649
Long-term outlook could not be addressed by the Finnish study. McNally and colleagues in Leicester, UK, have lately reported their findings for nephropathyll and more briefly retinopathy.12 They
reported only 23 cases of nephropathy in 211 patients who had had diabetes for longer than 20 years, whereas it had been thought that nephropathy developed in 30-50% of childhood-onset cases. to The Leicester workers likewise found a low frequency of retinopathy. If the results are analysed on an intention-to-treat basis, the complication rates are even lower 4 These observations suggest that the only time children or adults need to be admitted is when they have decompensated diabetes. Where do we go from here? In terms of cost, outpatient treatment is almost certainly cheapen, 13 and larger savings might accrue if nurses who specialised in diabetes looked after adults or children. Some improvements could be introduced if doctors were to encourage patients or relatives to telephone them (at home or at work) and provide a specific phoneconsultation time. 1. British Paediatric Association Working Party. The organisation of services for children with diabetes in the United Kingdom: report of the British Paediatric Association Working Party. Diabetic Med 1990; 7: 457-64. 2. Walker JB. Fieldwork of a diabetic clinic. Lancet 1953; ii: 445-47. 3. Walker JB. Chronicle of a diabetic service. London: British Diabetic Association, 1989. 4. Hearnshaw JR. Childhood and after—a review of childhood diabetes in an English Community 1930-1985. In: Serano-Rios M, Lefèbvre PJ, eds. Diabetes 1985. Amsterdam: Elsevier, 1986: 31-42. 5. Spaulding RH, Spaulding WB. The diabetic day care unit II. Comparison of patients and costs of initiating insulin therapy in the unit and a hospital. Can Med Assoc J 1976; 114: 780-87. 6. Laron Z, Galazer A, Amir S, Gil R, Karp M, Minouni M. A multidisciplinary, comprehensive, ambulatory treatment scheme for diabetes mellitus in children. Diabetes Care 1979; 2: 342-48. 7. Schneider A. Starting insulin therapy in children with newly diagnosed diabetes. Am J Dis Child 1983; 137: 782-86. 8. Miller LV, Goldstein J. More efficient care of diabetic patients in a country hospital setting. N Engl J Med 1972; 286: 1388-91. 9. Craig O. Childhood diabetes and its management. 2nd ed. London: Butterworths, 1981. 10. Shah SC, Malone JI, Simpson NE. A randomised trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989; 320: 550-54. 11. McNally PG, Burden AC, Swift PGF, Walls J, Hearnshaw JR. The prevalence and risk factors associated with the onset of diabetic nephropathy in juvenile onset (insulin-dependent) diabetics diagnosed under the age of 17 years in Leicestershire 1930-1985. QJ Med 1990; 76: 831-44. 12. Hearnshaw JR, McNally P, Swift PG, Burden AC. Factors associated with the development of diabetic retinopathy in juvenile onset (under 16 years) insulin-dependent diabetes. Diabetes Res Clin Pract 1988; 5 (suppl): S298. 13. Rayner PHW. A home care unit for diabetic children. Pract Diabetes
1984; 1: 5-8.
