Mannose-binding Lectin (MBL) and Vascular Complications in Diabetes

Abstract

The complement system has evolved over time as an effective part of the immune system, acting effectively in frontline combat against invading microorganisms. Unfortunately, any war might involve ”collateral damage”, and emerging data indicate that activation of the complement system may cause damage to innocent bystander cells and tissues in some situations. This may apply to complement activation and inflammation as it occurs following myocardial ischemia and reperfusion, which is know to aggravate the subsequent myocardial injury; and it has recently been proposed that complement activation may be an important factor in the development of diabetic renal complications. Mannose-binding lectin (MBL, also known as mannan-binding lectin) is a plasma protein that activates the complement cascade after binding to carbohydrate structures. Circulating MBL levels vary widely from person to person, which is mainly due to frequently occurring polymorphisms within the encoding gene on chromosome 10. One may speculate that these genetically determined differences in MBL levels and hence in complement activation may play a role in existing familial clustering in both cardiovascular disease and diabetes-related vascular complications. The present review will focus on the function of MBL and the complement system, and on recent data indicating an association between MBL status and diabetic micro- and macrovascular complications.

Key words

MBL - Mannose-binding lectin - Diabetic nephropathy - Type 1 diabetes - Complement

References

• 1 Walport M J. Complement. First of two parts.  N Engl J Med. 2001;  344 1058-1066
• 2 Walport M J. Complement. Second of two parts.  N Engl J Med. 2001;  344 1140-1144
• 3 Thiel S, Reid K B. Structures and functions associated with the group of mammalian lectins containing collagen-like sequences.  FEBS Lett. 1989;  250 78-84
• 4 Petersen S V, Thiel S, Jensenius J C. The mannan-binding lectin pathway of complement activation: biology and disease association.  Mol Immunol. 2001;  38 133-149
• 5 Hansen T K, Thiel S, Wouters P J. et al . Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels.  J Clin Endocrinol Metab. 2003;  88 1082-1088
• 6 Steffensen R, Thiel S, Varming K. et al . Detection of structural gene mutations and promoter polymorphisms in the mannan-binding lectin (MBL) gene by polymerase chain reaction with sequence-specific primers.  J Immunol Methods. 2000;  241 33-42
• 7 Hansen T K, Thiel S, Dall R. et al . GH strongly affects serum concentrations of mannan-binding lectin: evidence for a new IGF-I independent immunomodulatory effect of GH.  J Clin Endocrinol Metab. 2001;  86 5383-5388
• 8 Nielsen S L, Andersen P L, Koch C. et al . The level of the serum opsonin, mannan-binding protein in HIV-1 antibody-positive patients.  Clin Exp Immunol. 1995;  100 219-222
• 9 Hansen T K, Tarnow L, Thiel S. et al . Association between mannose-binding lectin and vascular complications in type 1 diabetes.  Diabetes. 2004;  53 1570-1576
• 10 Naito H, Ikeda A, Hasegawa K. et al . Characterization of human serum mannan-binding protein promoter.  J Biochem (Tokyo). 1999;  126 1004-1012
• 11 Turner M W. Mannose-binding lectin: the pluripotent molecule of the innate immune system.  Immunol Today. 1996;  17 532-540
• 12 Thiel S, Vorup-Jensen T, Stover C M. et al . A second serine protease associated with mannan-binding lectin that activates complement.  Nature. 1997;  386 506-510
• 13 Neth O, Jack D L, Dodds A W. et al . Mannose-binding lectin binds to a range of clinically relevant microorganisms and promotes complement deposition.  Infect Immun. 2000;  68 688-693
• 14 Super M, Thiel S, Lu J. et al . Association of low levels of mannan-binding protein with a common defect of opsonisation.  Lancet. 1989;  2 1236-1239
• 15 Summerfield J A, Ryder S, Sumiya M. et al . Mannose binding protein gene mutations associated with unusual and severe infections in adults.  Lancet. 1995;  345 886-889
• 16 Summerfield J A, Sumiya M, Levin M. et al . Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series.  BMJ. 1997;  314 1229-1232
• 17 Garred P, Madsen H O, Hofmann B. et al . Increased frequency of homozygosity of abnormal mannan-binding-protein alleles in patients with suspected immunodeficiency.  Lancet. 1995;  346 941-943
• 18 Garred P, Madsen H O, Balslev U. et al . Susceptibility to HIV infection and progression of AIDS in relation to variant alleles of mannose-binding lectin.  Lancet. 1997 ;  349 236-240
• 19 Garred P, Pressler T, Madsen H O. et al . Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis.  J Clin Invest. 1999;  104 431-437
• 20 Koch A, Melbye M, Sorensen P. et al . Acute respiratory tract infections and mannose-binding lectin insufficiency during early childhood.  JAMA. 2001;  285 1316-1321
• 21 Peterslund N A, Koch C, Jensenius J C. et al . Association between deficiency of mannose-binding lectin and severe infections after chemotherapy.  Lancet. 2001;  358 637-638
