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Complement receptors and histamine degradation
THE JOURNAL
OF
ALLERGY AND
CLINICAL
IMMUNOLOGY
VOLUME 66
NUMBER 4
Editorial Complement degradation Michael
receptors
and histamine
M. Frank, M.D. Bethesda, Md.
In years gone by, the knowledgeable allergist was required to understand the clinical expression of hypersensitivity states, the situations in which those hypersensitivities might be expressed, and the useful therapeutic modalities available to alter their expression. The pathophysiologic events that led to the clinical manifestations of disease were mercifully surrounded by mystery. With the passage of time those mysteries have been examined, one by one, in the light of modem, rigorous, scientific methodologies. Principles of cellular function as identified by biochemists, pharmacologists, cell biologists, and a host of modern investigators are gradually allowing us to understand the delicate homeostatic balance in normal individuals. This in turn allows us to frame complex questions about what happens in abnormal clinical states. The paper by Herman and Colten is an excellent example of the transformation that this field is now experiencing. ’ At first glance the paper deals with an observation in cell biology and biochemistry; a factor is shown to regulate the biologic function of one of the complex series of surface receptors that one cell type possesses. Why is this important, and why publish it in THE JOURNAL OF ALLERGY AND CLINICAL From the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Reprint requeststo: Michael M. Frank, M.D., Clinical Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20205.
IMMUNOLOGY? Let us examine that question a bit
more carefully. The triggering of surface receptors appears to be critical in determining the way cells behave and the way they regulate complex biologic phenomena. The biochemical response under study is the release of granule-associated histaminase, one enzyme that is thought to play a major role in the degradation of histamine.’ The point of the paper is that one of the metabolic products of histamine degradation, imidazole acetic acid, modulates the amount of the enzyme that is released when the receptor is stimulated. The control is quite specific, since other indices of cell function are unaltered by this regulatory stimulus. In this case the cell is the neutrophil and the stimulus for histaminase release is the engaging of the C3b receptor by an opsonized particle. It is interaction with the receptor that is critical. Phagocytosis of the opsonized particle can be blocked by cytochalasin B and the effect on histaminase release is still observed. Thus, triggering of the C3b receptor can potentially regulate certain facets of the hypersensitivity response. What is the C3b receptor and what do we know of its function? The receptor is a trypsin-sensitive glycoprotein present in the membrane of all phagocytic cells, as well as certain other cell types, that recognizes the major cleavage fragment of C3, C3b.” This fragment, composed of the entire /3 chain and most of the (Y chain of C3, is deposited on particles or on immune complexes during complement activation. It serves as a major opsonin, allowing the opsonized Vol. 66, No. 4, pp. 267-268
268 Frank
particle to attach to the surface membrane of the phagocytic cell, thus aiding phagocytosis. In many of the systems that have been examined in detail, the binding of a particle coated with C3b alone to a phagocytic cell is an insufficient stimulus for phagocytosis. For ingestion to proceed the phagocytic cell needs a second signal. Such a second signal can be provided by the interaction of particle-bound IgG with the cellular Fc receptor. The C3b receptor has been purified recently and has been shown by Fearon to be a multisubunit glycoprotein of 1.2 x lo6 daltons.4 It appears that the same protein is present on the surface of all cells with C3b receptors. In man this includes neutrophils, macrophages, most B lymphocytes, and erythrocytes. In some cells such as erythrocytes, the function of the receptor is totally unknown. It has been suggested recently that triggering the C3b receptor of neutrophils with particle-bound C3b stimulates superoxide generation even in the absence of phagocytosis, and it is of interest that such was not found to be the case in the present study.5 When C3 is cleaved to C3b by immunologic or enzymatic reactions, another small fragment of C3, C3a, is released. Importantly, this fragment causes mast cells to degranulate and release their content of pharmacologic mediators. As every reader knows, immunologic reactions are often the initiating factors in mast cell degranulation and histamine release. The release of histamine has potent local effects. The local vasculature is affected and there is local hyperemia and edema formation. Histamine is reported to be chemotactic for eosinophils and there is accumulation of these cells.6 Moreover, histamine appears to be an important regulator of cellular function. As an immunoregulatory substance it regulates suppressor T cell activity via interaction with specific H-2 receptors.’ The control of tissue histamine, once released, is of obvious importance and multiple mechanisms of degradation are expected to be icvolved. There are at least two major pathways of histamine degradation in man-that mediated by histaminase and that mediated by histamine methyl transferase.2 Histaminase activity appears to be associated with the granule fraction of certain cells, including the neutrophil. Histamine methyl transferase may be found in the cytoplasm of certain cells, such as that of the monocyte, but may also be present in tissue fluids. At present it is believed that most tissue histamine is degraded via the histamine methyl transferase pathway; however, the precise contribution of either pathway to histamine degradation in an allergic reaction site is unknown. Thus, in an immunologic reaction in the tissues that involves the formation of immune complexes, the mast cells may degranulate either through an IgE-
J. ALLERGY
CLIN. IMMUNOL. OCTOBER 1980
dependent release mechanism or through the formation of anaphylatoxic fragments released via the complement-activation sequence. The released histamine would have potent local regulatory and vascular effects. At the same time that the histamine is released, chemotactic factors for neutrophils are formed via the immune complex-mediated complement-activation sequence and there is local accumulation of neutrophils. Interaction of complementcoated immune complexes or opsonized particles with C3b receptors on neutrophils leads to histaminase release, histamine degradation, and ultimate suppression of the local response. Moreover, the products of histamine degradation (imidazole acetic acid) may also regulate the release of histaminase and the rate of destruction of histamine. This is obviously a highly complex and exquisitely regulated response. Thus, we can rnake a case that the process is of interest and probably of importance to students of the allergic response. One reason for presenting this type of biochemical and cellular detail in the JOURNAL is to acquaint the readership with the direction of a field and with the type of technologies presently available. All one has to do is examine the incredible range of the materials and methods section of this paper to see what a single modern, sophisticated laboratory can do. This paper has not explained all of the details of how tissue and blood histamine Ievels are controlled. It has not even approached attempting to determine whether this control is awry in certain disease states. However, it should be clear that this type of approach and this type of methodology will have greater and greater impact on the clinical allergist. REFERENCES
1. Herman JJ, Colten HR: Specific modulation of complementdependent human granulocyte function by imidazole acetic acid.J ALLERGY CLIN IMMUNOL 66274, 1980. 2. Beaven MA: Histamine. New Engl J Med 294:30; 295320. 3. Bianco C: Plasma membranereceptors for complement: Comprehensiveimmunology, vol. 2, in Day NK, Good RA, editors: Biological amplification systems in immunology. New York, 1977, Plenum Medical Book Co., pp. 69-84. 4. Fearon DT: Regulation of the amplification C3 convertase of human complement by an inhibitory protein isolated from human erythrocyte membrane. Proc Nat1 Acad Sci USA 76:5867, 1979. 5. Goldstein IM, Kaplan HB, Radin A, Frosch M: Independent effects of IgG and complementupon human polymorphonuclear leukocyte function. J Immunol 117:1282, 1976. 6. Clark RAF, Gallin JI, Kaplan AP: The selective eosinophil chemotacticactivity of histamine. J Exp Med 142:1462, 1975. 7. Plaut M, Lichtenstein LM, Henney CS: Propertiesof a subpopulation of T cells bearing histamine receptors. J Clin Invest 55:856, 1975. 8. Wang SR, Zweiman B: Histamine suppressionof human lymphocyte responsesto mitogens. Cell Immunol 36:28, 1976.
OF
ALLERGY AND
CLINICAL
IMMUNOLOGY
VOLUME 66
NUMBER 4
Editorial Complement degradation Michael
receptors
and histamine
M. Frank, M.D. Bethesda, Md.
In years gone by, the knowledgeable allergist was required to understand the clinical expression of hypersensitivity states, the situations in which those hypersensitivities might be expressed, and the useful therapeutic modalities available to alter their expression. The pathophysiologic events that led to the clinical manifestations of disease were mercifully surrounded by mystery. With the passage of time those mysteries have been examined, one by one, in the light of modem, rigorous, scientific methodologies. Principles of cellular function as identified by biochemists, pharmacologists, cell biologists, and a host of modern investigators are gradually allowing us to understand the delicate homeostatic balance in normal individuals. This in turn allows us to frame complex questions about what happens in abnormal clinical states. The paper by Herman and Colten is an excellent example of the transformation that this field is now experiencing. ’ At first glance the paper deals with an observation in cell biology and biochemistry; a factor is shown to regulate the biologic function of one of the complex series of surface receptors that one cell type possesses. Why is this important, and why publish it in THE JOURNAL OF ALLERGY AND CLINICAL From the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Reprint requeststo: Michael M. Frank, M.D., Clinical Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20205.
