IgE Antibody Synthesis Research Articles

"Allergic breakthrough" after antigen sensitization: height of IgE synthesis is temporally related to diurnal variation in endogenous steroid production.

Mice of the SJL strain normally display the low IgE responder phenotype. In the course of extensive studies on IgE responses with this strain of mice, it because apparent that the magnitudes of IgE antibody synthesis by SJL mice varied after antigen sensitization either alone or in conjunction with exposure to optimal enhancing doses of whole body irradiation. Analysis of the basis for this variability revealed that SJL respond to antigen sensitization by displaying cyclical IgE response curves determined by the time of day the sensitization is carried out. Moreover, when these low responders are converted to the high responder phenotype by low dose irradiation, the time of irradiation determines the magnitude of the IgE response obtained, whereas the time of antigen challenge determines the potential for generating a good response. The diurnal curve of IgE responses in both unirradiated and irradiation-enhanced low responder mice appears to be determined by normal variations in levels of endogenous corticosteroids, as indicated by the correlation between the normal diurnal curve of endogenous steroid production with the cyclical pattern of IgE responses. This apparent effect of endogenous steroid production on IgE antibody synthesis is supported by experiments demonstrating that the normal IgE pattern in both unirradiated and irradiated mice can be perturbed by administration of cortisone at the proper time of day. These results indicate that IgE antibody synthesis displays unique sensitivity to fluctuations in plasma steroid levels and may have significant implications for the role of steroids in the pathogenesis and management of allergic diseases.

Regulation of IgE Antibody Production by Serum Molecules

Abstract Experiments presented in this paper were designed to test a new concept concerning the possible pathogenesis of the allergic phenotype. This concept, termed “allergic breakthrough” considers that one of the avenues toward the allergic phenotype involves coincidental sensitization combined with an imbalance in the normal damping mechanism that serves to limit IgE antibody production. The three predictions of this concept that can be tested experimentally are: 1) manipulations that are effective in heightening or re-establishing the damping mechanism should manifest persistence insofar as IgE antibody synthesis to the relevant allergen is concerned; 2) once allergic breakthrough has occurred, the height of production of IgE antibodies specific for the sensitizing agent should remain elevated at levels characteristic of the allergic phenotype, even after the threshold of damping activity has returned to a normal level; and 3) allergic breakthrough should display specificity in that breakthrough would occur in response to subsequent exposure to the specific antigen to which coincidental sensitization initially occurred, but not for other unrelated antigens. The studies presented herein confirm each one of these predictions, thereby providing substantial support for the validity of this concept as one possible distinguishing feature between individuals manifesting the nonallergic and allergic phenotypes, respectively.

Regulation of IgE Antibody Production by Serum Molecules

Abstract Two biologically active serum molecules manifesting precisely opposite biologic effects, both of which are selective for IgE antibody synthesis, can be detected in the serum and ascites fluids of CFA-immune mice. One activity, described previously, is suppressive and hence termed suppressive factor of allergy (SFA); the other, reported for the first time herein, is enhancing and has been termed enhancing factor of allergy (EFA). The ability to detect one vs the other activity requires certain special manipulations such as different doses of low dose x-irradiation. Conclusive evidence for the existence of two distinct factors mediating these two opposing biologic effects was obtained in studies demonstrating that affinity chromatography on concanavalin A-Sepharose segregated the two molecular entities. Thus, SFA binds poorly or not at all to Con A-Sepharose, whereas EFA binds to Con A and can be recovered in the eluate eluted with the competitive sugar α-methyl-D-glucopyranoside.

Induction of a ragweed-specific allergic state in Ir-gene-restricted nonresponder mice.

Mice of the inbred strains, C57BL/6 and C57BL/10 (H-2b), are genetically incapable of developing IgE antibody responses to ragweed pollen extract (RE) or its dinitrophenylated derivative, DNP-RE. This nonresponsiveness has previously been thought to reflect the absence of a relevant H-2-linked Ir genes controlling responses of inbred mice to these antigens. However, pretreatment of H-2b mice with either low doses of ionizing X irradiation or cyclophosphamide abrogates the nonresponder status of such animals, apparently by removal of a suppressive mechanism normally inhibiting development of IgE responses to these antigens. The implications of these findings for mechanisms of genetic control of IgE antibody synthesis and the Ir-gene concept are discussed.

