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

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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.

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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

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Acknowledgments

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.

Author information

Authors and Affiliations

  1. Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California-San Diego, 9500 Gilman Dr. MC 0635, La Jolla, CA, 92093, USA

    Lori Broderick, Chhavi Gandhi, Seema S. Aceves & Hal M. Hoffman

  2. San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA, USA

    James L. Mueller, Christopher D. Putnam & Hal M. Hoffman

  3. Department of Medicine, University of California-San Diego School of Medicine, La Jolla, CA, USA

    Lori Broderick, Chhavi Gandhi, James L. Mueller, Christopher D. Putnam, Seema S. Aceves & Hal M. Hoffman

  4. Department of Pathology, University of California-San Diego, La Jolla, CA, USA

    Katayoon Shayan & Robert O. Newbury

  5. Rady Children’s Hospital, San Diego, CA, USA

    Katayoon Shayan, Karin S. Peterson, Seema S. Aceves, Robert M. Sheets, Bradley M. Peterson, Robert O. Newbury, Hal M. Hoffman & John F. Bastian

  6. ADx Complement Laboratory and Department of Pediatrics, Allergy and Immunology Division, National Jewish Health, Denver, CO, USA

    Patricia C. Giclas

  7. Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of California-San Diego, La Jolla, CA, USA

    Karin S. Peterson, Seema S. Aceves, Robert M. Sheets, Hal M. Hoffman & John F. Bastian

  8. Division of Pediatric Critical Care, Department of Pediatrics, University of California-San Diego, La Jolla, CA, USA

    Bradley M. Peterson

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  1. Lori Broderick
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  2. Chhavi Gandhi
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Corresponding author

Correspondence to Hal M. Hoffman.

Additional information

Hal M. Hoffman and John F. Bastian contributed equally to the work.

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Broderick, L., Gandhi, C., Mueller, J.L. et al. Mutations of Complement Factor I and Potential Mechanisms of Neuroinflammation in Acute Hemorrhagic Leukoencephalitis. J Clin Immunol 33, 162–171 (2013). https://doi.org/10.1007/s10875-012-9767-z

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