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The role of interleukin-4 in IgE and IgG subclass formation

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Conclusions

Over the last 5 years, three major new findings were made regarding the mechanism of regulation of IgE and IgG subclass antibody formation. First, it was shown that IL-4 induces B cells to secrete IgE, murine IgG1 and human IgG4 and that IFN-γ and IL-2 inhibit this effect. Second, it was found that cloned murine T helper cells can be divided into two types: Th1, secreting IL-2 and IFN-γ; and Th2, secreting IL-4 and IL-5. Third, murine mast cells, like Th2, secrete IL-4 and IL-5 but not IL-2 and IFN-γ. Soon after these in vitro data were obtained, direct and indirect evidence was obtained demonstrating that IL-4 and IFN-γ also act antagonistically on IgE formation in vivo. Collectively, this new information is a major breakthrough and demonstrates the important role of lymphokines in determining the Ig isotype secreted by B cells, particularly IgE and certain IgG subclasses. However, many aspects of IgE and IgG subclass regulation are not yet resolved and in particular, it is not clear what is abnormal in the lymphokine-regulated IgE antibody formation in atopic patients.

The questions regarding isotype regulation which are presently studied extensively in many laboratories are the following: what is the precise molecular mechanism of the switch from IgM to IgE or IgG subclass. In particular, what is the effect of IL-4 in the induction of the switch mechanism? Also, is IL-4 only affecting the IgM to IgE switch or is it also important in the differentiation of IgE-secreting cells as some in vitro experiments suggest? In the mouse, many experiments indicate that IgGl can be formed in vivo independently of IL-4 and this may also be the case for IgG4 in man. The strict linkage of IL-4-induced IgE and IgG1 in vitro does not always seem to occur in vivo.

A very important question: how do allergens or helminthic parasites selectively induce the apparent T helper cell and IL-4-dependent IgE and IgG4 antibody formation in man? It is unlikely that two lineages of T helper cells exist and that allergens and helminthic parasites interact only with the IL-4 producing Th2 cells. Instead, it appears that allergens and parasites affect the Th0 to Th2 differentiation through interaction with accessory cells or perhaps by a direct effect on B cells. The latter is suggested by the fact that not all polyclonal B cell activators prepare B cells to respond to IL-4 with IgE secretion. In the mouse, LPS is a far better B cell activator than PRP for IL-4-induced IgE secretion, whereas PRP is equal to LPS in IL-4-induced IgG1 formation. Another mechanism by which allergens and helminthic parasites could induce IgE formation is via mast cell activation. If these antigens “nonspecifically” activate mast cells to secrete IL-4, this IL-4 could induce the IgM to IgE switch and may also induce the Th0 to Th2 differentiation. Allergens presumably immunize the host via penetration of the skin and respiratory and gastrointestinal tract, anatomic sites which are rich in mast cells. Helminthic infections induce a large mastocytosis in the intestinal tract and GVHD which also induces polyclonal IgE formation, causes degranulation of the skin mast cells. These observations support the notion that mast cells may play a role in the IgE formation. Although highly speculative at this time, it is possible and worthwhile to test this interesting hypothesis.

Another unresolved question is: what is abnormal in the regulation of IgE antibody production in atopic patients? Do the patient's T helper cell produce too much IL-4 or not enough IFN-γ? Does IL-4 preferentially induce the IgM to IgE rather than IgM to IgG4 switch? These questions are being addressed experimentally at this time, however, no clear cut answers have been obtained.

Despite the many unresolved questions regarding the IL-4-dependent IgE-regulatory mechanism, the availability of purified lymphokines together with advanced methods in molecular and cell biology currently available will result in rapid progress of the understanding of the IgE and IgG subclass regulation both in normals and atopic patients. Furthermore, the new information is likely to lead to new therapeutic interventions that may normalize the IgE antibody formation in atopic patients. It should be possible to manufacture drugs, soluble IL-4 receptors or neutralizing monoclonal antibodies to IL-4 that down-regulate IL-4 effects and inhibit excess IgE antibody formation. Alternatively, enhancers of IFN-γ or IL-2 formation may become useful as new therapeutic agents for allergic disorders. Finally, mast cell stabilizers that prevent mast cells from forming IL-4 or that interfere with the postulated role of mast cells in the IgE antibody up-regulation may be developed. Although it is not possible to predict where these findings will lead us, future research on the role of cytokines in allergy is likely to bear fruit in the next decade.

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  1. Department of Pediatrics, Pediatric Immunology and Allergy Division/0609D, University of California, San Diego, School of Medicine, 92093-0609, La Jolla, CA, USA

    Hans L. Spiegelberg

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Spiegelberg, H.L. The role of interleukin-4 in IgE and IgG subclass formation. Springer Semin Immunopathol 12, 365–383 (1990). https://doi.org/10.1007/BF00225324

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