Lectin pathway proteins deficiency of the complement system activation in the Arctic population
Introduction. The genetically determined defects in the lectin pathway of the complement system activation have various clinical consequences for a particular individual. The hypothesis of lectin pathway redundancy suggests that it is not required for the normal functioning of the immune system in modern humans other than early childhood.
The aim of the study was to analyze the prevalence of polymorphic variants FCN3 and MASP2 among newborns of the Siberian Arctic populations (Nenets and Dolgans-Nganasans) and Russians of Eastern Siberia along with genetic data on the frequency of genotypes and haplotypes for the genes of other lectin pathway proteins of the complement system (MBL and L-ficolin).
Material and methods. DNA samples from newborns represented by three populations, i.e. Nenets, Dolgans-Nganasans and Russians (Caucasoids) analyzed by RT-PCR.
Results. The prevalence of the del rs532781899 FCN3 variant, which associated with reduced production of H-ficolin, was found to be increased in Russians compared to the aboriginal population of the Nenets (p = 0.002). The G rs72550870 MASP2 allele, which associated with low activity of the serum protease MASP-2, is increased in Russians compared to the Nenets and Dolgans-Nganasans (p < 0.001 and p = 0.03, respectively). The deficient variant of the MBL2 haplotype is more common in Russians than in other populations (p < 0.001).
Conclusion. The results of our studies have confirmed a hypothesis that human evolution in populations with historically higher hygienic and medical protection at an early age was aimed at accumulating the genotypes associated with low lectin pathway activity of complement activation.
Keywords:lectin pathway; complement; lectins; ficolins; serine proteases; MBL; FCN; MASP; gene polymorphism; Arctic populations
For citation: Smolnikova M.V., Tereshchenko S.Yu. Lectin pathway proteins deficiency of the complement system activation in the Arctic population. Immunologiya. 2023; 44 (4): 455–62. DOI: https://doi.org/10.33029/0206-4952-2023-44-4-455-462 (in Russian)
Funding. The study was supported within the framework of the state budgetary theme for Federal Research Center «Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences», Research Institute of Medical Problems of the North, Krasnoyarsk, Russian Federation
Conflict of interests. The authors declare no conflict of interests.
Authors’ contribution. Study conception, statistical analysis, text writing and editing – Tereshchenko S.Yu., Smolnikova M.V.; collection and processing of material – Smolnikova M.V.
1. Janeway C.A. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989; 54 (1): 1–13. DOI: https://www.doi.org/10.1101/sqb.1989.054.01.003
2. Pinegin B.V., Khaitov R.M. Modern principles of immunotropic drugs creation. Immunologiya. 2019; 40. DOI: https://www.doi.org/10.24411/0206-4952-2019-16008 (in Russian)
3. Sancho D., Reis e Sousa C. Signaling by myeloid C-type lectin receptors in immunity and homeostasis. Annu Rev Immunol. 2012; 30: 491–529. DOI: https://www.doi.org/10.1146/annurev-immunol-031210-101352
4. Garred P., Genster N., Pilely K., et al. A journey through the lectin pathway of complement-MBL and beyond. Immunol Rev. 2016; 274: 74–97. doi:10.1111/imr.12468.
5. Hummelshoj T., Munthe-Fog L., Madsen H.O., et al. Polymorphisms in the FCN2 gene determine serum variation and function of Ficolin-2 Hum Mol Genet. 2005; 14: 1651–1658. doi:10.1093/hmg/ddi173.
6. Sallenbach S., Thiel S., Aebi C., et al. Serum concentrations of lectin-pathway components in healthy neonates, children and adults: mannan-binding lectin (MBL), M-, L-, and H-ficolin, and MBL-associated serine protease-2 (MASP-2). Pediatr Allergy Immunol Off Publ Eur Soc Pediatr Allergy Immunol. 2011; 22: 424–430. DOI: https://www.doi.org/10.1111/j.1399-3038.2010.01104.x
7. Michalski M., St. Swierzko A., Lukasiewicz J., et al. Ficolin-3 activity towards the opportunistic pathogen, Hafnia alvei. Immunobiology. 2015; 220: 117–23. DOI: https://www.doi.org/10.1016/j.imbio.2014.08.012
8. Bjarnadottir H., Arnardottir M., Ludviksson B.R. Frequency and distribution of FCN2 and FCN3 functional variants among MBL2 genotypes. Immunogenetics. 2016; 68: 315–25.
