Idiotipos y antiidiotipos: estructura y función en autoinmunidad / Anti-idiotypes and idiotypes: structure and autoimmunity function

Se presenta una revisión sobre la estructura de las inmunoglobulinas y los idiotipos que constituyen las regiones hipervariables que unen al antígeno; según la teoría de jerne, un idiotipo genera otro anticuerpo (antiidiotipo) que reconoce los epitopos de las regiones hipervariables, creando una red que en teoría regula la síntesis de anticuerpos. Funcionalmente existen dos clases: 1) Los idiotipos que constituyen imágenes internas del sitio de unión con el antígeno y 2) Los que reconocen sitios diferentes. Cuando los idiotipos son compartidos por individuos de una misma especie se denominan públicos y son generados vía línea germinal, y los que están presentes en un solo individuo corresponden a idiotipos privados y son producto de mutación somática. En autoinmunidad los idiotipos identifican autoanticuerpos patogénicos órgano-específicos como en pénfigo o penfigoide; éstos son capaces de inducir directamente lesión tisular, que es reproducible en animales. Los órgano-inespecíficos como los autoanticuerpos antinucleares de lupus, generalmente no inducen lesión directa. Finalmente, se revisan las evidencias y modelos experimentales que sugieren que un idiotipo autoinmune humano inyectado en un animal genera un antiidiotipo, que simula al antígeno, este genera un tercer anticuerpo idéntico al autoanticuerpo humano y los animales desarrollan síntomas similares a los observados en padecimientos autoinmunes como lupus

Anti-IgA antibodies in IgA-deficient children.

IgG and IgM isotype antibodies to polyclonal human IgA, myeloma IgA1, and myeloma IgA2 were estimated in 38 IgA-deficient children aged between 0.9 and 15 years. All children had IgM anti-IgA antibodies. IgG antibodies against either polyclonal IgA, IgA1, or IgA2 were present in 63% of the IgA-deficient children. IgG anti-IgA antibodies were detected against all three antigens in 8 of 11 severely IgA-deficient children and in 7 of 27 partially IgA-deficient children, but in only 1 of 23 healthy adult controls. The proportion of children with IgG anti-IgA antibodies was significantly greater in the severely IgA-deficient group in comparison with the partially IgA-deficient group and the adult controls (chi-square test, P less than 0.01 and P less than 0.005, respectively). There was a strong correlation within each IgG subclass between antibody responses toward each of the three IgA antigens. Twenty-four children were followed over a period ranging from 0.9 to 11 years (mean, 2.3 years). Three children who were initially IgG anti-IgA antibody negative became antibody positive and three who were antibody positive became antibody negative. Five children with severe IgA deficiency remained severely IgA deficient and IgG antibodies to IgA persisted in all five at follow-up. The presence of IgG anti-IgA antibodies did not influence the normalization of serum IgA at follow-up in 14 of 19 children who were initially partially IgA deficient.

Importance of antibody isotype in monoclonal anti-idiotype therapy of a murine B cell lymphoma. A study of hybridoma class switch variants.

An initial panel of four syngeneic monoclonal antibodies directed against the idiotype of a murine B cell lymphoma was used to treat this tumor in vivo. The antibody in the panel of the IgG2a isotype was more effective in treatment than the other antibodies, which were of the IgG1 and IgG2b isotypes. To independently assess the role of antibody isotype in mediating antitumor effects, switch variant hybridoma families were isolated from the hybridomas secreting the less effective IgG1 and IgG2b antibodies. A family isolated from an IgG1-secreting parent consisted of IgG1-, IgG2b-, and IgG2a-secreting members, and an IgG2a variant was isolated from an IgG2b-secreting parent for another family. Antibody members of each family differed only in heavy chain composition and were the same with respect to their light chains and their affinity and specificity for idiotype. The IgG2a members of both families were superior to the other members in inhibiting tumor growth with an order of effectiveness of IgG2a greater than IgG1 greater than IgG2b. These in vivo results paralleled the abilities of these different isotype antibodies to mediate antibody-dependent cellular cytolysis in vitro. For the IgG2b----IgG2a family, in vivo treatment with the IgG2a member given i.p. after i.p. tumor challenge at one-tenth the dose of the IgG2b member was still superior to the latter. At one-hundredth the dose of the IgG2b, the IgG2a was still superior to the latter when the antibodies were given i.p. and tumors subcutaneously. These data and those showing that the clearance of these antibodies from the serum differed in only a relatively minor way indicate that the IgG2a antibodies in this system had greater antitumor effects primarily by virtue of their greater capacity for host effector interaction.

