Role of CD22 in the Germinal Center Reaction

CD22 在生发中心反应中的作用

• 批准号: 10240471
• 负责人: Matthew Scott Macauley
• 金额: $ 27万
• 依托单位: UNIVERSITY OF ALBERTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240471
• 关键词: Accounting; Address; Affect; Affinity; Antibodies; Antibody Affinity; Antibody Response; Antibody Therapy; Antigens; Arthritis; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; B cell differentiation; B cell repertoire; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; Binding Proteins; Biochemical; Bone Marrow; CD22 gene; Cell Communication; Cell Cycle Kinetics; Cell surface; Cells; Chimera organism; Clinical; Development; Disease; Disease Progression; Effectiveness; Enzymes; Family; Genetic; Goals; Health; Immune response; Immunity; Immunization; Immunoglobulin Somatic Hypermutation; Immunologist; Impairment; K/BxN model; Knowledge; Lead; Ligands; Light; Mediating; Modeling; Mouse Strains; Mus; PTPN6 gene; Phosphoric Monoester Hydrolases; Play; Polysaccharides; Reaction; Receptor Signaling; Role; Serum; Stains; Structure; Structure of germinal center of lymph node; Surface; Testing; Time; Transgenic Mice; Vaccines; base; design; experimental study; glycosylation; immunoregulation; insight; member; mouse model; novel; novel strategies; pathogen; pathogenic autoantibodies; prevent; receptor; recruit; response; secondary lymphoid organ; sialic acid binding Ig-like lectin; therapeutic target

Cell surface glycosylation is dynamic and often changes in response to cellular differentiation. Changes in glycosylation can impart a function to cells through glycan-binding proteins. Well-documented changes in cellular glycosylation occur in an immune response when B-cells differentiate into germinal center (GC) B cells. Immunologists routinely use these changes in glycosylation to identify the GC, using the antibody GL7, which is a structure within secondary lymphoid organs where antibody affinity maturation takes place. Remarkably, no function has been attributed to these changes in glycosylation. The change in glycosylation detected by GL7 is intriguing because of its relevance to CD22, a glycan-binding protein and member of the Siglec family of immunomodulatory receptors. CD22 is a negative regulator of the B-cell receptor (BCR) through its ability to recruit the phosphatase SHP-1, although its function in GC B-cells has remained largely unexplored. Specifically, GL7 recognizes a glycan that is a low affinity ligand for CD22; hence, GC B-cells loose the high affinity glycan ligand of CD22 found abundantly on naïve B-cells. High affinity glycan ligands of CD22 regulate its spatial organization on the surface of naïve B-cells, maintaining CD22 and BCR in different microdomains. Accordingly, we hypothesize that loss of high affinity CD22 ligands in GC B-cells promotes the association of CD22 with the BCR. This hypothesis is particularly intriguing in light of recent findings demonstrating that BCR signaling is inhibited in GC B-cells through constitutive co-localization of SHP-1 with the BCR. This project aims to test this hypothesis by assessing: (Aim1) the functional consequence of modulating expression of CD22 or its glycan ligands specifically in GC B-cells; (Aim2) whether changes in glycan ligands in GC B-cells drives co-localization of CD22 with the BCR, which is responsible for recruitment SHP-1 and inhibiting BCR signaling; and (3) the consequence of disrupting the function of CD22 in the context of an antibody-mediated autoimmune disease. Key to testing the hypothesis is a transgenic mouse we have established that maintains expression of high affinity glycan ligands for CD22 in GC B-cells. Preliminary results demonstrate that maintaining high affinity CD22 ligands in GC B-cells results in decreased competitiveness for the GC B-cell repertoire in competition with WT GC B-cells; an effect that requires expression of CD22. If preliminary results reflect a truly GC-specific role for CD22, we expect that modulating expression of CD22 or its glycan ligands in a GC-specific manner will likewise impair GC B-cell responses, increase BCR signaling in GC B-cells, and abrogate disease progression in a mouse model of antibody- mediated autoimmune disease. The long-term objective of this project is to establish the role(s) played by CD22 in the GC reaction in both health and disease. This knowledge will provide new insights into how an ongoing immune response can be modulated to treat an antibody-mediated autoimmune disease.

