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The role of immunoglobulin E in allergy
J C&on Dis1971, Vol. 23, pp. 521-525.PergamonPress. Printed in Great Britain
Editorial
THE ROLE OF IMMUNOGLOBULIN
E IN ALLERGY
(Received 23 June 1970; is revised jbrm 23 July 1970)
ALLERGIC diseases are those hypersensitivity diseases which result from immunologic reactions. The immunologic systems which produce these reactions may be broadly divided into the immunoglobulin system which includes all circulating antibodies or the cellular or delayed-type hypersensitivity system; the latter mediated by lymphoid cells themselves. The types of allergic reactions due to circulating antibodies may be further subdivided into three categories. The first is immediate-type hypersensitivity. The second is the cytotoxic type of reaction in which cells are destroyed by antibody reacting with antigens on their surface. The third type of hypersensitivity disease results from complexes of antigen and antibody which are toxic to tissues or to cells by virtue of the ability of the complexes to fix complement and attract neutrophilic leukocytes. The result is an inflammatory reaction and a release of chemical substances, as yet poorly defined, which produces tissue damage. The first type of reaction is the one in which IgE is of major importance. This type of allergic reaction has come to be called immediate-type hypersensitivity because of the sudden onset of the clinical symptoms of the experimental reaction which distinguishes it from all other clinical immunologic hypersensitivity reactions The diseases associated with this type of reaction include the common allergic diseases of hay fever, asthma resulting from inhaled allergens, true food allergies and many, perhaps all, cases of human anaphylaxis. These diseases compose a large group of clinical problems in the general population. It was recognised many years ago that there were a variety of reasons for considering human allergic reactions of the immediate-type as being immunologic in nature. For example, the reactions were found to be specific-a person reacting to ragweed pollen, for example, is specifically reactive to that antigen (although he might have more than one specific hypersensitivity reaction). When it was found that this type of allergic reaction could be transferred with the serum of an allergic patient to the skin of another person (Prausnitz-Kiistner reaction) a whole new method of study was available. Using the technique of passive skin sensitization, a variety of studies indicated that the active factor present in the serum of allergic patients was an antibody. The term reaginic antibody was applied to the skin-sensitizing, heat labile protein in the serum of patients with immediate-type hypersensitivity. As new biochemical and immunologic techniques became available for the studies of antibodies, these were applied to the definition of reaginic antibody. Although the electrophoretic mobility 5'1
522
ROY PAITERSON
of this antibody and a few other characteristics were defined, the degree of definition that could be applied to other non-reaginic antibodies by use of quantitative measurements was not applicable for the study of reaginic antibody. This was because reaginic antibody is present in such low concentrations that it could not be measured by the techniques that were useful for other antibodies. Although studies of reaginic antibodies continued, their definition lagged behind that of other types of antibodies. A major advance occurred when the Ishizakas demonstrated in a series of studies that reaginic antibody could not be classified as IgA, IgG, IgM or IgD and therefore must exist in a separate immunoglobulin class which they termed IgE [l]. This immunoglobulin was isolated from human allergic serum and antiserum prepared against it. A variety of studies have confirmed that human reaginic antibody is in the IgE class. The most important further step was the discovery of a case of multiple myeloma in Sweden which was found to produce a myeloma protein of the IgE class. The availability of an IgE myeloma serum not only confirmed the presence of IgE but provided a much greater source of IgE. Since IgE is usually present in human sera in little more than trace amounts, the availability of myeloma IgE in large quantities provided a means of study of its molecular configuration and also produced the protein in such amounts that antibody useful for defining normal IgE could be prepared with greater ease. It is now accepted that the reaginic antibody which mediates immediate type allergy in man is localized to the E class of immunoglobulins. It is still not certain that all human reaginic antibody is in this class of immunoglobulin. There are some studies suggesting that human reaginic antibody in certain sera may exist in other immunoglobulin classes. Studies of reaginic antibodies in species other than man have indicated the presence of reaginic antibodies of more than one type and in different immunoglobulin classes and it is not unlikely that an analogous situation will finally be defined in man. For example, induced reaginic antibody due to penicillin and other injected antigens which in some cases is transient in nature may, in some patients, reside in a class of immunoglobulin other than IgE. In a limited series however it was shown that induced antibody in diabetic subjects against insulin was an IgE type of immunoglobulin. Immediate-type allergy in animals other than man has been shown to be related to chronic clinical disease in only one other species. This clinical allergic problem occurs in dogs which may have cutaneous, ocular and respiratory disease due to immediatetype allergy. It has been shown that those canine reaginic sera which have been studied sufficiently have been localized to an immunoglobulin class which is considered to be analagous to human IgE. Spontaneous allergic disease of the immediate-type has not been described in primates other than man. That is, no case of pollen allergy or extrinsic asthma has been described or studied in any monkey. IgE mediated reactions can, however, be transferred to monkeys and provide very interesting animal models of immediate-type allergy. The reactions transferred from man to monkey include cutaneous reactions, respiratory reactions and anaphylaxis. Equally important are the in vitro lung reactions in which primate lung is sensitizied with human IgE and then reacted with the specific antigen. The mediator release from the sensitized lung can be measured and is a new and important immunopharmacologic tool.