9. Boldyreva M.N. SARS-CoV-2 virus and other epidemic coronaviruses: pathogenetic and genetic factors for the development of infections. Immunologiya. 2020; 41: 197–205. DOI: https://www.doi.org/10.33029/0206-4952-2020-41-3-197-205 (in Russian)
10. Ali Y.M., Ferrari M., Lynch N.J., et al. Lectin pathway mediates complement activation by SARS-CoV-2 proteins. Frontiers in Immunology. 2021; 12. DOI: https://doi.org/10.3389/fimmu.2021.714511
11. Smolnikova M.V., Freidin M.B., Tereshchenko S.Yu. The prevalence of the variants of the L-ficolin gene (FCN2) in the arctic populations of East Siberia. Immunogenetics. 2017; 69: 409–13. DOI: https://www.doi.org/10.1007/s00251-017-0984-8
12. Tereshchenko S.Y., Smolnikova M.V., Freidin M.B. Mannose-binding lectin gene polymorphisms in the East Siberia and Russian Arctic populations. Immunogenetics 2020; 72: 347–54. DOI: https://www.doi.org/10.1007/s00251-020-01175-5
13. Smolnikova M.V., Tereshchenko S.Yu. Prevalence of the polymorphic H-ficolin (FCN3) genes and mannose-binding lectin-associated serine protease-2 (MASP2) in indigenous populations from the Russian Arctic regions. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2022; 25 (8): 847–54. DOI: https://www.doi.org/10.18699/VJ21.098 (in Russian)
14. Michalski M., Szala A., St. Swierzko A., et al. H-ficolin (ficolin-3) concentrations and FCN3 gene polymorphism in neonates. Immunobiology. 2012; 217: 730–7. DOI: https://www.doi.org/10.1016/j.imbio.2011.12.004
15. Metzger M.L., Michelfelder I., Goldacker S., et al. Low ficolin-2 levels in common variable immunodeficiency patients with bronchiectasis. Clin Exp Immunol 2015; 179: 256–64. DOI: https://www.doi.org/10.1111/cei.12459
16. Fu J., Wang J., Luo Y., et al. Association between MASP-2 gene polymorphism and risk of infection diseases: A meta-analysis. Microb Pathog. 2016; 100: 221–8. DOI: https://www.doi.org/10.1016/j.micpath.2016.10.004
17. Garred P., Honoré C., Ma Y.J., et al. MBL2, FCN1, FCN2 and FCN3-The genes behind the initiation of the lectin pathway of complement. Mol Immunol. 2009; 46: 2737–44. DOI: https://www.doi.org/10.1016/j.molimm.2009.05.005
18. Monsey L., Best L.G., Zhu J., et al. The association of mannose binding lectin genotype and immune response to Chlamydia pneumoniae: The Strong Heart Study. PLoS One. 2019; 14: e0210640. DOI: https://www.doi.org/10.1371/journal.pone.0210640
19. Wallis R., Lynch N. J. Biochemistry and genetics of the collectins. In: Collagen-related lectins in innate immunity Research Signpost, Kerala. Kilpatrick D., eds. 2007: 33–56.
