Activation of clones producing self-reactive antibodies by foreign antigen and antiidiotype antibody carrying the internal image of the antigen.

Bailey, Naila C.; Fidanza, Vincenzo; Mayer, R; Mazza, Gilbert; Fougereau, Michel; Bona, Constantin A.

doi:10.1172/jci114232

Cited by 24 publications

(3 citation statements)

References 39 publications

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“…mAb 2C4C2 is identical in itsVH to two anti-DNA mAb, BW16 [23] and 17s.128 [11], isolated independently from (NZB x NZW)Fl mice (Table 6). Four more mAb which were isolated from lupusprone mice were found to share high homology with mAb 2C4C2 in theVH [11,34,351. All those mAb differ in their VH by one to three amino acids from mAb 2C4C2 VH (Table 6).…”

Section: Discussionmentioning

confidence: 99%

Variable region sequences of autoantibodies from mice with experimental systemic lupus erythematosus

Waisman

Mozes

1993

Eur J Immunol

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We have sequenced nine monoclonal antibodies (mAb) derived from C3H.SW mice in which experimental systemic lupus erythematosus (SLE) was induced. The hybridomas were selected for binding to DNA or to HeLa nuclear extract (NE). Three mAb were found to bind DNA, and are shown to exhibit sequence characteristics of pathogenic anti-DNA antibodies. One, mAb 2C4C2, is shown to use a heavy chain V region gene (VH) identical to the VH of anti-DNA mAb isolated from other lupus-prone mice, namely (NZB x NZW)F1. The light chain V region gene (VL) of mAb 2C4C2 is 98% homologous to the VL of another anti-DNA mAb, also isolated from (NZB x NZW)F1 mice. The other two anti-DNA mAb, 5G12-4 and 5G12-6, share 93% of their VH sequences with that of mAb 2C4C2. Six mAb bound proteins of HeLa NE. Four of these six antibodies were found to use the VH124 VH and V-L7 VL. The nine mAb use a total of five VH and four VL germ-line genes, demonstrating that the autoantibodies induced in mice with experimental SLE do not originate from one B cell clone. Three of these nine VH and VL were identical in sequence to germ-line genes, while at least three others had somatic mutations. The latter suggests that the above autoantibodies arise in mice by both usage of existing (pre-immune) B cells, and through an antigen-driven process. Furthermore, it appears that autoantibodies found in mice with experimental SLE use genetic elements similar to those used by mAb that were isolated from mouse strains which develop lupus spontaneously.

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Section: Discussionmentioning

confidence: 99%

Variable region sequences of autoantibodies from mice with experimental systemic lupus erythematosus

Waisman

Mozes

1993

Eur J Immunol

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“…T h e V~ and VL region gene family utilization by the five anti-id mAb is GAG GTG CAG CTG GTG GAG TCT GGG GGA GGC TTA GTG CAG CCT GGA GGG TCC CTG AAA CTC TCC TGT ACA GTC TCT GGA TTC ............... .-G .................................... G--...... G-. -c-. and of mAb R18-9 are compared with those of anti-hemagglutinin mAb H36-4 [21], of murine lupus anti-DNA autoantibody BXW-16 [22] and of putative germ-line geneVH-Ox2 [4), respectively. Sequences of the JH gene segments of the five anti-id mAb are compared with those of the germ-line J H gene segments [18].…”

Section: V and V Region Gene Utilization By Anti-id Mab Elicited Bymentioning

confidence: 99%

“…The VH segments of mAb K03-34, K03-256 and K03-335 are at least 94% homologous at the nucleotide level and at least 89% at the amino acid level to the rearranged VH gene segment of anti-hemagglutinin mAb H36-4 [21]. The V, gene segment of mAb R1-38 displays a 89% and a 80% homology at the nucleotide and amino acid level, respectively, to that of murine lupus anti-DNA autoantibody BXW-16 [22]. The V, gene seg-ment of mAb R18-9 displays a 98% and a 97% homology at the nucleotide and amino acid level, respectively, to the putative germ-line gene vH-ox2 …”

Section: V Region Sequences Of Anti-id Mab Elicited By Syngeneic Antmentioning

confidence: 99%

Structural profile of idiotype, anti‐idiotype and anti‐anti‐idiotype monoclonal antibodies in the HLA‐DQ3 antigenic system

