- Email: [email protected]
Mannose-binding lectin and meningococcal disease
protein in infections: another case of heterosis? Eur J Immunogenet 1994; 21: 125–31.
Sir—A functional complement system is essential for the immune defence against meningococci. 1 The importance of activation of the complement system via mannosebinding lectin (MBL) in defence against meningococci is not completely understood. MBL binds to carbohydrate structures present in cell walls of gram-positive and gram-negative bacteria and activates the complement cascade by two MBL-associated serine proteases.2 The serum concentration of MBL is genetically determined by mutations in the promotor and coding regions of the gene. Martin Hibberd and co-workers3 conclude that patients homozygous for one or heterozygous for two MBL variant genes were more susceptible for serogroup B or C meningococcal disease, whereas Garred and colleagues4 showed no association between serum concentrations of MBL and the occurrence of serogroup B or C meningococcal disease.3 Patients with infections by bacteria of serogroups other than B or C were not included in these studies. This omission may be of importance, since abnormalities of the complement system especially predispose to infections with uncommon meningococcal serogroups and MBL shows a considerable difference in binding to various bacterial pathogens of meningitis.5 We assessed MBL concentrations in serum of 58 patients who had meningococcal disease caused by uncommon meningococcal serogroups (X, Y, W135, and 29E) and investigated whether the development of meningococcal disease in complementdeficient individuals was associated with low serum MBL concentrations, since it is unclear why meningococcal infections develop only in 50% of the complement-deficient patients. Blood samples were taken at least 8 months after the onset of meningitis. 24 patients had complement deficiency. Serum samples from 19 complement-deficient individuals without meningococcal infection were also tested. Controls consisted of 37 healthy blood donors with an intact complement system. MBL was measured with an antibody sandwich ELISA with one polyclonal rabbit antiMBL antibody as capture antibody and another polyclonal biotinylated anti-MBL antibody as the developing antibody. A great variation in MBL concentrations was seen among healthy blood donors. A similar pattern was noted in individuals with
338
an intact complement system who had had meningitis. High serum concentrations of MBL (>1000 ng/mL) were present in 11 of 14 complement-deficient (C5, C6, C7, or C8) patients who had had meningitis, compared with one of ten properdin (factor from the alternative route) deficient patients and 17 of 34 patients with an intact complement system and a history of meningitis. Low serum concentrations of MBL (<100 ng/mL) were present in three of nine properdin-deficient individuals, in one of ten terminal route complementdeficient individuals, and in three of 37 complement-sufficient blood donors without a history of meningitis. Low serum MBL concentration in normal and complement-deficient individuals is not associated with an increased risk of meningococcal infection due to uncommon serogroups. *Ed J Kuijper, Cees A Fijen, Jacob Dankert, Steffen Thiel *Reference Laboratory for Bacterial Meningitis, University of Amsterdam, 1105 AZ Amsterdam, Netherlands; Department of Medical Microbiology, Academic Medical Centre, Amsterdam; and Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark Fijen CAP, Kuijper EJ, te Bulte MT, Daha MR, Dankert J. Assessment of complement deficiency in patients with meningococcal disease in the Netherlands. Clin Infect Dis 1999; 28: 98–105. 2 Thiel S, Vorup-Jensen T, Stover CM, et al. A second serine protease associated with mannan-binding lectin that activates complement. Nature 1997; 386: 506–10. 3 Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M, Meningococcal Research Group. Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Lancet 1999; 353: 1049–53. 4 Garred P, Michaelsen TE, Bjune G, Thiel S, Svejgaard A. A low serum concentration of mannan-binding lectin is not associated with serogroup B or C meningococcal disease. Scand J Immunol 1993; 37: 468–70. 5 van Emmerick LC, Kuijper EJ, Fijen CAP, Dankert J, Thiel S. Binding of mannanbinding protein to various bacterial pathogens of meningitis. Clin Exp Immunol 1994; 98: 411–16.
