it could alternatively be postulated, that this developmentally regulated autoreactive Ej-cell repertoire has a selective advantage to undergo malignant transformation. The reasons accounting for overexpression of these recurrent genes are not clear as yet. The role of selective environmental influences such as the continuous challenge by autoantigens or idiotype-antiidiotype interactions needs to be more precisely defined. The study of the expression of these recurrent V genes in pre-B cell malignancies which do not express functional surface Igs, should allow one to conclude this matter. In the case that stimulation through an antigen receptor could be excluded, the possibility that overexpression of these developmentally regulated recurrent V genes, could be accounted for by the existence of putative transcriptional enhancers located upstream of these genes, needs to be further explored57.
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