Antibodies to endothelial cells Vascular endothelial cells have many molecules on their luminal cell surface and their expression may be constitutive or regulated in response to signals received through the cell membrane. Some of these endothelial cell surface molecules carry epitopes which are targets for autoantibodies or alloantibodies. Anti-endothelial cell antibodies (AECA) have been detected by their ability to bind to cultured human
endothelial cells in vitro. Living or lightly fixed whole cells are used because target antigens have not been completely characterised. AECA have also been detected with functional assays, in which the endpoint is complement-dependent or leucocyte-
dependent cytolysis. AECA have been detected in many disorders
including systemic lupus erythematosus (SLE), scleroderma, rheumatoid arthritis, Kawasaki’s disease, haemolytic uraemic syndrome, heparinassociated thrombocytopenia, allograft rejection, and, most recently, Wegener’s granulomatosis and microscopic polyarteritis. The common factor appears to be immune/inflammatory damage to the vessel wall, so there is increasing interest in determining whether AECA are pathogenic in these disorders. In one of the earliest studies, in patients with SLE, Cines et all found serum AECA that were capable of initiating complement binding and of disrupting the cultured endothelial cell monolayer. Later studies confirmed the presence of AECA in SLE but did not find direct evidence for cytotoxicity in the presence of complement.In both SLE and scleroderma, a small proportion of patients manifest AECA that are capable of damaging cultured endothelial cells in the presence of mononuclear cells-antibody-dependent cellular cytotoxicity. 3-5 Studies undertaken in Kawasaki’s disease and haemolytic uraemic syndrome are especially interesting because they emphasise the potentially dynamic role of endothelium in antibody interactions. AECA present in these disorders mediate complement-dependent cytolysis and recognise a series of determinants on the endothelial cell surface that can be selectively modulated in vitro by tumour necrosis factor, interleukin-1, or interferon-y. It is likely that increased cytokine concentrations also occur in vivo and alter the expression of endothelial cell surface molecules. Heparin administration can lead to the appearance of AECA that recognise heparin-like glycans on the surface of platelets and endothelial cells. Concurrent stimulation of platelet aggregation and endothelial cell expression of procoagulant tissue factor by these antibodies may contribute to the simultaneous occurrence of thrombocytopenia and thrombosis in these patients.9 AECA have been implicated in the development of allograft rejection and may contribute to accelerated atherosclerosis in the graft. Antibodies can recognise major histocompatibility complex (MHC) antigens in MHC-mismatched allografts (endothelial cells express class I antigens and may be induced to express class II antigens), but even well-matched allografts may be targeted by antibodies that recognise antigens of the endothelial-cell/monocyte system or other endothelial-cell-specific determinants. Under these circumstances AECA may damage endothelial cells via complement-mediated1O or antibody-dependent cellular cytotoxic mechanisms.l1I
650
Four groups have lately detected AECA in patients with systemic vasculitis, both Wegener’s granulomatosis and microscopic polyarteritis.12-15 One group used a cross-matching technique in the presence of complement,12 whereas the others used direct binding assays. AECA were largely of the IgG class and recognised determinants on cultured endothelial cells derived from human umbilical veins. Except in the first study, 12 AECA did not mediate complement-dependent cytolysis13,15 but could mediate antibody-dependent cellular cytotoxicity in some patients.15 Increased circulating concentrations of von Willebrand factor, a likely indicator of endothelial cell damage, were reported in two studies. 14,15 There is considerable interest in determining whether AECA contribute to vascular injury, perhaps in combination with the characteristic
autoantibodies to neutrophil cytoplasm enzymes which develop in these patients. These two antibody populations appear to recognise different targets,15 but bound AECA could bring neutrophils whose cytotoxic potential has been upregulated by the autoantibodies to neutrophil cytoplasm enzymes16 closer to the endothelium. Thus, endothelium is readily accessible to circulating antibodies and presents many potentially antigenic determinants whose expression may change in response to cytokines or other inflammatory mediators. Bound antibody could engage humoral or cellular components of the immune system by activating complement or by interacting with Fc receptors of cytotoxic leucocytes, thereby damaging the endothelial surface. Further study of the frequency, nature, and relation to disease activity of AECA in vascular diseases, as well as identification of antigenic targets, will allow full assessment of the pathogenic role of these antibodies and may open up new
approaches to therapy.
1. Cines
DB, Lyss AP, Reeber M, Bina M. DeHoratius RJ. Presence of complement-fixing anti-endothelial cell antibodies in systemic lupus erythematosus. J Clin Invest 1984; 73: 611-25. 2. Rosenbaum J, Pottinger BE, Woo P, et al. Measurement and characterisation of circulating anti-endothelial cell IgG in connective tissue diseases. Clin Exp Immunol 1988; 72: 450-56. 3. Penning CA, French MAH, Rowell NR, Hughes P. Antibodydependent cellular cytotoxicity of human vascular endothelium in systemic lupus erythematosus. Clin Lab Immunol 1985; 17: 125-30. 4. Marks RM, Czerniecki M, Andrews BS, Penny R. The effects of scleroderma serum on human microvascular endothelial cells. Arthritis Rheum 1988; 31: 1524-34. 5. Holt CM, Lindsey N, Moult J, et al. Antibody-dependent cellular cytotoxicity of vascular endothelium: characterisation and pathogenic associations in systemic sclerosis. Clin Exp Immunol 1989; 78: 359-65. 6. Leung DYM, Geha RS, Newburger JW, et al. Two monokines, interleukin 1 and tumor necrosis factor, render cultured vascular endothelial cells susceptible to lysis by antibodies circulating during Kawasaki disease. J Exp Med 1986; 164: 1958-72. 7. Leung DYM, Collins T, Lapierre LA, Geha RS, Pober JS. Immunoglobulin M antibodies present in the acute phase of Kawasaki syndrome lyse cultured vascular endothelial cells stimulated by gamma interferon. J Clin Invest 1986; 77: 1428-35. 8. Leung DYM, Moake JL, Havens PL, Kim M, Pober JS. Lytic anti-endothelial cell antibodies in haemolytic-uraemic syndrome. Lancet 1988; ii: 183-86.
