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Complete Factor I Deficiency Due to Dysfunctional Factor I with Recurrent Aseptic Meningo-Encephalitis

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Abstract

Purpose

Complement regulators control the activated complement system. Defects in this homeostasis can result in tissue damage and autoimmune diseases with a heterogeneity in clinical presentation. Complement factor I (FI), a serine protease, is an important regulator of alternative pathway activation. We report a diagnostic work-up of a patient with relapsing inflammatory mediated meningo-encephalitis. Our work-up revealed a rare genetic factor I (FI) deficiency. So far, all cases of reported complete factor I deficiency have absent serum levels of FI. We present here a unique case of a complete factor I deficiency based on a functional FI defect.

Methods

Complement assays and measurement of FI activity were performed in the patient, her family, factor H-deficient patients, a patient with C3-nephritic factor and 11 healthy controls. Genetic sequencing of the FI coding regions in the patient and her parents was performed.

Results

The patient had absent alternative pathway activity with low levels of C3 and normal serum level of FI. The patient’s plasma FI did not degrade C3b, with normalisation of C3b degradation after adding purified FI. Mutation analysis of the complement factor I gene revealed two heterozygous mutations (I322T and D506V).

Conclusion

To our knowledge, this paper describes a complete FI deficiency caused by a defect of FI activity for the first time. Normal FI concentration does not exclude a complete FI defect, additional functional analysis of FI is required in any patient with a defect of complement activation. Recurrent aseptic meningo-encephalitis is a rare clinical presentation of complete FI deficiency.

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Abbreviations

AP50:

Alternative pathway activity

aHUS:

Atypical haemolytic uremic syndrome

CSF:

Cerebrospinal fluid

CH50:

Classical pathway activity

C1:

Complement factor 1

C3:

Complement factor 3

C4BP:

Complement factor 4 binding protein

CR1:

Complement receptor 1

FB:

Complement factor B

FBb:

Complement factor Bb

FD:

Complement factor D

FDG-PET scan:

FluoroDeoxyGlucose-Position Emission Tomography

FI:

Complement factor I

FIMAC:

Factor I membrane attack complex

FH:

Complement factor H

iC3b:

Inactivated C3b

LDLr-1 and 2:

Low-density lipoprotein receptor 1 and 2 domains

MAC:

Membrane attack complex

MBL:

Mannose binding lectin

MCP:

Membrane cofactor protein

MRI:

Magnetic Resonance Imaging

PCR:

Polymerase chain reaction

PE:

plasma exchange

SP:

Serine protease domain

sSRBC:

Sensitized sheep red blood cells

References

  1. Vyse TJ, Spath PJ, Davies KA, Morley BJ, Philippe P, Athanassiou P, et al. Hereditary complement factor I deficiency. QJM. 1994;87(7):385–401. PubMed PMID: 7922290. Epub 1994/07/01. eng.

    PubMed  CAS  Google Scholar 

  2. Nilsson SC, Sim RB, Lea SM, Fremeaux-Bacchi V, Blom AM. Complement factor I in health and disease. Mol Immunol. 2011;48(14):1611–20. PubMed PMID: 21529951. Epub 2011/05/03.

    Article  PubMed  CAS  Google Scholar 

  3. Broderick L, Gandhi C, Mueller JL, Putnam CD, Shayan K, Giclas PC, et al. Mutations of complement factor I and potential mechanisms of neuroinflammation in acute hemorrhagic leukoencephalitis. J Clin Immunol. 2013;33(1):162–71. PubMed PMID: 22926405. Pubmed Central PMCID: 3540165.

    Article  PubMed  CAS  Google Scholar 

  4. Gonzalez-Rubio C, Ferreira-Cerdan A, Ponce IM, Arpa J, Fontan G, Lopez-Trascasa M. Complement factor I deficiency associated with recurrent meningitis coinciding with menstruation. Arch Neurol. 2001;58(11):1923–8. PubMed PMID: 11709004. Epub 2001/11/16. eng.

    Article  PubMed  CAS  Google Scholar 

  5. Bonnin AJ, Zeitz HJ, Gewurz A. Complement factor I deficiency with recurrent aseptic meningitis. Arch Intern Med. 1993;153(11):1380–3. PubMed PMID: 8507128. Epub 1993/06/14. eng.

    Article  PubMed  CAS  Google Scholar 

  6. Bienaime F, Dragon-Durey MA, Regnier CH, Nilsson SC, Kwan WH, Blouin J, et al. Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. Kidney Int. 2010;77(4):339–49. PubMed PMID: 20016463. Epub 2009/12/18. eng.

    Article  PubMed  CAS  Google Scholar 

  7. Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009;9(10):729–40. PubMed PMID: 19730437.

    PubMed  CAS  Google Scholar 

  8. de Cordoba SR, Tortajada A, Harris CL, Morgan BP. Complement dysregulation and disease: From genes and proteins to diagnostics and drugs. Immunobiology. 2012;217(11):1034–46. PubMed PMID: 22964229.

