Autoimmune encephalitis: novel therapeutic targets at the preclinical level

ABSTRACT

Introduction

Antibody-mediated encephalitides (AE) with pathogenic autoantibodies (aAB) against neuronal surface antigens are a growing group of diseases characterized by antineuronal autoimmunity in the brain. AE patients typically present with rapidly progressive encephalitis and characteristic disease symptoms dependent on the target antigen. Current treatment consists of an escalating immunotherapy strategy including plasma exchange, steroid application, and B cell depletion.

Areas covered

For this review, we searched Medline database and google scholar with inclusive dates from 2000. We summarize current treatment strategies and present novel therapeutic approaches of target-specific interventions at the pre-clinical level as well as immunotherapy directed at antibody-induced pathology. Treatment options include modulation of target proteins, intervention with downstream pathways, antibody modification, and depletion of antibody-secreting cells.

Expert opinion

Although current therapies in AE are effective in many patients, recovery is often prolonged and relapses as well as persistent deficits can occur. Specific immunotherapy together with supportive target-specific therapy may provide faster control of severe symptoms, shorten the disease course, and lead to long-lasting disease stability. Among the various novel therapeutic approaches, modulation of targeted receptors by small molecules crossing the blood-brain barrier as well as prevention of aAB binding is of particular interest.

KEYWORDS:

• Autoimmune encephalitis
• bortezomib ephrin-B2
• Fab fragments
• immunotherapy
• oxysterole
• NMDA receptor
• plasma cell depletion
• positive allosteric modulators

Article highlights

• Antibody mediated encephalitis (AE) with pathogenic autoantibodies (aAB) against neuronal surface antigens is a disease group of severe autoimmune central nervous system (CNS) disorders preferentially targeting chemical synapses

• Clinical syndromes of patients with AE are determined by the respective target antigen of the pathogenic aAB

• Current treatment strategies consist of immunotherapy with use of corticosteroids, plasma exchange, and B cell depletion

• New therapeutic strategies include target-specific therapies in addition to immunotherapy and more specific immunotherapy directly targeting antibody-secreting cells or interfering with aAB binding

• Potential future target-directed therapeutics may include substances for activation of accessory proteins, allosteric modulators, and interference with downstream mechanisms.

This box summarizes key points contained in the article.

Declaration of interest

CG received speaker honoraria and salary for advisory boards from Alexion and Roche, both unrelated to the subject matters discussed in the manuscript. JS, HH, SH, and MH declare no conflicts of interest. The authors have no further relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The work was funded by the Deutsche Forschungsgemeinschaft (DFG) (FOR 3004; GE 2519/8-1; GE 2519/9-1 to CG, HU 1715/9-1 to MH; HA 6386/10-1 to SH), the Federal Ministry of Education and Research (BMBF; 01EW1901, 01GM1908B, 01GM1908E to CG), and the Schilling Foundation.