CCA-13896; No of Pages 4 Clinica Chimica Acta xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Invited critical review
Biological role of mannose binding lectin: From newborns to centenarians Manuela Scorza a,b, Renato Liguori a,b, Ausilia Elce a,c, Francesco Salvatore a,b, Giuseppe Castaldo a,b,⁎ a b c
CEINGE-Biotecnologie Avanzate scarl, Naples, Italy Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy Università Telematica Pegaso, Naples, Italy
a r t i c l e
i n f o
Article history: Received 11 September 2014 Received in revised form 4 March 2015 Accepted 8 March 2015 Available online xxxx Keywords: MBL Innate immunity Haplotypes Polymorphism
a b s t r a c t Mannose binding lectin (MBL) is a protein of innate immunity that activates the complement and promotes opsonophagocytosis. The deficiency of MBL due to several common gene polymorphisms significantly enhances the risk of severe infections, particularly in the neonatal age and in childhood. On the contrary, the role of the protein in carcinogenesis and atherogenesis is still debated: MBL has a relevant role against neoplastic cells, but some studies described a protective effect of low levels of MBL toward breast cancer and a longer survival of lung cancer patients with a reduced MBL activity. Similarly, some studies concluded on the protective role of low levels of MBL toward cardiovascular diseases while other focused on a higher risk of myocardial infarction in subjects with a deficient activity of the protein. More recently, a role of MBL in the clearance of senescent cells emerged, and a study in two large cohorts of centenarians demonstrated that a high biological activity of the protein enhances the risk of autoimmune diseases. This body of data strongly suggests that the optimal levels of MBL activity depend on the age and on the environmental context of each subject. © 2015 Elsevier B.V. All rights reserved.
Contents 1. Biological and genetic aspects of mannose binding lectin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. MBL deficiency significantly increases the risk for infections from neonatal age to adulthood . . . . . . . . . . . . . . 3. MBL deficiency and malignancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. MBL and cardiovascular diseases: a conflicting relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. If MBL deficiency has a series of negative effects, why is there a very high occurrence of MBL deficient subjects worldwide? 6. The word end to centenarians? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. To conclude … . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Biological and genetic aspects of mannose binding lectin Mannose binding lectin (MBL) is an acute phase protein bearing to the family of collectins produced by the liver as a monomer that forms a triple helix. Once released in serum, it further polymerizes forming dimers to octamers. The degree of serum polymerization is critical for the biological activity of MBL [1].
Abbreviations: MBL, mannose binding lectin (protein); MBL2, mannose binding lectin (gene). ⁎ Corresponding author at: CEINGE-Biotecnologie Avanzate, via G. Salvatore 486, 80145 Naples, Italy. E-mail address: [email protected] (G. Castaldo).
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Mannose binding lectin plays a pivotal role in innate immunity interacting with surface sugars of a wide series of microorganisms as a pattern-recognition receptor. Thus, MBL: i) activates the lectincomplement pathway; ii) promotes opsonophagocytosis [2]; and iii) modulates inflammation [1]. In detail: the binding of MBL and MBL-associated serine proteases (MASPs) to carbohydrates on the surface of microorganisms led to the activation of C2 and C4 that are cleaved to the C4bC2a complex that has a C3 convertase activity [3]. The MBL2 gene maps on the long arm of chromosome 10 at position 11.2 and includes 4 exons. Three polymorphisms in the promoter region of MBL2 were identified: H/L (nucleotide − 550), X/Y (nucleotide − 221) and P/Q (at the + 4 in the 5′ UTR). These
http://dx.doi.org/10.1016/j.cca.2015.03.007 0009-8981/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Scorza M, et al, Biological role of mannose binding lectin: From newborns to centenarians, Clin Chim Acta (2015), http:// dx.doi.org/10.1016/j.cca.2015.03.007
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M. Scorza et al. / Clinica Chimica Acta xxx (2015) xxx–xxx
polymorphisms reduce synthesis, serum levels and biological activity of the protein. Three other polymorphisms are found in exon 1 (codons 52, 54 and 57, called D, B and C alleles, respectively). They impair serum polymerization thus reducing the biological activity of MBL [1]. The six MBL2 polymorphisms are in linkage disequilibrium and their combination gives rise to seven more common haplotypes that display a high (HYPA and LYQA haplotypes), intermediate (LYPA haplotype), low (LXPA haplotype) or null (HYPD, LYPB, LYQC haplotypes) biological activity [4,5]. 2. MBL deficiency significantly increases the risk for infections from neonatal age to adulthood Low and null haplotypes of MBL2 confer a higher risk of severe infections, particularly in neonatal age when the specific protection by adaptive immunity is not yet active [1,6]. In particular, a reduced activity of MBL is a relevant risk factor for premature birth [7]. Another study on 365 critically ill neonates demonstrated that 104 neonates that had one or more septic events had significantly lower levels of serum MBL [8], and similarly, Schlapbach et al. [9] concluded that low serum MBL is a susceptibility factor for gram-negative neonatal sepsis. Also during childhood, the deficiency of MBL biological activity is related to a higher incidence and morbidity for infectious diseases like bronchiolitis [10] or pneumococcal [11] and meningococcal infections [12]. This is particularly true in critical patients, where the deficiency of MBL strongly predisposes to severe sepsis