Some aspects of idiopatyc regulation in Chagas disease and human schistosomiasis

We developed an approach for the examination of antiidiotypic cell-mediated reactivity during chronic human infections. Antibodies against Schistosoma mansoni egg antigens (anti-SEA) and against Trypanosoma cruzi epimastigotes (anti-EPI) prepared from pooled and individual sera from patients with either schistosomiasis mansoni or Chagas disease were immunoaffinity purified on appropriate columns and used to stimulate patients' T cells. These antibodies preparations and their F (ab)2 fragments stimulated in a dose-dependent assay the proliferations of peripheral blood mononuclear cells (PBMC) and T lymphocytes from some, but not all actively infected individuals. Anti-idiotypic T cells can recognize and respond to anti-SEA or anti-EPI idiotypes directly. We contend that the most likely explanation of this stimulations is that the idiotype expressed on these anti-SEA or anti-EPI antibodies are acting as immunogens to stimulate antiidiotypic T lymphocytes that develop during the course of the infection. Immunization of rabbits with these antibodies (anti-SEA or anti-EPI) preparations, followed by absorption of the rabbit antisera on absorbants of normal Ig, produced specific anti-id reagents. Use of these reagents in competitive ELISA distinguished the idiotypic expression on anti-SEA or anti-EPI preparations obtained from patients' sera with different clinical forms of schistosomiasis or Chagas disease, respectively. The anti-SEA Id-reactive T cells from S. mansoni infected patients were capable of regulating autologous in vitro granuloma formation.

Development of anti-idiotypic antibodies to HLA antigens during pregnancy.

Thirty one pregnant women whose sera were initially positive for anti HLA antibodies were retested for lymphocytotoxicity 7-9 months after delivery. In the second testing 10 women were found to have lost the cytotoxic antibodies. These sera were tested for presence of anti-idiotypic antibodies by complement dependent cytotoxicity (CDC). In all ten sera tested, CDC blocking antibody was detected by inhibition technique at different dilutions. These antibodies directed specifically against the HLA antigen of the spouse. This CDC blocking factor could be the anti-idiotypic antibody (Ab2) directed against the cytotoxic anti-HLA antibody (Ab1). In one woman who conceived a second time, repeat sample obtained at the 7th month of the second pregnancy showed reappearance of the specific anti-HLA antibody. This may suggest that the Ab1-Ab2 network is under dynamic regulation.

Immunoregulation by processed immunoglobulin on B-cells.

According to Jerne's network hypothesis, the unique amino acid sequences of Ig variable regions, that is, the idiotypic determinants can function in immunoregulatory mechanisms and cellular interactions. Indeed, Id-specific T-cells (mostly CD4+) have since been described, but the nature of Id-positive Ig on B-cells involved in recruiting T-cells is unclear. Studies from our ongoing investigation presented here clearly show that Id can evoke both CD4+ and CD8+ T cells, and exist not only as the integral components of a bona fide antigen-binding receptor Ig but also as distinct molecular entities in processed forms on the cell surface of B-lymphocytes. Using a B-cell hybridoma, 2C3, that expresses anti-hapten (phthalate) antibody receptors on the cell surface, we induced both Id-specific CD4+ and CD8+ T effector cells. The CD4+ T cells were suppressive and mediated generation of Id-loss 2C3 variants, whereas CD8+ T cells were highly cytotoxic and selectively eliminated 2C3 cells both in vitro and in vivo. These effector cells could be induced by cell membrane-associated Ig but not by its soluble form, secreted by 2C3 cells. Antibodies to MHC class I but not class II molecules were inhibitory to this induction. Furthermore, brefeldin A (BFA), an inhibitor of MHC class I mediated processing, blocked induction of CTL but had no effect on the expression of membrane Ig. Moreover, chloroquine, an inhibitor of class II-mediated processing, had no effect. A few reports have recently appeared indicating that an exogenous Ig can be processed by B-cells in the context of MHC class II proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Human schistosomiasis mansoni: studies on in vitro granuloma modulation