Significance of multiple types of antibodies on red blood cells of patients with positive direct antiglobulin test: a study of monospecific antiglobulin reactions in 85 patients.

Blood samples from 85 patients with a positive direct antiglobulin test were tested with monospecific antiglobulin reagents: anti-IgG, anti-IgM, anti-IgA, and anti-C3. No typical pattern of antiglobulin reaction could be correlated with specific diseases except for the patients with methyldopa-induced positive direct antiglobulin test, all of whom had only IgG on their red blood cells. The presence of more than 1 type of antibody on red blood cells was associated with severe haemolysis. These patients responded less frequently to steroids, and in most of them no underlying disease could be found. Most patients with complement alone on red blood cells had no evidence of haemolysis, and when present it was never severe.

Subclass restriction of the antiidiotypic antibody response in the rat.

Antiidiotypic antibodies were induced in LOU/M rats by immunization with two myeloma proteins of LOU origin: IR-162 (IgE) and IR-418 (IgG2a). Antibodies to IR-162 were easily obtained after a limited number of immunizations with protein in soluble form; polymerization with glutaraldehyde did not enhance immunogenicity. Antibodies to IR-418 appeared only after a large number of immunizations with protein in polymerized form or with protein copolymerized with rabbit IgG. All of the antibodies, either to IR-162 or to IR-418, were found to be idiotype-specific. In every case for which significant levels of antiidiotypic antibodies were produced, most or all of the antibodies belonged to rat IgG1 subclass. Since, in mice, antiidiotypic antibodies are restricted to the IgG1 subclass, our results indicate a functional analogy between rat and mouse IgG1. Our studies also suggest that the rat IgG1 subclass may be predominantly expressed in T-cell-dependent antibody responses, such as production of antiidiotypic antibodies.

[Enzymo-immunologic determination of the class of antiglobulin factors]. / Détermination enzymo-immunologique de la classe des facteurs antiblobuliniques.

The authors describe an enzymo-immunologic method of determination of the class of rheumatoid factors (RF). This technic includes 3 main stages : 1) extraction of RF by fixation on aggregated rabbit IgG previously adsorbed on the walls of a plastic tube; 2) recognition of RF linked to the solid phase by anti-IgG addition, and addition of human IgA and IgM linked to glucose oxidase; 3) revelation of the enzyme activity linked to the solid phase : this enzyme activity directly depends on the levels of RF to be estimated. The results are expressed as a percentage of the fixation of a reference serum obtained from a patient with rheumatoid arthritis (RA). This serum presents an antiglobulin activity in the 3 major classes of immunoglobulins. The coefficients of variation of intra- and intersystem reproductibility lay between 5,6 and 17.8%. The specificity of the estimation was controlled by the localisation of the antiglobulin activity of the sera after chromatography on Sephadex G200 and by estimation of RF after their absorption by an aggregated IgG immunoadsorbant. This technic was applied to the identification of RF in RA (90 cases); in diseases not related to RA and in control subjects : the sensitivity of this method appears greater than that of technics previously described (immuno-fluorescence, Rose-Waaler reaction) in fact, only 12,2% of sera of patients with RA remain negative with this new test. However, this greater sensitivity does not seem to have altered the clinical specificity of the test : in fact, only 8,4% of the sera of patients with diseases unrelated to RA are positive by this method, which, moreover, may be explained by the age of these subjects (average age 71.5 years).