and septic shock [13]. For example, a study of 100 pediatric patients in intensive care unit demonstrated that the deficiency of MBL is a critical factor to determine the progression of sepsis to septic shock [14], while another study in leukemic patients during chemotherapy demonstrated a significantly higher susceptibility to bacterial infections in patients with low circulating levels of MBL [15]. An interesting topic is the role of MBL as a modifier factor of the phenotype in cystic fibrosis (CF) patients. In fact, it is long known that the clinical expression of CF is widely heterogeneous also among patients with the same genotype, and several studies described a discordant clinical expression at liver [16] and pulmonary level also in CF sib pairs, suggesting that modifier genes would modulate CF clinical expression [17]. A body of evidence indicates that the reduced activity of MBL or of MASP-2 in serum may be responsible for a poorer outcome in CF patients promoting the development of pulmonary bacterial colonization, and a meta-analysis related MBL insufficiency to an earlier acquisition of Pseudomonas aeruginosa colonization to a reduced pulmonary function in CF patients [18]. Our group also demonstrated that the risk in developing liver disease in CF patients may be modulated by an MBL2 deficient haplotype [19]. Finally, also in adulthood the deficiency of MBL activity may be responsible for more severe infections, while MBL2 haplotypes with higher activity have a protective role [20]. All body of evidence triggered a possible use of recombinant MBL in subjects bearing MBL insufficiency. A study in the mouse model demonstrated the efficacy of recombinant chimeric lectins again influenza A virus, most likely due to the cytokine activation by MBL [21]. More interestingly, recombinant MBL seems to be effective against Ebola in mice [22] because MBL binds to Ebola and Marburg envelope glycoproteins contributing to neutralization of the virus [23]. In humans, topical recombinant MBL treatment improved the therapy against Candida albicans vaginitis [24] and the use of systemic MBL recombinant therapy in CF patients with MBL deficiency has also been suggested [18].
of MBL. In fact, an MBL mediated complement effect was demonstrated on glioma cells 20 years ago and from that study, a series of evidences supported a role of MBL against neoplastic cells [25]. In fact, starting from that results pioneering therapeutic approaches based on MBL were evaluated with very encouraging results, such as the virusmediated MBL treatment of tumor cells [26] or the injection in mice tumors [27]. More recently, the deficiency of MBL was related to the risk of a large series of human neoplasia: our group [28] demonstrated a higher risk of gastric cancer in subjects colonized by Helicobacter pylori with a deficient MBL2 haplotype. In particular, we suggested that low MBL activity would enhance bacterial colonization of the gastric mucosa and reduce the down-regulation of IL-1 beta production, causing a reduced production of chloridric acid secretion thus increasing the risk of gastric cancer. Similar results were reported for liver cancer induced by Hepatitis C and several other human malignancies [25]. In addition to confer a higher risk for human malignancies, the deficiency of MBL may be responsible for a significantly higher rate of infectious complications in neoplastic patients during chemotherapy or after surgery [25]. This body of data suggested the use of an MBL replacement therapy in neoplastic patients with MBL deficiency, but among all such results, two discordant evidences appeared: a protective effect toward breast cancer of a variant MBL haplotype reported by Bernig et al. [29], and an improved survival in lung cancer patients with a defective MBL variant [30]. These last data strongly suggested performing large, multicentric studies in order to clarify the relationships between MBL and human neoplasia. 4. MBL and cardiovascular diseases: a conflicting relationship Myocardial reperfusion after ischemia triggers an inflammatory response that paradoxically counteracts the beneficial effects of the improved blood flow [31] and recruits either inflammatory or innate immunity mediators. Subsequently, studies in the mice model confirmed the disadvantageous effects of high biological activity of MBL in myocardial ischemic diseases, e.g., a high deposition of the protein in ischemic hearth, and the advantages of reduced MBL activity, e.g., the protection by cardiac damage and the reduction of the infarct area in MBL deficient mice [32]. More recent evidences in humans confirmed the beneficial effects of MBL deficiency in ischemic diseases: the reduced mortality for acute myocardial infarction reported in patients with MBL deficiency undergoing percutaneous coronary intervention; the long-lasting protection toward cerebral ischemia after the inhibition of MBL; the higher levels of MBL found in patients with unstable angina; and finally, the fatal outcome in an MBL deficient patient with myocardial infarction after MBL transfusion [31]. Opposite results were found by other studies: a prospective observation of about 20,000 subjects demonstrated a lower risk for myocardial infarction in subjects with high serum levels of MBL [32], and a higher occurrence of MBL deficiency was found in patients that experienced AMI [33]. Finally, we studied MBL haplotypes from 376 acute coronary syndrome patients and from 859 acute coronary syndrome with early onset patients, all from southern Italy at least from three generations [34]. As control group we referred to the data obtained in 553 subjects from the general population of southern Italy [28]. Our data exclude any association between MBL2 haplotypes and acute coronary syndrome [35], confirming the results of the DIGAMI 2 trial [36]. 5. If MBL deficiency has a series of negative effects, why is there a very high occurrence of MBL deficient subjects worldwide?
