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 is its ability Abl and Ab3 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 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 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 . In at the antigen binding site (known as ) 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 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 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 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 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 (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 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. . 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 of antibodies to DNA, Sm, public idiotypes, such as those recently identified on RNP, Ro, and cardiolipin were noted, as were anti-DNA, anti-Ro, and anti-Sm antibodies,37 may immune complexes in the kidneys which contained be an effective means of down regulating autoanti- the 16/6 idiotype. Injection of a common idiotype body production. This response may provide the thus appears to have induced a lupus-like disease.27 fine tuning needed by the immune system to rid The existence of cross reactive idiotypes on itself of unwanted autoantibodies and provide a autoantibodies from unrelated people and on anti- therapeutic approach without the dangers of con- bodies binding foreign antigens suggests that highly ventional intensive immunosuppressive therapy. conserved germline genes may be involved and that Perhaps plasma exchange coupled with passage of they arise from a restricted number of V genes. plasma over anti-idiotype columns could one day be Datta et al have shown that the cross reactive a feasible proposition. idiotype 16/6, originally described on a human In conclusion, analysis of idiotypes and anti- monoclonal anti-DNA antibody, is present in nor- idiotypes is casting light on the genetic origins of Ann Rheum Dis: first published as 10.1136/ard.47.9.705 on 1 September 1988. Downloaded from

Leading article: Idiotypes and anti-idiotypes 707 autoimmunity and the interrelations of antibodies of thyroglobulin autoantibodies derived from the serum of Hashi- various specificities, and may through manipulation moto patients and EB virus transformed cell lines. Clin Exp of these interactions lead to new treatments. Immunol 1984; 57: 33-40. 19 Atkinson P M, Lampman G W, Furie B C, et al. Homology of the NH2 terminal amino acid sequences of the heavy and light Bloomsbury Rheumatology Unit, R A WAITS* chains of human monoclonal lupus autoantibodies containing Dept of Rheumatology Research, DA ISENBERG the dominant 16/6 idiotype. J Clin Invest 1985; 75: 1138-43. University College and 20 Wassermann N H, Penn A S, Freimuth P I, etal. Anti-idiotypic Middlesex Hospital Medical School route to acetylcholine receptor antibodies and experimental myasthenia gravis. Proc Natl Acad Sci USA 1982; 79: 4810-4. *Correspondence to Dr R A Watts, Bloomsbury Rheuma- 21 Plotz P H. Autoantibodies are antiidiotypic antibodies to tology Unit, Arthur Stanley House, 40-50 Tottenham antiviral antibodies. Lancet 1983; ii: 824-6. Street, London WIP 9PG. 22 theGeltnerIgM fractionsD, Franklinof mixedE C, Frangionecryoglobulins.B. AntiidiotypicJ lmmunol 1980;activity125:in 1530-5. References150523 Cunningham-Rundles C. Naturally occurring anti-idiotypic 1 Jerne N K. Idiotypic networks and other preconceived ideas. antibodies: participation in formation in Immunol Rev 1984; 79: 5-24. selective IgA deficiency. J Exp Med 1982; 155: 711-9. 2 Kunkel H G, Mannick M, Williams R C. Individual antigenic 24 Dwyer D S, Bradley R J, Urquhart C K, Kearney J F. Naturally specificity of isolated antibodies. Science 1963; 140: 1218-9. occurring antiidiotypic antibodies in myasthenia gravis patients. 3 Jerne N K. Towards a netwdrk theory of the immune system. Nature 1983; 301: 611-4. Annales d'immunologie (Paris) 1974; 125c: 373-89. 25 Bose R, March D G, Duchateau J, Sehan A H, Delespesse G. 4 Schiff C, Milili M, Hue I, Rudikoff S, Fougereau M. Genetic Demonstration of autoantiidiotypic antibody cross-reacting basis for expression of the idiotypic network: one unique Ig VH with public idiotypic determinants in the serum of rye-sensitive germline gene accounts for the major family of Abl and Ab3 allergic patients. J Immunol 1984; 133: 2474-8. (Abli) antibodies of the GAT system. J Exp Med 1986; 163: 26 Schoelson S E, Marshall S, Horikoshi H, Kolterman 0 G, 573-87. Rubenstein A H, Olefsky J M. Antiinsulin receptor antibodies 5 Bruck C, Co M S, Slaoui M, et al. Nucleic acid sequence of an in an insulin dependent diabetic may arise as autoantiidiotypes. internal image-bearing monoclonal antiidiotype and its com- J Clin Endocrinol Metab 1986; 63: 56-61. parison to the sequence of the external antigen. Proc Natl Acad 27 Mendlovic S, Brocke S, Shoenfeld Y, et al. Induction of a Sci USA 1986; 83: 6578-82. disease in mice a human systemic lupus erythematosus-like by copyright. 