blood into the central nervous system. Lectin binding can substantially increase the uptake of pathogens with glycoprotein coat through the bloodbrain barrier,2 whereas mannose binding to a calcium-independent cerebellar soluble lectin in ependymal cells disrupts the cerebrospinal fluidbrain barrier.3 Possible prevention of these effects in patients homozygous for MBL variant alleles might cause a less severe meningococcal meningitis. *P Megyeri, M A Deli, C S Ábrahám *Department of Paediatrics, Albert SzentGyörgyi University Medical School, PO Box 471, H-6701 Szeged, Hungary; and Laboratory of Molecular Neurobiology, Biological Research Center, Szeged (e-mail: [email protected]) 1
2
3
Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M, and the Meningococcal Research Group. Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Lancet 1999; 353: 1049–53. Banks WA, Kastin AJ. Characterization of lectin-mediated brain uptake of HIV-1 gp120. J Neurosci Res 1998; 54: 522–29. Kuchler S Graff M-N, Gobaille S, et al. Mannose dependent tightening of the rat ependymal cell barrier. In vivo and in vitro study using neoglycoproteins. Neurochem Int 1994; 24: 43–55.
1
Sir—Martin Hibberd and colleagues 1 report a remarkable finding that patients homozygous for MBL variants developed a less severe meningococcal disease than individuals with heterozygous or wild-type genotypes. So, in case of Neisseria meningitidis infection, very low plasma concentrations of MBL may result not only in a defective innate complement activation, but a type of protection also. One can speculate that it might be a decreased penetration of bacteria from
S-nitrosothiols for nitrate tolerance Sir—Organic nitrates are an exogenous source of nitric oxide and should represent a suitable drug class for chronic treatment of patients with established cardiovascular disease in whom vascular responses mediated by nitric oxide are known to be impaired. Stephen Glasser’s May 8 commentary1 highlighted the limitations of long-term nitrate administration imposed by the development of tolerance to their haemodynamic effects. Although the mechanisms of nitrate tolerance are still unclear, Glasser identifies several potential therapeutic strategies to overcome tolerance including the use of inhibitors of angiotensin-converting enzyme, exogenous sulphydryl donors, antioxidants, and nitrate-free intervals. However, his review did not draw attention to an exciting new group of nitric oxide donor compounds: the Snitrosothiols. S-nitrosothiols (general formula RSNO, where R- is one of a range of chemical moieties) decompose to generate nitric oxide, a process that is accelerated in the presence of transition metal ions such as copper and reduced tissue thiols. Endogenous Snitrosothiols have been identified in human plasma, although their source
THE LANCET • Vol 354 • July 24, 1999
Sir—A functional complement system is essential for the immune defence against meningococci. 1 The importance of activation of the complement system via mannosebinding lectin (MBL) in defence against meningococci is not completely understood. MBL binds to carbohydrate structures present in cell walls of gram-positive and gram-negative bacteria and activates the complement cascade by two MBL-associated serine proteases.2 The serum concentration of MBL is genetically determined by mutations in the promotor and coding regions of the gene. Martin Hibberd and co-workers3 conclude that patients homozygous for one or heterozygous for two MBL variant genes were more susceptible for serogroup B or C meningococcal disease, whereas Garred and colleagues4 showed no association between serum concentrations of MBL and the occurrence of serogroup B or C meningococcal disease.3 Patients with infections by bacteria of serogroups other than B or C were not included in these studies. This omission may be of importance, since abnormalities of the complement system especially predispose to infections with uncommon meningococcal serogroups and MBL shows a considerable difference in binding to various bacterial pathogens of meningitis.5 We assessed MBL concentrations in serum of 58 patients who had meningococcal disease caused by uncommon meningococcal serogroups (X, Y, W135, and 29E) and investigated whether the development of meningococcal disease in complementdeficient individuals was associated with low serum MBL concentrations, since it is unclear why meningococcal infections develop only in 50% of the complement-deficient patients. Blood samples were taken at least 8 months after the onset of meningitis. 24 patients had complement deficiency. Serum samples from 19 complement-deficient individuals without meningococcal infection were also tested. Controls consisted of 37 healthy blood donors with an intact complement system. MBL was measured with an antibody sandwich ELISA with one polyclonal rabbit antiMBL antibody as capture antibody and another polyclonal biotinylated anti-MBL antibody as the developing antibody. A great variation in MBL concentrations was seen among healthy blood donors. A similar pattern was noted in individuals with
