- Email: [email protected]
IgE, Parasites, and Allergy
894
IgE, Parasites,
and
Allergy
PARASITE antigens are a potent stimulus for induction of antiparasite antibodies of the IgE class, and parasite infection can potentiate a pre-exist-
ing IgE antibody response to an unrelated antigen. IgE is also implicated in many allergic diseases and so it is logical to seek a connection between such diseases and parasite infections. An obvious approach was to investigate patients with diseases such as asthma for evidence of parasite infection, but a surprising report from Canada1 that 99% of asthmatic patients harboured parasites has not been confirmed .2On the contrary, there is evidence for an inverse relation between parasites and allergy: asthma and hayfever are rare in parts of the world where the population is heavily parasitised,suggesting that some factor associated with parasite infection may block or inactivate immediate-hypersensitivity reactions. A mast cell degranulates when the IgE antibodies fixed to its surface interact with antigen. Although there are some 100 000 IgE-binding sites on each mast cel1,5 in-vitro and in-vivo experiments have shown that high concentrations of IgE can saturate the receptors so as to prevent binding of other IgE molecules when these are presented to the mast cell some time later. Most in-vivo studies have been based on passive dermal sensitisationskin is passively sensitised by injection of serum which contains IgE antibodies; the antibodies attach themselves to skin mast cells; and, later, injection of antigen into the same site produces a weal-and-flare reaction. Patients with the exceptionally rare disease, IgE myeloma, have mast cells which are completely saturated with myeloma immunoglobulin, so that passive sensitisation cannot be induced.6When myeloma IgE is injected into the skin of normal subjects before attempted passive skin sensitisation, the myeloma IgE competes for mast-cell binding sites with the specific reaginic antibody, so that with appropriate doses of myeloma IgE passive sensitisation can be completely abolished.Passive skin sensitisation is hard to produce in parasitised individuals who have high levels of circulating IgE,8 and the same is true for rats in experiments employing reaginic antibodies to two antigens.9 When an animal is producing high titres of IgE antibody to one antigen, passive sensitisation to the second unrelated antigen is inhibited. In unimmunised animals, simultaneous injection of two unrelated reagins will reduce the Tullis, D. C. H. New Engl. J. Med. 1970, 282, 370. van Dellen, R. G., Thompson, J. H. ibid. 1971, 285, 146. Jarrett, E. E. E., Kerr, J. W. Clin. Allergy, 1973, 3, 203. Godfrey, R. C. ibid. 1975, 5, 201. 5. Ishizaka, T., Soto, C. S., Ishizaka, K. J. Immun. 1973, 111, 500. 6. Ogawa, M., McIntyre, R., Ishizaka, K., Ishizaka, T., Terry, W. D., Waldman, T. A. Am. J. Med. 1971, 51, 193. 7. Stanworth, D. R., Humphrey, J. H., Bennich, H., Johansson, S. G. O. Lancet, 1967, ii, 330. 8. Bazarel, M., Orgel, H. A., Hamburger, R. N. Clin. exp. Immun. 1973, 14,
1. 2. 3. 4.
117.
reaction of passive cutaneous anaphylaxis to one of the antigens concerned.9 A suitable model for investigation of events related to mast-cell binding and competition for mast-cell sites is provided by passive sensitisation of human lung fragments. On incubation with IgE antibodies, the mast cells of lung fragments become sensitised and will release histamine on subsequent contact with the appropriate antigen. GODFREY and GRADIDGE 10 now report that if chopped lung frag. ments are first incubated with a serum from West African subjects (with high levels of total serum IgE) mast-cell sensitisation is blocked. The time sequence proved to be critical, for the high-IgE serum could not displace IgE antibodies which had already become attached to the mast cells.10 These observations have a number of clinical implications. Although total serum-IgE may be high in some patients with allergy, the severity of the disease does not parallel the serum-IgE concentration, Certainly, the cytophilic IgE on the membranes of tissue mast cells can rarely be detected or measured in the laboratory. However, intradermal or prick skin-tests can be and are used extensively for this purpose. Yet skin-tests may occasionally be negative in a person who, when tested by direct provocation, is quite clearly allergic to the antigen concerned. In such patients it is likely that a high concentration of circulating IgE, due to parasites, allergy, or even myeloma, has caused the skin-test to be negative because specific IgE molecules are sparsely distributed on the relevant mast cells. Since IgE itself can modulate the severity of a hypersensitivity reaction due to antibodies of its own class, one theoretical approach to prevention or treatment of allergic diseases would be deliberately to induce high IgE responsiveness-for example, by artificial infection with parasites. Continuing stimulation of IgE by parasite infection was probably the norm for the human race until the past few centuries, and allergic diseases may be the price man has had to pay for increasing hygiene in an environment abounding in highly allergenic materials.
...
AND A PHARMACOLOGICAL APPROACH
ANOTHER possible way of blocking IgE receptors was discussed at the second Charles Blackley Symposium organised in Nottingham by that enterprising body, the Midlands Asthma and Allergy Association-namely, to identify a pharmacological compound with the property of blocking these receptors. Binding of IgE to its receptor occurs via the Fc region of the immunoglobulin molecule, and complement is not required for this bind9. Jarrett, E. E. E., Orr, T. S. C., Riley, P. ibid. 1971, 9, 585. 10. Godfrey, R. C., Gradidge, C. F. Nature, 1976, 259, 484.