9. Cines DB, Tomaski A, Tannenbaum S. Immune endothelial cell injury in heparin-associated thrombocytopenia. N Engl J Med 1987; 316: 581-89. 10. Soulillou PJ, Peyrat MA, Guenel J. Studies of pre- and postgraft antibodies against endothelial cells (umbilical cord) in kidney allografts. Transpl Proc 1981; 13: 1551-55. 11. Miltenberg AMM, Meijer-Paape ME, Weening JJ, Daha MR, van Es LA, Van der Woude FJ. Induction of antibody-dependent cellular cytotoxicity against endothelial cells by renal transplantation. Transplantation 1989; 48: 681-88. 12. Brasile L, Kremer JM, Clarke JL, Cenlli J. Identification of an autoantibody to vascular endothelial cell-specific antigens in patients with systemic vasculitis. Am J Med 1989; 87: 74-80. 13. Ferraro G, Meroni PL, Tincani A, et al. Anti-endothelial cell antibodies in patients with Wegener’s granulomatosis and micropolyarteritis. Clin Exp Immunol 1990; 79: 47-53. 14. Frampton G, Jayne DRW, Perry GJ, Lockwood CM, Cameron JS. Autoantibodies to endothelial cells and neutrophil cytoplasmic antigens in systemic vasculitis. Clin Exp Immunol 1990; 82: 227-32. 15. Savage COS, Pottinger B, Gaskin G, Lockwood CM, Pusey CD, Pearson J. Vascular damage in Wegener’s granulomatosis and microscopic polyarteritis: presence of anti-endothelial cell antibodies and their relation to anti-neutrophil cytoplasm antibodies. Clin Exp Immunol (in press). 16. Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci USA 1990; 87: 4115-19.
If at first you do succeed In an editorial last year, we reviewed the merits of 5-HT uptake blockers (or specific serotonin uptake inhibitors) in the treatment of depression. These compounds are pharmacologically interesting because they improve the response of postsynaptic neurons to serotonin (the underlying theory is that deficient serotonin transmission causes depression). They appeal to patients because they seem easy to take. These drugs are often prescribed as a single morning dose and their side-effects are different from, and possibly more benign than, those of traditional heterocyclics. Since they selectively inhibit serotonin receptors (with very slight inhibition of other for histamine and acetylcholine-that produce drowsiness and atropinelike side-effects) patients may experience nausea, headache, anxiety, insomnia, and mild transient sexual dysfunction. The first of these new agents to reach the market was fluoxetine (’Prozac’, Eli Lilly) which has made great headway, especially in North America, despite the cost of$1.50 daily for the 2 mg dose. Annual sales are now approaching a remarkable$1 billion. Fluoxetine (N-methyl-3-phenyl-3-propylamine) is a bicyclic antidepressant which seems to work by desensitising both inhibitory somatodendritic and terminal 5-HT autoreceptors, with a resultant increase in central nervous system serotonin synaptic transmission. The main worries so far are that this drug, and its active metabolite, norfluoxetine, have collective half-lives of 8-13 days and a steady state is achieved only at 4-6 weeks. Moreover, fluoxetine treatment may be associated with weight loss, and enhanced suicidal ideation has been reported, although cause and effect remain to be established.2 The long half-life increases the chances of drug