3. MBL deficiency and malignancy During neoplastic transformation, the cell-surface glycosylation is strongly modified and this renders neoplastic cells as potential target
Mannose binding lectin plays a relevant role in the immune system, in fact its sequence is among the most conserved in the phylogenesis [37]. On the other hand, we revised the myriad of negative effects due
Please cite this article as: Scorza M, et al, Biological role of mannose binding lectin: From newborns to centenarians, Clin Chim Acta (2015), http:// dx.doi.org/10.1016/j.cca.2015.03.007
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to MBL deficiency, particularly the higher morbidity and mortality for infectious and neoplastic diseases. Thus, it is surprising that MBL2 variants are so frequent worldwide that MBL deficiency is considered as the most frequent human immunodeficiency [1]. For example, we identified MBL variant haplotypes corresponding to intermediate, low or null activity in about 50% of the 550 subjects from the general population of southern Italy [28] and it has been estimated that 20–25% of subjects worldwide carry MBL2 haplotypes associated to low activity, and up to 8% of subjects have no detectable levels of serum MBL [38]. The selection of a very high percentage of MBL deficient subjects worldwide suggests that such condition must represent an evolutionary advantage and it has even been suggested that MBL plays a redundant role in human immunity and that MBL2 variants do not affect population fitness and thus, their frequency can increase [4]. On the other hand, differently from mice, that have two functioning MBL genes, in humans one of the two genes was silenced. A series of hypotheses were formulated on the possible advantages associated to MBL deficiency [38], namely, a less severe expression of rheumatoid arthritis, Sjögren disease, vasculitis, and Crohn's disease, whereas high MBL activity would cause more severe infections by intracellular pathogens that use C3 receptor to enter the host [1], e.g., visceral leishmaniasis and malaria. More recently, a protection of MBL deficient subjects toward lethal manifestation of atherosclerosis has been suggested [39] but also at this point the results are conflicting as discussed above.
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7. To conclude … The role of MBL in humans is a topic that is still open. In addition to its pivotal role in innate immunity, the protein participates in a myriad of biological processes, including carcinogenesis, atherogenesis and the clearance of senescent cells. The levels of MBL activity are widely heterogeneous in the general population and probably, the optimal levels of the protein change at different ages and in environmental contexts. In neonates and in childhood a high activity of MBL protects against infectious diseases and fatal sepsis; in adulthood, the optimal activity of the protein would confer some protection against cancer but a higher risk for cardiovascular diseases; while, the most advantageous MBL2 haplotypes for successful aging are those associated to intermediate levels of activity, and they seem to protect against the risk of autoimmune diseases. Globally, MBL in humans appears as the example of a system in a strong evolutionary equilibrium between factors that would reduce its biological activity (in the evolution between mice and humans one of the two genes encoding MBL was suppressed) and factors that press to maintain a high activity of the protein. Acknowledgments Grants from Regione Campania (DGRC 1901/09 and POR, FSE 2007–13, project CREME) are gratefully acknowledged. References
6. The word end to centenarians? In order to define the most advantageous MBL2 haplotype in humans, we studied such haplotypes in two large cohorts of healthy centenarians [40]. We recruited the first cohort in the frame of the AKEA study, in Sardinia island (Italy), in an area characterized by exceptional longevity, where an extraordinary number of validated centenarians had been observed [41]. The second cohort was recruited from Campania (southern Italy), particularly in the areas of Naples and Avellino. The study revealed that the frequency of MBL2 haplotypes associated to null activity was significantly low in centenarians (as expected, considering the adverse effects carried by such