Fabienne Brilot

Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis

Objective: To study the longitudinal dynamics of anti–myelin oligodendrocyte glycoprotein (MOG) autoantibodies in childhood demyelinating diseases. Methods: We addressed the kinetics of anti-MOG immunoglobulins in a prospective study comprising 77 pediatric patients. This was supplemented by a cross-sectional study analyzing 126 pediatric patients with acute demyelination and 62 adult patients with multiple sclerosis (MS). MOG-transfected cells were used for detection of antibodies by flow cytometry. Results: Twenty-five children who were anti-MOG immunoglobulin (Ig) positive at disease onset were followed for up to 5 years. Anti-MOG antibodies rapidly and continuously declined in all 16 monophasic patients with acute disseminated encephalomyelitis and in one patient with clinically isolated syndrome. In contrast, in 6 of 8 patients (75%) eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during an observation period of up to 5 years. Antibodies to MOG were mainly IgG 1 and their binding was largely blocked by pathogenic anti-MOG antibodies derived from a spontaneous animal model of autoimmune encephalitis. The cross-sectional part of our study elaborated that anti-MOG Ig was present in about 25% of children with acute demyelination, but in none of the pediatric or adult controls. Sera from 4/62 (6%) adult patients with MS had anti-MOG IgG at low levels. Conclusions: The persistence or disappearance of antibodies to MOG may have prognostic relevance for acute childhood demyelination.

Antibodies to Native Myelin Oligodendrocyte Glycoprotein in Children with Inflammatory Demyelinating Central Nervous System Disease

Myelin oligodendrocyte glycoprotein (MOG) is a candidate target antigen in demyelinating diseases of the central nervous system (CNS). Although MOG is encephalitogenic in different animal models, the relevance of this antigen in human autoimmune diseases of the CNS is still controversial.

Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders

Recent reports of autoantibodies that bind to neuronal surface receptors or synaptic proteins have defined treatable forms of autoimmune encephalitis. Despite these developments, many cases of encephalitis remain unexplained. We have previously described a basal ganglia encephalitis with dominant movement and psychiatric disease, and proposed an autoimmune aetiology. Given the role of dopamine and dopamine receptors in the control of movement and behaviour, we hypothesized that patients with basal ganglia encephalitis and other putative autoimmune basal ganglia disorders harboured serum autoantibodies against important dopamine surface proteins. Basal ganglia encephalitis sera immunolabelled live surface cultured neurons that have high expression of dopamine surface proteins. To detect autoantibodies, we performed flow cytometry cell-based assays using human embryonic kidney cells to express surface antigens. Twelve of 17 children (aged 0.4-15 years, nine males) with basal ganglia encephalitis had elevated immunoglobulin G to extracellular dopamine-2 receptor, compared with 0/67 controls. Immunofluorescence on wild-type mouse brain showed that basal ganglia encephalitis sera immunolabelled microtubule-associated protein 2-positive neurons in striatum and also in cultured striatal neurons, whereas the immunolabelling was significantly decreased in dopamine-2 receptor knock-out brains. Immunocytochemistry confirmed that immunoreactivity localized to the surface of dopamine-2 receptor-transfected cells. Immunoabsorption of basal ganglia encephalitis sera on dopamine-2 receptor-transfected human embryonic kidney cells decreased immunolabelling of dopamine-2 receptor-transfected human embryonic kidney cells, neurons and wild-type mouse brain. Using a similar flow cytometry cell-based assay, we found no elevated immunoglobulin G binding to dopamine 1, 3 or 5 receptor, dopamine transporter or N-methyl-d-aspartate receptor. The 12 dopamine-2 receptor antibody-positive patients with encephalitis had movement disorders characterized by parkinsonism, dystonia and chorea. In addition, the patients had psychiatric disturbance with emotional lability, attention deficit and psychosis. Brain magnetic resonance imaging showed lesions localized to the basal ganglia in 50% of the patients. Elevated dopamine-2 receptor immunoglobulin G was also found in 10/30 patients with Sydenhams chorea, 0/22 patients with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and 4/44 patients with Tourettes syndrome. No dopamine-1 receptor immunoglobulin G was detected in any disease or control groups. We conclude that assessment of dopamine-2 receptor antibodies can help define autoimmune movement and psychiatric disorders.

N-Methyl-D-Aspartate Receptor Antibodies in Pediatric Dyskinetic Encephalitis Lethargica

Encephalitis lethargica (EL) describes an encephalitis with psychiatric, sleep, and extrapyramidal movement disorders. Dyskinetic and Parkinsonian forms have been described. EL shares clinical features with the anti–N‐methyl‐D‐aspartate receptor (NMDAR‐Ab) encephalitis. We studied 20 sera from pediatric patients with contemporary EL. Ten sera (from 2 males and 8 females, aged 1.3–13 years) and 6/6 cerebrospinal fluid samples were positive for NMDAR‐Ab. NMDAR‐Ab–positive patients had dyskinesias, agitation, seizures, and insomnia, whereas Parkinsonism and somnolence dominated in the NMDAR‐Ab–negative children. We were unable to identify any tumors. The dyskinetic form of EL is an NMDAR‐Ab encephalitis and can affect very young children. Ann Neurol 2009;66:704–709

Noncytotoxic Functions of NK Cells: Direct Pathogen Restriction and Assistance to Adaptive Immunity

Natural killer cells were named after their ability to mediate spontaneous cytotoxicity during innate immune responses. However, it has become clear in recent years that they play an equally important role in restricting infections and assisting the development of adaptive immune responses via their ability to produce cytokines. In humans, a dedicated NK cell subset primarily fulfills these later functions. In this review we discuss the noncytotoxic effector functions of NK cells and how they could be harnessed for immunotherapy and vaccine development.

Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease

Objective: To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS. Methods: Multicenter retrospective study. Results: A total of 144 children and adolescents (median age 8 years, range 0.7–17; 103 female) with NMDA receptor (NMDAR) encephalitis (n = 39), opsoclonus myoclonus ataxia syndrome (n = 32), neuromyelitis optica spectrum disorders (n = 20), neuropsychiatric systemic lupus erythematosus (n = 18), and other neuroinflammatory disorders (n = 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05–9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range 0.1–8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0–2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0–2 was greater in patients given rituximab early in their disease course compared to those treated later. Conclusion: While limited by the retrospective nature of this analysis, our data support an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality. Classification of evidence: This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections.

Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-Methyl-D-aspartate receptor or dopamine-2 receptor

Movement disorder relapses after herpes simplex virus 1 (HSV1) encephalitis have been hypothesized to be secondary to postviral autoimmunity. Recently, a proportion of patients with HSV1 encephalitis (HSE) were shown to produce autoantibodies against N‐methyl‐D‐aspartate receptor (NMDAR).

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses.

Dendritic cells (DCs) express many endocytic receptors that deliver antigens for major histocompatibility class (MHC) I and II presentation to CD8(+) and CD4(+) T cells, respectively. Here, we show that targeting Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) to one of them, the human multilectin DEC-205 receptor, in the presence of the DC maturation stimulus poly(I:C), expanded EBNA1-specific CD4(+) and CD8(+) memory T cells, and these lymphocytes could control the outgrowth of autologous EBV-infected B cells in vitro. In addition, using a novel mouse model with reconstituted human immune system components, we demonstrated that vaccination with alphaDEC-205-EBNA1 antibodies primed EBNA1-specific IFN-gamma-secreting T cells and also induced anti-EBNA1 antibodies in a subset of immunized mice. Because EBNA1 is the one EBV antigen that is expressed in all proliferating cells infected with this virus, our data suggest that DEC-205 targeting should be explored as a vaccination approach against symptomatic primary EBV infection and against EBV-associated malignancies.

NK cell survival mediated through the regulatory synapse with human DCs requires IL-15Rα

DCs activate NK cells during innate immune responses to viral infections. However, the composition and kinetics of the immunological synapse mediating this interaction are largely unknown. Here, we report the rapid formation of an immunological synapse between human resting NK cells and mature DCs. Although inhibitory NK cell receptors were polarized to this synapse, where they are known to protect mature DCs from NK cell lysis, the NK cell also received activation signals that induced mobilization of intracellular calcium and CD69 upregulation. The high-affinity component of the receptor for IL-15, IL-15Ralpha, accumulated at the synapse center on NK cells, and blocking of IL-15Ralpha increased NK cell apoptosis and diminished NK cell survival during their interaction with DCs. Furthermore, IL-15Ralpha-deficient NK cells, obtained from donors with a history of infectious mononucleosis, showed diminished survival in culture with DCs. Synapse formation was required for IL-15Ralpha-mediated NK cell survival, because synapse disruption by adhesion molecule blocking decreased DC-induced NK cell survival. These results identify what we believe to be a novel regulatory NK cell synapse with hallmarks of spatially separated inhibitory and activating interactions at its center. We suggest that this synapse formation enables optimal NK cell activation by DCs during innate immune responses.

VGKC antibodies in pediatric encephalitis presenting with status epilepticus

Background: Voltage-gated potassium channel antibodies (VGKC Ab) are associated with limbic encephalitis and neuromyotonia in adults. There have been no systematic investigations in children to date. Methods: We looked for antibodies that are associated with CNS syndromes in adults including antibodies to VGKCs, NMDARs, glutamic acid decarboxylase (GAD), and glycine receptor (GlyR) in the stored acute serum from 10 children with unexplained encephalitis presenting with encephalopathy and status epilepticus. We also looked for antibodies to leucine-rich glioma-inactivated 1 (Lgi1) and contactin-associated protein-like 2 (Caspr2), which are now known to be tightly complexed with VGKCs in vivo. Sixty-nine pediatric controls were used for comparison. Results: An elevated VGKC Ab (>100 pM) was detected in 4/10 patients with encephalitis compared to only 1/69 controls (p < 0.001). The outcome in the 4 VGKC Ab-positive patients with encephalitis was variable including good recovery (n = 1), cognitive impairment (n = 3), temporal lobe epilepsy (n = 2), and mesial temporal sclerosis (n = 1). No other antibodies were detected, including those to Lgi1 and Caspr2. Conclusion: Encephalitis associated with VGKC Ab occurs in children and presents with status epilepticus and focal epilepsy. These antibodies are not directed against Lgi1 or Caspr2.