receptors—eg,
those
Long-term outlook could not be addressed by the Finnish study. McNally and colleagues in Leicester, UK, have lately reported their findings for nephropathyll and more briefly retinopathy.12 They
reported only 23 cases of nephropathy in 211 patients who had had diabetes for longer than 20 years, whereas it had been thought that nephropathy developed in 30-50% of childhood-onset cases. to The Leicester workers likewise found a low frequency of retinopathy. If the results are analysed on an intention-to-treat basis, the complication rates are even lower 4 These observations suggest that the only time children or adults need to be admitted is when they have decompensated diabetes. Where do we go from here? In terms of cost, outpatient treatment is almost certainly cheapen, 13 and larger savings might accrue if nurses who specialised in diabetes looked after adults or children. Some improvements could be introduced if doctors were to encourage patients or relatives to telephone them (at home or at work) and provide a specific phoneconsultation time. 1. British Paediatric Association Working Party. The organisation of services for children with diabetes in the United Kingdom: report of the British Paediatric Association Working Party. Diabetic Med 1990; 7: 457-64. 2. Walker JB. Fieldwork of a diabetic clinic. Lancet 1953; ii: 445-47. 3. Walker JB. Chronicle of a diabetic service. London: British Diabetic Association, 1989. 4. Hearnshaw JR. Childhood and after—a review of childhood diabetes in an English Community 1930-1985. In: Serano-Rios M, Lefèbvre PJ, eds. Diabetes 1985. Amsterdam: Elsevier, 1986: 31-42. 5. Spaulding RH, Spaulding WB. The diabetic day care unit II. Comparison of patients and costs of initiating insulin therapy in the unit and a hospital. Can Med Assoc J 1976; 114: 780-87. 6. Laron Z, Galazer A, Amir S, Gil R, Karp M, Minouni M. A multidisciplinary, comprehensive, ambulatory treatment scheme for diabetes mellitus in children. Diabetes Care 1979; 2: 342-48. 7. Schneider A. Starting insulin therapy in children with newly diagnosed diabetes. Am J Dis Child 1983; 137: 782-86. 8. Miller LV, Goldstein J. More efficient care of diabetic patients in a country hospital setting. N Engl J Med 1972; 286: 1388-91. 9. Craig O. Childhood diabetes and its management. 2nd ed. London: Butterworths, 1981. 10. Shah SC, Malone JI, Simpson NE. A randomised trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989; 320: 550-54. 11. McNally PG, Burden AC, Swift PGF, Walls J, Hearnshaw JR. The prevalence and risk factors associated with the onset of diabetic nephropathy in juvenile onset (insulin-dependent) diabetics diagnosed under the age of 17 years in Leicestershire 1930-1985. QJ Med 1990; 76: 831-44. 12. Hearnshaw JR, McNally P, Swift PG, Burden AC. Factors associated with the development of diabetic retinopathy in juvenile onset (under 16 years) insulin-dependent diabetes. Diabetes Res Clin Pract 1988; 5 (suppl): S298. 13. Rayner PHW. A home care unit for diabetic children. Pract Diabetes
1984; 1: 5-8.
