IgG3 + B cells are associated with the development of multiple sclerosis.,Clinical & Translational Immunology

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IgG3 + B cells are associated with the development of multiple sclerosis.
Clinical & Translational Immunology ( IF 4.6 ) Pub Date : 2020-04-29 , DOI: 10.1002/cti2.1133
Felix Marsh-Wakefield _{1,

2,

3} , Thomas Ashhurst _{1,

3,

4,

5,

6} , Stephanie Trend _{7,

8} , Helen M McGuire _{1,

3,

5,

9} , Pierre Juillard _{1,

2} , Anna Zinger ₂ , Anderson P Jones ₇ , Allan G Kermode _{8,

10} , Simon Hawke _{2,

11} , Georges E Grau _{1,

2} , Prue H Hart ₇ , Scott N Byrne _{1,

3,

12}

Affiliation

School of Medical Sciences Faculty of Medicine and Health The University of Sydney Sydney NSW Australia.
Vascular Immunology Unit Department of Pathology The University of Sydney Sydney NSW Australia.
Charles Perkins Centre The University of Sydney Sydney NSW Australia.
Viral Immunopathology Laboratory Department of Pathology The University of Sydney Sydney NSW Australia.
Ramaciotti Facility for Human Systems Biology The University of Sydney Sydney NSW Australia.
Sydney Cytometry Facility Charles Perkins Centre The University of Sydney and Centenary Institute Sydney NSW Australia.
Telethon Kids Institute University of Western Australia Perth WA Australia.
Centre for Neuromuscular and Neurological Disorders Perron Institute for Neurological and Translational Science University of Western Australia Perth WA Australia.
Translational Immunology Laboratory Department of Pathology The University of Sydney Sydney NSW Australia.
Institute for Immunology and Infectious Disease Murdoch University Perth WA Australia.
Central West Neurology and Neurosurgery Orange NSW Australia.
Centre for Immunology and Allergy Research Westmead Institute for Medical Research Westmead NSW Australia.

Objectives Disease-modifying therapies (DMTs) targeting B cells are amongst the most effective for preventing multiple sclerosis (MS) progression. IgG3 antibodies and their uncharacterised B-cell clones are predicted to play a pathogenic role in MS. Identifying subsets of IgG3 + B cells involved in MS progression could improve diagnosis, could inform timely disease intervention and may lead to new DMTs that target B cells more specifically. Methods We designed a 31-parameter B-cell-focused mass cytometry panel to interrogate the role of peripheral blood IgG3 + B cells in MS progression of two different patient cohorts: one to investigate the B-cell subsets involved in conversion from clinically isolated syndrome (CIS) to MS; and another to compare MS patients with inactive or active stages of disease. Each independent cohort included a group of non-MS controls. Results Nine distinct CD20+IgD-IgG3 + B-cell subsets were identified. Significant changes in the proportion of CD21+CD24+CD27-CD38- and CD27+CD38hiCD71hi memory B-cell subsets correlated with changes in serum IgG3 levels and time to conversion from CIS to MS. The same CD38- double-negative B-cell subset was significantly elevated in MS patients with active forms of the disease. A third CD21+CD24+CD27+CD38- subset was elevated in patients with active MS, whilst narrowband UVB significantly reduced the proportion of this switched-memory B-cell subset. Conclusion We have identified previously uncharacterised subsets of IgG3 + B cells and shown them to correlate with autoimmune attacks on the central nervous system (CNS). These results highlight the potential for therapies that specifically target IgG3 + B cells to impact MS progression.

中文翻译：

IgG3 + B 细胞与多发性硬化症的发展相关。

目标针对 B 细胞的疾病修饰疗法 (DMT) 是预防多发性硬化症 (MS) 进展最有效的疗法之一。 IgG3 抗体及其未表征的 B 细胞克隆预计在 MS 中发挥致病作用。识别参与 MS 进展的 IgG3 + B 细胞亚群可以改善诊断，可以为及时的疾病干预提供信息，并可能导致更具体地针对 B 细胞的新 DMT。方法我们设计了一个以 31 参数为重点的 B 细胞质谱流式细胞术面板，以探讨外周血 IgG3 + B 细胞在两个不同患者队列的 MS 进展中的作用：其中一个用于研究参与临床孤立综合征转化的 B 细胞亚群(CIS) 至 MS；另一项是比较处于疾病非活动期或活动期的多发性硬化症患者。每个独立队列包括一组非 MS 对照。结果鉴定出九个不同的 CD20+IgD-IgG3+B 细胞亚群。 CD21+CD24+CD27-CD38- 和 CD27+CD38hiCD71hi 记忆 B 细胞亚群比例的显着变化与血清 IgG3 水平的变化以及从 CIS 转换为 MS 的时间相关。在患有活动性多发性硬化症的患者中，相同的 CD38-双阴性 B 细胞亚群显着升高。第三个 CD21+CD24+CD27+CD38- 亚群在活动性 MS 患者中升高，而窄谱 UVB 显着降低了这种切换记忆 B 细胞亚群的比例。结论我们已经鉴定出以前未表征的 IgG3 + B 细胞亚群，并表明它们与中枢神经系统 (CNS) 的自身免疫攻击相关。这些结果凸显了专门针对 IgG3 + B 细胞的疗法影响 MS 进展的潜力。

更新日期：2020-04-29

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