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Altered Peripheral Blood Leucocyte Phenotype and Responses in Healthy Individuals with Homozygous Deletion of FHR1 and FHR3 Genes

  • Angika Bhasym
  • Bahadur Singh Gurjar
  • Savit Prabhu
  • Mamta Puraswani
  • Priyanka Khandelwal
  • Himanshi Saini
  • Savita Saini
  • Priyadarshini Chatterjee
  • Vineeta Bal
  • Anna George
  • Poonam Coshic
  • Gopal Patidar
  • Pankaj Hari
  • Aditi Sinha
  • Arvind Bagga
  • Satyajit RathEmail author
  • Prasenjit GuchhaitEmail author
Original Article
  • 68 Downloads

Abstract

A homozygous 83-kb deletion encompassing the genes for complement factor-H-related proteins 1 and 3 (FHR 1, FHR3) is known as a risk factor for some immune inflammatory disorders. However, the functional relevance of this FHR1/3 deletion is relatively unexplored. Globally, healthy populations of all ethnic groups tested show an 8–10% prevalence of homozygosity for this deletion polymorphism. We have begun to compare the peripheral leucocyte phenotype and functionality between FHR1/3−/− and FHR1/3+/+ healthy adult individuals. We report that the two groups show significant differences in their peripheral blood innate leucocyte subset composition, although the adaptive immune subsets are similar between them. Specifically, FHR1/3−/− individuals show higher frequencies of patrolling monocytes and lower frequencies of classical monocytes than FHR1/3+/+ individuals. Similarly, FHR1/3−/− individuals show higher frequencies of plasmacytoid dendritic cells (pDCs) and lower frequencies of myeloid DCs (mDCs) than FHR1/3+/+ individuals. Notably, classical monocytes specifically showed cell-surface-associated factor H (FH), and cells from the FHR1/3−/− group had somewhat higher surface-associated FH levels than those from FHR1/3+/+ individuals. FHR1/3−/− monocytes also showed elevated secretion of TNF-α, IL-1β, and IL-10 in response to TLR7/8 or TLR4 ligands. Similarly, FHR1/3−/− mDCs and pDCs showed modest but evident hyper-responsiveness to TLR ligands. Our findings, that the FHR1/3−/− genotype is associated with significant alterations of both the relative prominence and the functioning of monocyte and DC subsets, may be relevant in understanding the mechanism underlying the association of the genotype with immune inflammatory disorders.

Keywords

FHR1/3 null genotype complement factor H monocytes dendritic cells 

Notes

Author Contributions

AB performed experiments, analyzed the data, and helped in writing the manuscript. BSG, SP, TMS, and MP developed critical tools and analyzed data. AB and SS developed critical methodologies and helped collect the data. AB, PK, HS, PoC, and GP conceptualized the approach, did the critical clinical components of the work, supervised the data collection, and analyzed the data. AKV, PrC, VB, AG, ArS, AB, AmS, PH, and AdS provided crucial conceptual inputs. AB, PG, and SR conceptualized the approach, designed the experiments, analyzed the data, and wrote the manuscript. All authors read, edited, and approved the final manuscript.

Funding Information

This study was financially supported by grants: BT/PR8591 and BT/PR22985 from the Department of Biotechnology, Govt. of India (GoI), and from Regional Centre for Biotechnology grants-in-aid from the DBT, GoI to PG.

Compliance with Ethical Standards

All procedures followed were in accordance with the ethical standards of the ethics committee for human research, and the study was approved by the Institutional Ethics Committee for Human Research of Regional Centre for Biotechnology (RCB, Reference No. RCB-IEC-H-8), Faridabad, India, and the Institutional Human Ethics Committee of the All India Institute of Medical Sciences (AIIMS, Reference No. IEC-/05. 02. 20, RP44/2016), New Delhi, India.

Conflict of Interest

SR is a non-executive director of Ahammune Biosciences Private Limited, Pune, India, and a member of the scientific advisory boards of Curadev Pharma Private Limited, NOIDA, India, and Mynvax Private Limited, Bangalore, India. Other authors have no financial or other interest to declare.

