Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis

Jiang, Feng; Fan, Siyuan; Sun, Yinwei; Ren, Haitao; Guan, Hongzhi; Wang, Jing

doi:10.3389/fimmu.2021.717598

Cited by 4 publications

(4 citation statements)

References 40 publications

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“…The levels of the type 1 T helper (Th1) axis (IFN-γ, TNF-α, CCL3, and CXCL10), Th2 axis (CCL1, CCL8, CCL17, CCL22), Treg axis (IL-10), Th17 axis (IL-7), B cell axis (CXCL13), cytokines, and T cells also contribute to the clinical stages of the disease ( 16 , 19 , 20 ). The immune system comprises a vast variety of cells in different states; however, previous studies conducting immunophenotypic analysis were based on low-flux assays confined to selected cell types and markers ( 21 , 22 ). Therefore, a better understanding of immune system modulation in response to anti-NMDARE using high-flux assays is required.…”

Section: Introductionmentioning

confidence: 99%

Single-cell transcriptomics reveals cell type–specific immune regulation associated with anti-NMDA receptor encephalitis in humans

Jiang

Dai

et al. 2022

Front. Immunol.

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IntroductionAnti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a rare autoimmune disease, and the peripheral immune characteristics associated with anti-NMDARE antibodies remain unclear.MethodsHerein, we characterized peripheral blood mononuclear cells from patients with anti-NMDARE and healthy individuals by single-cell RNA sequencing (scRNA-seq).ResultsThe transcriptional profiles of 129,217 cells were assessed, and 21 major cell clusters were identified. B-cell activation and differentiation, plasma cell expansion, and excessive inflammatory responses in innate immunity were all identified. Patients with anti-NMDARE showed higher expression levels of CXCL8, IL1B, IL6, TNF, TNFSF13, TNFSF13B, and NLRP3. We observed that anti-NMDARE patients in the acute phase expressed high levels of DC_CCR7 in human myeloid cells. Moreover, we observed that anti-NMDARE effects include oligoclonal expansions in response to immunizing agents. Strong humoral immunity and positive regulation of lymphocyte activation were observed in acute stage anti-NMDARE patients.DiscussionThis high-dimensional single-cell profiling of the peripheral immune microenvironment suggests that potential mechanisms are involved in the pathogenesis and recovery of anti-NMDAREs.

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Section: Introductionmentioning

confidence: 99%

Single-cell transcriptomics reveals cell type–specific immune regulation associated with anti-NMDA receptor encephalitis in humans

Jiang

Dai

et al. 2022

Front. Immunol.

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“…One study had transcriptionally analyzed 237 single CSF cells from one patient with anti-LGI AIE, but lacked power ( 41 ). Another previous study comparing LGI1-AIE to NMDAR-AIE did not unequivocally identify autoantigen-specific clones, but also lacked statistical power ( 42 ). Third , expanded clones were almost uniquely present in the CSF with some signs of somatic hypermutation in line with previous results in CSF and blood of six patients with LGI1 encephalitis ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

CSF plasma cell expansion in LGI1-/CASPR2-autoimmune encephalitis is associated with loss of regulatory MAIT cells