et al. 1994

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Interest in the characterization of idiotype cascades in the HLA antigenic system has been stimulated by their potential role in the immune response to mismatched HLA allospecificities and in the survival of kidney allografts. Since no information is available about the structural organization of idiotypic cascades in the HLA system, we have sequenced the variable regions of the heavy (VH) and light (VL) chains of mouse anti-HLA-DQ3 monoclonal antibody (mAb) KS13 elicited by cell membrane-bound antigens, of syngeneic anti-HLA-DQ3 mAb S2B154 elicited by anti-idiotypic (anti-id) mAb K03-34 and of five syngeneic anti-id mAb elicited by mAb KS13. mAb KS13 and S2B154, which have been previously shown to be very similar in their specificity and idiotypic profile, share several structural characteristics. Their VH and VL regions are encoded by the same VH, VK and JH genes, display relatively similar V(D)J rearrangements and differ only through a few amino acid substitutions. Among the five anti-id mAb elicited by mAb KS13, mAb R1-38 and R18-9 utilize multiple genetic elements that are different from those used by anti-id mAb KO3-34, K03-256 and K03-335. These results indicate that diverse V region combinations can confer an anti-id specificity in the antigenic system analyzed. mAb K03-34, K03-256 and K03-335 originate from the same B cell clone, since they use the same V, D and J genes and possess identical V(D)J rearrangements. The latter three anti-id mAb differ only by point mutations, which have dramatic effects on the HLA-DQ3 antigen mimicry properties of the three anti-id mAb. mAb K03-34 is the only one to induce anti-HLA-DQ3 antibodies both in syngeneic and xenogeneic hosts. The antigen mimicry properties of anti-id mAb K03-34 depend upon its three-dimensional conformation, since no significant amino acid sequence homology has been found between its VH and VL regions and alpha 1 and beta 1 domains of HLA-DQ3 antigens.

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Autoantibodies, ly‐1, and immunoglobulin v gene expression in hybridomas obtained from young and from old new zealand black mice

Fidanza

Mayer

Zaghouani

et al. 1990

Arthritis & Rheumatism

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We obtained a large number of hybridomas from l-month-old and 16-month-old New Zealand black mice to study the fine specificities of the autoantibodies produced, the expression of Ly-1, and the expression of the immunoglobulin V gene families in this autoimmune strain. Analysis of the autoantibody specificities yielded 2 major classifications: those specific for a single autoantigen and those that exhibited multispecific binding. Among the multispecific antibodies, 2 categories were found: an antigen-inhibitable group and an antigennoninhibitable group. A large proportion of V,J558 and V,7183 gene families was observed in hybridomas obtained from l-month-old mice, and in hybridomas obtained from 16-month-old mice, there was a large proportion of V,J558 and V,36-60 gene families. Among the autoantibody K chains secreted by the hybridomas, there was a higher frequency of the VJ, VJ3, and V Q gene families. Autoantibodies were produced by both the Ly-l+ and the Ly-l-B cell subsets.The New Zealand black (NZB) strain of mice is prone to the development of a lupus-like syndrome and autoimmune hemolytic anemia. This strain is therefore an excellent animal model for studying the immuno- chemical and molecular characteristics of both organspecific and non-organ-specific autoantibodies. Whereas Coombs anti-erythrocyte autoantibodies represent typical organ-specific pathogenic autoantibodies (1 ), anti-DNA, anti-Sm, antihistone, and anti-rheumatoid factor (RF) autoantibodies represent non-organ-specific autoantibodies that are associated with various systemic autoimmune diseases (2). There is evidence that a discrete subset of B cells bearing the CDS antigen (Ly-1 in mice and Leu-1 in humans) is the major contributor to the production of certain autoantibodies (3,4). It has been shown that the Ly-I B cell subset is larger in the NZB strain of mice (3.5) and that aged NZB mice show an unusual clonal expansion of Ly-1 B cells exhibiting premalignant properties, such as autonomous proliferation resistant to immunoregulatory signals (6,7). NZB mice, then, are a good model for studying the cellular origin of autoantibodies as well.In the past. the autoreactivity of antibodies was defined by the ability of a heterogenous population of immunoglobulin molecules to bind autoantigens. These Ig were isolated from the sera of patients with autoimmune diseases or from animals prone to developing autoimmune diseases. The development of hybridoma technology and sensitive cellular immunologic techniques has permitted a detailed analysis of the self-reactivity of homogenous populations of antibodies. Using these techniques, investigators have shown that an important proportion of antibodies is multispecific (8.9) and that these antibodies have a moderate affinity to g d i t e r ) for self antigens and for foreign antigens (10).Studies of the immunochemical and molecular properties of monoclonal antibodies can provide important information on the origin of autoantibodies. In particular, we can now examine the properties of the

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Activation of clones producing self-reactive antibodies by foreign antigen and antiidiotype antibody carrying the internal image of the antigen.

Cited by 24 publications

References 39 publications

Variable region sequences of autoantibodies from mice with experimental systemic lupus erythematosus

Variable region sequences of autoantibodies from mice with experimental systemic lupus erythematosus

Structural profile of idiotype, anti‐idiotype and anti‐anti‐idiotype monoclonal antibodies in the HLA‐DQ3 antigenic system

Autoantibodies, ly‐1, and immunoglobulin v gene expression in hybridomas obtained from young and from old new zealand black mice

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