Supplementary material

10875_2019_619_MOESM1_ESM.docx (1007 kb)
ESM 1 (DOCX 1006 kb)

References

  1. 1.
    Diaz-Guillen MA, Rodriguez de Cordoba S, Heine-Suner D. A radiation hybrid map of complement factor H and factor H-related genes. Immunogenetics. 1999;49(6):549–52.Google Scholar
  2. 2.
    Male DA, Ormsby RJ, Ranganathan S, Giannakis E, Gordon DL. Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, fHR-1 and fHR-3 genes. Mol Immunol. 2000;37(1–2):41–52.Google Scholar
  3. 3.
    Goicoechea de Jorge E, Caesar JJ, Malik TH, Patel M, Colledge M, Johnson S, et al. Dimerization of complement factor H-related proteins modulates complement activation in vivo. Proc Natl Acad Sci U S A. 2013;110(12):4685–90.Google Scholar
  4. 4.
    Heinen S, Hartmann A, Lauer N, Wiehl U, Dahse HM, Schirmer S, et al. Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood. 2009;114(12):2439–47.Google Scholar
  5. 5.
    McRae JL, Duthy TG, Griggs KM, Ormsby RJ, Cowan PJ, Cromer BA, et al. Human factor H-related protein 5 has cofactor activity, inhibits C3 convertase activity, binds heparin and C-reactive protein, and associates with lipoprotein. J Immunol. 2005;174(10):6250–6.Google Scholar
  6. 6.
    Oppermann M, Manuelian T, Jozsi M, Brandt E, Jokiranta TS, Heinen S, et al. The C-terminus of complement regulator factor H mediates target recognition: evidence for a compact conformation of the native protein. Clin Exp Immunol. 2006;144(2):342–52.Google Scholar
  7. 7.
    Jozsi M, Zipfel PF. Factor H family proteins and human diseases. Trends Immunol. 2008;29(8):380–7.Google Scholar
  8. 8.
    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;26(1):209–19.Google Scholar
  9. 9.
    Timmann C, Leippe M, Horstmann RD. Two major serum components antigenically related to complement factor H are different glycosylation forms of a single protein with no factor H-like complement regulatory functions. J Immunol. 1991;146(4):1265–70.Google Scholar
  10. 10.
    Tortajada A, Yebenes H, Abarrategui-Garrido C, Anter J, Garcia-Fernandez JM, Martinez-Barricarte R, et al. C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation. J Clin Invest. 2013;123(6):2434–46.Google Scholar
  11. 11.
    Eberhardt HU, Buhlmann D, Hortschansky P, Chen Q, Bohm S, Kemper MJ, et al. Human factor H-related protein 2 (CFHR2) regulates complement activation. PLoS One. 2013;8(11):e78617.Google Scholar
  12. 12.
    Skerka C, Zipfel PF. Complement factor H-related proteins in immune diseases. Vaccine. 2008;26(Suppl 8):I9–14.Google Scholar
  13. 13.
    Fritsche LG, Lauer N, Hartmann A, Stippa S, Keilhauer CN, Oppermann M, et al. An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). Hum Mol Genet. 2010;19(23):4694–704.Google Scholar
  14. 14.
    Wang G, Spencer KL, Scott WK, Whitehead P, Court BL, Ayala-Haedo J, et al. Analysis of the indel at the ARMS2 3'UTR in age-related macular degeneration. Hum Genet. 2010;127(5):595–602.Google Scholar
  15. 15.
    Medjeral-Thomas N, Pickering MC. The complement factor H-related proteins. Immunol Rev. 2016;274(1):191–201.Google Scholar
  16. 16.
    Reiss T, Rosa TFA, Blaesius K, Bobbert RP, Zipfel PF, Skerka C, et al. Cutting edge: FHR-1 binding impairs factor H-mediated complement evasion by the malaria parasite plasmodium falciparum. J Immunol. 2018;201(12):3497–502.Google Scholar
  17. 17.
    Skerka C, Chen Q, Fremeaux-Bacchi V, Roumenina LT. Complement factor H-related proteins (CFHRs). Mol Immunol. 2013;56(3):170–80.Google Scholar
  18. 18.
    Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP, et al. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood. 2010;115(2):379–87.Google Scholar
  19. 19.
    Dragon-Durey MA, Sethi SK, Bagga A, Blanc C, Blouin J, Ranchin B, et al. Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol. 2010;21(12):2180–7.Google Scholar
  20. 20.
    Zhao J, Wu H, Khosravi M, Cui H, Qian X, Kelly JA, et al. Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility. PLoS Genet. 2011;7(5):e1002079.Google Scholar
  21. 21.
    Chen Q, Wiesener M, Eberhardt HU, Hartmann A, Uzonyi B, Kirschfink M, et al. Complement factor H-related hybrid protein deregulates complement in dense deposit disease. J Clin Invest. 2014;124(1):145–55.Google Scholar
  22. 22.
    Chen Q, Manzke M, Hartmann A, Buttner M, Amann K, Pauly D, et al. Complement factor H-related 5-hybrid proteins anchor properdin and activate complement at self-surfaces. J Am Soc Nephrol. 2016;27(5):1413–25.Google Scholar
  23. 23.
    Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet. 2006;38(10):1173–7.Google Scholar
  24. 24.
    Gharavi AG, Kiryluk K, Choi M, Li Y, Hou P, Xie J, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. 2011;43(4):321–7.Google Scholar
  25. 25.
    Gurjar BS, 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;154:663–72.Google Scholar
  26. 26.
    Sinha A, Gulati A, Saini S, Blanc C, Gupta A, Gurjar BS, et al. Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children. Kidney Int. 2014;85(5):1151–60.Google Scholar
  27. 27.
    Hageman GS, Hancox LS, Taiber AJ, Gehrs KM, Anderson DH, Johnson LV, et al. Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med. 2006;38(8):592–604.Google Scholar
  28. 28.
    Holmes LV, Strain L, Staniforth SJ, Moore I, Marchbank K, Kavanagh D, et al. Determining the population frequency of the CFHR3/CFHR1 deletion at 1q32. PLoS One. 2013;8(4):e60352.Google Scholar
  29. 29.
    Rathore DK, Nair D, Raza S, Saini S, Singh R, Kumar A, et al. Underweight full-term Indian neonates show differences in umbilical cord blood leukocyte phenotype: a cross-sectional study. PLoS One. 2015;10(4):e0123589.Google Scholar
  30. 30.
    Prabhu SB, Rathore DK, Nair D, Chaudhary A, Raza S, Kanodia P, et al. Comparison of human neonatal and adult blood leukocyte subset composition phenotypes. PLoS One. 2016;11(9):e0162242.Google Scholar
  31. 31.
    Zhu H, Hu F, Sun X, Zhang X, Zhu L, Liu X, et al. CD16(+) monocyte subset was enriched and functionally exacerbated in driving T-cell activation and B-cell response in systemic lupus erythematosus. Front Immunol. 2016;7:512.Google Scholar
  32. 32.
    Ronnblom L, Eloranta ML, Alm GV. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum. 2006;54(2):408–20.Google Scholar
  33. 33.
    Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007;8(5):487–96.Google Scholar
  34. 34.
    Jongbloed SL, Benson RA, Nickdel MB, Garside P, McInnes IB, Brewer JM. Plasmacytoid dendritic cells regulate breach of self-tolerance in autoimmune arthritis. J Immunol. 2009;182(2):963–8.Google Scholar
  35. 35.
    Skrzeczynska J, Kobylarz K, Hartwich Z, Zembala M, Pryjma J. CD14+CD16+ monocytes in the course of sepsis in neonates and small children: monitoring and functional studies. Scand J Immunol. 2002;55(6):629–38.Google Scholar
  36. 36.
    Wildgruber M, Lee H, Chudnovskiy A, Yoon TJ, Etzrodt M, Pittet MJ, et al. Monocyte subset dynamics in human atherosclerosis can be profiled with magnetic nano-sensors. PLoS One. 2009;4(5):e5663.Google Scholar
  37. 37.