Esser,

Müller-Miny,

Heming

et al. 2023

Preprint

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Anti-Leucine-rich glioma inactivated-1 (LGI1) and anti-contactin-associated-protein-2 (CASPR2) associated autoimmune encephalitis (AIE) variants are characterized by directly pathogenic autoantibodies present in serum and CSF. The dynamics and drivers of intrathecal and systemic autoantibody production are incompletely understood. We aimed to elucidate the immunologic basis of the LGI1-/CASPR2-associated AIE variants by performing multi-omic profiling of CSF/blood in untreated patients. We validated findings by flow cytometry in independent cohorts and confirmed functionality using rodent immunization.We identified clonal IgG2 and IgG4 plasma cell expansion and affinity maturation in the CSF together with clonally restricted, activated, antigen-experienced CD8 and CD4 T cells as a hallmark of these encephalitis variants. Using recombinant cloning, we confirmed that expanded CSF plasma cell clones almost exclusively bound the respective neuronal autoantigen. In addition, we found a loss of regulatory mucosa-associated invariant T (MAIT) cells and gamma delta T cells in the CSF and – to a lesser degree – in blood. We validated the functional role of these invariant T cells using a novel murine active immunization paradigm using both autoantigens: MAIT cells suppressed systemic formation of LGI1 and CASPR2-specific anti-neuronal antibodies.We propose that loss of systemic and intrathecal regulatory mechanisms mediated by innate-like T cells promote plasma cell expansion and autoantibody production as a shared mechanism in AIE.One sentence summaryCerebrospinal fluid (CSF) and peripheral blood (PB) single cell transcriptomics of patients with untreated anti-LGI1 and anti-CASPR2 autoimmune encephalitis demonstrated CSF specific expansion of autoantigen-specific plasma cell clones and systemic loss of invariant mucosa-associated T-cells (MAIT).

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“…This heterogeneous clinical picture reflects the different distributions of NMDAR in the CNS. The underlying mechanism is mediated by IgG antibodies against the N-terminal of the NR1 subunit of NMDAR, which induces capping, cross-linking and internalization of NMDA receptors [ 72 , 73 ]. Although IgA and IgM NMDAR antibodies have also been identified, they are not pathogenic [ 73 ].…”

Section: Autoimmune Encephalitismentioning

confidence: 99%

“…The underlying mechanism is mediated by IgG antibodies against the N-terminal of the NR1 subunit of NMDAR, which induces capping, cross-linking and internalization of NMDA receptors [ 72 , 73 ]. Although IgA and IgM NMDAR antibodies have also been identified, they are not pathogenic [ 73 ]. The hallmark of psychiatric presentation is the polymorphic coexistence of several features, such as anxiety, agitation, disinhibition, abnormal behavior, hallucinations, and delusions, mimicking the first episode of psychosis [ 74 , 75 ].…”

Section: Autoimmune Encephalitismentioning

confidence: 99%

Epilepsy, Immunity and Neuropsychiatric Disorders

Fortunato

Giugno

Sammarra

et al. 2023

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Several studies have focused on the emerging role of immunity and inflammation in a wide range of neurological disorders. Autoimmune diseases involving central nervous system share well defined clinical features including epileptic seizures and additional neuropsychiatric symptoms, like cognitive and psychiatric disturbances. The growing evidence about the role of immunity in the pathophysiologic mechanisms underlying these conditions lead to the concept of autoimmune epilepsy. This relatively-new term has been introduced to highlight the etiological and prognostic implications of immunity in epileptogenesis. In this review, we aim to discuss the role of autoimmunity in epileptogenesis and its clinical, neurophysiological, neuroimaging and therapeutic implications. Moreover, we wish to address the close relationship between immunity and additional symptoms, particularly cognitive and psychiatric features, which deeply impact clinical outcome in these patients. To assess these aspects, we have first analyzed Rasmussen’s encephalitis. Subsequently, we have covered autoimmune encephalitis, particularly those associated with autoantibodies against surface neuronal antigens, as these autoantibodies express a direct immune-mediated mechanism, different from those against intracellular antigens. Then, we have discussed about the connection between systemic immune disorders and neurological manifestations. This review aims to highlight the need to expand knowledge about the role of inflammation and autoimmunity in the pathophysiology of neurological disorders and the importance to early recognize these clinical entities. Indeed, early identification may result in faster recovery and a better prognosis.

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Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis

Cited by 4 publications

References 40 publications

Single-cell transcriptomics reveals cell type–specific immune regulation associated with anti-NMDA receptor encephalitis in humans

Single-cell transcriptomics reveals cell type–specific immune regulation associated with anti-NMDA receptor encephalitis in humans

CSF plasma cell expansion in LGI1-/CASPR2-autoimmune encephalitis is associated with loss of regulatory MAIT cells

Epilepsy, Immunity and Neuropsychiatric Disorders

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