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Leading Article: Idiotypes and Anti-Idiotypes Ann Rheum Dis: first published as 10.1136/ard.47.9.705 on 1 September 1988. Downloaded from Annals of the Rheumatic Diseases, 1988; 47, 705-707 Leading article: Idiotypes and anti-idiotypes: What are they trying to tell us? A cardinal feature of the immune system is its ability Abl and Ab3 antibodies and that immunisation with to generate an enormous number of different Ab2 preferentially stimulates direct expression of antibodies (approximately 100 million in the VH germline genes.4 Furthermore, Ab2 may bear mouse). 1 Antibodies are classically identified by structural similarity to the stimulating antigen their antigen binding properties. A second method because the combining site of Abl will be comple- ofdescribing antibodies serologically is by an analysis mentary to a structure on the antigen and the of their idiotypes. The variable (V) region of the combining site on Ab2 will be complementary to immunoglobulin molecule was first shown to be that on Abl. The amino acid sequence of reovirus antigenic by the injection of V region polypeptides haemagglutinin (antigen) has a region of sequence into experimental animals.2 These antigenic deter- homology with the light chain of anti-anti-haemag- minants are known as idiotopes and collectively glutinin (anti-idiotype Ab2).5 The immune system comprise the idiotype. The three dimensional shape may therefore have within the idiotype network an of the idiotype may involve structures on either the internal image of potential antigens available before heavy or light chains or both. Idiotypes can be meeting an antigen for the first time. This notion is divided into two main types based on their precise being extensively investigated to determine whether location within the variable region: (a) those located anti-idiotypes may have a role as vaccines. In at the antigen binding site (known as paratopes) and particular, this approach is being explored as a (b) those adjacent to it (known as framework possible method of vaccination against human determinants). Antibodies (anti-idiotypes) may be immunodeficiency virus (HIV) infection. Mono- copyright. raised against idiotypes in either the same or clonal anti-CD4 (the CD4 antigen is an essential different species by suitable immunisation. Further- component of the cell surface receptor for HIV6) is more, it is evident that the immune system may -used to induce an anti-idiotype which mimics the provide its own anti-idiotypes. Anti-idiotypes binding molecular structure of the CD4 molecule and to the paratope will inhibit binding of the antigen to thereby neutralises HIV.7 The potential advantages antibodies bearing the homologous idiotype, whereas of this approach include the ability of anti-idiotypes those against framework determinants will not to act as surrogate antigens without attendant to a infection or adjuvant risk problems. Anti-idiotypes usually do so. Idiotypes may be restricted http://ard.bmj.com/ particular immunoglobulin molecule-a private could also in theory be manufactured easily in large idiotype, or appear on antibodies of different amounts. There are additional theoretical reasons antigen binding specificity-a common or public for thinking that anti-idiotypes may stimulate a idiotype. Idiotypes represent the phenotypic products more effective cytotoxic T cell response than of variable (V) region genes, and analysis of inactivated virus. idiotypes permits study of the genetic relation As idiotypes, composed of several idiotopes, are between antibodies. present on the surface of B cells, T helper and T Consideration of idiotype-anti-idiotype interac- suppressor cells, a mechanism for regulation of the on September 29, 2021 by guest. Protected tions led Jerne to propose the network theory.3 immune system is evident. Both enhancement and Stimulation of the immune system by antigen results suppression of idiotypes in response to anti-idiotype in a cascade with formation of antibody 1 (Abl), have been demonstrated (reviewed in ref 8). Re- which in turn induces formation of anti-idiotype ciprocal changes in idiotype and anti-idiotype have antibody 2 (Ab2), which has its own anti-idiotype been demonstrated in man after booster immunisa- antibody Ab3. These three antibodies and antigen tion with tetanus toxoid,9 and there is some evi- can form a simple circuit because Abl and Ab3 may dence that idiotype-anti-idiotype interaction ma, have structural similarity. In the mouse immunisa- play a part in matemal suppression of fetal rejection. tion with the synthetic random polymer (Glu6m Ala30 In a single patient with systemic lupus erythematosus Tyrl')(GAT) induces formation of the idiotype (SLE) reciprocal changes in levels of anti-DNA cascade Abl (anti-GAT), Ab2 (anti-idiotype), and antibodies