Sofia Akrivou

GAD65 epitope mapping and search for novel autoantibodies in GAD-associated neurological disorders.

Antibodies against Glutamic-acid-decarboxylase (GAD65) are seen in various CNS excitability disorders including stiff-person syndrome, cerebellar ataxia, encephalitis and epilepsy. To explore pathogenicity, we examined whether distinct epitope specificities or other co-existing antibodies may account for each disorder. The epitope recognized by all 27 tested patients, irrespective of clinical phenotype, corresponded to the catalytic core of GAD. No autoantibodies against known GABAergic antigens were found. In a screen for novel specificities using live hippocampal neurons, three epilepsy patients, but no other, were positive. We conclude that no GAD-specific epitope defines any neurological syndrome but other antibody specificities may account for certain phenotypes.

Glycine receptor antibodies in stiff-person syndrome and other GAD-positive CNS disorders

Stiff-person syndrome (SPS) is characterized by stiffness in trunk and limb muscles, phobic anxiety, and sudden spasms. A disturbance in inhibitory GABAergic pathways, presumably by autoantibodies against GAD (the main GABA-synthesizing enzyme), is considered fundamental for SPS pathogenesis.1 As the precise role of anti-GAD antibodies in SPS remains unclear,2,3 several other candidate disease-specific autoantibodies associated with inhibitory pathways have been explored3,4 or are actively pursued. Recently, McKeon et al.5 described anti-glycine-α1 receptor (GlyR) antibodies in a subset of patients with SPS. Glycine is a neurotransmitter in spinal inhibitory interneurons and GlyR are primarily expressed in the spinal cord, brainstem, and cerebellum. Anti-GlyR antibodies have been associated with progressive encephalomyelitis with rigidity and myoclonus (PERM), a syndrome resembling SPS.6 Our aims were to search for GlyR antibodies in a large number of patients with well-characterized SPS and other CNS autoimmune controls and other GAD-positive disorders; and to correlate anti-GlyR titers with clinical symptomatology using quantitative scales of stiffness and spasms.7

Anti-aquaporin-4 autoantibodies in systemic lupus erythematosus persist for years and induce astrocytic cytotoxicity but not CNS disease

Anti-aquaporin-4 autoantibodies are specific for the neuromyelitis optica spectrum disorders (NMOSD) and they have also been described in patients with systemic lupus erythematosus (SLE) with neurological signs consistent with NMOSD. Our objective was to test for the presence and pathogenicity of anti-AQP4 antibodies in SLE patients without neurological disease. Sera from 89 non-CNS-SLE patients were screened for anti-AQP4 autoantibodies. Two of the 89 patients were positive. Archived samples dating back 11 years were also positive. A brain and spinal cord MRI did not reveal any NMOSD-compatible lesions. An in vitro cytotoxicity assay showed that either sera or purified IgG from these patients induced a complement-mediated damage in cultured astrocytes comparable to antibodies obtained from typical NMO patients. We conclude that AQP4-antibodies can be present in SLE patients and persist for many years, without concurrent clinical or radiological NMOSD signs. It is unclear why the anti-AQP4 antibodies did not induce CNS disease.

Immunotherapy-responsive limbic encephalitis with antibodies to glutamic acid decarboxylase

Glutamic acid decarboxylase (GAD) has been recently identified as a target of humoral autoimmunity in a small subgroup of patients with non-paraneoplastic limbic encephalitis (NPLE). We present a patient with NPLE and positive anti-GAD antibodies who showed significant improvement after long-term immunotherapy. A 48-year old female was admitted with a two-year history of anterograde amnesia and seizures. Brain MRI revealed bilateral lesions of medial temporal lobes. Screening for anti-neuronal antibodies showed high anti-GAD titers in both serum and cerebrospinal fluid (CSF) with strong evidence of intrathecal production. The patient received treatment with prednisolone and long-term plasma exchange. During a 12-month follow-up, she exhibited complete seizure remission and an improvement in memory and visuo-spatial skills. Anti-GAD antibodies may serve as a useful marker to identify a subset of NPLE patients that respond to immunoregulatory treatment.

Autoimmune encephalitis with GABAB antibodies, thymoma, and GABAB receptor thymic expression

Antibody-mediated autoimmune encephalopathies comprise a group of severe conditions with a varying degree of motor and cognitive symptoms that respond to immunotherapies.1 The associated antibodies are directed against intracellular targets, such as the classic paraneoplastic autoantigens Hu, Yo, Ri, CV2, Ma2/Ta, or the enzyme GAD, or against cell surface antigens such as receptors and ion channels.

