KH.M. EMIROVA^1, 2, O.O. CHERNYSHEVA¹, S.A. MSTISLAVSKAYA^1, 2, O.V. ZAITSEVA¹, V.K. VAKHITOV³, T.P. MAKAROVA³, D.A. KUDLAY^4-6, O.M. ORLOVA^1, 2, T.YU. ABASEEVA^1, 2, A.L. MUZUROV^2, 7, E.M. TOLSTOVA¹

 ¹Russian University of Medicine, Moscow

²St. Vladimir Children’s Clinical Hospital, Moscow

³Kazan State Medical University, Kazan

⁴Sechenov First Moscow State Medical University, Moscow

⁵Lomonosov Moscow State University, Moscow

⁶State Research Center Institute of Immunology of FMBA, Moscow

⁷Russian Medical Academy of Continuous Postgraduate Education, Moscow

  Contact details:

Emirova Kh.M. — PhD (Medicine), Associate Professor, Professor of the Department of Pediatrics, nephrologist

Address: 1/3 Rubtsovsko-Dvortsovaya St., Moscow, Russian Federation, 107014, tel.: +7-926-605-15-31, е-mail: kh.emirova@outlook.com

Atypical hemolytic-uremic syndrome (aHUS) is a rare disease of the group of thrombotic microangiopathies caused by hyperactivation of an alternative pathway of the complement system. One of the mechanisms of aHUS development is the change in the functional activity of proteins of the factor H (FH) family. We analyzed the available data on the influence of factor H protein family on aHUS development. A total of 43 studies published in 2003-2021, including 41 foreign ones, were reviewed. PubMed, Web of Science, Scopus, еLibrary, Google Scholar databases were searched using keywords: aHUS, factor H, factor H-like protein, factor H-related proteins (FHRs). Priority was given to the results of randomized controlled trials, systematic reviews with meta-analysis. Duplicate articles were excluded. Based on the analysis results, conclusions were drawn that disruption of C3b subunit inactivation as a result of changes in the functional activity of FH family proteins mediates the formation of a membrane-attacking complex. Among the mechanisms of FH, FHR1, and FHR3 inhibition are genetic aberrations (missense mutations, reading frame shift), formation of hybrid proteins, and synthesis of autologous antibodies. Other mechanisms of alternative pathway hyperactivation include decreased concentration or complete absence of FH, FHR1, FHR3, and FHR4 as a result of deletion of 1q31.3 fragments or formation of hybrid proteins. The change in the FH functional activity is also possible due to autoinactivation or competitive inhibition when the FHRs concentration increases.

Key words: atypical hemolytic-uremic syndrome, factor H, factor H-like protein, factor H-related proteins, complement system.