haplotypes). Surprisingly, also the frequency of high activity MBL2 haplotypes was significantly lower in centenarians as compared to the general population of the same ethnic group. On the contrary, most centenarians had intermediate activity haplotypes suggesting that such haplotypes would be the most advantageous to reach the finish line of 100 years. Furthermore, serum MBL concentration (also after normalization to serum albumin) was significantly lower in centenarians as compared to the general population. Thus, we tried to explain which would be the advantage carried by the intermediate MBL2 haplotypes. It was known that senescent cells remodulate their carbohydrate expression at membrane level [42], thus we hypothesized a role of MBL in the clearance of senescent cells. We assessed in vitro the effect of MBL on various human cells at different stages of senescence and demonstrated that MBL is bound to senescent IMR90 fibroblasts thereby causing cell lysis. In vivo we also speculated that MBL interacts with senescent cells contributing to their lysis and consequently, an excessively high activity of MBL may result in stronger activation of the complement that promotes the lysis of senescent cells. Increased activity of this system may lead to overexposure of antigens thereby trigging autoimmunity. Reduced activity of serum MBL (as observed in our centenarians that bear the intermediate MBL2 haplotype) may be associated to a less intense activity of MBL toward senescent cells, with the advantage of reduced autoimmune triggering. In fact, none of our centenarians has clinically evident autoimmune diseases and a review of their clinical record excludes previous relevant autoimmune disorders [40].
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[18] Chalmers JD, Fleming GB, Hill AT, Kilpatrick DC. Impact of mannose-binding lectin insufficiency on the course of cystic fibrosis: a review and meta-analysis. Glycobiology 2011;21:271–82. [19] Tomaiuolo R, Degiorgio D, Coviello DA, Baccarelli A, Elce A, Raia V, et al. An MBL2 haplotype and ABCB4 variants modulate the risk of liver disease in cystic fibrosis patients: a multicentric study. Dig Liver Dis 2009;41:817–22. [20] Scudiero O, Monaco ML, Nigro E, Capasso M, Guida M, Di Spiezio Sardo A. Mannosebinding lectin genetic analysis: possible protective role of the HYPA haplotype in the development of recurrent urinary tract infections in men. Int J Infect Dis 2014;19: 100–2. [21] Takahashi K, Moyo P, Chigweshe L, Chang WC, White MR, Hartshorn KL. Efficacy of recombinant chimeric lectins, consisting of mannose binding lectin and L-ficolin, against influenza A viral infection in mouse model study. Virus Res 2013;178: 495–501. [22] Michelow IC, Lear C, Scully C, Prugar LI, Longley CB, Yantosca LM, et al. High-dose mannose-binding lectin therapy for Ebola virus infection. J Infect Dis 2011;203: 175–9. [23] Ji X, Olinger GG, Aris S, Chen Y, Gewurz H, Spear GT. Mannose-binding lectin binds to Ebola and Marburg envelope glycoproteins, resulting in blocking of virus interaction with DC-SIGN and complement-mediated virus neutralization. J Infect Dis 2011;203: 175–9. [24] Clemons KV, Martinez M, Axelsen M, Thiel S, Stevens DA. Efficacy of recombinant human mannose binding lectin alone and in combination with itraconazole against murine Candida albicans vaginitis. Immunol Invest 2011;40:553–68. [25] Swierzko AS, Kilpatrick DC, Cedzynski M. Mannan-binding lectin in malignancy. Mol Immunol 2013;55:16–21. [26] Ma Y, Uemura K, Oka S, Kozutsumi Y, Kawasaki N, Kawasaki T. Antitumor activity of mannan-binding protein in vivo as revealed by a virus expression system: mannanbinding protein dependent cell-mediated cytotoxicity. Proc Natl Acad Sci U S A 1999;96:371–5. [27] Hirano M, Ma BY, Kawasaki N, Okimura K, Baba M, Nakagawa T, et al. Mannanbinding protein blocks the activation of metalloproteases meprin alpha and beta. J Immunol 2005;175:3177–85. [28] Scudiero O, Nardone G, Omodei D, Tatangelo F, Vitale DF, Salvatore F, et al. A mannose-binding lectin defective haplotype is a risk factor for gastric cancer. Clin Chem 2006;52:1625–7. [29] Bernig T, Boersma BJ, Howe TM, Welch R, Yadavalli S, Staats B, et al. The mannosebinding lectin (MBL2) haplotype and breast cancer: an association study in African-American and Caucasian women. Carcinogenesis 2007;28:828–36.