The Role of Immunoglobulin
E in Allergy
51.3
A technique of great potential for studies of immediate-type hypersensitivity in monkeys has resulted from the observation that antiserum against human IgE will cross react with monkey IgE. This demonstrates that IgE occurs in monkeys and provides a system for studying reactions in the skin and lung of monkeys by means of reverse passive cutaneous anaphylaxis. Finally, an active system of immediate-type hypersensitivity in rhesus monkeys has been defined. This is an animal model using monkeys sensitive to parasites. The animals have IgE antibody against ascaris antigens and a spectrum of reactions ranging from cutaneous through respiratory responses appear analagous to the human counterpart. These reactions can be reproduced for the study of the immunology, pathology and pharmacology of the immediatetype responses in primates. The structure of the IgE molecule is particularly interesting since its structure appears related to its biologic function. IgE is a larger molecule than IgG, with IgE having a molecular weight of 200,000 and JgG having a molecular weight of 150,000. The difference in the two molecules lies in the longer heavy chain of the IgE molecule and this greater length occurs in the portion of the heavy chain called the Fc region. A diagram of the basic structure of the immunoglobulin molecule is shown in Fig. 1. PAPAIN
CLEAVES
PEPSIN CLEAVES LIGHT
CHAIN
HEAVY
CHAIN
HEAVY
CHAIN
LIGHT
CHAIN
F tab’& Fro. 1.
FRAGMENT
Basic structure of an immunoglobulin monomeric molecule. The antigen combining sites are located on the left. Papain and pepsin cleave the molecule in different sites.+
The Fc region is the portion of the antibody molecule which does not contain the antigen combining sites. The Fc portion of the IgG molecule appears to be that portion of the molecule which fixes to the surface of the receptor cell. The receptor cell is the biologically active cell which releases the mediators leading to the changes in the effector tissues in the immediate-type response. These tissues may be the smooth muscle which responds with contraction and the vascular system which responds with vasodilation and increased capillary permeability. IgE is produced in plasma cells of lymph nodes. This has been shown to occur in lymph nodes in the respiratory tract. From these lymph nodes and possibly from nodes *From Advances in Internal Medicine, Voi 16. Edited by Gene H Stollerrnan. Copyright Book Medical Publishers, Inc. Used by permission.
