Journal of Clinical Immunology

, Volume 33, Issue 1, pp 162–171

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

DOI: 10.1007/s10875-012-9767-z

Cite this article as:
Broderick, L., Gandhi, C., Mueller, J.L. et al. J Clin Immunol (2013) 33: 162. doi:10.1007/s10875-012-9767-z

Abstract

Purpose

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.

Keywords

Acute hemorrhagic leukoencephalitiscomplement factor IIL-1IL-1 receptor antagonist

Abbreviations

AHLE

Acute hemorrhagic leukoencephalitis

aHUS

Atypical hemolytic uremic syndrome

CFI

Complement factor I gene

CNS

Central nervous system

CSF

Cerebrospinal fluid

EAE

Experimental autoimmune encephalitis

FI

Complement factor I

FIMAC

Factor I/membrane attack complex

IL-1β

Interleukin-1β

IL-1Ra

IL-1 receptor antagonist

MAC

Membrane attack complex

SRCR

Scavenger receptor cysteine-rich

Supplementary material

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

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