Idiotypes are unique determinants of an immunoglobulin or T‐cell receptor that can function as antigens. Responses to idiotypes, which include anti‐idiotypic (Id) antibody (Ab)‐producing B cells and idiotype‐specific T cells, form a network that regulates their production, referred to as the idiotypic network. In an immune response, antibody 1 (Ab1) is produced in response to an antigen, and anti‐Id Ab produced to Ab1 (Ab2) may bind in the antigen‐combining site (Ab2β) or the framework region (Ab2γ) of Ab1. As Ab2β can fit in the paratope of an antigen receptor of B or T cells, it mimics the three‐dimensional structure and is the internal image of antigen, and has the potential to activate Ab1 precursors reactive with the antigen. These findings have led to the use of Ab2β as an immunogen to elicit specific immune responses to foreign pathogens, as probes to study cell surface receptors and as immune therapy for tumours.

Key Concepts:

  • Idiotypes are unique determinants located in the variable region of antigen receptors on B cells (immunoglobulin, Ig) and T cells (T‐cell receptor, TCR).

  • Antibody 1 (Ab1) is produced in response to an antigen and Ab2 produced to Ab1 may react with the antigen‐combining site (Ab2β, internal image of antigen) or the framework region (AB2γ) of the antibody molecule.

  • The interaction of clones of B and T cells that express distinct idiotypic specificities to regulate the immune response is referred to as the idiotypic network.

  • The idiotypic network can be exploited to elicit specific immune responses to foreign pathogens, to study cell surface receptors and as immune therapy for tumours.

Keywords: idiotype; idiotypic network; Jerne; antiidiotype

Figure 1.

An antigenic epitope (x) is processed and presented by an antigen‐presenting cell (APC) in association with Class II MHC to an antigen‐specific T‐helper cell or, in association with Class I MHC, to an antigen‐specific cytotoxic T cell. Signals from the T‐helper cell lead to the activation of B cells that produce antiepitope x antibody (Ab1), which will express idiotype y. Anti‐x producing B cells, as APCs, present idiotypic peptide y in association with Class II to idiotype y‐reactive or specific T‐helper cell and, in association with Class I, to idiotype y‐specific cytotoxic T cells. Signals from the activated idiotype y‐reactive T cells lead to the activation of antiidiotope y‐producing B cells (Ab2). Dendritic cells may also present idiotypic peptides to T cells.

Figure 2.

Idiotypic cascade. A foreign antigenic epitope (x) induces an immune response characterized by the production of Ab1 antibody, which is anti‐x and contains several idiotopes, which can either be paratopic or nonparatopic (framework). Ab1 can elicit an antiidiotypic response (Ab2), which can be of three types: (1) Ab2β, which is directed to the paratope of Ab1, and presents the internal image of antigen epitope x; (2) Ab2γ, which is directed to the paratope of Ab1 but does not carry the internal image; (3) Ab2α, which is directed to nonparatopic or framework idiotopes of Ab1.



Abbas AK, Perry LL, Bach BA and Greene MI (1980) Idiotype‐specific T cell immunity. I. Generation of effector and suppressor T lymphocytes reactive with myeloma idiotypic determinants. Journal of Immunology 124: 1160–1166.

Abdalla AO, Hansson L, Eriksson I et al. (2007) Idiotype protein vaccination in combination with adjuvant cytokines in patients with multiple myeloma‐evaluation of T‐cell responses by different read‐out systems. Haematologica 92: 110–114.

Alfonso S, Diaz RM, de la Torre A et al. (2007) 1E10 anti‐idiotype vaccine in non‐small lung cancer. Experience in stage IIIb/IV patients. Cancer Biology & Therapy 6: 1847–1852.

Bendandi M, Gocke CD, Kobrin CB et al. (1999) Complete molecular remissions induced by patient‐specific vaccination plus granulocyte–monocyte colony‐stimulating factor against lymphoma. Nature Medicine 5: 1171–1177.

Beninati M, Oggioni M, Mancuso G et al. (2001) Anti‐idiotypic vaccination against group B streptococci. International Reviews of Immunology 20: 263–273.

Bigazzi PE, Michaelson JH and Potter NT (1989) Epibodies in autoimmunity: antisera against autoantibodies to the renal glomerular basement membrane react with idiotypes as well as with autoantigens. Autoimmunity 5: 3–16.

Blank M, Anafi L, Zandman‐Goddard G et al. (2007) The efficacy of specific IVIG anti‐idiotypic antibodies in antiphospholipid syndrome (APS): trophoblast invasiveness and APS animal model. International Immunology 7: 857–865.