[30] Pine SR, Mechanic LE, Ambs S, Bowman ED, Chanock SJ, Loffredo C, et al. Lung cancer survival and functional polymorphisms in MBL2, an innate-immunity gene. J Natl Cancer Inst 2007;99:1401–9. [31] Pągowska-Klimek I, Cedzyński M. Mannan-binding lectin in cardiovascular disease. Biomed Res Int 2014;2014:616817. [32] Saevarsdottir S, Oskarsson OO, Aspelund T, Eiriksdottir G, Vikingsdottir T, Gudnason V, et al. Mannan binding lectin as an adjunct to risk assessment for myocardial infarction in individuals with enhanced risk. J Exp Med 2005;201:117–25. [33] Vengen IT, Madsen HO, Garred P, Platou C, Vatten L, Videm V. Mannose-binding lectin deficiency is associated with myocardial infarction: the HUNT2 study in Norway. PLoS One 2012;7:e42113. [34] Tomaiuolo R, Bellia C, Di Micco P, Elce A, Amato F, Lo Sasso B, et al. The implication of MBL deficient haplotypes in acute coronary syndrome. Exp Clin Cardiol 2014;20: 2716–9. [35] Tomaiuolo R, Bellia C, Caruso A, Di Fiore R, Quaranta S, Noto D, et al. Prothrombotic gene variants as risk factors of acute myocardial infarction in young women. J Transl Med 2012;10:235–9. [36] Mellbin LG, Hamsten A, Malmberg K, Steffensen R, Rydén L, Ohrvik J, et al. Mannosebinding lectin genotype and phenotype in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Diabetes Care 2010;33: 2451–6. [37] Verga Falzacappa MV, Segat L, Puppini B, Amoroso A, Crovella S. Evolution of the mannose binding lectin gene in primates. Genes Immunol 2004;5:653–61. [38] Eisen DP, Osthoff M. If there is an evolutionary selection pressure for the high frequency of MBL2 polymorphisms, what is it? Clin Exp Immunol 2013;176:165–71. [39] Hellmann D, Larsson A, Madsen HO, Bonde J, Jarlov JO, Wiis J, et al. Heterozygosity of mannose-binding lectin (MBL2) genotypes predicts advantage (heterosis) in relation to fatal outcome in intensive care patients. Hum Mol Genet 2007;16:3071–80. [40] Tomaiuolo R, Ruocco A, Salapete C, Carru C, Baggio G, Franceschi C, et al. Activity of mannose-binding lectin (MBL) in centenarians. Aging Cell 2012;11:394–400. [41] Deiana L, Ferrucci L, Pes GM, Carru C, Delitala G, Ganau A, et al. AKentAnnos. The Sardinia study of extreme longevity. Aging 1999;11:142–9. [42] Blondal JA, Dick JE, Wright JA. Membrane glycoprotein changes during the senescence of normal human diploid fibroblasts in culture. Mech Ageing Dev 1985;30: 273–83.
Please cite this article as: Scorza M, et al, Biological role of mannose binding lectin: From newborns to centenarians, Clin Chim Acta (2015), http:// dx.doi.org/10.1016/j.cca.2015.03.007
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Invited critical review
Biological role of mannose binding lectin: From newborns to centenarians Manuela Scorza a,b, Renato Liguori a,b, Ausilia Elce a,c, Francesco Salvatore a,b, Giuseppe Castaldo a,b,⁎ a b c
CEINGE-Biotecnologie Avanzate scarl, Naples, Italy Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy Università Telematica Pegaso, Naples, Italy
a r t i c l e
i n f o
Article history: Received 11 September 2014 Received in revised form 4 March 2015 Accepted 8 March 2015 Available online xxxx Keywords: MBL Innate immunity Haplotypes Polymorphism
a b s t r a c t Mannose binding lectin (MBL) is a protein of innate immunity that activates the complement and promotes opsonophagocytosis. The deficiency of MBL due to several common gene polymorphisms significantly enhances the risk of severe infections, particularly in the neonatal age and in childhood. On the contrary, the role of the protein in carcinogenesis and atherogenesis is still debated: MBL has a relevant role against neoplastic cells, but some studies described a protective effect of low levels of MBL toward breast cancer and a longer survival of lung cancer patients with a reduced MBL activity. Similarly, some studies concluded on the protective role of low levels of MBL toward cardiovascular diseases while other focused on a higher risk of myocardial infarction in subjects with a deficient activity of the protein. More recently, a role of MBL in the clearance of senescent cells emerged, and a study in two large cohorts of centenarians demonstrated that a high biological activity of the protein enhances the risk of autoimmune diseases. This body of data strongly suggests that the optimal levels of MBL activity depend on the age and on the environmental context of each subject. © 2015 Elsevier B.V. All rights reserved.
