Journal of Clinical Immunology

, Volume 33, Issue 1, pp 162–171 | Cite as

Mutations of Complement Factor I and Potential Mechanisms of Neuroinflammation in Acute Hemorrhagic Leukoencephalitis

  • Lori Broderick
  • Chhavi Gandhi
  • James L. Mueller
  • Christopher D. Putnam
  • Katayoon Shayan
  • Patricia C. Giclas
  • Karin S. Peterson
  • Seema S. Aceves
  • Robert M. Sheets
  • Bradley M. Peterson
  • Robert O. Newbury
  • Hal M. Hoffman
  • John F. Bastian
Original Research



Acute Hemorrhagic Leukoencephalitis (AHLE) is a rare demyelinating disorder of acute onset, rapid deterioration and significant morbidity and mortality. Most often described as a post-infectious complication of an upper respiratory illness, its precise pathophysiology remains unclear. We describe two pediatric patients with AHLE with partial complement factor I (FI) deficiency whose successful treatment included the interleukin-1 (IL-1) receptor antagonist, anakinra, implicating a role for FI and IL-1 in this disorder.


Extensive clinical workup of two patients presenting with AHLE revealed complement abnormalities, specifically related to the alternative pathway and its regulator, FI. Aggressive management with steroids, immunoglobulin, and anakinra ultimately led to improvement of clinical status and near return to neurologic baseline in both patients. Genetic sequencing of the FI coding regions of the patients and their families was performed. In vitro protein expression studies and immunohistochemistry of fixed brain tissue was used to investigate pathogenic mechanisms.


Two novel mutations in FI were identified in our patients, which result in failure to secrete FI. Immunohistochemical evaluation of brain tissue demonstrated positive staining for C3, membrane attack complex (MAC) and IL-1.


We propose AHLE is an unreported, rare phenotype for partial FI deficiency. The upregulation of C3, MAC and IL-1 with subsequent demyelination support a pathologic role for complement activation in AHLE, and suggest anakinra as an important adjunctive therapy in this disease.


Acute hemorrhagic leukoencephalitis complement factor I IL-1 IL-1 receptor antagonist 



Acute hemorrhagic leukoencephalitis


Atypical hemolytic uremic syndrome


Complement factor I gene


Central nervous system


Cerebrospinal fluid


Experimental autoimmune encephalitis


Complement factor I


Factor I/membrane attack complex




IL-1 receptor antagonist


Membrane attack complex


Scavenger receptor cysteine-rich



The authors would like to thank Dr. Sara C. Nilsson and Dr. Anna M. Blom (Lund University, Malmo, Sweden) for generously providing the FI cDNA, Nikki Bowen (San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA and University of California-San Diego School of Medicine, La Jolla, CA) for guidance with protein purification, the Ludwig Institute for Cancer Research (San Diego, CA) for sequencing support, Jeff Murray (University of Iowa, Iowa City, IA) for providing Filipino DNA control samples, and Keith Rapp, Justin Breisch, Barbara Carter and Gordon Pendergrass (Rady Children’s Hospital, San Diego, CA) for assistance with immunohistochemistry. Funding was provided by National Institutes of Health Training Grant T32 AI007469 (CG, LB).

Declaration of Funding

NIH Training Grant T32 AI007469 (CG, LB)

Conflict of Interest

Dr. Hoffman is a consultant for Sobi Biovitrum.

Supplementary material

10875_2012_9767_MOESM1_ESM.docx (8.3 mb)
ESM 1 (DOCX 8499 kb)


