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Autoantibodies to beta-adrenergic receptors and asthma
Editorial Autoantibodies and asthma
to beta-adrenergic
Modulation of the function of hormone and neurotransmitter receptors associated with the autonomic nervous system may occur at many different levels. The generation of autonomic responses involves the interplay of a finite number of transmitters, acetylcholine, and norepinephrine, and the hormone epinephrine with their more numerous and more specific receptor proteins associated with the plasma membrane of the effector cells.’ Although substantial changes in transmitter concentrations are clearly implicated in certain disorders such as pheochromocytoma, it has been difficult to attribute the changes in effector organ responsiveness associated with certain disease states such as allergic respiratory disease? or cardiac disorders3 to altered levels of neurotransmitters. When changes in the neurotransmitter concentrations are not implicated in a particular disorder, variations in receptor density, activity, and/or coupling to effector proteins may be involved. Although many of the factors directly affecting neurotransmitter receptor density are known and are being studied at a molecular leveL3j 4 modulation of receptor coupling to effector proteins (such as adenylate cyclase or calcium channels) is much more difficult to quantitate. One example of this latter type of receptor regulation is found in pseudohypoparathyroidism, where a documented decrease in the amount of the guanine nucleotide coupling protein present in the cell membrane results in a reduced coupling of parathyroid hormone receptors to adenylate cyclase with consequent loss of normal parathyroid function.5 Bronchial asthma is a disease that is closely linked to receptor function. For example, in the airways, cholinergic input via muscarinic cholinergic receptors affects airway tone6 and influences mucus secretion.7 Beta,-adrenergic, alpha-adrenergic, histamine, and other receptors are also intimately involved in the control of airway diameter. At the level of the mast cell, beta,-adrenergic receptor stimulation attenuates IgE-induced mast cell degranulation, a process thought to be enhanced by cholinergic and alphaadrenergic activation.2 Data to date suggest that a
receptors
carefully modulated balance exists between the cholinergic and alpha-adrenergic response on one side of the autonomic nervous system and the beta,adrenergic response on the other and that alterations in one side of the autonomic system may induce derangements in the responses mediated by the opposing components.’ Beta,-adrenergic receptor stimulation, which is central to the treatment of asthma, produces bronchodilation, reduced tracheobronchial secretions, and impairment of the IgE-mediated mast cell degranulation. As is most likely the case with a wide variety of cell-surface receptors, the concentration of beta-adrenergic receptors in the plasma membrane of cells, both in terms of the number of total and active receptor molecules, is determined by a multitude of factors. Beta-receptor density is affected by the rate of receptor synthesifs and degradation,* the cell cycle,s cell density and cell to cell contact,4 self-regulation through desensitization,1° hormones such as thyroid hormone” and glucocorticoids ,4, 8 and in some instances by circulating autoantibodies to the receptor.‘, ‘*-14 Autoimmunity and cell-surface receptors are clearly linked in diseases such as Craves’ disease, myasthenia gravis, and in a small group of patients with type B insulin-resistant diabetes (see reference 15 for a review). In 1980, we along with Len Harrison reported that three patients with allergic respiratory disease had circulating autoantibodies specific for the beta,-adrenergic receptor.” In subsequent studies it was demonstrated that the presence of beta-receptor autoantibodies correlated with abnormalities of the autonomic nervous system, particularly beta-adrenergic responsiveness13 and that the antibodies could directly inhibit beta-receptor activation of adenylate cyclase. Harrison et al. l4 have recently identified beta,-receptor-specific autoantibodies in patients with COPD (personal communication). However, important questions as to the importance of the antibodies to asthma, their correlation with disease and its severity, and their overall incidence remained to be answered.16 In this issue of the JOURNAL, a study by Blecher et al.‘? attempts to answer some of the outstanding 227
228
Fraser
and Venter