Bogen B, Malissen B and Haas W (1986) Idiotope‐specific T cell clones that recognize syngeneic immunoglobulin fragments in the context of class II molecules. European Journal of Immunology 16: 1373–1378.

Bona CA, Heber‐Katz E and Paul WE (1981) Idiotype‐anti‐idiotype regulation I. Immunization with a levan‐binding myeloma protein leads to the appearance of auto‐anti‐(anti‐idiotype) antibodies and to the activation of silent clones. Journal of Experimental Medicine 153: 951–967.

Bottomly K (1984) All idiotypes are equal, but some are more equal than others. Immunological Reviews 79: 45–61.

Bottomly K and Mosier DE (1981) Antigen‐specific helper T cells required for dominant idiotype expression are not H‐2 restricted. Journal of Experimental Medicine 154: 411–421.

Brient BW and Nisonoff A (1970) Quantitative investigation of idiotypic antibodies. IV. Inhibition of specific haptens of the reaction of anti‐hapten antibody with its idiotypic antibody. Journal of Experimental Medicine 132: 951–962.

Burdette S and Schwartz RS (1987) Idiotypes and idiotypic networks. New England Journal of Medicine 317: 219–224.

Chen PP, Houghtent RA, Fong S et al. (1984) Anti‐hypervariable region antibody induced by a defined peptide: An approach for studying the structural correlates of idiotypes. Proceedings of the National Academy of Sciences of the USA 81: 1784–1788.

Cosenza H, Apgustin AA and Julius MH (1977) Idiotypes and anti‐idiotypes as probes in analysis of immunoregulation. Cold Spring Harbor Symposia on Quantitative Biology 41(Part 2): 709–718.

Ehrlich P and Morgenroth J (1901) Ueber Haemolysine. Berlin klin Wchnschr 38: 599–604.

Ertl HC and FinbergRW (1984) Sendai virus‐specific T‐cell clones: induction of cytolytic T cells by an anti‐idiotypic antibody directed against a helper T‐cell clone. Proceedings of the National Academy of Sciences of the United States of America 81: 2850–2854.

Ertl HC, Homans E, Tournas S and Finberg RW (1984) Sendai virus‐specific T cell clones. V. Induction of a virus‐specific response by antiidiotypic antibodies directed against a T helper cell clone. The Journal of Experimental Medicine 159: 1778–1783.

Eyerman MC, Zhang X and Wysocki LJ (1996) T cell recognition and tolerance of antibody diversity. Journal of Immunology 157: 1037–1046.

Falorni A and Brozzetti A (2005) Diabetes‐related antibodies in adult diabetic patients. Best Practice & Research. Clinical Endocrinology & Metabolism 19: 119–133.

Foon KA, John WJ, Chakraborty M et al. (1997) Clinical and immune responses in advanced colorectal cancer patients treated with antiidiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen. Clinical Cancer Research 3: 1267–1276.

Foon KA, John WJ, Chakraborty M et al. (1999) Clinical and immune responses in resected colon cancer patients treated with anti‐idiotype monoclonal antibody vaccine that mimics the carcinoembryonicantigen. Journal of Clinical Oncology 17: 2889–2895.

Foon KA, Lutzsky J, Baral RN et al. (2000) Clinical and immune responses in advanced melanoma patients immunized with an anti‐idiotype antibody mimicking disialoganglioside GD2. Journal of Clinical Oncology 18: 376–384.

Ghiotto F, Fais F, Valetto A et al. (2004) Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia. The Journal of Clinical Investigation 113: 1008–1016.

Hall TR, Bogdani M, LeBoeuf RC et al. (2008) Modulation of diabetes in NOD mice by GAD65‐specific monoclonal antibodies is epitope specific and accompanied by anti‐idiotypic antibodies. Immunology 123: 547–554.

Hilchey SP, Hyrien O, Mosmann TR et al. (2009) Rituximab immunotherapy results in the induction of a lymphoma idiotype‐specific T‐cell response in patients with follicular lymphoma: support for a vaccinal effect of rituximab. Blood 113: 3809–3812.

Hong J, Zang YC, Tejada‐Simon MV et al. (2000) Reactivity and regulatory properties of human anti‐idiotypic antibodies induced by T cell vaccination. Journal of Immunology 165: 6858–6864.

Huang JH, Ward RE and Kohler H (1986) Idioptype antigens (Ab2α and Ab2β) can induce in vitro B cell proliferation and antibody production. Journal of Immunology 137: 770–776.

Infante AJ, Infante PD, Gillis S and Fathman CG (1982) Definition of T cell idiotypes using anti‐idiotypic antisera produced by immunization with T cell clones. Journal of Experimental Medicine 155: 1100–1107.