1970, Year
524
ROY PATTERSON
in other sites, IgE is released for local sensitization of tissues and IgE also reaches the vascular system since it is detected in the blood of all normal humans, IgE is a cytotrophic molecule. It has the ability to fix to the surface of cells, probably in a highly selective reaction involving only certain cells with specific receptor sites. It is established that IgE is basophilotrophic and from consideration of work in other species it is almost certainly mast cell sensitizing although the experimental confirmation of this in primates has not yet been accomplished. Thus, the immediate-type hypersensitivity reaction can be visualized as the combination of the antigen with reaginic (IgE) antibody molecules which are fixed on the surface of the mast cell or basophil. The reaction of antigen with the antibody initiates the intracellular events which result in the release of the biologically active chemicals from the granules of the sensitized cells. The studies of IgE concentrations in human subjects with allergic disease and in normal subjects have already provided useful information. IgE concentrations during childhood rise slowly, similarly to IgA. The highest levels are found between 20 and 30 yr of age. Markedly elevated levels of IgE have been associated with parasitic infestations. They are often high in extrinisc bronchial asthma but generally normal in intrinsic asthma. IgE is often normal in hay fever but higher levels have been observed after the hay fever season. IgE levels are often very high in atopic dermatitis. This is curious since reaginic antibody appears to play little role in a majority of the patients with this disease. Elimination of relevant antigens results in a decline in IgE. The type of studies outlined above should provide the type of information which will help unravel the many aspects of reaginic allergy which have been so confusing for so many years. A variety of other aspects of IgE could be discussed, such as the possible useful biological role of IgE which has not been established and is currently only speculative. Another important topic concerns the potential analogues of IgE in rodents since the definition of IgE in species other than man and particularly in inbred laboratory animals is certain to help clarify the immunologic aspects of IgE in man. Previously advances in understanding of immediate-type hypersensitivity have progressed slowly because of real problems in analyzing the basic immunology of these reactions. This has been reflected in the slowness of progress of clinical therapy. More rapid advances can now be expected in both basic and applied aspects of immediate-type allergy. Potential new therapeutic measures might result from one of several approaches. These include such possibilities as the specific inhibition of IgE induction. It might be possible to inhibit the mastocytotrophic action of IgE by specific synthetic fragmentswhich could inhibit the attachment of IgE to cell surfaces. It is quite possible that other inhibitors of mast cell systems, similar to the action proposed for disodium cromoglycate, will be developed, and methods such as these alone, or in combination may significantly alter current methods of management of IgE mediated allergic disease. ROY PATTERSON, M.D. Prqfessor of Medicine and Chief Allergy/Immunology Northwestern University Medical SchoolMcGaw Medical Center, Chicago, Illinois 60611
The Role of Immunoglobulin
I. 2. 3.
E in Allergy
525
REFERENCES Ishizaka K, Ishizaka T: Biologic function of yE antibodies and mechanisms of reaginic hypersensitivity. CIin Exp Tmmun 6: 2542, 1970 Johansson SGO, Bennich H, Berg T, et al: Some factors influencing the serum IgE levels in atopic disease. Clin Exp Immun 6: 43-47, 1970 Patterson R: Laboratory models of reaginic allergy. Progr Allerg, Vol XIII. Kailos P and Waksman BH (Eds). Base], Karger S, 1969
Editorial
THE ROLE OF IMMUNOGLOBULIN
E IN ALLERGY
(Received 23 June 1970; is revised jbrm 23 July 1970)
ALLERGIC diseases are those hypersensitivity diseases which result from immunologic reactions. The immunologic systems which produce these reactions may be broadly divided into the immunoglobulin system which includes all circulating antibodies or the cellular or delayed-type hypersensitivity system; the latter mediated by lymphoid cells themselves. The types of allergic reactions due to circulating antibodies may be further subdivided into three categories. The first is immediate-type hypersensitivity. The second is the cytotoxic type of reaction in which cells are destroyed by antibody reacting with antigens on their surface. The third type of hypersensitivity disease results from complexes of antigen and antibody which are toxic to tissues or to cells by virtue of the ability of the complexes to fix complement and attract neutrophilic leukocytes. The result is an inflammatory reaction and a release of chemical substances, as yet poorly defined, which produces tissue damage. The first type of reaction is the one in which IgE is of major importance. This type of allergic reaction has come to be called immediate-type hypersensitivity because of the sudden onset of the clinical symptoms of the experimental reaction which distinguishes it from all other clinical immunologic hypersensitivity reactions The diseases associated with this type of reaction include the common allergic diseases of hay fever, asthma resulting from inhaled allergens, true food allergies and many, perhaps all, cases of human anaphylaxis. These diseases compose a large group of clinical problems in the general population. It was recognised many years ago that there were a variety of reasons for considering human allergic reactions of the immediate-type as being immunologic in nature. For example, the reactions were found to be specific-a person reacting to ragweed pollen, for example, is specifically reactive to that antigen (although he might have more than one specific hypersensitivity reaction). When it was found that this type of allergic reaction could be transferred with the serum of an allergic patient to the skin of another person (Prausnitz-Kiistner reaction) a whole new method of study was available. Using the technique of passive skin sensitization, a variety of studies indicated that the active factor present in the serum of allergic patients was an antibody. The term reaginic antibody was applied to the skin-sensitizing, heat labile protein in the serum of patients with immediate-type hypersensitivity. As new biochemical and immunologic techniques became available for the studies of antibodies, these were applied to the definition of reaginic antibody. Although the electrophoretic mobility 5'1