338
an intact complement system who had had meningitis. High serum concentrations of MBL (>1000 ng/mL) were present in 11 of 14 complement-deficient (C5, C6, C7, or C8) patients who had had meningitis, compared with one of ten properdin (factor from the alternative route) deficient patients and 17 of 34 patients with an intact complement system and a history of meningitis. Low serum concentrations of MBL (<100 ng/mL) were present in three of nine properdin-deficient individuals, in one of ten terminal route complementdeficient individuals, and in three of 37 complement-sufficient blood donors without a history of meningitis. Low serum MBL concentration in normal and complement-deficient individuals is not associated with an increased risk of meningococcal infection due to uncommon serogroups. *Ed J Kuijper, Cees A Fijen, Jacob Dankert, Steffen Thiel *Reference Laboratory for Bacterial Meningitis, University of Amsterdam, 1105 AZ Amsterdam, Netherlands; Department of Medical Microbiology, Academic Medical Centre, Amsterdam; and Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark Fijen CAP, Kuijper EJ, te Bulte MT, Daha MR, Dankert J. Assessment of complement deficiency in patients with meningococcal disease in the Netherlands. Clin Infect Dis 1999; 28: 98–105. 2 Thiel S, Vorup-Jensen T, Stover CM, et al. A second serine protease associated with mannan-binding lectin that activates complement. Nature 1997; 386: 506–10. 3 Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M, Meningococcal Research Group. Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Lancet 1999; 353: 1049–53. 4 Garred P, Michaelsen TE, Bjune G, Thiel S, Svejgaard A. A low serum concentration of mannan-binding lectin is not associated with serogroup B or C meningococcal disease. Scand J Immunol 1993; 37: 468–70. 5 van Emmerick LC, Kuijper EJ, Fijen CAP, Dankert J, Thiel S. Binding of mannanbinding protein to various bacterial pathogens of meningitis. Clin Exp Immunol 1994; 98: 411–16.
blood into the central nervous system. Lectin binding can substantially increase the uptake of pathogens with glycoprotein coat through the bloodbrain barrier,2 whereas mannose binding to a calcium-independent cerebellar soluble lectin in ependymal cells disrupts the cerebrospinal fluidbrain barrier.3 Possible prevention of these effects in patients homozygous for MBL variant alleles might cause a less severe meningococcal meningitis. *P Megyeri, M A Deli, C S Ábrahám *Department of Paediatrics, Albert SzentGyörgyi University Medical School, PO Box 471, H-6701 Szeged, Hungary; and Laboratory of Molecular Neurobiology, Biological Research Center, Szeged (e-mail: [email protected]) 1
2
3
Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M, and the Meningococcal Research Group. Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Lancet 1999; 353: 1049–53. Banks WA, Kastin AJ. Characterization of lectin-mediated brain uptake of HIV-1 gp120. J Neurosci Res 1998; 54: 522–29. Kuchler S Graff M-N, Gobaille S, et al. Mannose dependent tightening of the rat ependymal cell barrier. In vivo and in vitro study using neoglycoproteins. Neurochem Int 1994; 24: 43–55.
1
Sir—Martin Hibberd and colleagues 1 report a remarkable finding that patients homozygous for MBL variants developed a less severe meningococcal disease than individuals with heterozygous or wild-type genotypes. So, in case of Neisseria meningitidis infection, very low plasma concentrations of MBL may result not only in a defective innate complement activation, but a type of protection also. One can speculate that it might be a decreased penetration of bacteria from
S-nitrosothiols for nitrate tolerance Sir—Organic nitrates are an exogenous source of nitric oxide and should represent a suitable drug class for chronic treatment of patients with established cardiovascular disease in whom vascular responses mediated by nitric oxide are known to be impaired. Stephen Glasser’s May 8 commentary1 highlighted the limitations of long-term nitrate administration imposed by the development of tolerance to their haemodynamic effects. Although the mechanisms of nitrate tolerance are still unclear, Glasser identifies several potential therapeutic strategies to overcome tolerance including the use of inhibitors of angiotensin-converting enzyme, exogenous sulphydryl donors, antioxidants, and nitrate-free intervals. However, his review did not draw attention to an exciting new group of nitric oxide donor compounds: the Snitrosothiols. S-nitrosothiols (general formula RSNO, where R- is one of a range of chemical moieties) decompose to generate nitric oxide, a process that is accelerated in the presence of transition metal ions such as copper and reduced tissue thiols. Endogenous Snitrosothiols have been identified in human plasma, although their source
THE LANCET • Vol 354 • July 24, 1999