Infection with Schistosoma mansoni induces humoral and T cell mediated responses and leads to delayed hipersensitivity that results in granulomatous inflamatory disease around the parasite eggs. Regulation of these responses resulting in a reduction in this anti-egg inflamatory disease is appsrently determined by idiotypic repertoires of the patient, associated with genetic background and multiple external factors. We have previously reported on idiotype/anti-idiotype-receptor transactions in clinical human schistosomiasis. These findings support a hypothesis that anti-SEA cross-reactive idiotypes develop in some patients during the course of a chronic infection and participate in regulation of anti-SEA cellular immune responses. We repport here on experiments wich extend those observations to the regulation of granulomatous hypersensitivity measured by an in vitro granuloma model. T cells from chronic intestinal schistosomiasis patients were stimulated in vitro with anti-SEA idiotypes and assayed in an autologous in vitro granuloma assay for modulation of granuloma formation. These anti-SEA idiotype reactive T cells were capable of regulating autologous in vitro granuloma formation. This regulatory activity, initiated with stimulatory anti-SEA idiotypic antibodies, was antigenically specific and was dependent on the present of intact (F(ab')2 immunoglobulin molecules. The ability to elicit this regulatory activity appears to be dose dependent and is more easily demonstrated in chronically infected intestinal patients or SEA sensitized individuals. These data support the hypothesis that anti-SEA cross reactive idiotypes are important in regulating granulomatous hypersensitivy in chronic intestinal schistosomiasis patients and these cross-reactive idiotypes appear to play a major role in cell-cell interactions which result in the regulation of anti-SEA cellular immune responses

La red de idiotipos-antiidiotipos: I. su relación con la autoinmunidad / The idiotype-antiidiotype network: I. Its association with autoimmunity

Las inmunoglobulinas presentan determinantes antigénicos en su región variable que estimulan la producción de anticuerpos específicos con lo cual se establece una red de estimulaciones y supresiones sucesivas, que es funcionalmente cerrada y con predominio de las interacciones supresoras. Sobre la base de recientes investigaciones se ha planteado la hipótesis de que la red inmunológica no se establece por generación al azar de los paratopes, sino de modo determinista a través del código de reconocimiento molecular. La red inmunològica tiene carácter regulador, se describen redes estimuladoras de la respuesta inmune y redes supresoras. Especial interés cobra la presencia de idiotipos comunes en los autoanticuerpos presentes en diversas enfermedades autoinmunes para la comprensión de su patogenia

Idiotipos y anti-idiotipos / Idiotypes and anti-idiotypes

De acuerdo a la teoría del network (red de circuitos), se considera al sistema inmune como una red de idiotipos a nivel humoral y celular. En este sentido el autor enfoca los aspectos que evidencian el sostenimiento de la teoría en cuanto a la autoinmunogenicidad de los idiotipos determinantes expresados sobre receptores de linfocitos B y T que regulan sus funciones, uso e implicaciones de idiotipos y anti-idiotipos y presenta tablas que indican la reacción cruzada con suero humano de los idiotipos

Autoimmunogens, autoantigens, autoantibodies and autoimmune diseases: one-to-one or many-to-many relationships?

Cells with receptors capable of binding self-antigens constitute a normal component of the B cell repertoire; these specificities appear to be represented in low levels within the expressed antibody population. In autoimmune disease, this potential-actual repertoire is skewed in favor of exaggerated autoantibody expression. The clones or specificities affected are characteristic, even diagnostic of the particular disease, yet individuals express but a relatively small subset of this complexity. "Marker" autoantibodies may or may not be included, but autoantibodies more typical of other, related diseases are usually present. Certain specificities are clearly implicated in the pathogenesis of the corresponding disease; others contribute to- or exacerbate pre-existing pathological conditions, and still others appear at present as epiphenomena. Organ-/tissue-specific autoantibodies largely fall into the first or perhaps second categories; those associated with the systemic rheumatic diseases fit better into the latter or latter two categories. As we learn eventually more about these antibodies and the full spectra of autoantigens with which they react, many more may be found to exert more central roles in pathogenesis. The distortion of the expressed repertoire represents but one aspect of a far more complex set of pre-dispositions, conditions, stimuli, contributory factors and perhaps coincidences involved in the onset and perpetuation of the disease. The AAb arise within the context of a disease more pervasive than just the autoantibodies themselves, however, in certain diseases the subsequent autoimmune response may surpass all other variables to constitute the single most clinically significant factor. In attempting to account for these individual specificities and their disease associations, certain models seem applicable to selected autoantibodies but not to others. Even in these selected cases, the models remain speculative; in no case can we categorically state how the specificities arose. Non-specific activation may contribute to- and expand the expressed autoantibodies, but such mechanisms generally fall short in terms of adequately explaining the specificities of autoantibodies, the overlapping sets, the polyclonality of the response against single autoantigens or the specific disease associations. Despite this theoretical criticism, empirically, non-specific mechanisms have given rise to mixtures of autoantibodies which appear identical at least in terms of specificities to their spontaneous counterparts in various rheumatic diseases.(ABSTRACT TRUNCATED AT 400 WORDS)