Postherpes simplex encephalitis: a case series of viral-triggered autoimmunity, synaptic autoantibodies and response to therapy

Background: Recent evidence suggests that patients with herpes simplex virus (HSV) encephalitis may relapse because of autoimmunity against the N-methyl-D-aspartate receptor (NMDAR). We present a case series of post-HSV relapsing encephalopathy associated with antibodies to central nervous system (CNS) synaptic antigens. Patient/Methods: Sera and cerebrospinal fluid (CSF) from five patients with HSV encephalitis who relapsed after antiviral therapy were tested for anti-NMDAR, gamma-aminobutyric acid b receptor (GABAbR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), Leucine-rich, glioma inactivated 1 (LGI1), anti -contactin-associated protein-like 2 (CASPR2) and dipeptidyl-peptidase-like protein-6 (DDPX) antibodies using cell-based assays. Results: Five patients (two infants, one child and two adults) developed post-HSV autoimmune encephalitis. The infants, aged 9 months and 10 months, after prompt and seemingly successful anti-HSV therapy, were readmitted with typical signs of NMDAR-encephalitis evolving within days, with NMDAR antibodies detected in both serum and CSF. Although they were promptly treated with intravenous immunoglobulin (IVIg) and with IVIg followed by rituximab, respectively, they were both left with psychomotor deficits. A 14-year-old girl with seizures due to HSV encephalitis improved with anti-HSV therapy. Later, she manifested intractable seizures and she was found positive for anti-NMDAR antibodies which persist. The two adults were women, aged 58 and 33 years. The first recovered after anti-HSV therapy and remained asymptomatic for 6 months, until she developed generalized seizures with persisting CSF anti-NMDAR antibodies; the second, who continued to be encephalopathic after 2 weeks of anti-HSV therapy, tested positive for anti-NMDAR antibodies in the serum and anti-GABAbR antibodies in the serum and CSF. She recovered fully following IVIg therapy but her serum anti-GABAbR antibodies persist 34 months later. Discussion: Infection of the CNS with HSV can trigger CNS autoimmunity associated not only with anti-NMDAR but also with anti-GABAbR antibodies. These antibodies can persist in the serum, even without associated symptoms, but their presence in the CSF is firmly associated with disease development. In contrast to children and adults who responded well to therapies, the infants had an incomplete recovery with severe psychomotor deficits probably due to the interference of anti-NMDAR antibodies with neuro-developmental processes.

Recurrent optic neuritis is characterised by anti-MOG antibodies: A follow-up study

Mature antigen-loaded dendritic cells (DCs) are well-known antigen (Ag)-presenting cells with a high potential of activating T cells and inducing inflammation, whereas steady-state DCs are known to maintain T cell homeostasis and peripheral tolerance. T cell recognition of self-antigen presented by peripheral immature DC, may lead to apoptosis, tolerance or the conversion into peripheral-induced Treg (iTreg). The main goals of this study are to define the underlying mechanisms by which DCs control peripheral tolerance of activated T cells. Experimental autoimmune encephalomyelitis (EAE) is a T cell mediated autoimmune disease of the CNS widely used as a model for multiple sclerosis. EAE is induced by immunization using Myelin Oligodendrocyte Glycoprotein peptide (MOGp35–55). To study Aginduce peripheral tolerance, we used a mouse where the invariant chain CLIP sequence is replaced by MOGp35–55 peptide (iI). By crossing the iI to the inducible CD11c-creER, we generated mice where we are able to induce MOGp35–55 presentation on MHC class II by CD11c cells after tamoxifen (TAM) injection without further maturation/activation signals (iDC). Upon TAM injection, about 5% of all CD11c cells present the MOGp35–55. iDC mice exhibit complete resistant to EAE induction by administration of TAM 2 days before active immunization. This is in line with previous studies showing tolerance induction by resting DCs. When we injected TAM 2 days after active immunization, the iDC mice display again complete resistance to EAE. The same was true for TAM administration at day 7 post active immunization, a time where the first T cell priming and differentiation is thought to already take place. When analysing splenocytes 21 days after immunization (14 days after TAM), we observed a reduced percentage of interleukin-17A (IL-17A)-producing cells as well as IL-17A and interferon gamma (IFNg) coproducing cells in the iDC mice. TCR transgenic T cells (2D2) are able to proliferate when adoptively transferred into TAM treated iDC mice. However, the 2D2 cells show a strong upregulation of PD-1 and a moderate elevation of BTLA when transferred into iDC mice compared to the controls. Both PD-1 and BTLA are known co-inhibitory molecules associated with tolerance. Our results show that the MOG-presenting steady state DCs can block the induction of EAE even after the initial priming phase of the disease, in a process that possibly involve PD-1 and BTLA.