Serum immunoglobulin levels in the course of bacterial meningitis in children.

Serum levels of 5 immunoglobulins (IgG, IgA, IgM, IgD and IgE) were determined at frequent intervals in the course of bacterial meningitis in children. 59 patients were examined; 27 with Haemophilus influenzae meningitis, 23 with meningococcal and 9 with pneumococcal meningitis. All 5 immunoglobulins increased during the 2-week course of bacterial meningitis. IgM was the immunoglobulin class responding most rapidly, regularly and intensively. IgG increased moderately. However, practically no rise of the IgG level was observed in children with H. influenzae meningitis. The elevation of the IgA and IgE levels possibly suggests that meningitis may also cause synthesis of IgA and IgE antibodies. The results of the study indicate that antibodies of all the 5 immunoglobulin classes are probably involved in the defense against the causative microbes in bacterial meningitis.

Hapten-Specific IgE Antibody Responses in Mice

Abstract Mice of the inbred strains SJL (H-2s) and AKR (H-2k) are “non-responders” and “low-responders,” respectively, in terms of their capacity to develop antibody responses of the IgE class when immunized with conventional proteins and hapten-protein conjugates under conditions optimal for eliciting IgE responses in “high-responder” mice, such as BALB/c (H-2d), to these same antigens. For example, BALB/c mice preimmunized with ASC and then challenged 7 days later with DNP-ASC develop peak augmented primary IgE anti-DNP antibody responses of 320 PCA units, whereas SJL and AKR mice develop responses which are 16-fold and 4-fold lower, respectively. However, pretreatment of the latter two strains with appropriate doses of either x-irradiation (150 R), cyclophosphamide (100 mg/kg) or ALS (150 µl) before carrier-preimmunization strikingly enhances the magnitude of IgE antibody responses in such mice to levels as high as 64-fold above those of untreated control mice of the same strains. Evidence obtained in these experiments indicates that the capacity of such maneuvers to convert poor IgE responders to high responder status reflects elimination of nonantigen-specific suppressor T lymphocytes which are naturally present and normally function to suppress or “dampen” the IgE antibody response in a relatively selective manner. It appears that these cells modulate IgE responses by acting at least at two distinct points: 1) The most effective activity seems to be at the level of induction of carrier-specific helper T cells; 2) A second locus of inhibitory activity is more distal in the response, either impeding helper T cell-B cell cooperative interactions or suppressing B cell differentiation and/or function directly. Taken collectively, these observations demonstrate that the state of poor responsiveness of the SJL and AKR strains for the IgE antibody class is not a reflection of a genetic inability to develop IgE responses but rather a manifestation of a genetic capability to actively inhibit IgE antibody synthesis.

Immunology and microbiology in acute otitis media.

Various immunological parameters were measured in serum, middle ear fluid (MEF), and lymphocytes from peripheral blood and MEF of infants with acute otitis media due to S. pneumoniae or H. influenzae. Approximately half of 131 patients had IgE specific antibody to the infecting bacterium as determined by the indirect fluorescent antibody (IFA) technique. Seventy-one percent of these IgE positive patients had IgE specific antibody in the MEF. Total IgE concentration was found to be from an average of 1.5 to 3.0 times higher in the MEF when compared to the simultaneously drawn serum. In addition, antibody to pneumococcal capsular polysaccharides and to pneumococcal C-carbohydrate was demonstrated in the MEF by radioimmunoassay. When MEF specific antibody was compared to serum antibody it appeared that antibody to C-carbohydrate was more concentrated in the MEF. That this antibody was of the IgE class was suggested by IFA but not conclusively proven. Evidence exists that conditions for enhanced IgE synthesis is concomitantly associated with a decrease in T-cell activity. T-cell function in MEF derived lymphocytes as determined by rosette formation and by phytohemagglutinin (PHA) stimulation was approximately one-tenth that of the peripheral blood lymphocytes. However, that T-cells may participate in the immune response to polysaccharides was suggested by the observation that polysaccharide stimulated peripheral blood lymphocytes from infants immunized with octavalent pneumococcal capsular vaccine underwent protein synthesis two to three times that of the PHA stimulated cells. The clinical significance of this finding as well as the nature of the cell responsible for the increased protein synthesis remains to be established. It is hypothesized that acute otitis media results from local synthesis of bacteria specific IgE antibody which is enhanced by a paucity of local T-cell activity.