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

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) and anti-leucine-rich glioma-inactivated 1 encephalitis (anti-LGI1E) are the two most common types of antibody-mediated autoimmune encephalitis. We performed a comprehensive analysis of the B-cell immune repertoire in patients with anti-NMDARE (n = 7) and anti-LGI1E (n = 10) and healthy controls (n = 4). The results revealed the presence of many common clones between patients with these two types of autoimmune encephalitis, which were mostly class-switched. Additionally, many differences were found among the anti-NMDARE, anti-LGI1E, and healthy control groups, including the diversity of the B-cell immune repertoire and gene usage preference. These findings suggest that the same adaptive immune responses occur in patients with anti-NMDARE and anti-LGI1E, which deserves further exploration.

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Anti-neuron antibody syndrome: clinical features, cytokines/chemokines and predictors

Journal of Neuroinflammation ◽

10.1186/s12974-021-02259-z ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Shaohua Liao ◽

Chuanfen Li ◽

Xiaoying Bi ◽

Hongwei Guo ◽

Ying Qian ◽

...

Keyword(s):

Clinical Features ◽

Transforming Growth Factor ◽

Autoimmune Encephalitis ◽

Transforming Growth Factor Β1 ◽

Good Prognosis ◽

Paraneoplastic Neurological Syndrome ◽

Control Groups ◽

Aspartate Receptor ◽

Poor Outcomes ◽

And Control

Abstract Background Neuroimmunology is a rapidly expanding field, and there have been recent discoveries of new antibodies and neurological syndromes. Most of the current clinical studies have focused on disorders involving one specific antibody. We have summarized a class of antibodies that target common neuronal epitopes, and we have proposed the term “anti-neuron antibody syndrome” (ANAS). In this study, we aimed to clarify the clinical range and analyse the clinical features, cytokines/chemokines and predictors in ANAS. Methods This was a retrospective cohort study investigating patients with neurological manifestations that were positive for anti-neuron antibodies. Results A total of 110 patients were identified, of which 43 patients were classified as having autoimmune encephalitis (AE) and the other 67 were classified as having paraneoplastic neurological syndrome (PNS). With regards to anti-neuron antibodies, 42 patients tested positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibody, 19 for anti-Hu, 14 for anti-Yo and 12 for anti-PNMA2 (Ma2). There were significant differences between the ANAS and control groups in serum B cell-activating factor (BAFF) levels and in cerebrospinal fluid (CSF) C-X-C motif chemokine10 (CXCL10), CXCL13, interleukin10 (IL10), BAFF and transforming growth factor β1 (TGFβ1) levels. Predictors of poor outcomes included having tumours (P = 0.0193) and having a chronic onset (P = 0.0306), and predictors of relapses included having lower levels of CSF BAFF (P = 0.0491) and having a larger ratio of serum TGFβ1/serum CXCL13 (P = 0.0182). Conclusions Most patients with ANAS had a relatively good prognosis. Having tumours and a chronic onset were both associated with poor outcomes. CSF BAFF and the ratio of serum TGFβ1/serum CXCL13 were associated with relapses.

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T and B Cell Receptor Immune Repertoire Analysis using Next-generation Sequencing

Journal of Visualized Experiments ◽

10.3791/61792 ◽

2021 ◽

Author(s):

Lael Werner ◽

Chen Dor ◽

Naomi Salamon ◽

Meital Nagar ◽

Dror S. Shouval

Keyword(s):

Next Generation Sequencing ◽

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Next Generation ◽

Immune Repertoire ◽

Repertoire Analysis ◽

Generation Sequencing ◽

Immune Repertoire Analysis

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Autoimmune encephalitis mediated by B-cell response against N-methyl-d-aspartate receptor

Brain ◽

10.1093/brain/awaa250 ◽

2020 ◽

Vol 143 (10) ◽

pp. 2957-2972 ◽

Cited By ~ 2

Author(s):

Isabelle Wagnon ◽

Pauline Hélie ◽

Isabelle Bardou ◽

Caroline Regnauld ◽

Léonie Lesec ◽

...