522
ROY PAITERSON
of this antibody and a few other characteristics were defined, the degree of definition that could be applied to other non-reaginic antibodies by use of quantitative measurements was not applicable for the study of reaginic antibody. This was because reaginic antibody is present in such low concentrations that it could not be measured by the techniques that were useful for other antibodies. Although studies of reaginic antibodies continued, their definition lagged behind that of other types of antibodies. A major advance occurred when the Ishizakas demonstrated in a series of studies that reaginic antibody could not be classified as IgA, IgG, IgM or IgD and therefore must exist in a separate immunoglobulin class which they termed IgE [l]. This immunoglobulin was isolated from human allergic serum and antiserum prepared against it. A variety of studies have confirmed that human reaginic antibody is in the IgE class. The most important further step was the discovery of a case of multiple myeloma in Sweden which was found to produce a myeloma protein of the IgE class. The availability of an IgE myeloma serum not only confirmed the presence of IgE but provided a much greater source of IgE. Since IgE is usually present in human sera in little more than trace amounts, the availability of myeloma IgE in large quantities provided a means of study of its molecular configuration and also produced the protein in such amounts that antibody useful for defining normal IgE could be prepared with greater ease. It is now accepted that the reaginic antibody which mediates immediate type allergy in man is localized to the E class of immunoglobulins. It is still not certain that all human reaginic antibody is in this class of immunoglobulin. There are some studies suggesting that human reaginic antibody in certain sera may exist in other immunoglobulin classes. Studies of reaginic antibodies in species other than man have indicated the presence of reaginic antibodies of more than one type and in different immunoglobulin classes and it is not unlikely that an analogous situation will finally be defined in man. For example, induced reaginic antibody due to penicillin and other injected antigens which in some cases is transient in nature may, in some patients, reside in a class of immunoglobulin other than IgE. In a limited series however it was shown that induced antibody in diabetic subjects against insulin was an IgE type of immunoglobulin. Immediate-type allergy in animals other than man has been shown to be related to chronic clinical disease in only one other species. This clinical allergic problem occurs in dogs which may have cutaneous, ocular and respiratory disease due to immediatetype allergy. It has been shown that those canine reaginic sera which have been studied sufficiently have been localized to an immunoglobulin class which is considered to be analagous to human IgE. Spontaneous allergic disease of the immediate-type has not been described in primates other than man. That is, no case of pollen allergy or extrinsic asthma has been described or studied in any monkey. IgE mediated reactions can, however, be transferred to monkeys and provide very interesting animal models of immediate-type allergy. The reactions transferred from man to monkey include cutaneous reactions, respiratory reactions and anaphylaxis. Equally important are the in vitro lung reactions in which primate lung is sensitizied with human IgE and then reacted with the specific antigen. The mediator release from the sensitized lung can be measured and is a new and important immunopharmacologic tool.
The Role of Immunoglobulin
E in Allergy
51.3
A technique of great potential for studies of immediate-type hypersensitivity in monkeys has resulted from the observation that antiserum against human IgE will cross react with monkey IgE. This demonstrates that IgE occurs in monkeys and provides a system for studying reactions in the skin and lung of monkeys by means of reverse passive cutaneous anaphylaxis. Finally, an active system of immediate-type hypersensitivity in rhesus monkeys has been defined. This is an animal model using monkeys sensitive to parasites. The animals have IgE antibody against ascaris antigens and a spectrum of reactions ranging from cutaneous through respiratory responses appear analagous to the human counterpart. These reactions can be reproduced for the study of the immunology, pathology and pharmacology of the immediatetype responses in primates. The structure of the IgE molecule is particularly interesting since its structure appears related to its biologic function. IgE is a larger molecule than IgG, with IgE having a molecular weight of 200,000 and JgG having a molecular weight of 150,000. The difference in the two molecules lies in the longer heavy chain of the IgE molecule and this greater length occurs in the portion of the heavy chain called the Fc region. A diagram of the basic structure of the immunoglobulin molecule is shown in Fig. 1. PAPAIN
CLEAVES
PEPSIN CLEAVES LIGHT
CHAIN
HEAVY
CHAIN
HEAVY
CHAIN
LIGHT
CHAIN
F tab’& Fro. 1.