20. Koch A., Melbye M., Sørensen P., et al. Acute respiratory tract infections and mannose-binding lectin insufficiency during early childhood. JAMA. 2001; 285: 1316–21. DOI: https://www.doi.org/10.1001/jama.285.10.1316
21. Swierzko A.S., Atkinson A.P., Cedzynski M., et al. Two factors of the lectin pathway of complement, l-ficolin and mannan-binding lectin, and their associations with prematurity, low birthweight and infections in a large cohort of Polish neonates. J Clin Immunol. 2009; 46 (4): 551–8. DOI: https://www.doi.org/10.1016/j.molimm.2008.07.025
22. García-Laorden M.I., Hernández-Brito E., Muñoz-Almagro C., et al. Should MASP-2 deficiency be considered a primary immunodeficiency? Relevance of the lectin pathway. Journal of Clinical Immunology. 2020; 40: 203–10. DOI: https://www.doi.org/10.1007/s10875-019-00714-4
23. van Kempen G., Meijvis S., Endeman H., et al. Mannose-binding lectin and l-ficolin polymorphisms in patients with community-acquired pneumonia caused by intracellular pathogens. Immunology. 2017; 151: 81–88. doi:10.1111/imm.12705
24. Young J.A., Pallas C.R., Knovich M.A. Transplant-associated thrombotic microangiopathy: theoretical considerations and a practical approach to an unrefined diagnosis. Bone Marrow Transplant. 2021; 56: 1805–17. DOI: https://www.doi.org/10.1038/s41409-021-01283-0
25. Rambaldi A., Gritti G., Micò M.C., et al. Endothelial injury and thrombotic microangiopathy in COVID-19: Treatment with the lectin-pathway inhibitor narsoplimab. Immunobiology. 2020; 225: 152001. DOI: https://www.doi.org/10.1016/j.imbio.2020.152001
26. Garred P., Tenner A.J., Mollnes T.E. Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics. Pharmacol Rev. 2021; 73: 792–827. DOI: https://www.doi.org/10.1124/pharmrev.120.000072
27. Boldt A.B., Culpi L., Tsuneto L.T., et al. Diversity of the MBL2 gene in various brazilian populations and the case of selection at the mannose-binding lectin locus. Hum Immunol. 2006; 67: 722–34. DOI: https://www.doi.org/10.1016/j.humimm.2006.05.009
28. Madsen H.O., Satz M.L., Hogh B., et al. Different molecular events result in low protein levels of mannan-binding lectin in populations from southeast Africa and South America. J Immunol. 1998; 161: 3169–75. DOI: https://www.doi.org/10.4049/jimmunol.161.6.3169
29. Bernig T., Breunis W., Brouwer N., et al. An analysis of genetic variation across the MBL2 locus in Dutch Caucasians indicates that 3’ haplotypes could modify circulating levels of mannose-binding lectin. Hum Genet. 2005; 118: 404–15. DOI: https://www.doi.org/10.1007/s00439-005-0053-5
30. Ojurongbe O., Ouf E.A., Van Tong H., et al. Reliable and rapid characterization of functional FCN2 gene variants reveals diverse geographical patterns. BMC Med Genet. 2012; 13: 37. DOI: https://www.doi.org/10.1186/1471-2350-13-37
31. Thiel S., Steffensen R., Christensen I.J., et al. Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms. Genes Immun. 2007; 8: 154–3. DOI: https://www.doi.org/10.1038/sj.gene.6364373
32. Eisen D.P., Osthoff M. If there is an evolutionary selection pressure for the high frequency of MBL2 polymorphisms, what is it? Clin Exp Immunol. 2014; 176: 165–71. DOI: https://www.doi.org/10.1111/cei.12241
33. Verdu P., Barreiro L.B., Patin E., et al. Evolutionary insights into the high worldwide prevalence of MBL2 deficiency alleles. Hum Mol Genet. 2006; 15: 2650–8. DOI: https://www.doi.org/10.1093/hmg/ddl193
34. Vallès X., Sarrias M.R, Casals F., et al. Genetic and structural analysis of MBL2 and MASP2 polymorphisms in south-eastern African children. Tissue Antigens. 2009; 74: 298–307. DOI: https://www.doi.org/10.1111/j.1399-0039.2009.01328.x
35. Sandoval J.R., Madsen H.O., De Stefano G., et al. Extreme high prevalence of a defective mannose-binding lectin (MBL2) genotype in native South American West Andean populations. PLoS One. 2014; 9: e108943. DOI: https://www.doi.org/10.1371/journal.pone.0108943