6 Dalgleish A G, Besgley P C L, Clapham P R. Crawford D H, common anti-DNA idiotype. Proc Natl Acad Sci USA 1988; 85: Greaves M F, Weiss R A. The CD4 (T4) antigen is an essential 2260-4. component of the receptor for thc AIDS retrovirus. Nature 28 Datta S K, Naparstek Y, Schwartz R S. In vitro production of 1984; 313: 763-6. an anti-idiotype by of normal subjects and patients 7 Capra J D, Bona C. Idiotypes: practical advances from with systemic lupus erythematosus. Clin Immunol Immuno- fundamental concepts. Today 1988; 9: 98-100. pathol 1986; 38: 302-18. 8 Rajewsky K, Takemori T. Genetics, expression and function of 29 Fong S, Chen P P, Gilbertson T A, Weber J R, Fox R I, Carson idiotypes. Anniu Rev Immunol 1983; 1: 569-607. D A. Expression of three cross reactive idiotypes on rheumatoid 9 Geha R S. Presence of auto-antiidiotypic antibody during the factor autoantibodies from patients with autoimmune diseases normal human immune response to tetanus toxoid antigen. and seropositive adults. J Immunol 1986; 137: 122-8. J Immunol 1982; 129: 139-44. 30 Dersimonian H, Schwartz R S, Barrett K J, Stollar B D. http://ard.bmj.com/ 10 Anonymous. Maternal blocking antibodies, the fetal allograft, Relationship of human variable region heavy chain germline and recurrent abortion. lEditoriall Latncet 1983; ii: 1175-6. genes to genes encoding antiDNA autoantibodies. J Immunol 11 Zouali M, Eyquem A. Idiotypiclantiidiotypic interaction in 1987; 139: 2496-501. systemic erythematosus: demonstration of oscillatory levels of 31 Chen P P, Albrandt K, Orida N K, et al. Genetic basis for the anti-DNA autoantibodies and reciprocal antiidiotypic activity in cross reactive idiotypes on the light chains of human IgM anti- a single patient. Annales d'Iminunologie (Paris) 1983; 134c: IgG autoantibodies. Proc NatlAcad Sci USA 1986; 83: 8318-22. 377-91. 32 Radoux V. Chen P P, Sorge J A, Carson D A. A conserved 12 Abdou N 1, Wall H, Lindsley H B, Halsey J F, Suzuki T. human germline Vk gene directly encodes rheumatoid factor

Network theory in autoimmunity. In vitro suppression of serum light chains. J Exp Med 1986; 164: 2119-24. on September 29, 2021 by guest. Protected anti-DNA antibody binding to DNA by antiidiotypic antibody 33 Hahn B H, Ebling F M. Suppression of murine lupus nephritis in systemic lupus erythematosus. J Clin Invest 1981; 67: by administration of an anti-idiotypic antibody to anti-DNA. J 1297-304. Immunol 1984; 134: 187-90. 13 Abe T, Takeuchi T. Kiyotaki M. et al. Anti-idiotypic antibodies 34 Zouali M, Jolivet M, Leclerc C, et al. Suppression of murine in a patient with monoclonal rheumatoid factor after pneumo- lupus autoantibodies to DNA by administration of muramyl coccal bacteraemia. J Immunol 1984; 132: 2381-5. dipeptide and syngeneic anti-DNA IgG. J Immunol 1985; 135: 14 Horsfall A C, Isenberg D A. Idiotypes and autoimmunity: a 1091-6. review of their role in human disease. Journal ofAutoimmunity 35 Sasaki T, Muryoi T, Takai 0, et al. Selective elimination of 1988; 1: 7-30. anti-DNA antibody producing cells by antiidiotypic antibody 15 Shoenfeld Y. Isenberg D A, Rauch J, Madaio M P, Stollar B D, conjugated with neocarzinostatin. J Clinz Invest 1986; 77: Schwartz R S. Idiotypic cross reactions of monoclonal human 1382-6. lupus autoantibodies. J Exp Med 1983; 158: 718-30. 36 De Shambo R M, Krolick K A. Selective inhibition of an 16 Pisetsky D S. Lerner E A. Idiotypic analysis of a response to purified acetylcholine receptor using anti-Sm antibody. J Immunol 1982; 129: 1489-92. antiidiotypic antibodies coupled to the A chain of ricin. J 17 Lefvert A K, James R W, Alliod C, Fulpius B W. A Immunol 1986; 137: 3135-9. monoclonal anti-idiotypic antibody against anti-receptor anti- 37 Kaburachi J, Stollar B D. Identification of human anti-DNA, bodies from myasthenic sera. Eur J Immunol 1982; 12: 790-2. anti-RNP, anti-Sm and anti-SSA serum antibodies bearing the 18 Delves P J, Roitt I M. Idiotypic determinants on human cross-reactive 16/6 idiotype. J Immunol 1987; 139: 385-92.