REFERENCES

1. Bayko S.V. Atypical hemolytic-uremic syndrome in children: practical aspects of differential diagnosis and treatment. Pediatriya im. G.N. Speranskogo, 2021, vol. 100, no. 4, pp. 64–73 (in Russ.). DOI: 10.24110/0031-403X-2021-100-4-64-73
2. Pollack S., Eisenstein I., Mory A., Paperna T., Ofir A., Baris-Feldman H. et al. A novel homozygous in-frame deletion in complement factor 3 underlies early-onset autosomal recessive atypical hemolytic uremic syndrome. Case Report. Front. Immunol, 2021, vol. 12, pp. 1–7.
3. Yan K., Desai K., Gullapalli L., Druyts E. Epidemiology of atypical hemolytic uremic syndrome: a systematic literature review. Clin. Epidemiol, 2020, vol. 12, pp. 295–305.
4. Dixon B.P., Gruppo R.A. Atypical hemolytic uremic syndrome. Pediatr. Clin. North Am, 2018, vol. 65 (3), pp. 509–525. DOI: 10.1016/j.pcl.2018.02.003
5. Mallett A., Patel C., Salisbury A., Wang Z., Healy H. The prevalence and epidemiology of genetic renal disease amongst adults with chronic kidney disease in Australia. Orphanet J. Rare Dis, 2014, vol. 9, pp. 1–9.
6. Wühl E., Stralen K.J., van Wanner C., Ariceta G., Heaf J.G., Bjerre A.K. et al. Original article renal replacement therapy for rare diseases affecting the kidney : an analysis of the ERA – EDTA Registry. Nephrol. Dial. Transpl, 2014, vol. 4, pp. 1–8.
7. Jokiranta T.S. HUS and atypical HUS. Blood, 2017, vol. 129 (21), pp. 2847–2856.
8. Wijnsma K.L., Duineveld C., Wetzels JFM van de KN. Eculizumab in atypical hemolytic uremic syndrome : strategies toward restrictive use. Pediatr. Nephrol, 2019, vol. 34 (11), pp. 2261–2277.
9. Yoshida Y., Kato H., Ikeda Y., Nangaku M. Pathogenesis of atypical hemolytic uremic syndrome. J. Atheroscler. Thromb, 2019, vol. 26 (2), pp. 99–110.
10. Bakshi S., Cunningham F., Nichols E.M., Biedzka-Sarek M., Neisen J., Petit-Frere S. et al. Mathematical modelling of alternative pathway of complement system. Bull. Math. Biol, 2020, vol. 82 (2), pp. 32–64.
11. Butylin A.A., Filippova A.E., Shakhidzhanov S.S. AFI. Pathologies of the complement system. Voprosy gematologii / onkologii i immunopatologii v pediatrii, 2020, vol. 19, no. 1, pp. 131–138 (in Russ.).
12. Romano R., Giardino G., Cirillo E., Prencipe R., Romano R., Giardino G. et al. Complement system network in cell physiology and in human diseases. Int. Rev. Immunol, 2021, vol. 40 (3), pp. 159–170. DOI: 10.1080/08830185.2020.1833877
13. Meri S. Alternative pathway of complement. Encycl. Immunobiol, 2016, vol. 2, P. 325–331. DOI: 10.1016/B978-0-12-374279-7.02015-4
14. Zewde N., Gorham R.D., Dorado A., Morikis D. Quantitative modeling of the alternative pathway of the complement system, 2016, pp. 1–26.
15. Mellors J., Tipton T., Longet S., Carroll M. Viral evasion of the complement system and its importance for vaccines and therapeutics. Front. Immunol, 2020, vol. 11, pp. 1–20.
16. Van Essen M.F., Ruben J.M., De Vries A.P.J., Van Kooten C. Role of properdin in complement-mediated kidney diseases. Nephrol. Dial. Transpl, 2018, vol. 34 (5), pp. 742–750.
17. Lachmann P.J. The story of complement factor I. Immunobiology, 2019, vol. 224 (4), pp. 511–517. DOI: 10.1016/j.imbio.2019.05.003
18. Poppelaars F., Thurman J.M. Complement-mediated kidney diseases. Mol. Immunol, 2020, vol. 128, pp. 175–187. DOI: 10.1016/j.molimm.2020.10.015
19. Cantsilieris S., Nelson B.J., Huddleston J., Baker C., Harshman L., Penewit K. et al. Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H (CFH) gene family. Proc. Natl. Acad. Sci. USA, 2018, vol. 115 (19), pp. E4433–E4442.
20. Poppelaars F., De Jorge E.G., Jongerius I., Baeumner A.J. A family affair : addressing the challenges of factor H and the related proteins. Front. Immunol, 2021, vol. 12, pp. 1–17.
21. Józsi M., Schneider A.E., Kárpáti É, Sándor N. Complement factor H family proteins in their non-canonical role as modulators of cellular functions. Semin. Cell. Dev. Biol, 2019, vol. 85 (2017), pp. 122–131. DOI: 10.1016/j.semcdb.2017.12.018
22. Toomey C.B., Johnson L.V., Bowes Rickman C. Complement factor H in AMD: Bridging genetic associations and pathobiology. Prog. Retin. Eye Res, 2018, vol. 62, pp. 38–57. DOI: 10.1016/j.preteyeres.2017.09.001
23. Cserhalmi M., Papp A., Brandus B., Uzonyi B., Józsi M. Regulation of regulators: Role of the complement factor H-related proteins. Semin. Immunol, 2019, vol. 45, 101341. DOI: 10.1016/j.smim.2019.101341
24. Van Beek A.E., Pouw R.B., Brouwer M.C., van Mierlo G., Geissler J., Ooijevaar-de Heer P. et al. Factor H-related (FHR)-1 and FHR-2 form homo- and heterodimers, while FHR-5 circulates only as homodimer in human plasma. Front. Immunol, 2017, vol. 8.