    Article  PubMed  Google Scholar 

  9. Walport MJ. Complement. First of two parts. N Engl J Med. 2001;344(14):1058–66. PubMed PMID: 11287977.

    Article  PubMed  CAS  Google Scholar 

  10. DiScipio RG. Ultrastructures and interactions of complement factors H and I. J Immunol. 1992;149(8):2592–9. PubMed PMID: 1401896. Epub 1992/10/15.

    PubMed  CAS  Google Scholar 

  11. Vyse TJ, Bates GP, Walport MJ, Morley BJ. The organization of the human complement factor I gene (IF): A member of the serine protease gene family. Genomics. 1994;24(1):90–8. PubMed PMID: 7896293. Epub 1994/11/01. eng.

    Article  PubMed  CAS  Google Scholar 

  12. Baracho GV, Nudelman V, Isaac L. Molecular characterization of homozygous hereditary factor I deficiency. Clin Exp Immunol. 2003;131(2):280–6. PubMed PMID: 12562389. Pubmed Central PMCID: 1808620. Epub 2003/02/04. eng.

    Article  PubMed  CAS  Google Scholar 

  13. Nilsson SC, Trouw LA, Renault N, Miteva MA, Genel F, Zelazko M, et al. Genetic, molecular and functional analyses of complement factor I deficiency. Eur J Immunol. 2009;39(1):310–23. PubMed PMID: 19065647. Epub 2008/12/10. eng.

    Article  PubMed  CAS  Google Scholar 

  14. Nita IM, Genel F, Nilsson SC, Smart J, Truedsson L, Choo S, et al. Molecular characterization of two novel cases of complete complement inhibitor Factor I deficiency. Mol Immunol. 2011;48(8):1068–72. PubMed PMID: 21316765.

    Article  PubMed  CAS  Google Scholar 

  15. Saunders RE, Abarrategui-Garrido C, Fremeaux-Bacchi V, de JE G, Goodship TH, Lopez Trascasa M, et al. The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: Update and integration of membrane cofactor protein and Factor I mutations with structural models. Hum Mutat. 2007;28(3):222–34. PubMed PMID: 17089378. Epub 2006/11/08. eng.

    Article  PubMed  CAS  Google Scholar 

  16. Roversi P, Johnson S, Caesar JJ, McLean F, Leath KJ, Tsiftsoglou SA, et al. Structural basis for complement factor I control and its disease-associated sequence polymorphisms. Proc Natl Acad Sci U S A. 2011;108(31):12839–44. PubMed PMID: 21768352. Pubmed Central PMCID: 3150940.

    Article  PubMed  CAS  Google Scholar 

  17. Vyse TJ, Morley BJ, Bartok I, Theodoridis EL, Davies KA, Webster AD, et al. The molecular basis of hereditary complement factor I deficiency. J Clin Invest. 1996;97(4):925–33. PubMed PMID: 8613545. Pubmed Central PMCID: 507137. Epub 1996/02/15. eng.

    Article  PubMed  CAS  Google Scholar 

  18. Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C, Kuypers D, Boudailliez B, et al. Complement factor I: A susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet. 2004;41(6):e84. PubMed PMID: 15173250. Pubmed Central PMCID: 1735822. Epub 2004/06/03. eng.

    Article  PubMed  CAS  Google Scholar 

  19. Geelen J, van den Dries K, Roos A, van de Kar N, de Kat AC, Klasen I, et al. A missense mutation in factor I (IF) predisposes to atypical haemolytic uraemic syndrome. Pediatr Nephrol. 2007;22(3):371–5. PubMed PMID: 17106690. Epub 2006/11/16. eng.

    Article  PubMed  Google Scholar 

  20. Pangburn MK. Cutting edge: Localization of the host recognition functions of complement factor H at the carboxyl-terminal: implications for hemolytic uremic syndrome. J Immunol. 2002;169(9):4702–6. PubMed PMID: 12391176.

    PubMed  CAS  Google Scholar 

  21. Kavanagh D, Richards A, Noris M, Hauhart R, Liszewski MK, Karpman D, et al. Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome. Mol Immunol. 2008;45(1):95–105. PubMed PMID: 17597211. Epub 2007/06/29. eng.

    Article  PubMed  CAS  Google Scholar 

  22. Nilsson SC, Kalchishkova N, Trouw LA, Fremeaux-Bacchi V, Villoutreix BO, Blom AM. Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I. Eur J Immunol. 2010;40(1):172–85. PubMed PMID: 19877009. Epub 2009/10/31. eng.

    Article  PubMed  CAS  Google Scholar 

  23. Westra D, Volokhina E, van der Heijden E, Vos A, Huigen M, Jansen J, et al. Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS). Nephrol Dial Transplant. 2010;25(7):2195–202. PubMed PMID: 20106822. Epub 2010/01/29.