IgE, Parasites,
and
Allergy
PARASITE antigens are a potent stimulus for induction of antiparasite antibodies of the IgE class, and parasite infection can potentiate a pre-exist-
ing IgE antibody response to an unrelated antigen. IgE is also implicated in many allergic diseases and so it is logical to seek a connection between such diseases and parasite infections. An obvious approach was to investigate patients with diseases such as asthma for evidence of parasite infection, but a surprising report from Canada1 that 99% of asthmatic patients harboured parasites has not been confirmed .2On the contrary, there is evidence for an inverse relation between parasites and allergy: asthma and hayfever are rare in parts of the world where the population is heavily parasitised,suggesting that some factor associated with parasite infection may block or inactivate immediate-hypersensitivity reactions. A mast cell degranulates when the IgE antibodies fixed to its surface interact with antigen. Although there are some 100 000 IgE-binding sites on each mast cel1,5 in-vitro and in-vivo experiments have shown that high concentrations of IgE can saturate the receptors so as to prevent binding of other IgE molecules when these are presented to the mast cell some time later. Most in-vivo studies have been based on passive dermal sensitisationskin is passively sensitised by injection of serum which contains IgE antibodies; the antibodies attach themselves to skin mast cells; and, later, injection of antigen into the same site produces a weal-and-flare reaction. Patients with the exceptionally rare disease, IgE myeloma, have mast cells which are completely saturated with myeloma immunoglobulin, so that passive sensitisation cannot be induced.6When myeloma IgE is injected into the skin of normal subjects before attempted passive skin sensitisation, the myeloma IgE competes for mast-cell binding sites with the specific reaginic antibody, so that with appropriate doses of myeloma IgE passive sensitisation can be completely abolished.Passive skin sensitisation is hard to produce in parasitised individuals who have high levels of circulating IgE,8 and the same is true for rats in experiments employing reaginic antibodies to two antigens.9 When an animal is producing high titres of IgE antibody to one antigen, passive sensitisation to the second unrelated antigen is inhibited. In unimmunised animals, simultaneous injection of two unrelated reagins will reduce the Tullis, D. C. H. New Engl. J. Med. 1970, 282, 370. van Dellen, R. G., Thompson, J. H. ibid. 1971, 285, 146. Jarrett, E. E. E., Kerr, J. W. Clin. Allergy, 1973, 3, 203. Godfrey, R. C. ibid. 1975, 5, 201. 5. Ishizaka, T., Soto, C. S., Ishizaka, K. J. Immun. 1973, 111, 500. 6. Ogawa, M., McIntyre, R., Ishizaka, K., Ishizaka, T., Terry, W. D., Waldman, T. A. Am. J. Med. 1971, 51, 193. 7. Stanworth, D. R., Humphrey, J. H., Bennich, H., Johansson, S. G. O. Lancet, 1967, ii, 330. 8. Bazarel, M., Orgel, H. A., Hamburger, R. N. Clin. exp. Immun. 1973, 14,
1. 2. 3. 4.
117.
reaction of passive cutaneous anaphylaxis to one of the antigens concerned.9 A suitable model for investigation of events related to mast-cell binding and competition for mast-cell sites is provided by passive sensitisation of human lung fragments. On incubation with IgE antibodies, the mast cells of lung fragments become sensitised and will release histamine on subsequent contact with the appropriate antigen. GODFREY and GRADIDGE 10 now report that if chopped lung frag. ments are first incubated with a serum from West African subjects (with high levels of total serum IgE) mast-cell sensitisation is blocked. The time sequence proved to be critical, for the high-IgE serum could not displace IgE antibodies which had already become attached to the mast cells.10 These observations have a number of clinical implications. Although total serum-IgE may be high in some patients with allergy, the severity of the disease does not parallel the serum-IgE concentration, Certainly, the cytophilic IgE on the membranes of tissue mast cells can rarely be detected or measured in the laboratory. However, intradermal or prick skin-tests can be and are used extensively for this purpose. Yet skin-tests may occasionally be negative in a person who, when tested by direct provocation, is quite clearly allergic to the antigen concerned. In such patients it is likely that a high concentration of circulating IgE, due to parasites, allergy, or even myeloma, has caused the skin-test to be negative because specific IgE molecules are sparsely distributed on the relevant mast cells. Since IgE itself can modulate the severity of a hypersensitivity reaction due to antibodies of its own class, one theoretical approach to prevention or treatment of allergic diseases would be deliberately to induce high IgE responsiveness-for example, by artificial infection with parasites. Continuing stimulation of IgE by parasite infection was probably the norm for the human race until the past few centuries, and allergic diseases may be the price man has had to pay for increasing hygiene in an environment abounding in highly allergenic materials.
...
AND A PHARMACOLOGICAL APPROACH
ANOTHER possible way of blocking IgE receptors was discussed at the second Charles Blackley Symposium organised in Nottingham by that enterprising body, the Midlands Asthma and Allergy Association-namely, to identify a pharmacological compound with the property of blocking these receptors. Binding of IgE to its receptor occurs via the Fc region of the immunoglobulin molecule, and complement is not required for this bind9. Jarrett, E. E. E., Orr, T. S. C., Riley, P. ibid. 1971, 9, 585. 10. Godfrey, R. C., Gradidge, C. F. Nature, 1976, 259, 484.