Contents 1. Biological and genetic aspects of mannose binding lectin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. MBL deficiency significantly increases the risk for infections from neonatal age to adulthood . . . . . . . . . . . . . . 3. MBL deficiency and malignancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. MBL and cardiovascular diseases: a conflicting relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. If MBL deficiency has a series of negative effects, why is there a very high occurrence of MBL deficient subjects worldwide? 6. The word end to centenarians? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. To conclude … . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Biological and genetic aspects of mannose binding lectin Mannose binding lectin (MBL) is an acute phase protein bearing to the family of collectins produced by the liver as a monomer that forms a triple helix. Once released in serum, it further polymerizes forming dimers to octamers. The degree of serum polymerization is critical for the biological activity of MBL [1].
Abbreviations: MBL, mannose binding lectin (protein); MBL2, mannose binding lectin (gene). ⁎ Corresponding author at: CEINGE-Biotecnologie Avanzate, via G. Salvatore 486, 80145 Naples, Italy. E-mail address: [email protected] (G. Castaldo).
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Mannose binding lectin plays a pivotal role in innate immunity interacting with surface sugars of a wide series of microorganisms as a pattern-recognition receptor. Thus, MBL: i) activates the lectincomplement pathway; ii) promotes opsonophagocytosis [2]; and iii) modulates inflammation [1]. In detail: the binding of MBL and MBL-associated serine proteases (MASPs) to carbohydrates on the surface of microorganisms led to the activation of C2 and C4 that are cleaved to the C4bC2a complex that has a C3 convertase activity [3]. The MBL2 gene maps on the long arm of chromosome 10 at position 11.2 and includes 4 exons. Three polymorphisms in the promoter region of MBL2 were identified: H/L (nucleotide − 550), X/Y (nucleotide − 221) and P/Q (at the + 4 in the 5′ UTR). These
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Please cite this article as: Scorza M, et al, Biological role of mannose binding lectin: From newborns to centenarians, Clin Chim Acta (2015), http:// dx.doi.org/10.1016/j.cca.2015.03.007
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M. Scorza et al. / Clinica Chimica Acta xxx (2015) xxx–xxx
polymorphisms reduce synthesis, serum levels and biological activity of the protein. Three other polymorphisms are found in exon 1 (codons 52, 54 and 57, called D, B and C alleles, respectively). They impair serum polymerization thus reducing the biological activity of MBL [1]. The six MBL2 polymorphisms are in linkage disequilibrium and their combination gives rise to seven more common haplotypes that display a high (HYPA and LYQA haplotypes), intermediate (LYPA haplotype), low (LXPA haplotype) or null (HYPD, LYPB, LYQC haplotypes) biological activity [4,5]. 2. MBL deficiency significantly increases the risk for infections from neonatal age to adulthood Low and null haplotypes of MBL2 confer a higher risk of severe infections, particularly in neonatal age when the specific protection by adaptive immunity is not yet active [1,6]. In particular, a reduced activity of MBL is a relevant risk factor for premature birth [7]. Another study on 365 critically ill neonates demonstrated that 104 neonates that had one or more septic events had significantly lower levels of serum MBL [8], and similarly, Schlapbach et al. [9] concluded that low serum MBL is a susceptibility factor for gram-negative neonatal sepsis. Also during childhood, the deficiency of MBL biological activity is related to a higher incidence and morbidity for infectious diseases like bronchiolitis [10] or pneumococcal [11] and meningococcal infections [12]. This is particularly true in critical patients, where the deficiency of MBL strongly predisposes to severe sepsis and septic shock [13]. For example, a study of 100 pediatric patients in intensive care unit demonstrated that the deficiency of MBL is a critical factor to determine the progression of sepsis to septic shock [14], while another study in leukemic patients during chemotherapy demonstrated a significantly higher susceptibility to bacterial infections in patients with low circulating levels of MBL [15]. An interesting topic is the role of MBL as a modifier factor of the phenotype in cystic fibrosis (CF) patients. In fact, it is long known that the clinical expression of CF is widely heterogeneous also among patients with the same genotype, and several studies described a discordant clinical expression at liver [16] and pulmonary level also in CF sib pairs, suggesting that modifier genes would modulate CF clinical expression [17]. A body of evidence indicates that the reduced activity of MBL or of MASP-2 in serum may be responsible for a poorer outcome in CF patients promoting the development of pulmonary bacterial colonization, and a meta-analysis related MBL insufficiency to an earlier acquisition of Pseudomonas aeruginosa colonization to a reduced pulmonary function in CF patients [18]. Our group also demonstrated that the risk in developing liver disease in CF patients may be modulated by an MBL2 deficient haplotype [19]. Finally, also in adulthood the deficiency of MBL activity may be responsible for more severe infections, while MBL2 haplotypes with higher activity have a protective role [20]. All body of evidence triggered a possible use of recombinant MBL in subjects bearing MBL insufficiency. A study in the mouse model demonstrated the efficacy of recombinant chimeric lectins again influenza A virus, most likely due to the cytokine activation by MBL [21]. More interestingly, recombinant MBL seems to be effective against Ebola in mice [22] because MBL binds to Ebola and Marburg envelope glycoproteins contributing to neutralization of the virus [23]. In humans, topical recombinant MBL treatment improved the therapy against Candida albicans vaginitis [24] and the use of systemic MBL recombinant therapy in CF patients with MBL deficiency has also been suggested [18].