questions concerning beta-adrenergic receptor autoantibodies and asthma, particularly in children. Blecher et al. screened sera from 376 mild to severe asthmatic children by assessing the effect of a constant serum dilution (1: 100) on high-affinity radioligand binding to dog lung beta-adrenergic receptors. In this assay the sera from 58 nonasthmatic control subjects demonstrated no differences compared to pooled normal serum. In contrast, sera from 58 general (mild) asthmatic subjects effected a significant reduction in the average beta-adrenergic ligand binding compared to the control population, although only two serum samples reduced beta-receptor binding below two standard deviations of the mean. Moreover, in the high-risk asthmatic group (3 18 patients), sera from 28 patients reduced beta-adrenergic receptor binding by more than two standard deviations from the mean. Blecher et al. identified the factor(s) in the sera responsible for the decreases in beta-receptor binding as immunoglobulin molecules (presumably IgG) on the basis of immunodepletion experiments where removal of IgG and IgA from the sera restored receptor binding to control levels. Receptor immunoprecipitation studies were not conducted. This study provides at least two important new pieces of information concerning beta-receptor autoantibodies and asthma. The first relates to the significant size of the patient population studied, 376 asthmatic and 58 nonasthmatic controls, which permitted the first statistical analysis of the possible incidence of beta-receptor autoantibodies in asthmatic subjects. The second new finding is with regard to the apparent correlation between the severity of asthma and the incidence of beta-receptor autoantibodies. Of the high-risk asthmatic subjects studied, 8.8% were confirmed to have receptor-blocking antibodies in their sera, whereas only 3.4% of the mild asthmatic subjects and none of the control group appeared to have such antibodies. It is clear from this and from the earlier studies that autoantibodies to beta-adrenergic receptors are not the cause of asthma”* 13; however, if as Blecher et al. have documented, approximately 9% of severe asthmatic subjects have circulating antibodies with the ability to block up to 80% of beta receptors at a dilution of 1: 100, it does not appear unreasonable to assume that these same antibodies circulating undiluted through a patient’s system might have a profound effect on normal (or compromised) receptor physiology. While progress is continuing, numerous questions remain to be answered concerning beta-adrenergic receptor autoantibodies and human diseases. For example, do high-risk asthmatic subjects with auto-
J. ALLERGY
CLIN. IMMUNOL. SEPTEMBER 1984
antibodies respond poorly to direct beta-adrenergic therapy? Is there a unique syndrome or disease associated with the presence of the autoantibodies (as with the type B insulin-resistant diabetes)? Does the presence (or absence) of anti-receptor antibodies have any prognostic value? How do the autoantibodies arise? Is it poss:lble that asthma therapy with synthetic betaadrenergic ligands leads to the production of antiidiotyplN.c antibodies that then affect beta receptors directly? As research in this area progresses, these questions will surely be answered. Dr. Blecher’s study has provided important new information toward the understanding of this autoimmune-related disorder. Claire hf. Fraser, Ph.D. J. Craig Venter, Ph.D. Department of Molecular Immunology Roswell Park Memorial Institute Buffalo, N. Y. REFERENCES recep1. Venter JC, Robinson DA, Fraser CM: Beta-adrenergic tor amibodies, receptor structure, and human disease. In Morley J, editor: Beta-adrenoreceptors in asthma. London, 1984, Academic Press, Inc., pp 147-180 2. Kaliner M, Shelhamer JH, Davis PB, Smith LJ, Venter JC: Autonomic nervous system abnormalities and allergy. Ann Intern Med 96349, 1982 3. Venter JC: Beta-adrenoreceptors, adenylate cyclase, and the adrenergic control of cardiac contractility. In Kunos G, editor: Adrenoreceptors and catecholamine action. New York, 1981, John Wiley & Sons, Inc, pp 213-245 4. Fraser CM, Venter JC: Regulation of beta-adrenergic receptor density in the control of adrenergic responsiveness. In Cohen E, Kohler H, editors: Membranes, receptors, and the immune respome: eighty years after Ehrlich’s side chain theory. New York, 1980, Alan R. Liss, Inc, pp 127-144 5. Farfel Z, Brickman AS, Kaslow HR, Brothers VM, Boume HR: Defect of receptor-cyclase coupling protein in pseudohypoparathyroidism. N Engl J Med 303:237, 1980 6. Cabezas GA, Graf PD, Nadel JA: Sympathetic versus parasympathetic nervous regulation of airways in dogs. J Appl Physiol 31:651, 1971 7. Boat TF, Kleineman JI: Human respiratory tract secretions: effect of cholinergic and adrenergic agents on in vitro release of proteins and mucous glycoprotein. Chest 67:325, 1975 8. Fraser CM, Venter JC: The synthesis of beta-adrenergic receptors in cultured human lung cells: induction by glucocorticoids. Biochem Biophys Res Commun 94390, 1980 9 Charltor RR, Venter JC: Cell cycle specific changes in betaadrenergic receptor concentrations in C-6 glioma cells. Biothem Biophys Res Commun 94: 1221, 1980 10 Harden TK, Su Y-F, Perkins JP: Catecholamine induced desensitization involves an uncoupling of beta-adrenergic receptors and adenylate cyclase. J Cyclic Nucleotide Protein Phosphor Re:. 599, 1979 11 Williams LT, Lefkowitz RJ, Wantanabe AM, Besch HR; Thyroid hormone regulation of beta-adrenergic receptor number. J Biol Chem 252:2787, 1977 12 Venter JC, Fraser CM, Harrison LC: Autoantibodies to beta,-
VOLUME NUMBER
74 3, PART 1
Autoantibodies
adrenergic receptors: a possible cause of adrenergic hyporesponsiveness in allergic rhinitis and asthma. Science 207: 1361, 1980 13. Fraser CM, Venter JC, Kaliner M: Autonomic abnormalities and autoantibodies to beta-adrenergic receptors. N Engl J Med 305: 1165, 1981 14.