Antibodies to endothelial cells Vascular endothelial cells have many molecules on their luminal cell surface and their expression may be constitutive or regulated in response to signals received through the cell membrane. Some of these endothelial cell surface molecules carry epitopes which are targets for autoantibodies or alloantibodies. Anti-endothelial cell antibodies (AECA) have been detected by their ability to bind to cultured human
endothelial cells in vitro. Living or lightly fixed whole cells are used because target antigens have not been completely characterised. AECA have also been detected with functional assays, in which the endpoint is complement-dependent or leucocyte-
dependent cytolysis. AECA have been detected in many disorders
including systemic lupus erythematosus (SLE), scleroderma, rheumatoid arthritis, Kawasaki’s disease, haemolytic uraemic syndrome, heparinassociated thrombocytopenia, allograft rejection, and, most recently, Wegener’s granulomatosis and microscopic polyarteritis. The common factor appears to be immune/inflammatory damage to the vessel wall, so there is increasing interest in determining whether AECA are pathogenic in these disorders. In one of the earliest studies, in patients with SLE, Cines et all found serum AECA that were capable of initiating complement binding and of disrupting the cultured endothelial cell monolayer. Later studies confirmed the presence of AECA in SLE but did not find direct evidence for cytotoxicity in the presence of complement.In both SLE and scleroderma, a small proportion of patients manifest AECA that are capable of damaging cultured endothelial cells in the presence of mononuclear cells-antibody-dependent cellular cytotoxicity. 3-5 Studies undertaken in Kawasaki’s disease and haemolytic uraemic syndrome are especially interesting because they emphasise the potentially dynamic role of endothelium in antibody interactions. AECA present in these disorders mediate complement-dependent cytolysis and recognise a series of determinants on the endothelial cell surface that can be selectively modulated in vitro by tumour necrosis factor, interleukin-1, or interferon-y. It is likely that increased cytokine concentrations also occur in vivo and alter the expression of endothelial cell surface molecules. Heparin administration can lead to the appearance of AECA that recognise heparin-like glycans on the surface of platelets and endothelial cells. Concurrent stimulation of platelet aggregation and endothelial cell expression of procoagulant tissue factor by these antibodies may contribute to the simultaneous occurrence of thrombocytopenia and thrombosis in these patients.9 AECA have been implicated in the development of allograft rejection and may contribute to accelerated atherosclerosis in the graft. Antibodies can recognise major histocompatibility complex (MHC) antigens in MHC-mismatched allografts (endothelial cells express class I antigens and may be induced to express class II antigens), but even well-matched allografts may be targeted by antibodies that recognise antigens of the endothelial-cell/monocyte system or other endothelial-cell-specific determinants. Under these circumstances AECA may damage endothelial cells via complement-mediated1O or antibody-dependent cellular cytotoxic mechanisms.l1I
650
Four groups have lately detected AECA in patients with systemic vasculitis, both Wegener’s granulomatosis and microscopic polyarteritis.12-15 One group used a cross-matching technique in the presence of complement,12 whereas the others used direct binding assays. AECA were largely of the IgG class and recognised determinants on cultured endothelial cells derived from human umbilical veins. Except in the first study, 12 AECA did not mediate complement-dependent cytolysis13,15 but could mediate antibody-dependent cellular cytotoxicity in some patients.15 Increased circulating concentrations of von Willebrand factor, a likely indicator of endothelial cell damage, were reported in two studies. 14,15 There is considerable interest in determining whether AECA contribute to vascular injury, perhaps in combination with the characteristic
autoantibodies to neutrophil cytoplasm enzymes which develop in these patients. These two antibody populations appear to recognise different targets,15 but bound AECA could bring neutrophils whose cytotoxic potential has been upregulated by the autoantibodies to neutrophil cytoplasm enzymes16 closer to the endothelium. Thus, endothelium is readily accessible to circulating antibodies and presents many potentially antigenic determinants whose expression may change in response to cytokines or other inflammatory mediators. Bound antibody could engage humoral or cellular components of the immune system by activating complement or by interacting with Fc receptors of cytotoxic leucocytes, thereby damaging the endothelial surface. Further study of the frequency, nature, and relation to disease activity of AECA in vascular diseases, as well as identification of antigenic targets, will allow full assessment of the pathogenic role of these antibodies and may open up new
approaches to therapy.
1. Cines
DB, Lyss AP, Reeber M, Bina M. DeHoratius RJ. Presence of complement-fixing anti-endothelial cell antibodies in systemic lupus erythematosus. J Clin Invest 1984; 73: 611-25. 2. Rosenbaum J, Pottinger BE, Woo P, et al. Measurement and characterisation of circulating anti-endothelial cell IgG in connective tissue diseases. Clin Exp Immunol 1988; 72: 450-56. 3. Penning CA, French MAH, Rowell NR, Hughes P. Antibodydependent cellular cytotoxicity of human vascular endothelium in systemic lupus erythematosus. Clin Lab Immunol 1985; 17: 125-30. 4. Marks RM, Czerniecki M, Andrews BS, Penny R. The effects of scleroderma serum on human microvascular endothelial cells. Arthritis Rheum 1988; 31: 1524-34. 5. Holt CM, Lindsey N, Moult J, et al. Antibody-dependent cellular cytotoxicity of vascular endothelium: characterisation and pathogenic associations in systemic sclerosis. Clin Exp Immunol 1989; 78: 359-65. 6. Leung DYM, Geha RS, Newburger JW, et al. Two monokines, interleukin 1 and tumor necrosis factor, render cultured vascular endothelial cells susceptible to lysis by antibodies circulating during Kawasaki disease. J Exp Med 1986; 164: 1958-72. 7. Leung DYM, Collins T, Lapierre LA, Geha RS, Pober JS. Immunoglobulin M antibodies present in the acute phase of Kawasaki syndrome lyse cultured vascular endothelial cells stimulated by gamma interferon. J Clin Invest 1986; 77: 1428-35. 8. Leung DYM, Moake JL, Havens PL, Kim M, Pober JS. Lytic anti-endothelial cell antibodies in haemolytic-uraemic syndrome. Lancet 1988; ii: 183-86.