Keyword(s):

B Cell ◽

Cell Response ◽

Clinical Symptoms ◽

Autoimmune Encephalitis ◽

Brain Parenchyma ◽

Autoimmune Response ◽

Autoimmune Reaction ◽

Aspartate Receptor ◽

Nmdar Encephalitis ◽

B Cell Response

Abstract Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease characterized by an antibody-mediated autoimmune response against NMDAR. Recent studies have shown that anti-NMDAR antibodies are involved in the pathophysiology of the disease. However, the upstream immune and inflammatory processes responsible for this pathogenic response are still poorly understood. Here, we immunized mice against the region of NMDA receptor containing the N368/G369 amino acids, previously implicated in a pathogenic response. This paradigm induced encephalopathy characterized by blood–brain barrier opening, periventricular T2-MRI hyperintensities and IgG deposits into the brain parenchyma. Two weeks after immunization, mice developed clinical symptoms reminiscent of encephalitis: anxiety- and depressive-like behaviours, spatial memory impairment (without motor disorders) and increased sensitivity to seizures. This response occurred independently of overt T-cell recruitment. However, it was associated with B220+ (B cell) infiltration towards the ventricles, where they differentiated into CD138+ cells (plasmocytes). Interestingly, these B cells originated from peripheral lymphoid organs (spleen and cervical lymphoid nodes). Finally, blocking the B-cell response using a depleting cocktail of antibodies reduced the severity of symptoms in encephalitis mice. This study demonstrates that the B-cell response can lead to an autoimmune reaction against NMDAR that drives encephalitis-like behavioural impairments. It also provides a relevant platform for dissecting encephalitogenic mechanisms in an animal model, and enables the testing of therapeutic strategies targeting the immune system in anti-NMDAR encephalitis.

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Cytokines/Chemokines: Potential Biomarkers for Non-paraneoplastic Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Frontiers in Neurology ◽

10.3389/fneur.2020.582296 ◽

2020 ◽

Vol 11 ◽

Author(s):

Jingwen Liu ◽

Lei Liu ◽

Wenting Kang ◽

Gongxin Peng ◽

Di Yu ◽

...

Keyword(s):

B Cell ◽

Antibody Titer ◽

Autoimmune Encephalitis ◽

Cell Axis ◽

Severity Of Disease ◽

Aspartate Receptor ◽

Nmdar Encephalitis ◽

Tnf Α ◽

Titer Group ◽

New Biomarkers

Objective: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common type of autoimmune encephalitis. This study focuses on finding new biomarkers to evaluate the clinical condition and provide new directions for treatment.Methods: A total of 44 cytokines/chemokines in the cerebrospinal fluid of 10 non-paraneoplastic patients and nine controls were measured. We selected some of the cytokines/chemokines that significantly increased in patients. Six selected cytokines/chemokines, including IL-10, CXCL10, CCL22, CCL3, IL-7, TNF-α, and three previously reported (IL-2, IL-6, and IL-17A), were measured in seven other patients who provided repeat samples. We compared their levels and explored correlations with severity of disease and antibody titers.Results: The levels of Th1 axis (CXCL10, TNF-α, IFN-γ, CCL3), Th2 axis (CCL1, CCL8, CCL17, CCL22), Treg axis (IL-10), Th17 axis (IL-7), and B cell axis (CXCL13) cytokines, as well as IL-12 p40 and IL-16, were significantly higher in patients compared to those in controls. The level of IL-2 was significantly decreased at the intermediate stage of treatment compared with that before treatment. The severity of disease is positively correlated with levels of CXCL10, CCL3, IL-10, CCL22, and IL-6. The level of CCL3 in the high antibody titer group was greater than that in the low antibody titer group.Conclusion: The pathogenesis of anti-NMDAR encephalitis involves T cell and B cell cytokines. T cells likely assist B cells to produce antibodies. IL-2, CXCL10, CCL3, IL-10, CCL22, and IL-6 may represent new biomarkers in anti-NMDAR encephalitis. Given the lack of research on IL-10, CCL3, and CCL22 in this disease, it will be informative to explore their potential role in pathogenesis in larger studies.

