title: Mutations of complement factor I and potential mechanisms of neuroinflammation in acute hemorrhagic leukoencephalitis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California-San Diego, 9500 Gilman Dr. MC 0635, La Jolla, CA 92093, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Broderick
authors.forename: Chhavi
authors.initials: C
authors.lastname: Gandhi
authors.forename: James L
authors.initials: JL
authors.lastname: Mueller
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Putnam
authors.forename: Katayoon
authors.initials: K
authors.lastname: Shayan
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Giclas
authors.forename: Karin S
authors.initials: KS
authors.lastname: Peterson
authors.forename: Seema S
authors.initials: SS
authors.lastname: Aceves
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sheets
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Peterson
authors.forename: Robert O
authors.initials: RO
authors.lastname: Newbury
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.forename: John F
authors.initials: JF
authors.lastname: Bastian
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003167:Complement Activation / Q000235:genetics / Q000276:immunology; D003176:Complement C3 / Q000502:physiology; D017244:Complement Factor I / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D016130:Immunophenotyping; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007375:Interleukin-1 / Q000502:physiology; D004684:Leukoencephalitis, Acute Hemorrhagic / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008297:Male; D020125:Mutation, Missense / Q000276:immunology*; D009474:Neurons / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D010375:Pedigree
chemical_list: D003176:Complement C3; D015938:Complement Membrane Attack Complex; D007375:Interleukin-1; D017244:Complement Factor I