    Kawanaka N, Yamamura M, Aita T, Morita Y, Okamoto A, Kawashima M, et al. CD14+,CD16+ blood monocytes and joint inflammation in rheumatoid arthritis. Arthritis Rheum. 2002;46(10):2578–86.Google Scholar
  38. 38.
    Farrugia M, Baron B. The role of toll-like receptors in autoimmune diseases through failure of the self-recognition mechanism. Int J Inflam. 2017;2017:8391230.Google Scholar
  39. 39.
    Puchner A, Saferding V, Bonelli M, Mikami Y, Hofmann M, Brunner JS, et al. Non-classical monocytes as mediators of tissue destruction in arthritis. Ann Rheum Dis. 2018;77(10):1490–7.Google Scholar
  40. 40.
    Matsuda H, Suda T, Hashizume H, Yokomura K, Asada K, Suzuki K, et al. Alteration of balance between myeloid dendritic cells and plasmacytoid dendritic cells in peripheral blood of patients with asthma. Am J Respir Crit Care Med. 2002;166(8):1050–4.Google Scholar
  41. 41.
    Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL. Plasmacytoid dendritic cells (natural interferon- alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions. Am J Pathol. 2001;159(1):237–43.Google Scholar
  42. 42.
    Zhang X, Lewkowich IP, Kohl G, Clark JR, Wills-Karp M, Kohl J. A protective role for C5a in the development of allergic asthma associated with altered levels of B7-H1 and B7-DC on plasmacytoid dendritic cells. J Immunol. 2009;182(8):5123–30.Google Scholar
  43. 43.
    Liu Y, Jing F, Yi W, Mendelson A, Shi P, Walsh R, et al. HO-1(hi) patrolling monocytes protect against vaso-occlusion in sickle cell disease. Blood. 2018;131(14):1600–10.Google Scholar
  44. 44.
    Jozsi M, Licht C, Strobel S, Zipfel SL, Richter H, Heinen S, et al. Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood. 2008;111(3):1512–4.Google Scholar
  45. 45.
    Lee BH, Kwak SH, Shin JI, Lee SH, Choi HJ, Kang HG, et al. Atypical hemolytic uremic syndrome associated with complement factor H autoantibodies and CFHR1/CFHR3 deficiency. Pediatr Res. 2009;66(3):336–40.Google Scholar
  46. 46.
    Olivar R, Luque A, Cardenas-Brito S, Naranjo-Gomez M, Blom AM, Borras FE, et al. The complement inhibitor factor H generates an anti-inflammatory and tolerogenic state in monocyte-derived dendritic cells. J Immunol. 2016;196(10):4274–90.Google Scholar
  47. 47.
    Svoboda E, Schneider AE, Sandor N, Lermann U, Staib P, Kremlitzka M, et al. Secreted aspartic protease 2 of Candida albicans inactivates factor H and the macrophage factor H-receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18). Immunol Lett. 2015;168(1):13–21.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Angika Bhasym
    • 1
    • 2
  • Bahadur Singh Gurjar
    • 3
  • Savit Prabhu
    • 4
  • Mamta Puraswani
    • 5
  • Priyanka Khandelwal
    • 5
  • Himanshi Saini
    • 5
  • Savita Saini
    • 5
  • Priyadarshini Chatterjee
    • 1
  • Vineeta Bal
    • 3
    • 4
    • 6
  • Anna George
    • 3
  • Poonam Coshic
    • 7
  • Gopal Patidar
    • 7
  • Pankaj Hari
    • 5
  • Aditi Sinha
    • 5
  • Arvind Bagga
    • 5
  • Satyajit Rath
    • 3
    • 4
    Email author
  • Prasenjit Guchhait
    • 1
    Email author
  1. 1.Regional Centre for BiotechnologyFaridabadIndia
  2. 2.Department of BiotechnologyManipal Academy of Higher EducationManipalIndia
  3. 3.National Institute of ImmunologyNew DelhiIndia
  4. 4.Translational Health Science and Technology InstituteFaridabadIndia
  5. 5.Department of PediatricsAll India Institute of Medical SciencesNew DelhiIndia
  6. 6.Indian Institute of Science Education and ResearchPuneIndia
  7. 7.Department of Transfusion MedicineAll India Institute of Medical SciencesNew DelhiIndia

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