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Analysis of Peripheral Blood T Cell Receptor and B Cell Receptor Repertoires Reveals Dynamic Adaptive Immune Responses in COVID-19 Patients

SSRN Electronic Journal ◽

10.2139/ssrn.3575132 ◽

2020 ◽

Cited By ~ 2

Author(s):

Xuefeng Niu ◽

Song Li ◽

Pingchao Li ◽

Wenjing Pan ◽

Qian Wang ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

B Cell ◽

T Cell Receptor ◽

Peripheral Blood ◽

Cell Receptor ◽

B Cell Receptor ◽

Adaptive Immune Responses ◽

Adaptive Immune

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VEGF as a potential molecular target in periodontitis: a meta-analysis and microarray data validation

Journal of Inflammation ◽

10.1186/s12950-021-00281-9 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Bo Ren ◽

Que Feng ◽

Shan He ◽

Yanfeng Li ◽

Jiadong Fan ◽

...

Keyword(s):

Growth Factor ◽

Clinical Sample ◽

Meta Analysis ◽

Enrichment Analysis ◽

Therapeutic Drug ◽

Data Validation ◽

Control Groups ◽

Vegf Expression ◽

Healthy Control

Abstract Background Anti-vascular endothelial growth factor (VEGF) has been used as a therapeutic drug for the treatment of some human diseases. However, no systematic evidence is performed for assessing the role of VEGF in periodontitis. We carried out a comprehensive analysis to explore the role of VEGF in patients with periodontitis. Methods Multiple databases were searched for eligible studies. The pooled standardized mean difference (SMD) and odds ratio (OR) with the corresponding 95% confidence interval (CI) were applied to evaluate the effect sizes. Clinical data validation from microarray analysis was used. Pathway and process enrichment analysis were also investigated. Results Finally, 16 studies were included in this analysis. Overall, there was a significantly higher level of VEGF expression in periodontitis than in healthy control groups (OR = 16.64, 95% CI = 6.01–46.06, P < 0.001; SMD = 2.25, 95% CI = 1.25–3.24, P < 0.001). Subgroup analysis of ethnicity showed that VEGF expression was still correlated with periodontitis in the Asian and European populations. No correlation was observed between VEGF expression and age, gender, and pathological type. A large clinical sample data (427 periodontitis patients and 136 healthy controls) further validated that VEGF expression was higher in periodontitis than in healthy control groups (P = 0.023). VEGF was involved in many functions such as blood vessel development, response to growth factor, cell proliferation, and cell adhesion. Conclusions High levels of VEGF were credible implications for the development of periodontitis. Anti-VEGF therapy may be valuable for the treatment of periodontitis in clinical management.

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Use of immune repertoire sequencing to resolve discordant microscopic and immunochemical findings in a case of T cell-rich large B cell lymphoma in a young dog

BMC Veterinary Research ◽

10.1186/s12917-021-02783-3 ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

Gary Kwok Cheong Lee ◽

Dorothee Bienzle ◽

Stefan Matthias Keller ◽

Mei-Hua Hwang ◽

Nikos Darzentas ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Immune Repertoire ◽