Jacobsen JT, Lunde E, Sundvold‐Gjerstad V, Munthe LA and Bogen B (2010) The cellular mechanism by which complementary Id+ and anti‐Id antibodies communicate: T cells integrated into idiotypic regulation. Immunology and Cell Biology 88: 515–522.

Jerne NK (1974) Towards a network theory of the immune system. Annals of Immunology 125C: 373–389.

Kaye J, Porcelli S, Tite J, Jones B and Janeway CA (1983) Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen‐presenting cells in the activation of T cells. Journal of Experimental Medicine 158: 836–856.

Kennedy RC, Ionescu‐Matiu I, Sanchez Y and Dreesman GR (1983) Detection of interspecies idiotypic cross‐reactions associated with antibodies to hepatitis B surface antigen. European Journal of Immunology 13: 232–235.

Knupp CJ, Uner AH, Tatum AH, Kakanar JR and Gavalchin J (1995) IdLNF1‐specific T cell clones accelerate the production of IdLNF1+ IgG and nephritis in SNF1 mice. Journal of Autoimmunity 8: 367–380.

Kunkel HG, Mannick M and Williams RC (1963) Individual antigenic specificity of isolated antibodies. Science 140: 1218–1219.

Ladjemi MZ, Chardes T, Corgnac S et al. (2011) Vaccination with human anti‐trastuzumab anti‐idiotype scFv reverses HER2 immunological tolerance and induces tumor immunity in MMTV.f.huHER2(Fo5) mice. Breast Cancer Research 13: R17.

Mendlovic S, Brocke S, Shoenfeld Y et al. (1988) Induction of a systemic lupus erythematosus‐like disease in mice by a common human anti‐DNA idiotype. Proceedings of the National Academy of Sciences of the USA 85: 2260–2264.

Mudgett M, Coligan JE and Kindt TJ (1978) Isolation and characterization of distinct antibody populations from antisera directed against idiotypes of rabbit homogenous antibodies. Journal of Immunology 120: 293–301.

Neninger E, Diaz RM, de la Torre A et al. (2007) Active immunotherapy with 1E10 anti‐idiotype vaccine in patients with small cell lung cancer. Cancer Biology & Therapy 6: 145–150.

Nisonoff A and Lamoyi E (1981) Implications of the presence of an internal image of the antigen in antiidiotypic antibodies: possible application to vaccine production. Clinical Immunology and Immunopathology 21: 397–406.

Oak S, Gilliam LK, Landin‐Olsson M et al. (2008) The lack of anti‐idiotypic antibodies, not the presence of the corresponding autoantibodies to glutamate decarboxulase, defines type 1 diabetes. Proceedings of the National Academy of Sciences of the USA 105: 5471–5476.

Oudin J and Michel M (1969) Idiotypy of rabbit antibodies‐II. Comparison of idiotypy of various kinds of antibodies formed in the same rabbits against Salmonella typhi. Journal of Experimental Medicine 130: 619–642.

Parra CC, Lima MS and Gazzinelli G (1988) Immune responses during human Schistosomiasis mansonii XV. Anti‐idiotypic T cells can recognize and respond to anti‐SEA idiotypes directly. Journal of Experimental Medicine 140: 2401–2405.

Price K, Knupp CJ, Tatum AH et al. (2002) Molecular identification of pathogenic IdLNF+1 autoantibody idiotypes derived from the NZB×SWR F1 model for systemic lupus erythematosus. Journal of Autoimmunity 19: 87–101.

Reichardt VL, Okada CY, Liso A et al. (1999) Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma – a feasibility study. Blood 93: 2411–2419.

Reinartz S, Homback A, Kohler S et al. (2003) Interleukin‐6 fused to an anti‐idiotype antibody in a vaccine increase the specific humoral immune response against CA125+ (MUC‐16) ovarian cancer. Cancer Research 63: 3234–3240.

Roitt IM, Male DK, Guarnotta G et al. (1981) Idiotype networks an their possible exploitation for manipulation of the immune response. Lancet 1: 1041–1045.

Sacks DL, Esser KM and Sher A (1982) Immunization of mice against African trypanosomiasis using anti‐idiotypic antibodies. Journal of Experimental Medicine 55: 1108–1119.

Saeki Y, Chen JJ, Shi LF, Okuda Y and Kohler H (1990) Idiotype‐specific T helper clones recognize a variable H chain determinant. Journal of Immunology 144: 1625–1628.