细胞表面糖基化是动态的，并且经常响应于细胞分化而改变。变化 糖基化可以通过聚糖结合蛋白赋予细胞功能。有据可查的变化 当B细胞分化为生发中心（GC）B时，在免疫应答中发生细胞糖基化 细胞免疫学家通常使用这些糖基化的变化来鉴定GC，使用抗体GL 7， 其是次级淋巴器官内的一种结构，抗体亲和力在此成熟。 值得注意的是，没有功能归因于糖基化的这些变化。糖基化的变化 GL 7检测到的抗体是有趣的，因为它与CD 22相关，CD 22是一种聚糖结合蛋白，也是 免疫调节受体的Siglec家族。CD 22是B细胞受体（BCR）的负调节因子 通过其募集磷酸酶SHP-1的能力，尽管其在GC B细胞中的功能在很大程度上仍然存在， 未开发的具体地，GL 7识别作为CD 22的低亲和力配体的聚糖;因此，GC B细胞 释放在幼稚B细胞上大量发现的CD 22的高亲和力聚糖配体。高亲和力聚糖配体 CD 22调节其在幼稚B细胞表面的空间组织，维持CD 22和BCR在不同的细胞中的表达。 微域因此，我们假设GC B细胞中高亲和力CD 22配体的缺失促进了GCB的表达。 CD 22与BCR的结合。根据最近的发现，这一假设特别有趣 证明BCR信号传导在GC B细胞中通过SHP-1与BCR的组成性共定位而被抑制， BCR。本项目旨在通过评估来检验这一假设：（目标1） 特异性调节GC B细胞中的CD 22或其聚糖配体的表达; GC B细胞中的聚糖配体驱动CD 22与BCR的共定位，BCR负责募集 SHP-1和抑制BCR信号传导的作用;和（3）破坏CD 22在细胞中的功能的结果。 抗体介导的自身免疫性疾病的背景。检验这一假设的关键是一只转基因小鼠 我们已经建立了在GC B细胞中维持CD 22的高亲和力聚糖配体的表达。 初步结果表明，在GC B细胞中维持高亲和力的CD 22配体会导致GC B细胞中CD 22受体的减少。 在与WT GC B细胞的竞争中，GC B细胞库的竞争力;需要 CD 22的表达。如果初步结果反映了CD 22真正的GC特异性作用，我们预计， 以GC特异性方式表达CD 22或其聚糖配体同样会损害GC B细胞应答， 增加GC B细胞中的BCR信号传导，并在抗体的小鼠模型中消除疾病进展， 介导的自身免疫性疾病。该项目的长期目标是确定以下方面所发挥的作用： CD 22在健康和疾病中的GC反应。这些知识将提供新的见解， 可以调节持续的免疫应答以治疗抗体介导的自身免疫疾病。

项目成果

Glycoengineering of NK Cells with Glycan Ligands of CD22 and Selectins for B-Cell Lymphoma Therapy.

• DOI: 10.1002/anie.202005934
• 发表时间: 2021-02-15
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Hong S;Yu C;Wang P;Shi Y;Cao W;Cheng B;Chapla DG;Ma Y;Li J;Rodrigues E;Narimatsu Y;Yates JR 3rd;Chen X;Clausen H;Moremen KW;Macauley MS;Paulson JC;Wu P
• 通讯作者: Wu P

Hypersialylation in Cancer: Modulation of Inflammation and Therapeutic Opportunities.

• DOI: 10.3390/cancers10060207
• 发表时间: 2018-06-18
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Rodrigues E;Macauley MS
• 通讯作者: Macauley MS

Pre-treatment with high molecular weight free PEG effectively suppresses anti-PEG antibody induction by PEG-liposomes in mice.

• DOI: 10.1016/j.jconrel.2020.10.011
• 发表时间: 2021-01-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: McSweeney MD;Shen L;DeWalle AC;Joiner JB;Ciociola EC;Raghuwanshi D;Macauley MS;Lai SK
• 通讯作者: Lai SK