  1. 1.
    Payne ET, Rutka JT, Ho TK, Halliday WC, Banwell BL. Treatment leading to dramatic recovery in acute hemorrhagic leukoencephalitis. J Child Neurol. 2007;22:109–13.PubMedCrossRefGoogle Scholar
  2. 2.
    Leake JA, Billman GF, Nespeca MP, Duthie SE, Dory CE, Meltzer HS, et al. Pediatric acute hemorrhagic leukoencephalitis: report of a surviving patient and review. Clin Infect Dis. 2002;34:699–703.PubMedCrossRefGoogle Scholar
  3. 3.
    Peterson B, Khanna S, Fisher B, Marshall L. Prolonged hypernatremia controls elevated intracranial pressure in head-injured pediatric patients. Crit Care Med. 2000;28:1136–43.PubMedCrossRefGoogle Scholar
  4. 4.
    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;45:2764–71.PubMedCrossRefGoogle Scholar
  5. 5.
    Nilsson SC, Karpman D, Vaziri-Sani F, Kristoffersson AC, Salomon R, Provot F, et al. A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation. Mol Immunol. 2007;44:1835–44.PubMedCrossRefGoogle Scholar
  6. 6.
    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;39:310–23.PubMedCrossRefGoogle Scholar
  7. 7.
    Kovacs GG, Gasque P, Strobel T, Lindeck-Pozza E, Strohschneider M, Ironside JW, et al. Complement activation in human prion disease. Neurobiol Dis. 2004;15:21–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Chowdhury AR, Ehara T, Higuchi M, Hora K, Shigematsu H. Immunohistochemical detection of immunoglobulins and complements in formaldehyde-fixed and paraffin-embedded renal biopsy tissues; an adjunct for diagnosis of glomerulonephritis. Nephrology (Carlton). 2005;10:298–304.CrossRefGoogle Scholar
  9. 9.
    Rambach G, Maier H, Vago G, Mohsenipour I, Lass-Florl C, Defant A, et al. Complement induction and complement evasion in patients with cerebral aspergillosis. Microbes Infect. 2008;10:1567–76.PubMedCrossRefGoogle Scholar
  10. 10.
    Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayar J, Mueller JL, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet. 2004;364:1779–85.PubMedCrossRefGoogle Scholar
  11. 11.
    Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355:581–92.PubMedCrossRefGoogle Scholar
  12. 12.
    Nilsson SC, Sim RB, Lea SM, Fremeaux-Bacchi V, Blom AM. Complement factor I in health and disease. Mol Immunol. 2011;48:1611–20.PubMedCrossRefGoogle Scholar
  13. 13.
    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;40:172–85.PubMedCrossRefGoogle Scholar
  14. 14.
    Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010;31:E1445–60.PubMedCrossRefGoogle Scholar
  15. 15.
    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;45:95–105.PubMedCrossRefGoogle Scholar
  16. 16.
    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;77:339–49.PubMedCrossRefGoogle Scholar
  17. 17.
    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;108:12839–44.PubMedCrossRefGoogle Scholar
  18. 18.
    Moller Rasmussen J, Teisner B, Jepsen HH, Svehag SE, Knudsen F, Kirstein H, et al. Three cases of factor I deficiency: the effect of treatment with plasma. Clin Exp Immunol. 1988;74:131–6.PubMedGoogle Scholar
  19. 19.
    Naked GM, Florido MP, Ferreira de Paula P, Vinet AM, Inostroza JS, Isaac L. Deficiency of human complement factor I associated with lowered factor H. Clin Immunol. 2000;96:162–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Thomas A, Gasque P, Vaudry D, Gonzalez B, Fontaine M. Expression of a complete and functional complement system by human neuronal cells in vitro. Int Immunol. 2000;12:1015–23.PubMedCrossRefGoogle Scholar
  21. 21.
    Atkinson JP, Liszewski MK, Richards A, Kavanagh D, Moulton EA. Hemolytic uremic syndrome: an example of insufficient complement regulation on self-tissue. Ann N Y Acad Sci. 2005;1056:144–52.PubMedCrossRefGoogle Scholar
  22. 22.
    Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102:7227–32.PubMedCrossRefGoogle Scholar
  23. 23.
    Francis K, van Beek J, Canova C, Neal JW, Gasque P. Innate immunity and brain inflammation: the key role of complement. Expert Rev Mol Med. 2003;5:1–19.PubMedCrossRefGoogle Scholar
  24. 24.
    van Beek J, Elward K, Gasque P. Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann N Y Acad Sci. 2003;992:56–71.PubMedCrossRefGoogle Scholar
  25. 25.
