Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation,Journal of Allergy and Clinical Immunology

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Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2021-08-09 , DOI: 10.1016/j.jaci.2021.07.033
Minghui He ₁ , Mezida B Saeed ₁ , Julien Record ₁ , Marton Keszei ₁ , Lia Gonçalves Pinho ₂ , Larissa Vasconcelos-Fontes ₂ , Roberta D'Aulerio ₁ , Rhaissa Vieira ₁ , Mariana M S Oliveira ₁ , Chiara Geyer ₁ , Lena Bohaumilitzky ₁ , Meike Thiemann ₁ , Ekaterina Deordieva ₃ , Lieselot Buedts ₄ , Joao Pedro Matias Lopes ₅ , Dmitry Pershin ₃ , Lennart Hammarström ₆ , Yu Xia ₇ , Xiaodong Zhao ₈ , Charlotte Cunningham-Rundles ₉ , Adrian J Thrasher ₁₀ , Siobhan O Burns ₁₁ , Vinicius Cotta-de-Almeida ₁₂ , Chaohong Liu ₁₃ , Anna Shcherbina ₃ , Peter Vandenberghe ₄ , Lisa S Westerberg ₁₄

Affiliation

Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Laboratory on Thymus Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
Department of Immunology, Dmitry Rogachev National Medical and Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
Center for Human Genetics, University Hospital Leuven, Leuven, Belgium.
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY; Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, UH Rainbow Babies and Children's Hospital, Cleveland, Ohio.
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen, China.
Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY.
UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom; Institute of Immunity and Transplantation, University College London, London, United Kingdom.
Laboratory on Thymus Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China.
Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom.

Background

B-cell affinity maturation in germinal center relies on regulated actin dynamics for cell migration and cell-to-cell communication. Activating mutations in the cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASp) cause X-linked neutropenia (XLN) with reduced serum level of IgA.

Objective

We investigated the role of B cells in XLN pathogenesis.

Methods

We examined B cells from 6 XLN patients, 2 of whom had novel R268W and S271F mutations in WASp. By using immunized XLN mouse models that carry the corresponding patient mutations, WASp L272P or WASp I296T, we examined the B-cell response.

Results

XLN patients had normal naive B cells and plasmablasts, but reduced IgA⁺ B cells and memory B cells, and poor B-cell proliferation. On immunization, XLN mice had a 2-fold reduction in germinal center B cells in spleen, but with increased generation of plasmablasts and plasma cells. In vitro, XLN B cells showed reduced immunoglobulin class switching and aberrant cell division as well as increased production of immunoglobulin-switched plasma cells.

Conclusions

Overactive WASp predisposes B cells for premature differentiation into plasma cells at the expense of cell proliferation and immunoglobulin class switching.

中文翻译：

X-连锁中性粒细胞减少症中过度活跃的 WASp 导致异常 B 细胞分裂和加速浆细胞生成

背景

生发中心的 B 细胞亲和力成熟依赖于细胞迁移和细胞间通讯的调节肌动蛋白动力学。激活细胞骨架调节因子 Wiskott-Aldrich 综合征蛋白 (WASp) 中的突变会导致 X 连锁中性粒细胞减少症 (XLN) 与血清 IgA 水平降低。

客观的

我们研究了 B 细胞在 XLN 发病机制中的作用。

方法

我们检查了 6 名 XLN 患者的 B 细胞，其中 2 名在 WASp 中有新的 R268W 和 S271F 突变。通过使用携带相应患者突变、WASp L272P 或 WASp I296T 的免疫 XLN 小鼠模型，我们检查了 B 细胞反应。

结果

XLN 患者的初始 B 细胞和浆母细胞正常，但 IgA ⁺ B 细胞和记忆 B 细胞减少，B 细胞增殖不良。免疫后，XLN 小鼠脾脏中的生发中心 B 细胞减少了 2 倍，但浆母细胞和浆细胞的生成增加。在体外， XLN B 细胞显示出免疫球蛋白类别转换减少和细胞分裂异常，以及免疫球蛋白转换浆细胞产生增加。