Harrison LC, Callaghan J, Venter JC, Fraser CM, Kaliner M: Atopy, autonomic function, and beta-adrenergic receptor autoantibodies. In Evered D, Whelan J, editors; Receptors, an-
to receptors
and asthma
229
tibodies, and disease. London, 1982, Pitman Publishing, Ltd, pp 248-262 15. Frac.erCM, Venter JC: Anti-receptor antibodies in human disease. J ALLERGY CLIN IMMUNOL (in press) 16. Parker CW: Autoantibodies and beta-adrenergic receptors. N Engl J Med 305:1212, 1981 17. Btecher M, Lewis S, Hicks JM, Josephs S: Beta-blocking autoantibodies in pediatric bronchial asthma. J ALLERGY CLIN IMMUNOL 74246, 1984
Bound volumes available to subscribers Boundvolumesof THEJOURNAL OF ALLERGY ANDCLINICAL IMMUNOLOGY are available to subscribers (only) for the 1984 issues from the Publisher, at a cost of $47.50 ($57.10 international) for Vol. 73 (January-June) and Vol. 74 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C. V. Mosby Co., Circulation Department, 11830 Westline Industrial Dr., St. Louis, MO. 63146; phone (800) 325-4117, ext. 351.
Subscriptionsmustbe in force to qualify. Bound volumesare not availablein placeof a regular journal subscription.
to beta-adrenergic
Modulation of the function of hormone and neurotransmitter receptors associated with the autonomic nervous system may occur at many different levels. The generation of autonomic responses involves the interplay of a finite number of transmitters, acetylcholine, and norepinephrine, and the hormone epinephrine with their more numerous and more specific receptor proteins associated with the plasma membrane of the effector cells.’ Although substantial changes in transmitter concentrations are clearly implicated in certain disorders such as pheochromocytoma, it has been difficult to attribute the changes in effector organ responsiveness associated with certain disease states such as allergic respiratory disease? or cardiac disorders3 to altered levels of neurotransmitters. When changes in the neurotransmitter concentrations are not implicated in a particular disorder, variations in receptor density, activity, and/or coupling to effector proteins may be involved. Although many of the factors directly affecting neurotransmitter receptor density are known and are being studied at a molecular leveL3j 4 modulation of receptor coupling to effector proteins (such as adenylate cyclase or calcium channels) is much more difficult to quantitate. One example of this latter type of receptor regulation is found in pseudohypoparathyroidism, where a documented decrease in the amount of the guanine nucleotide coupling protein present in the cell membrane results in a reduced coupling of parathyroid hormone receptors to adenylate cyclase with consequent loss of normal parathyroid function.5 Bronchial asthma is a disease that is closely linked to receptor function. For example, in the airways, cholinergic input via muscarinic cholinergic receptors affects airway tone6 and influences mucus secretion.7 Beta,-adrenergic, alpha-adrenergic, histamine, and other receptors are also intimately involved in the control of airway diameter. At the level of the mast cell, beta,-adrenergic receptor stimulation attenuates IgE-induced mast cell degranulation, a process thought to be enhanced by cholinergic and alphaadrenergic activation.2 Data to date suggest that a
receptors
carefully modulated balance exists between the cholinergic and alpha-adrenergic response on one side of the autonomic nervous system and the beta,adrenergic response on the other and that alterations in one side of the autonomic system may induce derangements in the responses mediated by the opposing components.’ Beta,-adrenergic receptor stimulation, which is central to the treatment of asthma, produces bronchodilation, reduced tracheobronchial secretions, and impairment of the IgE-mediated mast cell degranulation. As is most likely the case with a wide variety of cell-surface receptors, the concentration of beta-adrenergic receptors in the plasma membrane of cells, both in terms of the number of total and active receptor molecules, is determined by a multitude of factors. Beta-receptor density is affected by the rate of receptor synthesifs and degradation,* the cell cycle,s cell density and cell to cell contact,4 self-regulation through desensitization,1° hormones such as thyroid hormone” and glucocorticoids ,4, 8 and in some instances by circulating autoantibodies to the receptor.