FRAGMENT
Basic structure of an immunoglobulin monomeric molecule. The antigen combining sites are located on the left. Papain and pepsin cleave the molecule in different sites.+
The Fc region is the portion of the antibody molecule which does not contain the antigen combining sites. The Fc portion of the IgG molecule appears to be that portion of the molecule which fixes to the surface of the receptor cell. The receptor cell is the biologically active cell which releases the mediators leading to the changes in the effector tissues in the immediate-type response. These tissues may be the smooth muscle which responds with contraction and the vascular system which responds with vasodilation and increased capillary permeability. IgE is produced in plasma cells of lymph nodes. This has been shown to occur in lymph nodes in the respiratory tract. From these lymph nodes and possibly from nodes *From Advances in Internal Medicine, Voi 16. Edited by Gene H Stollerrnan. Copyright Book Medical Publishers, Inc. Used by permission.
1970, Year
524
ROY PATTERSON
in other sites, IgE is released for local sensitization of tissues and IgE also reaches the vascular system since it is detected in the blood of all normal humans, IgE is a cytotrophic molecule. It has the ability to fix to the surface of cells, probably in a highly selective reaction involving only certain cells with specific receptor sites. It is established that IgE is basophilotrophic and from consideration of work in other species it is almost certainly mast cell sensitizing although the experimental confirmation of this in primates has not yet been accomplished. Thus, the immediate-type hypersensitivity reaction can be visualized as the combination of the antigen with reaginic (IgE) antibody molecules which are fixed on the surface of the mast cell or basophil. The reaction of antigen with the antibody initiates the intracellular events which result in the release of the biologically active chemicals from the granules of the sensitized cells. The studies of IgE concentrations in human subjects with allergic disease and in normal subjects have already provided useful information. IgE concentrations during childhood rise slowly, similarly to IgA. The highest levels are found between 20 and 30 yr of age. Markedly elevated levels of IgE have been associated with parasitic infestations. They are often high in extrinisc bronchial asthma but generally normal in intrinsic asthma. IgE is often normal in hay fever but higher levels have been observed after the hay fever season. IgE levels are often very high in atopic dermatitis. This is curious since reaginic antibody appears to play little role in a majority of the patients with this disease. Elimination of relevant antigens results in a decline in IgE. The type of studies outlined above should provide the type of information which will help unravel the many aspects of reaginic allergy which have been so confusing for so many years. A variety of other aspects of IgE could be discussed, such as the possible useful biological role of IgE which has not been established and is currently only speculative. Another important topic concerns the potential analogues of IgE in rodents since the definition of IgE in species other than man and particularly in inbred laboratory animals is certain to help clarify the immunologic aspects of IgE in man. Previously advances in understanding of immediate-type hypersensitivity have progressed slowly because of real problems in analyzing the basic immunology of these reactions. This has been reflected in the slowness of progress of clinical therapy. More rapid advances can now be expected in both basic and applied aspects of immediate-type allergy. Potential new therapeutic measures might result from one of several approaches. These include such possibilities as the specific inhibition of IgE induction. It might be possible to inhibit the mastocytotrophic action of IgE by specific synthetic fragmentswhich could inhibit the attachment of IgE to cell surfaces. It is quite possible that other inhibitors of mast cell systems, similar to the action proposed for disodium cromoglycate, will be developed, and methods such as these alone, or in combination may significantly alter current methods of management of IgE mediated allergic disease. ROY PATTERSON, M.D. Prqfessor of Medicine and Chief Allergy/Immunology Northwestern University Medical SchoolMcGaw Medical Center, Chicago, Illinois 60611
The Role of Immunoglobulin
I. 2. 3.
E in Allergy
525
REFERENCES Ishizaka K, Ishizaka T: Biologic function of yE antibodies and mechanisms of reaginic hypersensitivity. CIin Exp Tmmun 6: 2542, 1970 Johansson SGO, Bennich H, Berg T, et al: Some factors influencing the serum IgE levels in atopic disease. Clin Exp Immun 6: 43-47, 1970 Patterson R: Laboratory models of reaginic allergy. Progr Allerg, Vol XIII. Kailos P and Waksman BH (Eds). Base], Karger S, 1969