9. Cines DB, Tomaski A, Tannenbaum S. Immune endothelial cell injury in heparin-associated thrombocytopenia. N Engl J Med 1987; 316: 581-89. 10. Soulillou PJ, Peyrat MA, Guenel J. Studies of pre- and postgraft antibodies against endothelial cells (umbilical cord) in kidney allografts. Transpl Proc 1981; 13: 1551-55. 11. Miltenberg AMM, Meijer-Paape ME, Weening JJ, Daha MR, van Es LA, Van der Woude FJ. Induction of antibody-dependent cellular cytotoxicity against endothelial cells by renal transplantation. Transplantation 1989; 48: 681-88. 12. Brasile L, Kremer JM, Clarke JL, Cenlli J. Identification of an autoantibody to vascular endothelial cell-specific antigens in patients with systemic vasculitis. Am J Med 1989; 87: 74-80. 13. Ferraro G, Meroni PL, Tincani A, et al. Anti-endothelial cell antibodies in patients with Wegener’s granulomatosis and micropolyarteritis. Clin Exp Immunol 1990; 79: 47-53. 14. Frampton G, Jayne DRW, Perry GJ, Lockwood CM, Cameron JS. Autoantibodies to endothelial cells and neutrophil cytoplasmic antigens in systemic vasculitis. Clin Exp Immunol 1990; 82: 227-32. 15. Savage COS, Pottinger B, Gaskin G, Lockwood CM, Pusey CD, Pearson J. Vascular damage in Wegener’s granulomatosis and microscopic polyarteritis: presence of anti-endothelial cell antibodies and their relation to anti-neutrophil cytoplasm antibodies. Clin Exp Immunol (in press). 16. Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci USA 1990; 87: 4115-19.
If at first you do succeed In an editorial last year, we reviewed the merits of 5-HT uptake blockers (or specific serotonin uptake inhibitors) in the treatment of depression. These compounds are pharmacologically interesting because they improve the response of postsynaptic neurons to serotonin (the underlying theory is that deficient serotonin transmission causes depression). They appeal to patients because they seem easy to take. These drugs are often prescribed as a single morning dose and their side-effects are different from, and possibly more benign than, those of traditional heterocyclics. Since they selectively inhibit serotonin receptors (with very slight inhibition of other for histamine and acetylcholine-that produce drowsiness and atropinelike side-effects) patients may experience nausea, headache, anxiety, insomnia, and mild transient sexual dysfunction. The first of these new agents to reach the market was fluoxetine (’Prozac’, Eli Lilly) which has made great headway, especially in North America, despite the cost of$1.50 daily for the 2 mg dose. Annual sales are now approaching a remarkable$1 billion. Fluoxetine (N-methyl-3-phenyl-3-propylamine) is a bicyclic antidepressant which seems to work by desensitising both inhibitory somatodendritic and terminal 5-HT autoreceptors, with a resultant increase in central nervous system serotonin synaptic transmission. The main worries so far are that this drug, and its active metabolite, norfluoxetine, have collective half-lives of 8-13 days and a steady state is achieved only at 4-6 weeks. Moreover, fluoxetine treatment may be associated with weight loss, and enhanced suicidal ideation has been reported, although cause and effect remain to be established.2 The long half-life increases the chances of drug
receptors—eg,
those
