Jiménez-Saiz Rodrigo, Chu Derek K, Mandur Talveer S, Walker Tina D, Gordon Melissa E, Chaudhary Roopali, Koenig Joshua, Saliba Sarah, Galipeau Heather J, Utley Adam, King Irah L, Lee Kelvin, Ettinger Rachel, Waserman Susan, Kolbeck Roland, Jordana Manel
McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Departments of Immunology and Medicine, Roswell Park Cancer Institute, Buffalo, NY.
J Allergy Clin Immunol. 2017 Dec;140(6):1604-1615.e5. doi: 10.1016/j.jaci.2017.01.018. Epub 2017 Feb 16.
A number of food allergies (eg, fish, shellfish, and nuts) are lifelong, without any disease-transforming therapies, and unclear in their underlying immunology. Clinical manifestations of food allergy are largely mediated by IgE. Although persistent IgE titers have been attributed conventionally to long-lived IgE plasma cells (PCs), this has not been directly and comprehensively tested.
We sought to evaluate mechanisms underlying persistent IgE and allergic responses to food allergens.
We used a model of peanut allergy and anaphylaxis, various knockout mice, adoptive transfer experiments, and in vitro assays to identify mechanisms underlying persistent IgE humoral immunity over almost the entire lifespan of the mouse (18-20 months).
Contrary to conventional paradigms, our data show that clinically relevant lifelong IgE titers are not sustained by long-lived IgE PCs. Instead, lifelong reactivity is conferred by allergen-specific long-lived memory B cells that replenish the IgE PC compartment. B-cell reactivation requires allergen re-exposure and IL-4 production by CD4 T cells. We define the half-lives of antigen-specific germinal centers (23.3 days), IgE and IgG PCs (60 and 234.4 days, respectively), and clinically relevant cell-bound IgE (67.3 days).
These findings can explain lifelong food allergies observed in human subjects as the consequence of allergen exposures that recurrently activate memory B cells and identify these as a therapeutic target with disease-transforming potential.
许多食物过敏（如鱼、贝类和坚果过敏）是终身性的，没有任何可改变疾病进程的治疗方法，其潜在免疫学机制尚不清楚。食物过敏的临床表现很大程度上由IgE介导。尽管传统上认为持续的IgE滴度归因于长寿的IgE浆细胞（PCs），但这尚未得到直接和全面的验证。
我们试图评估食物过敏原持续IgE和过敏反应的潜在机制。
我们使用花生过敏和过敏反应模型、各种基因敲除小鼠、过继转移实验以及体外试验，来确定小鼠几乎整个生命周期（18 - 20个月）内持续IgE体液免疫的潜在机制。
与传统范式相反，我们的数据表明，临床上相关的终身IgE滴度并非由长寿的IgE PCs维持。相反，终身反应性是由补充IgE PC区室的过敏原特异性长寿记忆B细胞赋予的。B细胞再激活需要再次接触过敏原以及CD4 T细胞产生IL-4。我们确定了抗原特异性生发中心的半衰期（23.3天）、IgE和IgG PCs的半衰期（分别为60天和234.4天）以及临床上相关的细胞结合IgE的半衰期（67.3天）。
这些发现可以解释在人类受试者中观察到的终身食物过敏是反复激活记忆B细胞的过敏原暴露的结果，并将这些细胞确定为具有改变疾病进程潜力的治疗靶点。