‘, ‘*-14 Autoimmunity and cell-surface receptors are clearly linked in diseases such as Craves’ disease, myasthenia gravis, and in a small group of patients with type B insulin-resistant diabetes (see reference 15 for a review). In 1980, we along with Len Harrison reported that three patients with allergic respiratory disease had circulating autoantibodies specific for the beta,-adrenergic receptor.” In subsequent studies it was demonstrated that the presence of beta-receptor autoantibodies correlated with abnormalities of the autonomic nervous system, particularly beta-adrenergic responsiveness13 and that the antibodies could directly inhibit beta-receptor activation of adenylate cyclase. Harrison et al. l4 have recently identified beta,-receptor-specific autoantibodies in patients with COPD (personal communication). However, important questions as to the importance of the antibodies to asthma, their correlation with disease and its severity, and their overall incidence remained to be answered.16 In this issue of the JOURNAL, a study by Blecher et al.‘? attempts to answer some of the outstanding 227
228
Fraser
and Venter
questions concerning beta-adrenergic receptor autoantibodies and asthma, particularly in children. Blecher et al. screened sera from 376 mild to severe asthmatic children by assessing the effect of a constant serum dilution (1: 100) on high-affinity radioligand binding to dog lung beta-adrenergic receptors. In this assay the sera from 58 nonasthmatic control subjects demonstrated no differences compared to pooled normal serum. In contrast, sera from 58 general (mild) asthmatic subjects effected a significant reduction in the average beta-adrenergic ligand binding compared to the control population, although only two serum samples reduced beta-receptor binding below two standard deviations of the mean. Moreover, in the high-risk asthmatic group (3 18 patients), sera from 28 patients reduced beta-adrenergic receptor binding by more than two standard deviations from the mean. Blecher et al. identified the factor(s) in the sera responsible for the decreases in beta-receptor binding as immunoglobulin molecules (presumably IgG) on the basis of immunodepletion experiments where removal of IgG and IgA from the sera restored receptor binding to control levels. Receptor immunoprecipitation studies were not conducted. This study provides at least two important new pieces of information concerning beta-receptor autoantibodies and asthma. The first relates to the significant size of the patient population studied, 376 asthmatic and 58 nonasthmatic controls, which permitted the first statistical analysis of the possible incidence of beta-receptor autoantibodies in asthmatic subjects. The second new finding is with regard to the apparent correlation between the severity of asthma and the incidence of beta-receptor autoantibodies. Of the high-risk asthmatic subjects studied, 8.8% were confirmed to have receptor-blocking antibodies in their sera, whereas only 3.4% of the mild asthmatic subjects and none of the control group appeared to have such antibodies. It is clear from this and from the earlier studies that autoantibodies to beta-adrenergic receptors are not the cause of asthma”* 13; however, if as Blecher et al. have documented, approximately 9% of severe asthmatic subjects have circulating antibodies with the ability to block up to 80% of beta receptors at a dilution of 1: 100, it does not appear unreasonable to assume that these same antibodies circulating undiluted through a patient’s system might have a profound effect on normal (or compromised) receptor physiology. While progress is continuing, numerous questions remain to be answered concerning beta-adrenergic receptor autoantibodies and human diseases. For example, do high-risk asthmatic subjects with auto-
J. ALLERGY
CLIN. IMMUNOL. SEPTEMBER 1984
