Table_5_Gut Antibody Deficiency in a Mouse Model of CVID Results in Spontaneous Development of a Gluten-Sensitive Enteropathy.xlsx

Primary immunodeficiencies are heritable disorders of immune function. CD19 is a B cell co-receptor important for B cell development, and CD19 deficiency is a known genetic risk factor for a rare form of primary immunodeficiency known as “common variable immunodeficiency” (CVID); an antibody deficiency resulting in low levels of serum IgG and IgA. Enteropathies are commonly observed in CVID patients but the underlying reason for this is undefined. Here, we utilize CD19−/− mice as a model of CVID to test the hypothesis that antibody deficiency negatively impacts gut physiology under steady-state conditions. As anticipated, immune phenotyping experiments demonstrate that CD19−/− mice develop a severe B cell deficiency in gut-associated lymphoid tissues that result in significant reductions to antibody concentrations in the gut lumen. Antibody deficiency was associated with defective anti-commensal IgA responses and the outgrowth of anaerobic bacteria in the gut. Expansion of anaerobic bacteria coincides with the development of a chronic inflammatory condition in the gut of CD19−/− mice that results in an intestinal malabsorption characterized by defects in lipid metabolism and transport. Administration of the antibiotic metronidazole to target anaerobic members of the microbiota rescues mice from disease indicating that intestinal malabsorption is a microbiota-dependent phenomenon. Finally, intestinal malabsorption in CD19−/− mice is a gluten-sensitive enteropathy as exposure to a gluten-free diet also significantly reduces disease severity in CD19−/− mice. Collectively, these results support an effect of antibody deficiency on steady-state gut physiology that compliment emerging data from human studies linking IgA deficiency with non-infectious complications associated with CVID. They also demonstrate that CD19−/− mice are a useful model for studying the role of B cell deficiency and gut dysbiosis on gluten-sensitive enteropathies; a rapidly emerging group of diseases in humans with an unknown etiology.

原发性免疫缺陷病（Primary immunodeficiencies）是一类遗传性免疫功能异常疾病。CD19是一种对B细胞发育至关重要的B细胞共受体，而CD19缺陷是一类名为普通变异型免疫缺陷病（common variable immunodeficiency, CVID）的罕见原发性免疫缺陷病的已知遗传风险因素；该疾病属于抗体缺陷病，会导致血清免疫球蛋白G（immunoglobulin G, IgG）与免疫球蛋白A（immunoglobulin A, IgA）水平低下。肠病在CVID患者中较为常见，但其潜在发病机制尚未明确。本研究以CD19敲除小鼠（CD19−/− mice）作为CVID的疾病模型，旨在验证"稳态条件下抗体缺陷会对肠道生理产生负面影响"这一科学假说。正如预期，免疫表型分析实验结果显示，CD19敲除小鼠的肠道相关淋巴组织中出现严重的B细胞缺陷，进而导致肠腔中的抗体浓度显著下降。抗体缺陷与抗共生菌群IgA应答缺陷及肠道厌氧菌过度增殖密切相关。厌氧菌增殖与CD19敲除小鼠肠道慢性炎症的发生进程同步，最终引发以脂质代谢与转运异常为特征的肠道吸收不良。采用靶向肠道微生物群中厌氧菌的抗生素甲硝唑进行干预，可使小鼠免受疾病困扰，这表明肠道吸收不良是一种依赖于肠道微生物群的病理现象。进一步研究发现，CD19敲除小鼠的肠道吸收不良属于谷蛋白敏感性肠病：喂食无麸质饮食同样可显著减轻该小鼠的疾病严重程度。综上，本研究结果证实了抗体缺陷对稳态肠道生理的调控作用，这与当前人类研究中发现的IgA缺陷与CVID相关非感染性并发症的新兴数据相互印证。本研究同时证明，CD19敲除小鼠是研究B细胞缺陷与肠道菌群失调在谷蛋白敏感性肠病中作用的理想模型；谷蛋白敏感性肠病是一类病因不明、在人类中发病率快速上升的疾病群体。