and anti-idiotypic antibodies have been Ab3 (anti-anti-idiotype). It has been shown by shown to occur, with the anti-idiotype appearing as isolation and sequencing of immunoglobulin VH the patient went into remission.'1 Abdou et al also genes in the GAT system that a single VH germline demonstrated in vitro suppression of serum anti- gene accounts for the expressed VH sequences of DNA antibody binding to DNA by anti-idiotype in 705 Ann Rheum Dis: first published as 10.1136/ard.47.9.705 on 1 September 1988. Downloaded from 706 Watts, Isenberg SLE. 12 Similarly, anti-idiotype activity to rheumatoid mal individuals.21 Fong and coworkers showed that factor (RF) and RF levels have been shown to be most RF light chains from patients with rheumatoid reciprocally related in a patient with a monoclonal arthritis possess a cross reactive idiotype (designated IgM gammopathy with RF activity and pneumococcal PSL2) but not two other cross reactive idiotypes pneumonia. (PSL3 and 17-109).29 In contrast, elderly people Cross reactive idiotypes have been reported on and patients with Sjogren's syndrome bore all three, many human autoantibodies (reviewed in ref 14), and they suggested that this represents somatic includin anti-DNA autoantibodies,15 anti-Sm anti- diversification of a common RF light chain Vk bodies,'E antiacetylcholine receptor antibodies,'7 gene(s) or, alternatively, use of multiple possibly and antithyroglobulin antibodies.18 Furthermore, related Vk gene segments.29 Sequence analysis of amino acid sequence homology has been found anti-DNA antibodies derived from hybridomas from between the light chains of human hybridoma patients with SLE and leprosy has shown that those derived lupus antibodies bearing a public 16/6 bearing the 16/6 idiotype are products of the VH idiotype and a Waldenstrom IgM protein that binds germline gene VH26 (a member of the VHIII gene to the klebsiella K30 antigen.'9 Such cross reactivity family), whereas those bearing another idiotype, suggests a mechanism for initiation of autoimmunity 21/28, are products of a different VH germline through perturbation of the idiotype network. In the gene.30 Thus unmutated germline genes can encode rabbit experimental myasthenia gravis and anti- autoantibodies. Similar results have been reported acetylcholine receptor antibodies can be induced by for human RF.3' 32 It seems increasingly likely that immunisation with a synthetic ligand of the receptor.20 far from 'horror-autoxicus' autoantibodies are Viruses2' and bacteria have both been proposed as products of the normal human immunoglobulin initiators of an idiotypic cascade resulting in auto- repertoire and often detectable in healthy subjects. immunity. The stimulation leading to their expansion and their Spontaneous autoanti-idiotypes have been de- precise role in immunopathology are unknown. scribed in both organ and specific non-organ specific Modulation of the immune system with idiotypescopyright. autoimmune diseases, including mixed cryoglobu- or anti-idiotypes has been proposed as a therapeutic linaemia,22 IgA deficiency (anti-anticasein anti- approach in the management of SLE. In lupus prone bodies),23 myasthenia gravis (anti-antiacetylcholine mice anti-idiotype administration has been shown to receptor antibodies),24 rye sensitivity (anti-anti-re suppress both production of anti-DNA antibodies 1 antibodies),25 and insulin dependent diabetes and nephritis. The effect was transient, however, mellitus (anti-anti-insulin receptor antibodies).26 and anti-DNA antibodies appeared that did not bear The widespread existence of autoanti-idiotypes sug- the idiotype.33 Zouali et al innoculated mice with gests that they are important in terms of immuno- syngeneic anti-DNA IgG and muramyl dipeptide regulation and that they may be involved in the (an immunoadjuvant) and found that anti-DNAhttp://ard.bmj.com/ pathogenesis of autoimmunity. antibody levels were suppressed and that an anti- Further evidence that perturbation of the idiotype idiotype antibody specific for the injected IgG network can have deleterious effects has been appeared.34 Conjugation of anti-idiotype to a cyto- provided by Mendlovic et al, who injected C3H.SW toxic agent (neocarzinostatin) has been shown to female mice (a non-autoimmune prone strain) with eliminate anti-DNA antibody producing cells in human monoclonal antibodies bearing the public vivo.35 Similar results have been obtained in vitro 16/6 idiotype.27 High levels of murine anti-16/6 and using conjugates of the A chain of ricin and anti- on September 29, 2021 by guest. Protected anti-anti-16/6 antibodies (resembling anti-DNA idiotype to inhibit antibody response to acetyl- antibodies) were detected in the sera of the immu- choline receptor.36 Down regulation of a group of nised mice. High titres
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