25. Bernabéu-Herrero M.E., Jiménez-Alcázar M., Anter J., Pinto S., Chinchilla D.S., Garrido S. et al. Complement factor H, FHR-3 and FHR-1 variants associate in an extended haplotype conferring increased risk of atypical hemolytic uremic syndrome. Mol. Immunol, 2015, vol. 67 (2), pp. 276-286. DOI: 10.1016/j.molimm.2015.06.021
26. Eberhardt H.U., Buhlmann D., Hortschansky P., Chen Q., Böhm S., Kemper M.J. et al. Human factor H-related protein 2 (CFHR2) regulates complement activation. PLoS One, 2013, vol. 8 (11), pp. 1–11.
27. Caesar J.J.E., Lavender H., Ward P.N., Exley R.M., Eaton J., Chittock E. et al. Competition between antagonistic complement factors for a single protein on N. meningitidis rules disease susceptibility. Elife, 2014, vol. 3, pp. 1–14.
28. Turkmen K., Baloglu I., Ozer H. C3 glomerulopathy and atypical hemolytic uremic syndrome: an updated review of the literature on alternative complement pathway disorders. Int. Urol. Nephrol, 2021, vol. 53 (10), pp. 2067–2080. DOI: 10.1007/s11255-020-02729-y
29. Fremeaux-Bacchi V., Fakhouri F., Garnier A., Bienaimé F., Dragon-Durey M.A., Ngo S. et al. Genetics and outcome of atypical hemolytic uremic syndrome: A nationwide french series comparing children and adults. Clin. J. Am. Soc. Nephrol, 2013, vol. 8 (4), pp. 554–562.
30. Noris M., Caprioli J., Bresin E., Mossali C., Pianetti G., Gamba S. et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin. J. Am. Soc. Nephrol, 2010, vol. 5 (10), pp. 1844–1859.
31. Saunders R.E., Goodship T.H.J., Zipfel P.F., Ã S.J.P. An interactive web database of factor H- associated hemolytic uremic syndrome mutations: insights into the structural consequences of disease-associated mutations. Hum. Mutat, 2006, vol. 27 (1), pp. 21–30.
32. Manuelian T., Hellwage J., Meri S., Caprioli J., Noris M., Heinen S. et al. Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J. Clin. Invest, 2003, vol. 111 (8), pp. 1181–1190.
33. Hyvärinen S., Meri S., Jokiranta T.S. Disturbed sialic acid recognition on endothelial cells and platelets in complement attack causes atypical hemolytic uremic syndrome. Blood, 2016, vol. 127 (22), pp. 2701–2710.
34. Francis N.J., Mcnicholas B., Awan A., Waldron M., Reddan D., Sadlier D. et al. A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome. Blood, 2012, vol. 119 (2), pp. 591–602.
35. Challis R.C., Araujo G.S.R., Wong E.K.S., Anderson H.E., Awan A., Dorman A.M. et al. A de novo deletion in the regulators of complement activation cluster producing a hybrid complement factor H / complement factor H — related 3 gene in atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol, 2016, vol. 27 (6), pp. 1617–1624.
36. Zipfel P.F., Wiech T., Stea E.D., Skerka C. CFHR gene variations provide insights in the pathogenesis of the kidney diseases atypical hemolytic uremic syndrome and C3 glomerulopathy. J. Am. Soc. Nephrol, 2020, vol. 31 (2), pp. 241–256.
37. Maga T.K., Meyer N.C., Belsha C., Nishimura C.J., Zhang Y., Smith R.J.H. Exceptional Cases A novel deletion in the RCA gene cluster causes atypical hemolytic uremic syndrome. Nephrol. Dial. Transpl, 2011, vol. 26 (2), pp. 739–741.
38. Valoti E., Alberti M., Tortajada A., Garcia-Fernandez J., Gastoldi S., Besso L. et al. A novel atypical hemolytic uremic syndrome-associated hybrid CFHR1/CFH gene encoding a fusion protein that antagonizes factor H-dependent complement regulation. J. Am. Soc. Nephrol, 2015, vol. 26 (1), pp. 209–219.
39. Michael M., Turner N., Elenberg E., Shaffer L.G., Teruya J. Arar M et al. Deficiency of complement factor H-related proteins and autoantibody-positive hemolytic uremic syndrome in an infant with combined partial deficiencies and autoantibodies to complement factor H and ADAMTS13. Clin. Kidney J, 2018, vol. 11 (6), pp. 791–796.
40. Puraswani M., Khandelwal P., Saini H., Saini S., Gurjar B.S., Sinha A. et al. Clinical and immunological profile of anti-factor h antibody associated atypical hemolytic uremic syndrome: A nationwide database. Front. Immunol, 2019, vol. 10, pp. 1–12.
41. Gurjar B.S., Manikanta Sriharsha T., Bhasym A., Prabhu S., Puraswani M., Khandelwal P. et al. Characterization of genetic predisposition and autoantibody profile in atypical haemolytic-uraemic syndrome. Immunology, 2018, vol. 154 (4), pp. 663–672.
42. Hackl A., Ehren R., Kirschfink M., Zipfel P.F., Beck B.B., Weber L.T. et al. Successful discontinuation of eculizumab under immunosuppressive therapy in DEAP-HUS. Pediatr. Nephrol, 2017, vol. 32 (6), pp. 1081–1087.
43. Cugno M., Berra S., Depetri F., Tedeschi S., Griffini S., Grovetti E. et al. IgM autoantibodies to complement factor H in atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol, 2021, vol. 32 (5), p. 3.