Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jozsi M, Zipfel PF. Factor H family proteins and human diseases. Trends Immunol. 2008;29(8):380–7.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Skerka C, Zipfel PF. Complement factor H-related proteins in immune diseases. Vaccine. 2008;26(Suppl 8):I9–14.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Medjeral-Thomas N, Pickering MC. The complement factor H-related proteins. Immunol Rev. 2016;274(1):191–201.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  17. Skerka C, Chen Q, Fremeaux-Bacchi V, Roumenina LT. Complement factor H-related proteins (CFHRs). Mol Immunol. 2013;56(3):170–80.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ronnblom L, Eloranta ML, Alm GV. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum. 2006;54(2):408–20.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

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.

Author information

Authors and Affiliations

  1. Regional Centre for Biotechnology, Faridabad, India

    Angika Bhasym, Priyadarshini Chatterjee & Prasenjit Guchhait

  2. Department of Biotechnology, Manipal Academy of Higher Education, Manipal, India

    Angika Bhasym

  3. National Institute of Immunology, New Delhi, India

    Bahadur Singh Gurjar, Vineeta Bal, Anna George & Satyajit Rath

  4. Translational Health Science and Technology Institute, Faridabad, India

    Savit Prabhu, Vineeta Bal & Satyajit Rath

  5. Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India

    Mamta Puraswani, Priyanka Khandelwal, Himanshi Saini, Savita Saini, Pankaj Hari, Aditi Sinha & Arvind Bagga

  6. Indian Institute of Science Education and Research, Pune, India

    Vineeta Bal

  7. Department of Transfusion Medicine, All India Institute of Medical Sciences, New Delhi, India

    Poonam Coshic & Gopal Patidar

Authors
  1. Angika Bhasym
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bahadur Singh Gurjar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Savit Prabhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mamta Puraswani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Priyanka Khandelwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Himanshi Saini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Savita Saini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Priyadarshini Chatterjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vineeta Bal
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anna George
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Poonam Coshic
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gopal Patidar
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Pankaj Hari
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Aditi Sinha
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Arvind Bagga
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Satyajit Rath
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Prasenjit Guchhait
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

Correspondence to Satyajit Rath or Prasenjit Guchhait.

Ethics declarations

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(DOCX 1006 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bhasym, A., Gurjar, B.S., Prabhu, S. et al. Altered Peripheral Blood Leucocyte Phenotype and Responses in Healthy Individuals with Homozygous Deletion of FHR1 and FHR3 Genes. J Clin Immunol 39, 336–345 (2019). https://doi.org/10.1007/s10875-019-00619-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-019-00619-2

Keywords

Search

Navigation