    Article  PubMed  CAS  Google Scholar 

  24. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, et al. Genetics of HUS: The impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108(4):1267–79. PubMed PMID: 16621965. Pubmed Central PMCID: 1895874. Epub 2006/04/20.

    Article  PubMed  CAS  Google Scholar 

  25. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007;18(8):2392–400. PubMed PMID: 17599974. Epub 2007/06/30.

    Article  PubMed  CAS  Google Scholar 

  26. Boyer O, Noel LH, Balzamo E, Guest G, Biebuyck N, Charbit M, et al. Complement factor H deficiency and posttransplantation glomerulonephritis with isolated C3 deposits. American journal of kidney diseases: The official journal of the National Kidney Foundation. 2008;51(4):671–7. PubMed PMID: 18371543. Epub 2008/03/29.

    Article  Google Scholar 

  27. 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. PubMed PMID: 19861685. Pubmed Central PMCID: 2829859. Epub 2009/10/29.

    Article  PubMed  CAS  Google Scholar 

  28. Ponce-Castro IM, Gonzalez-Rubio C, Delgado-Cervino EM, Abarrategui-Garrido C, Fontan G, Sanchez-Corral P, et al. Molecular characterization of Complement Factor I deficiency in two Spanish families. Mol Immunol. 2008;45(10):2764–71. PubMed PMID: 18374984. Epub 2008/04/01. eng.

    Article  PubMed  CAS  Google Scholar 

  29. Alba-Dominguez M, Lopez-Lera A, Garrido S, Nozal P, Gonzalez-Granado I, Melero J, et al. Complement factor I deficiency: A not so rare immune defect: characterization of new mutations and the first large gene deletion. Orphanet journal of rare diseases. 2012;7:42. PubMed PMID: 22710145. Pubmed Central PMCID: 3458969.

    Article  PubMed  Google Scholar 

  30. Veerhuis R, Nielsen HM, Tenner AJ. Complement in the brain. Mol Immunol. 2011;48(14):1592–603. PubMed PMID: 21546088. Pubmed Central PMCID: 3142281.

    Article  PubMed  CAS  Google Scholar 

  31. Solal-Celigny P, Laviolette M, Hebert J, Atkins PC, Sirois M, Brun G, et al. C3b inactivator deficiency with immune complex manifestations. Clin Exp Immunol. 1982;47(1):197–205. PubMed PMID: 7094424. Pubmed Central PMCID: 1536350. Epub 1982/01/01.

    PubMed  CAS  Google Scholar 

  32. Negrini B, Kelleher KJ, Wald ER. Cerebrospinal fluid findings in aseptic versus bacterial meningitis. Pediatrics. 2000;105(2):316–9. PubMed PMID: 10654948.

    Article  PubMed  CAS  Google Scholar 

  33. Rhiannon JJ. Systemic lupus erythematosus involving the nervous system: presentation, pathogenesis, and management. Clin Rev Allergy Immunol. 2008;34(3):356–60. PubMed PMID: 18181036.

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Prof. Dr. Françoise Mascart (Immunobiology Laboratory, Erasme Hospital, Université Libre de Bruxelles, Belgium) for her support for the complement assays and Dr. Van den Kar and Dr. Van den Heuvel (Nijmegen, the Netherlands) for the MCP and FH gene sequencing. We also thank Ilse Coomans for the technical support.

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Authors and Affiliations

  1. Pediatric Pulmonology and Immunology, Ghent University Hospital, 9000, Ghent, Belgium

    Filomeen Haerynck, Frans De Baets & Petra Schelstraete

  2. Immunochemistry Laboratory, Immunobiology Clinics, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium

    Patrick Stordeur & Marie-Rose Bouvry

  3. Pediatric Nephrology and Rheumatology, Ghent University Hospital, Ghent, Belgium

    Johan Vandewalle & Joke Dehoorne

  4. Pediatric Neurology, Ghent University Hospital, Ghent, Belgium

    Rudy Van Coster

  5. Pediatric Hemato-oncology and Immunology, Ghent University Hospital, Ghent, Belgium

    Victoria Bordon

  6. Faculté de Médecine, Protein Chemistry Unit, Université Libre de Bruxelles, Brussels, Belgium

    Cédric Javaux

  7. Department of Immunobiology, Assistance Publique-Hôpitaux de Paris, European Georges Pompidou Hospital, Paris, France

    Véronique Fremeaux-Bacchi

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  1. Filomeen Haerynck
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Correspondence to Filomeen Haerynck.

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Haerynck, F., Stordeur, P., Vandewalle, J. et al. Complete Factor I Deficiency Due to Dysfunctional Factor I with Recurrent Aseptic Meningo-Encephalitis. J Clin Immunol 33, 1293–1301 (2013). https://doi.org/10.1007/s10875-013-9944-8

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  • DOI: https://doi.org/10.1007/s10875-013-9944-8

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