Schrater AF, Goidl EA, Thorbecke GJ and Siskind GW (1979) Production of auto‐anti‐idiotypic antibody during the normal immune response to TNP‐ficoll. III. Absence in nu/nu mice: evidence for T‐cell dependence of the anti‐idiotypic‐antibody response. Journal of Experimental Medicine 150: 808–817.

Schreiber JR and Dahlhauser P (1994) Immunogenicity of tetanus toxoid conjugates of anti‐idiotypes that mimic Pseudomonas aeruginosa surface polysaccharides. Infection and immunity 62: 308–312.

Schuster SJ, Neelapu SS, Gause BL et al. for the BiovaxID Phase III Study Investigators (2009) Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: Phase III clinical trial results. Journal of Clinical Oncology 27: 18s, abstr 2.

Sege K and Paterson PA (1978) Use of antiidiotypic antibodies as cell‐surface receptor probes. Proceedings of the National Academy of Sciences of the USA 75: 2443–2447.

Silke Reinartz S, Köhler S, Schlebusch H et al. (2004) Vaccination of patients with advanced ovarian carcinoma with the anti‐idiotype ACA125. Immunological response and survival (phase Ib/II). Clinical Cancer Research 10: 1580–1587.

Titzer S, Christenson O, Manzke O et al. (2000) Vaccination of multiple myeloma patients with idiotype‐pulsed dendritic cells: immunological and clinical aspects. British Journal of Haematology 108: 805–816.

Uner A, Tatum AH, Knupp CJ and Gavalchin J (1998) Characteristics of auto anti‐idiotypic antibodies reactive with antibodies expressing the pathogenic idiotype, IdLNF1, in the (NZB×SWR)F1 model for lupus nephritis and its parental strains. Journal of Autoimmunity 11: 233–240.

Westerink MA, Campagnari AA, Wirth MA and Apicella MA (1988) Development and characterization of an anti‐idiotype antibody to the capsular polysaccharide of Neisseria meningitidis serogroup C. Infection and immunity 56: 1120–1127.

Westerink MA, Giardina PC, Campagnari AA and ApicellaMA (1990) The thymus‐dependent nature of the murine antibody response to a monoclonal anti‐idiotypic antibody to the Neisseria meningitidis serogroup C capsular polysaccharide. Microbial pathogenesis 8: 411–419.

Weiyun ZA, Tibshirani R, Taidi B, Czerwinski D and Levy R (2009) Anti‐idiotypic antibody response after vaccination correlates with better overall survival in follicular lymphoma. Blood 113(23): 5743–5746.

Yagüe J, White J, Coleclough C et al. (1985) The T cell receptor: the alpha and beta chains define idiotype, and antigen and MHC specificity. Cell 42: 81–87.

Yi Q, Holm G and Lefvert AK (1996a) Idiotype‐induced T cell stimulation requires antigen presentation in association with HLA‐DR molecules. Clinical and Experimental Immunology 104: 359–365.

Yi Q, Pirskanen R and Lefvert AK (1996b) Anti‐idiotypic T cells in early stages of myasthenia gravis: increase in the number and prevalence correlated to clinical improvement in patients. Scandinavian Journal of Immunology 44: 630–637.

Yi Q, Szmania S, Freeman J et al. (2010) Optimizing dendritic cell‐based immunotherapy in multiple myeloma: intranodal injections of idiotype‐pulsed CD40 ligand‐matured vaccines led to induction of type‐1 and cytotoxic T‐cell immune responses in patients. British Journal of Haematology 150: 554–564.

Young JW and Inaba K (1996) Dendritic cells as adjuvants for class I major histocompatibility complex‐restricted antitumor immunity. Journal of Experimental Medicine 183: 87–97.

Zhang YC, Hong J, Rivera VM, Killian J and Zhang JZ (2000) Preferential recognition of TCR hypervariable regions by human anti‐idiotypic T cells induced by T cell vaccination. Journal of Immunology 164: 4011–4017.

Further Reading

Bona CA (1996) Internal image concept revisited. Proceedings of the Society for Experimental Biology and Medicine 213: 32–41.

Hefty PS and Kennedy RC (1999) Immunoglobulin variable regions as idiotype vaccines. Infectious Disease Clinic of North America 13(1): 27–37.

Lopez‐Diaz de Cerio A, Zabalegui N, Rodriguez‐Calvillo M, Inoges S and Bendandi M (2007) Anti‐idiotype antibodies in cancer treatment. Oncogene 26: 3594–3602.

Weathington NM and Blalock JE (2003) Rational design of peptide vaccines for autoimmune disease: harnessing molecular recognition to fix a broken network. Expert Review of Vaccines 2(1): 61–73.

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Gavalchin, Jerrie(Nov 2011) Idiotypes. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000912.pub2]