NeuroImmunology

A blog on multiple sclerosis research

An extensive microbiome comprised of bacteria, viruses, bacteriophages, and fungi is now understood to persist in nearly every human body site, including tissue and blood. The genomes of these microbes continually interact with the human genome in order to regulate .

By combining the precision of antibodies with toxic oxygen bursts, researchers have inactivated neural proteins to abolish fearful memories in mice.

Autophagy comprises a heterogeneous group of cellular pathways that enables eukaryotic cells to deliver cytoplasmic constituents for lysosomal degradation, to recycle nutrients and to survive during starvation. In addition to these primordial functions, autophagy has emerged as a key mechanism in orchestrating innate and adaptive immune responses and to shape CD4+ T cell immunity through delivery of peptides to MHC class II loading compartments. Individual autophagy proteins additionally modulate expression of MHC class I molecules for CD8+ T cell activation. The emergence and expansion of autoreactive CD4+ and CD8+ T cells are considered to play a key role in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Expression of the essential autophagy-related protein 5 (Atg5), which supports T lymphocyte survival and proliferation, is increased in T cells isolated from blood or brain tissues from patients with relapsing-remitting MS. Whether Atgs contribute to the activation of autoreactive T cells through autophagy-mediated antigen presentation is incompletely understood. Here, we discuss the complex functions of autophagy proteins and pathways in regulating T cell immunity and its potential role in the development and progression of MS.

Dendritic cells (DC) accumulate in the CNS during neuroinflammation, yet, how these cells contribute to CNS antigen drainage is still unknown.

This viewpoint review provides an integrative picture of seemingly contradictory work published on N-methyl-D-aspartate receptor1 (NMDAR1) autoantibodies (AB). Based on the present state-of-knowledge, it gives recommendations for the clinical decision process regarding immunosuppressive treatment. Brain antigen-directed AB in general and NMDAR1-AB in particular belong to a preexisting autoimmune repertoire of mammals including humans. Specific autoimmune-reactive B cells may get repeatedly boosted by various potential stimulants (e.g. microbiome, infections, or neoplasms) plus less efficiently suppressed over lifespan (gradual loss of tolerance), likely explaining the increasing seroprevalence upon aging (>20% NMDAR1-AB in 80 year-old humans). Pathophysiological significance emerges (I) when AB specific plasma cells settle in the brain and produce large amounts of brain antigen-directed AB intrathecally, and/or (II) in conditions of compromised blood-brain-barrier (BBB), for instance upon injury, infection, inflammation or genetic predisposition (APOE4 haplotype), which then allows substantial access of circulating AB to the brain. Regarding NMDAR1-AB, functional effects on neurons in vitro and elicitation of brain symptoms in vivo have been demonstrated for immunoglobulin (Ig) classes IgM, IgA, and IgG. Under conditions of brain inflammation, intrathecal production and class switch to IgG may provoke high NMDAR1-AB (and other brain antigen-directed AB) levels in cerebrospinal fluid (CSF) and serum, causing the severe syndrome named ‘anti-NMDAR encephalitis’, which then requires immunosuppressive therapy on top of the causal encephalitis treatment (if available). However, negative CSF NMDAR1-AB results cannot exclude chronic effects of serum NMDAR1-AB on the central nervous system, since the brain acts as ‘immunoprecipitator’, particularly in situations of compromised BBB. In any case of suspected symptomatic consequences of circulating AB directed against brain antigens, leakiness of the BBB should be evaluated by CSF analysis (albumin quotient) and magnetic resonance imaging before considering immunosuppression.

Background: Although rare, brain abnormalities without optic neuritis (ON) or transverse myelitis (TM) diagnosed with neuromyelitis optica spectrum disorder (NMOSD) have been reported in patients positive for the aquaporin-4 (AQP4) antibody. Objective: To analyze demographic and clinical differences among NMOSD patients without ON or TM, those with either ON or TM, and patients with simultaneous ON and TM at disease onset. Methods: In this retrospective study, patients were recruited who were positive for the AQP4 antibody, as detected using a cell-based assay, at the Second Affiliated Hospital of Guangzhou Medical University in China. Demographic and clinical data were obtained from each patient’s medical record. Results: A total of 292 patients were included in this study and were divided into four subgroups based on their initial manifestations: (i) NMOSD without ON or TM (NMOSD-ON-TM-, n = 70); (ii) NMOSD with ON (NMOSD-ON+, n = 95); (iii) NMOSD with TM (NMOSD-TM+, n = 116); and (iv) simultaneous ON and TM (NMO, n = 11). We found that age at onset was lower in the NMOSD-ON-TM- group than that in the other groups. The interval from the first episode to relapse was shorter in the NMOSD-ON-TM- group than that in NMOSD-TM+ group. Cerebral spinal fluid white cell counts and protein levels were significantly higher in the NMOSD-ON-TM- group than those in the other groups. Lower EDSS scores were observed in the NMOSD-ON-TM- group. Brain abnormalities, including in area postrema and hemisphere lesions, were more frequent in the NMOSD-ON-TM- group. Kaplan–Meier analysis showed that patients in the NMOSD-ON-TM- group experienced earlier relapse than those in other groups. Conversion to NMO in the NMOSD-ON+ group was greater than that in the other groups. Only 14 patients (4.8%, 14/292) had pure brain abnormalities, of which 12 had disease duration of several more years and eight (57.1%) experienced relapses. Conclusions: NMOSD patients with different initial manifestations present with significant differences in clinical features during follow-up. Patients with long-term AQP4 autoimmunity in the brain in the absence of ON or TM are not common.

Autoimmune epilepsy diagnostics: an interview with Dr. Joseph J. Higgins, Medical Director... https://t.co/SoIyGEEQWL https://t.co/yNR3XVsbLg