Helminth induced B1 IgE is protective against allergic disease

蠕虫诱导的 B1 IgE 可预防过敏性疾病

• 批准号: 9251646
• 负责人: Rebecca Kelley Martin
• 金额: $ 5.71万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-10 至 2019-03-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251646
• 关键词: 2,4-Dinitrophenol; Affinity; Allergic Disease; Anaphylaxis; Antibodies; Antibody Affinity; Antibody Formation; Antigens; Area; Asthma; Autoimmune Responses; B-Lymphocytes; Bacteria; CD4 Positive T Lymphocytes; Cell Compartmentation; Cell Degranulation; Cells; Country; Cutaneous; Data; Development; Drug or chemical Tissue Distribution; Environment; Gatekeeping; Helminths; IgE; IgE Receptors; Immunity; Immunize; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Switch Recombination; Immunoglobulins; In Vitro; Infection; Interleukin-4; Interleukin-5; Intestines; Link; Mature B-Lymphocyte; Membrane; Modeling; Mus; Nematoda; Nematospiroides dubius; Nippostrongylus; Output; Parasites; Passive Cutaneous Anaphylaxis; Pattern; Plasma Cells; Production; Proteins; Protocols documentation; Pyroglyphidae; Rag1 Mouse; Reporter; Reporting; Resistance; Role; Serum; Sorting - Cell Movement; Source; Surface; System; T-Lymphocyte; TNFRSF5 gene; Testing; Venus; Viral; airway hyperresponsiveness; cytokine; egg; in vivo; interest; mast cell; mouse model; particle; pathogen; prevent; public health relevance; receptor; reconstitution; response

 DESCRIPTION (provided by applicant): While antigen specific-IgE is important for immunity against intestinal helminths, these pathogens generate high levels of largely non-specific IgE. This hinders the parasite-specific IgE thereby reducing mast cell degranulation and anti-helminth immunity. Thus, this represents a protective response that has evolved for the helminth: non-specific or low affinity IgE blocks high affinity IgE receptors (FcεRI) and thereby protects the helminth. The initial studies in this proposal indicate that B1 cells are responsible for the large IgE induced by helminth infection, in which cytokines act on B1 cells, promoting IgE production. In this application I further examine B1 B cell IgE production as the source of non-specific IgE in helminth infection, and then investigate the protective capacity of B1 IgE as an explanation for why helminth infection is protective against allergic disease. To this end, I plan to utilize a mouse model with a membrane IgE reporter to track the development of IgE in B1 compartments during helminth infection as well as rounds of division needed to class switch to IgE. I will additionally use a Rag1-/- mice reconstitution model, in which B1 or B2 cell IgE contributions to helminth infection clearance can be examined. I also plan to investigate the role of the cytokine IL-5 as a priming agent for B1 cell IgE production. The class switch recombination patterns of IgE have never been examined in B1 cells. I plan to analyze the switch regions (s), sμ to sε for sγ1 fragments. This protocol will determine if B1 cells undergoa direct switch from μ to ε, which is typical for low-affinity antibody production. Next, I plan toshow the B1 IgE can block MC degranulation in models of anaphylaxis. Also B1 IgE production will be assessed utilizing the reconstituted RAG-/- mice that are helminth infected and then sensitized to house dust mite (HDM) in a MC-dependent HDM model of mouse asthma. The reduced airway hyper-responsiveness seen with concurrent helminth infection should be diminished in B2 only reconstituted mice without the presence of B1 IgE. Next, I will test the underlying factors that push B1 cells to IgE in helminth infection. Preliminary evidence indicates that IL-5 may prime B1 cells to switch to IgE, I will expand the B1 cells with IL-5 and compare the IgE production in RAG-/- mice reconstituted with the IL-5 expanded B1 versus B1 from naïve mice. I hypothesize that IL-5 will push B1 cells to IgE production and when these mice are subjected to a HDM asthma model, they will have a decreased response as compared to non-IL-5 primed B1 reconstituted mice.

 描述（由申请方提供）：虽然抗原特异性IgE对肠道蠕虫免疫很重要，但这些病原体产生高水平的非特异性IgE。这阻碍了寄生虫特异性IgE，从而减少肥大细胞脱粒和抗蠕虫免疫。因此，这代表了蠕虫进化的保护性反应：非特异性或低亲和力IgE阻断高亲和力IgE受体（FcεRI），从而保护蠕虫。该提案中的初步研究表明，B1细胞负责蠕虫感染诱导的大IgE，其中细胞因子作用于B1细胞，促进IgE产生。在本申请中，我进一步研究了B1 B细胞IgE的产生作为蠕虫感染中非特异性IgE的来源，然后研究了B1 IgE的保护能力作为蠕虫感染对过敏性疾病具有保护作用的解释。为此，我计划利用带有膜IgE报告基因的小鼠模型来跟踪蠕虫感染期间B1隔室中IgE的发展以及类别切换到IgE所需的几轮分裂。我将另外使用Rag 1-/-小鼠重建模型，其中可以检查B1或B2细胞IgE对蠕虫感染清除的贡献。我还计划研究细胞因子IL-5作为B1细胞IgE产生的引发剂的作用。IgE的类别转换重组模式从未在B1细胞中进行过研究。我计划分析sγ1片段的开关区域sμ到sε。该方案将确定B1细胞是否经历从μ到ε的直接转换，这对于低亲和力抗体生产是典型的。接下来，我计划在过敏反应模型中证明B1 IgE可以阻断MC脱颗粒。此外，还将使用蠕虫感染然后在MC依赖性HDM小鼠哮喘模型中对屋尘螨（HDM）致敏的重建RAG-/-小鼠评估B1 IgE产生。在不存在B1 IgE的仅B2重建小鼠中，伴随蠕虫感染观察到的气道高反应性降低应被减弱。接下来，我将测试潜在因素 在蠕虫感染中将B1细胞推向IgE。初步证据表明，IL-5可以引发B1细胞转换为IgE，我将用IL-5扩增B1细胞，并比较用IL-5扩增的B1与来自幼稚小鼠的B1重建的RAG-/-小鼠中的IgE产生。我假设IL-5将推动B1细胞产生IgE，当这些小鼠经受HDM哮喘模型时，与非IL-5致敏的B1重建小鼠相比，它们的反应将降低。