Large B Cell Lymphoma ◽

Repertoire Sequencing ◽

Reactive Lymphocytes ◽

Large B Cell

Abstract Background Lymphocytic neoplasms with frequent reactive lymphocytes are uncommonly reported in dogs, and can pose a diagnostic challenge. Different diagnostic modalities such as cytology, flow cytometry, histopathology, immunohistochemistry, and clonality testing, are sometimes required for a diagnosis. This report illustrates the value of using a multi-modal diagnostic approach to decipher a complex lymphocytic tumor, and introduces immune repertoire sequencing as a diagnostic adjunct. Case presentation A 10-month-old Great Dane was referred for marked ascites. Cytologic analysis of abdominal fluid and hepatic aspirates revealed a mixed lymphocyte population including numerous large lymphocytes, yielding a diagnosis of lymphoma. Flow cytometrically, abdominal fluid lymphocytes were highly positive for CD4, CD5, CD18, CD45, and MHC II, consistent with T cell lymphoma. Due to a rapidly deteriorating clinical condition, the dog was euthanized. Post mortem histologic evaluation showed effacement of the liver by aggregates of B cells surrounded by T cells, suggestive of hepatic T cell-rich large B cell lymphoma. Immune repertoire sequencing confirmed the presence of clonal B cells in the liver but not the abdominal fluid, whereas reactive T cells with shared, polyclonal immune repertoires were found in both locations. Conclusions T cell-rich large B cell lymphoma is a rare neoplasm in dogs that may be challenging to diagnose and classify due to mixed lymphocyte populations. In this case, the results of histopathology, immunohistochemistry and immune repertoire sequencing were most consistent with a hepatic B cell neoplasm and reactive T cells exfoliating into the abdominal fluid. Immune repertoire sequencing was helpful in delineating neoplastic from reactive lymphocytes and characterizing repertoire overlap in both compartments. The potential pitfalls of equating atypical cytomorphology and monotypic marker expression in neoplasia are highlighted.

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Mechanical ventilation-induced alterations of intracellular surfactant pool and blood–gas barrier in healthy and pre-injured lungs

Histochemistry and Cell Biology ◽

10.1007/s00418-020-01938-x ◽

2020 ◽

Author(s):

Jeanne-Marie Krischer ◽

Karolin Albert ◽

Alexander Pfaffenroth ◽

Elena Lopez-Rodriguez ◽

Clemens Ruppert ◽

...

Keyword(s):

Mechanical Ventilation ◽

Blood Gas ◽

Control Groups ◽

Gas Barrier ◽

Alveolar Epithelial ◽

Alveolar Surfactant ◽

Healthy Control ◽

Mean Size ◽

The Mean ◽

Injury Progression

AbstractMechanical ventilation triggers the manifestation of lung injury and pre-injured lungs are more susceptible. Ventilation-induced abnormalities of alveolar surfactant are involved in injury progression. The effects of mechanical ventilation on the surfactant system might be different in healthy compared to pre-injured lungs. In the present study, we investigated the effects of different positive end-expiratory pressure (PEEP) ventilations on the structure of the blood–gas barrier, the ultrastructure of alveolar epithelial type II (AE2) cells and the intracellular surfactant pool (= lamellar bodies, LB). Rats were randomized into bleomycin-pre-injured or healthy control groups. One day later, rats were either not ventilated, or ventilated with PEEP = 1 or 5 cmH2O and a tidal volume of 10 ml/kg bodyweight for 3 h. Left lungs were subjected to design-based stereology, right lungs to measurements of surfactant proteins (SP−) B and C expression. In pre-injured lungs without ventilation, the expression of SP-C was reduced by bleomycin; while, there were fewer and larger LB compared to healthy lungs. PEEP = 1 cmH2O ventilation of bleomycin-injured lungs was linked with the thickest blood–gas barrier due to increased septal interstitial volumes. In healthy lungs, increasing PEEP levels reduced mean AE2 cell size and volume of LB per AE2 cell; while in pre-injured lungs, volumes of AE2 cells and LB per cell remained stable across PEEPs. Instead, in pre-injured lungs, increasing PEEP levels increased the number and decreased the mean size of LB. In conclusion, mechanical ventilation-induced alterations in LB ultrastructure differ between healthy and pre-injured lungs. PEEP = 1 cmH2O but not PEEP = 5 cmH2O ventilation aggravated septal interstitial abnormalities after bleomycin challenge.

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