of MBL. In fact, an MBL mediated complement effect was demonstrated on glioma cells 20 years ago and from that study, a series of evidences supported a role of MBL against neoplastic cells [25]. In fact, starting from that results pioneering therapeutic approaches based on MBL were evaluated with very encouraging results, such as the virusmediated MBL treatment of tumor cells [26] or the injection in mice tumors [27]. More recently, the deficiency of MBL was related to the risk of a large series of human neoplasia: our group [28] demonstrated a higher risk of gastric cancer in subjects colonized by Helicobacter pylori with a deficient MBL2 haplotype. In particular, we suggested that low MBL activity would enhance bacterial colonization of the gastric mucosa and reduce the down-regulation of IL-1 beta production, causing a reduced production of chloridric acid secretion thus increasing the risk of gastric cancer. Similar results were reported for liver cancer induced by Hepatitis C and several other human malignancies [25]. In addition to confer a higher risk for human malignancies, the deficiency of MBL may be responsible for a significantly higher rate of infectious complications in neoplastic patients during chemotherapy or after surgery [25]. This body of data suggested the use of an MBL replacement therapy in neoplastic patients with MBL deficiency, but among all such results, two discordant evidences appeared: a protective effect toward breast cancer of a variant MBL haplotype reported by Bernig et al. [29], and an improved survival in lung cancer patients with a defective MBL variant [30]. These last data strongly suggested performing large, multicentric studies in order to clarify the relationships between MBL and human neoplasia. 4. MBL and cardiovascular diseases: a conflicting relationship Myocardial reperfusion after ischemia triggers an inflammatory response that paradoxically counteracts the beneficial effects of the improved blood flow [31] and recruits either inflammatory or innate immunity mediators. Subsequently, studies in the mice model confirmed the disadvantageous effects of high biological activity of MBL in myocardial ischemic diseases, e.g., a high deposition of the protein in ischemic hearth, and the advantages of reduced MBL activity, e.g., the protection by cardiac damage and the reduction of the infarct area in MBL deficient mice [32]. More recent evidences in humans confirmed the beneficial effects of MBL deficiency in ischemic diseases: the reduced mortality for acute myocardial infarction reported in patients with MBL deficiency undergoing percutaneous coronary intervention; the long-lasting protection toward cerebral ischemia after the inhibition of MBL; the higher levels of MBL found in patients with unstable angina; and finally, the fatal outcome in an MBL deficient patient with myocardial infarction after MBL transfusion [31]. Opposite results were found by other studies: a prospective observation of about 20,000 subjects demonstrated a lower risk for myocardial infarction in subjects with high serum levels of MBL [32], and a higher occurrence of MBL deficiency was found in patients that experienced AMI [33]. Finally, we studied MBL haplotypes from 376 acute coronary syndrome patients and from 859 acute coronary syndrome with early onset patients, all from southern Italy at least from three generations [34]. As control group we referred to the data obtained in 553 subjects from the general population of southern Italy [28]. Our data exclude any association between MBL2 haplotypes and acute coronary syndrome [35], confirming the results of the DIGAMI 2 trial [36]. 5. If MBL deficiency has a series of negative effects, why is there a very high occurrence of MBL deficient subjects worldwide?