    Silverman BA, Carney DF, Johnston CA, Vanguri P, Shin ML. Isolation of membrane attack complex of complement from myelin membranes treated with serum complement. J Neurochem. 1984;42:1024–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Vanguri P, Koski CL, Silverman B, Shin ML. Complement activation by isolated myelin: activation of the classical pathway in the absence of myelin-specific antibodies. Proc Natl Acad Sci U S A. 1982;79:3290–4.PubMedCrossRefGoogle Scholar
  27. 27.
    Gasque P, Dean YD, McGreal EP, VanBeek J, Morgan BP. Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology. 2000;49:171–86.PubMedCrossRefGoogle Scholar
  28. 28.
    Griffiths MR, Neal JW, Fontaine M, Das T, Gasque P. Complement factor H, a marker of self protects against experimental autoimmune encephalomyelitis. J Immunol. 2009;182:4368–77.PubMedCrossRefGoogle Scholar
  29. 29.
    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;58:1923–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Vyse TJ, Spath PJ, Davies KA, Morley BJ, Philippe P, Athanassiou P, et al. Hereditary complement factor I deficiency. QJM. 1994;87:385–401.PubMedGoogle Scholar
  31. 31.
    Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117:3720–32.PubMedCrossRefGoogle Scholar
  32. 32.
    Basu A, Krady JK, Levison SW. Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res. 2004;78:151–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Jauneau AC, Ischenko A, Chan P, Fontaine M. Complement component anaphylatoxins upregulate chemokine expression by human astrocytes. FEBS Lett. 2003;537:17–22.PubMedCrossRefGoogle Scholar
  34. 34.
    Palin K, Verrier D, Tridon V, Hurst J, Perry VH, Dantzer R, et al. Influence of the course of brain inflammation on the endogenous IL-1beta/IL-1Ra balance in the model of brain delayed-type hypersensitivity response to bacillus Calmette-Guerin in Lewis rats. J Neuroimmunol. 2004;149:22–30.PubMedCrossRefGoogle Scholar
  35. 35.
    Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol. 2005;5:629–40.PubMedCrossRefGoogle Scholar
  36. 36.
    Badovinac V, Mostarica-Stojkovic M, Dinarello CA, Stosic-Grujicic S. Interleukin-1 receptor antagonist suppresses experimental autoimmune encephalomyelitis (EAE) in rats by influencing the activation and proliferation of encephalitogenic cells. J Neuroimmunol. 1998;85:87–95.PubMedCrossRefGoogle Scholar
  37. 37.
    Barnum SR, Jones JL. Differential regulation of C3 gene expression in human astroglioma cells by interferon-gamma and interleukin-1 beta. Neurosci Lett. 1995;197:121–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Hansch GM, Seitz M, Betz M. Effect of the late complement components C5b-9 on human monocytes: release of prostanoids, oxygen radicals and of a factor inducing cell proliferation. Int Arch Allergy Appl Immunol. 1987;82:317–20.PubMedCrossRefGoogle Scholar
  39. 39.
    Holland MC, Morikis D, Lambris JD. Synthetic small-molecule complement inhibitors. Curr Opin Investig Drugs. 2004;5:1164–73.PubMedGoogle Scholar
  40. 40.
    Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11:785–97.PubMedCrossRefGoogle Scholar
  41. 41.
    DeLano W. The PyMOL molecular graphics system. San Carlos: DeLano Scientific; 2002.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Lori Broderick
    • 1
    • 3
  • Chhavi Gandhi
    • 1
    • 3
  • James L. Mueller
    • 2
    • 3
  • Christopher D. Putnam
    • 2
    • 3
  • Katayoon Shayan
    • 4
    • 5
  • Patricia C. Giclas
    • 6
  • Karin S. Peterson
    • 5
    • 7
  • Seema S. Aceves
    • 1
    • 3
    • 5
    • 7
  • Robert M. Sheets
    • 5
    • 7
  • Bradley M. Peterson
    • 5
    • 8
  • Robert O. Newbury
    • 4
    • 5
  • Hal M. Hoffman
    • 1
    • 2
    • 3
    • 5
    • 7
  • John F. Bastian
    • 5
    • 7
  1. 1.Division of Rheumatology, Allergy and Immunology, Department of MedicineUniversity of California-San DiegoLa JollaUSA
  2. 2.San Diego Branch, Ludwig Institute for Cancer ResearchLa JollaUSA
  3. 3.Department of MedicineUniversity of California-San Diego School of MedicineLa JollaUSA
  4. 4.Department of PathologyUniversity of California-San DiegoLa JollaUSA
  5. 5.Rady Children’s HospitalSan DiegoUSA
  6. 6.ADx Complement Laboratory and Department of Pediatrics, Allergy and Immunology DivisionNational Jewish HealthDenverUSA
  7. 7.Division of Allergy, Immunology and Rheumatology, Department of PediatricsUniversity of California-San DiegoLa JollaUSA
  8. 8.Division of Pediatric Critical Care, Department of PediatricsUniversity of California-San DiegoLa JollaUSA

Personalised recommendations