• 22 Neth O, Hann I, Turner M W. et al . Deficiency of mannose-binding lectin and burden of infection in children with malignancy: a prospective study.  Lancet. 2001;  358 614-618
• 23 Garred P, Strom J, Quist L. et al . Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome.  J Infect Dis. 2003;  188 1394-1403
• 24 Fidler K J, Wilson P, Davies J C. et al . Increased incidence and severity of the systemic inflammatory response syndrome in patients deficient in mannose-binding lectin.  Intensive Care Med.. 2004;  30 1438-1445
• 25 Turner M W, Hamvas R M. Mannose-binding lectin: structure, function, genetics and disease associations.  Rev Immunogenet. 2000;  2 305-322
• 26 Kilpatrick D C. Mannan-binding lectin and its role in innate immunity.  Transfus Med. 2002;  12 335-352
• 27 Lipscombe R J, Sumiya M, Hill A V. et al . High frequencies in African and non-African populations of independent mutations in the mannose binding protein gene [published erratum appears in Hum Mol Genet 1993 Mar; 2(3): 342].  Hum Mol Genet. 1992;  1 709-715
• 28 Malhotra R, Wormald M R, Rudd P M. et al . Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein.  Nat Med. 1995;  1 237-243
• 29 Collard C D, Lekowski R, Jordan J E. et al . Complement activation following oxidative stress.  Mol Immunol. 1999;  36 941-948
• 30 Collard C D, Vakeva A, Morrissey M A. et al . Complement activation after oxidative stress: role of the lectin complement pathway.  Am J Pathol. 2000;  156 1549-1556
• 31 Collard C D, Montalto M C, Reenstra W R. et al . Endothelial oxidative stress activates the lectin complement pathway: role of cytokeratin 1.  Am J Pathol. 2001;  159 1045-1054
• 32 Jordan J E, Montalto M C, Stahl G L. Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusion injury.  Circulation. 2001;  104 1413-1418
• 33 Granger C B, Mahaffey K W, Weaver W D. et al . Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction: the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial.  Circulation. 2003;  108 1184-1190
• 34 Schalkwijk C G, Poland D C, van Dijk W. et al . Plasma concentration of C-reactive protein is increased in type I diabetic patients without clinical macroangiopathy and correlates with markers of endothelial dysfunction: evidence for chronic inflammation.  Diabetologia. 1999;  42 351-357
• 35 Jager A, van Hinsbergh V W, Kostense P J. et al . von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study. Arterioscler.  Thromb Vasc Biol. 1999;  19 3071-3078
• 36 Mogensen C E. Genetics and Diabetic Renal Disease - Still a Big Black Hole.  Diabetes Care. 2003;  26 1631-1632
• 37 Seaquist E R, Goetz F C, Rich S. et al . Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy.  N Engl J Med. 1989;  320 1161-1165
• 38 Acosta J, Hettinga J, Fluckiger R. et al . Molecular basis for a link between complement and the vascular complications of diabetes.  Proc Natl Acad Sci USA. 2000;  97 5450-5455
• 39 Hsu S I, Couser W G. Chronic progression of tubulointerstitial damage in proteinuric renal disease is mediated by complement activation: a therapeutic role for complement inhibitors?.  J Am Soc Nephrol. 2003;  14 S186-S191
• 40 Uesugi N, Sakata N, Nangaku M. et al . Possible mechanism for medial smooth muscle cell injury in diabetic nephropathy: glycoxidation-mediated local complement activation.  Am J Kidney Dis. 2004;  44 224-238
• 41 Endo M, Ohi H, Ohsawa I. et al . Complement activation through the lectin pathway in patients with Henoch-Schonlein purpura nephritis.  Am J Kidney Dis. 2000;  35 401-407
• 42 Endo M, Ohi H, Ohsawa I. et al . Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy.  Nephrol Dial Transplant. 1998;  13 1984-1990
• 43 de Vries B, Walter S J, Peutz-Kootstra C J. et al . The mannose-binding lectin-pathway is involved in complement activation in the course of renal ischemia-reperfusion injury.  Am J Pathol. 2004;  165 1677-1688
• 44 Hansen T K, Thiel S, Knudsen S T. et al . Elevated levels of mannan-binding lectin in patients with type 1 diabetes.  J Clin Endocrinol Metab. 2003;  88 4857-4861
• 45 Saraheimo M, Forsblom C, Hansen T K. et al . Increased levels of mannan-binding lectin (MBL) in type 1 diabetic patients with incipient and overt nephropathy.  Diabetologia. 2005;  48 198-202
• 46 Fiane A E, Videm V, Lingaas P S. et al . Mechanism of Complement Activation and Its Role in the Inflammatory Response After Thoracoabdominal Aortic Aneurysm Repair.  Circulation. 2003;  108 849-856
• 47 Mathew V, Gersh B J, Williams B A. et al . Outcomes in patients with diabetes mellitus undergoing percutaneous coronary intervention in the current era: a report from the Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial.  Circulation. 2004;  109 476-480
• 48 Hovind P, Hansen T, Tarnow L. et al . Mannose-Binding Lectin as a predictor of microalbuminuria in type 1 diabetes - An inception cohort study.  Diabetes. 2005;  54 1523-1527