3. MBL deficiency and malignancy During neoplastic transformation, the cell-surface glycosylation is strongly modified and this renders neoplastic cells as potential target
Mannose binding lectin plays a relevant role in the immune system, in fact its sequence is among the most conserved in the phylogenesis [37]. On the other hand, we revised the myriad of negative effects due
Please cite this article as: Scorza M, et al, Biological role of mannose binding lectin: From newborns to centenarians, Clin Chim Acta (2015), http:// dx.doi.org/10.1016/j.cca.2015.03.007
M. Scorza et al. / Clinica Chimica Acta xxx (2015) xxx–xxx
to MBL deficiency, particularly the higher morbidity and mortality for infectious and neoplastic diseases. Thus, it is surprising that MBL2 variants are so frequent worldwide that MBL deficiency is considered as the most frequent human immunodeficiency [1]. For example, we identified MBL variant haplotypes corresponding to intermediate, low or null activity in about 50% of the 550 subjects from the general population of southern Italy [28] and it has been estimated that 20–25% of subjects worldwide carry MBL2 haplotypes associated to low activity, and up to 8% of subjects have no detectable levels of serum MBL [38]. The selection of a very high percentage of MBL deficient subjects worldwide suggests that such condition must represent an evolutionary advantage and it has even been suggested that MBL plays a redundant role in human immunity and that MBL2 variants do not affect population fitness and thus, their frequency can increase [4]. On the other hand, differently from mice, that have two functioning MBL genes, in humans one of the two genes was silenced. A series of hypotheses were formulated on the possible advantages associated to MBL deficiency [38], namely, a less severe expression of rheumatoid arthritis, Sjögren disease, vasculitis, and Crohn's disease, whereas high MBL activity would cause more severe infections by intracellular pathogens that use C3 receptor to enter the host [1], e.g., visceral leishmaniasis and malaria. More recently, a protection of MBL deficient subjects toward lethal manifestation of atherosclerosis has been suggested [39] but also at this point the results are conflicting as discussed above.
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7. To conclude … The role of MBL in humans is a topic that is still open. In addition to its pivotal role in innate immunity, the protein participates in a myriad of biological processes, including carcinogenesis, atherogenesis and the clearance of senescent cells. The levels of MBL activity are widely heterogeneous in the general population and probably, the optimal levels of the protein change at different ages and in environmental contexts. In neonates and in childhood a high activity of MBL protects against infectious diseases and fatal sepsis; in adulthood, the optimal activity of the protein would confer some protection against cancer but a higher risk for cardiovascular diseases; while, the most advantageous MBL2 haplotypes for successful aging are those associated to intermediate levels of activity, and they seem to protect against the risk of autoimmune diseases. Globally, MBL in humans appears as the example of a system in a strong evolutionary equilibrium between factors that would reduce its biological activity (in the evolution between mice and humans one of the two genes encoding MBL was suppressed) and factors that press to maintain a high activity of the protein. Acknowledgments Grants from Regione Campania (DGRC 1901/09 and POR, FSE 2007–13, project CREME) are gratefully acknowledged. References
6. The word end to centenarians? In order to define the most advantageous MBL2 haplotype in humans, we studied such haplotypes in two large cohorts of healthy centenarians [40]. We recruited the first cohort in the frame of the AKEA study, in Sardinia island (Italy), in an area characterized by exceptional longevity, where an extraordinary number of validated centenarians had been observed [41]. The second cohort was recruited from Campania (southern Italy), particularly in the areas of Naples and Avellino. The study revealed that the frequency of MBL2 haplotypes associated to null activity was significantly low in centenarians (as expected, considering the adverse effects carried by such haplotypes). Surprisingly, also the frequency of high activity MBL2 haplotypes was significantly lower in centenarians as compared to the general population of the same ethnic group. On the contrary, most centenarians had intermediate activity haplotypes suggesting that such haplotypes would be the most advantageous to reach the finish line of 100 years. Furthermore, serum MBL concentration (also after normalization to serum albumin) was significantly lower in centenarians as compared to the general population. Thus, we tried to explain which would be the advantage carried by the intermediate MBL2 haplotypes. It was known that senescent cells remodulate their carbohydrate expression at membrane level [42], thus we hypothesized a role of MBL in the clearance of senescent cells. We assessed in vitro the effect of MBL on various human cells at different stages of senescence and demonstrated that MBL is bound to senescent IMR90 fibroblasts thereby causing cell lysis. In vivo we also speculated that MBL interacts with senescent cells contributing to their lysis and consequently, an excessively high activity of MBL may result in stronger activation of the complement that promotes the lysis of senescent cells. Increased activity of this system may lead to overexposure of antigens thereby trigging autoimmunity. Reduced activity of serum MBL (as observed in our centenarians that bear the intermediate MBL2 haplotype) may be associated to a less intense activity of MBL toward senescent cells, with the advantage of reduced autoimmune triggering. In fact, none of our centenarians has clinically evident autoimmune diseases and a review of their clinical record excludes previous relevant autoimmune disorders [40].
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