IMMUNOLOGY? Let us examine that question a bit
more carefully. The triggering of surface receptors appears to be critical in determining the way cells behave and the way they regulate complex biologic phenomena. The biochemical response under study is the release of granule-associated histaminase, one enzyme that is thought to play a major role in the degradation of histamine.’ The point of the paper is that one of the metabolic products of histamine degradation, imidazole acetic acid, modulates the amount of the enzyme that is released when the receptor is stimulated. The control is quite specific, since other indices of cell function are unaltered by this regulatory stimulus. In this case the cell is the neutrophil and the stimulus for histaminase release is the engaging of the C3b receptor by an opsonized particle. It is interaction with the receptor that is critical. Phagocytosis of the opsonized particle can be blocked by cytochalasin B and the effect on histaminase release is still observed. Thus, triggering of the C3b receptor can potentially regulate certain facets of the hypersensitivity response. What is the C3b receptor and what do we know of its function? The receptor is a trypsin-sensitive glycoprotein present in the membrane of all phagocytic cells, as well as certain other cell types, that recognizes the major cleavage fragment of C3, C3b.” This fragment, composed of the entire /3 chain and most of the (Y chain of C3, is deposited on particles or on immune complexes during complement activation. It serves as a major opsonin, allowing the opsonized Vol. 66, No. 4, pp. 267-268
268 Frank
particle to attach to the surface membrane of the phagocytic cell, thus aiding phagocytosis. In many of the systems that have been examined in detail, the binding of a particle coated with C3b alone to a phagocytic cell is an insufficient stimulus for phagocytosis. For ingestion to proceed the phagocytic cell needs a second signal. Such a second signal can be provided by the interaction of particle-bound IgG with the cellular Fc receptor. The C3b receptor has been purified recently and has been shown by Fearon to be a multisubunit glycoprotein of 1.2 x lo6 daltons.4 It appears that the same protein is present on the surface of all cells with C3b receptors. In man this includes neutrophils, macrophages, most B lymphocytes, and erythrocytes. In some cells such as erythrocytes, the function of the receptor is totally unknown. It has been suggested recently that triggering the C3b receptor of neutrophils with particle-bound C3b stimulates superoxide generation even in the absence of phagocytosis, and it is of interest that such was not found to be the case in the present study.5 When C3 is cleaved to C3b by immunologic or enzymatic reactions, another small fragment of C3, C3a, is released. Importantly, this fragment causes mast cells to degranulate and release their content of pharmacologic mediators. As every reader knows, immunologic reactions are often the initiating factors in mast cell degranulation and histamine release. The release of histamine has potent local effects. The local vasculature is affected and there is local hyperemia and edema formation. Histamine is reported to be chemotactic for eosinophils and there is accumulation of these cells.6 Moreover, histamine appears to be an important regulator of cellular function. As an immunoregulatory substance it regulates suppressor T cell activity via interaction with specific H-2 receptors.’ The control of tissue histamine, once released, is of obvious importance and multiple mechanisms of degradation are expected to be icvolved. There are at least two major pathways of histamine degradation in man-that mediated by histaminase and that mediated by histamine methyl transferase.2 Histaminase activity appears to be associated with the granule fraction of certain cells, including the neutrophil. Histamine methyl transferase may be found in the cytoplasm of certain cells, such as that of the monocyte, but may also be present in tissue fluids. At present it is believed that most tissue histamine is degraded via the histamine methyl transferase pathway; however, the precise contribution of either pathway to histamine degradation in an allergic reaction site is unknown. Thus, in an immunologic reaction in the tissues that involves the formation of immune complexes, the mast cells may degranulate either through an IgE-
J. ALLERGY
CLIN. IMMUNOL. OCTOBER 1980
dependent release mechanism or through the formation of anaphylatoxic fragments released via the complement-activation sequence. The released histamine would have potent local regulatory and vascular effects. At the same time that the histamine is released, chemotactic factors for neutrophils are formed via the immune complex-mediated complement-activation sequence and there is local accumulation of neutrophils. Interaction of complementcoated immune complexes or opsonized particles with C3b receptors on neutrophils leads to histaminase release, histamine degradation, and ultimate suppression of the local response. Moreover, the products of histamine degradation (imidazole acetic acid) may also regulate the release of histaminase and the rate of destruction of histamine. This is obviously a highly complex and exquisitely regulated response. Thus, we can rnake a case that the process is of interest and probably of importance to students of the allergic response. One reason for presenting this type of biochemical and cellular detail in the JOURNAL is to acquaint the readership with the direction of a field and with the type of technologies presently available. All one has to do is examine the incredible range of the materials and methods section of this paper to see what a single modern, sophisticated laboratory can do. This paper has not explained all of the details of how tissue and blood histamine Ievels are controlled. It has not even approached attempting to determine whether this control is awry in certain disease states. However, it should be clear that this type of approach and this type of methodology will have greater and greater impact on the clinical allergist. REFERENCES
1. Herman JJ, Colten HR: Specific modulation of complementdependent human granulocyte function by imidazole acetic acid.J ALLERGY CLIN IMMUNOL 66274, 1980. 2. Beaven MA: Histamine. New Engl J Med 294:30; 295320. 3. Bianco C: Plasma membranereceptors for complement: Comprehensiveimmunology, vol. 2, in Day NK, Good RA, editors: Biological amplification systems in immunology. New York, 1977, Plenum Medical Book Co., pp. 69-84. 4. Fearon DT: Regulation of the amplification C3 convertase of human complement by an inhibitory protein isolated from human erythrocyte membrane. Proc Nat1 Acad Sci USA 76:5867, 1979. 5. Goldstein IM, Kaplan HB, Radin A, Frosch M: Independent effects of IgG and complementupon human polymorphonuclear leukocyte function. J Immunol 117:1282, 1976. 6. Clark RAF, Gallin JI, Kaplan AP: The selective eosinophil chemotacticactivity of histamine. J Exp Med 142:1462, 1975. 7. Plaut M, Lichtenstein LM, Henney CS: Propertiesof a subpopulation of T cells bearing histamine receptors. J Clin Invest 55:856, 1975. 8. Wang SR, Zweiman B: Histamine suppressionof human lymphocyte responsesto mitogens. Cell Immunol 36:28, 1976.