antibodies respond poorly to direct beta-adrenergic therapy? Is there a unique syndrome or disease associated with the presence of the autoantibodies (as with the type B insulin-resistant diabetes)? Does the presence (or absence) of anti-receptor antibodies have any prognostic value? How do the autoantibodies arise? Is it poss:lble that asthma therapy with synthetic betaadrenergic ligands leads to the production of antiidiotyplN.c antibodies that then affect beta receptors directly? As research in this area progresses, these questions will surely be answered. Dr. Blecher’s study has provided important new information toward the understanding of this autoimmune-related disorder. Claire hf. Fraser, Ph.D. J. Craig Venter, Ph.D. Department of Molecular Immunology Roswell Park Memorial Institute Buffalo, N. Y. REFERENCES recep1. Venter JC, Robinson DA, Fraser CM: Beta-adrenergic tor amibodies, receptor structure, and human disease. In Morley J, editor: Beta-adrenoreceptors in asthma. London, 1984, Academic Press, Inc., pp 147-180 2. Kaliner M, Shelhamer JH, Davis PB, Smith LJ, Venter JC: Autonomic nervous system abnormalities and allergy. Ann Intern Med 96349, 1982 3. Venter JC: Beta-adrenoreceptors, adenylate cyclase, and the adrenergic control of cardiac contractility. In Kunos G, editor: Adrenoreceptors and catecholamine action. New York, 1981, John Wiley & Sons, Inc, pp 213-245 4. Fraser CM, Venter JC: Regulation of beta-adrenergic receptor density in the control of adrenergic responsiveness. In Cohen E, Kohler H, editors: Membranes, receptors, and the immune respome: eighty years after Ehrlich’s side chain theory. New York, 1980, Alan R. Liss, Inc, pp 127-144 5. Farfel Z, Brickman AS, Kaslow HR, Brothers VM, Boume HR: Defect of receptor-cyclase coupling protein in pseudohypoparathyroidism. N Engl J Med 303:237, 1980 6. Cabezas GA, Graf PD, Nadel JA: Sympathetic versus parasympathetic nervous regulation of airways in dogs. J Appl Physiol 31:651, 1971 7. Boat TF, Kleineman JI: Human respiratory tract secretions: effect of cholinergic and adrenergic agents on in vitro release of proteins and mucous glycoprotein. Chest 67:325, 1975 8. Fraser CM, Venter JC: The synthesis of beta-adrenergic receptors in cultured human lung cells: induction by glucocorticoids. Biochem Biophys Res Commun 94390, 1980 9 Charltor RR, Venter JC: Cell cycle specific changes in betaadrenergic receptor concentrations in C-6 glioma cells. Biothem Biophys Res Commun 94: 1221, 1980 10 Harden TK, Su Y-F, Perkins JP: Catecholamine induced desensitization involves an uncoupling of beta-adrenergic receptors and adenylate cyclase. J Cyclic Nucleotide Protein Phosphor Re:. 599, 1979 11 Williams LT, Lefkowitz RJ, Wantanabe AM, Besch HR; Thyroid hormone regulation of beta-adrenergic receptor number. J Biol Chem 252:2787, 1977 12 Venter JC, Fraser CM, Harrison LC: Autoantibodies to beta,-
VOLUME NUMBER
74 3, PART 1
Autoantibodies
adrenergic receptors: a possible cause of adrenergic hyporesponsiveness in allergic rhinitis and asthma. Science 207: 1361, 1980 13. Fraser CM, Venter JC, Kaliner M: Autonomic abnormalities and autoantibodies to beta-adrenergic receptors. N Engl J Med 305: 1165, 1981 14.
Harrison LC, Callaghan J, Venter JC, Fraser CM, Kaliner M: Atopy, autonomic function, and beta-adrenergic receptor autoantibodies. In Evered D, Whelan J, editors; Receptors, an-
to receptors
and asthma
229
tibodies, and disease. London, 1982, Pitman Publishing, Ltd, pp 248-262 15. Frac.erCM, Venter JC: Anti-receptor antibodies in human disease. J ALLERGY CLIN IMMUNOL (in press) 16. Parker CW: Autoantibodies and beta-adrenergic receptors. N Engl J Med 305:1212, 1981 17. Btecher M, Lewis S, Hicks JM, Josephs S: Beta-blocking autoantibodies in pediatric bronchial asthma. J ALLERGY CLIN IMMUNOL 74246, 1984
Bound volumes available to subscribers Boundvolumesof THEJOURNAL OF ALLERGY ANDCLINICAL IMMUNOLOGY are available to subscribers (only) for the 1984 issues from the Publisher, at a cost of $47.50 ($57.10 international) for Vol. 73 (January-June) and Vol. 74 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C. V. Mosby Co., Circulation Department, 11830 Westline Industrial Dr., St. Louis, MO. 63146; phone (800) 325-4117, ext. 351.
Subscriptionsmustbe in force to qualify. Bound volumesare not availablein placeof a regular journal subscription.