B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection.
B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection.
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DOI：
10.4049/jimmunol.1601031
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发表时间：
2017-06-15
期刊：
影响因子：
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通讯作者：
Shaikh SR
中科院分区：
文献类型：
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作者：
Kosaraju R;Guesdon W;Crouch MJ;Teague HL;Sullivan EM;Karlsson EA;Schultz-Cherry S;Gowdy K;Bridges LC;Reese LR;Neufer PD;Armstrong M;Reisdorph N;Milner JJ;Beck M;Shaikh SR
肥胖与感染风险增加和疫苗接种反应不良有关，这可能是由于B细胞功能受损。然而，关于肥胖对B细胞功能的影响以及调节B细胞反应的潜在因素的信息有限。因此，我们研究了肥胖模型中的B细胞细胞因子分泌和/或抗体产生。在肥胖人群中，在离体抗BCR/TLR 9刺激后，B细胞IL-6分泌降低，IgM水平升高。在高脂饮食诱导的小鼠肥胖中，未刺激的B细胞的离体IgM和IgG升高。此外，高脂饮食降低骨髓B细胞频率，伴随着减少转录的早期淋巴承诺标志物。随后在不存在或存在二十二碳六烯酸（DHA 3）的情况下，使用西方饮食模型研究了流感A/波多黎各/8/34感染后的鼠B细胞应答。DHA是一种具有免疫调节特性的必需脂肪酸，由于其血浆水平在肥胖症中降低，因此对其进行了测试。相对于对照组，食用西方饮食的小鼠抗体滴度降低，而西方饮食+ DHA提高了滴度。从机理上讲，DHA并不直接靶向B细胞以提高抗体水平。相反，DHA增加了下游专门的促分解脂质介质（SPM）14-HDHA，17-HDHA和保护素DX的浓度。发现所有三种SPM在流感感染后有效提高鼠抗体水平。总之，结果表明，B细胞反应在人类和小鼠肥胖模型中受损，并表明必需脂肪酸状态是影响体液免疫的一个因素，可能通过SPM介导的机制。
Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B-cell function. However, there is limited information about the influence of obesity on B-cell function and underlying factors that modulate B-cell responses. Therefore, we studied B-cell cytokine secretion and/or antibody production across obesity models. In obese humans, B-cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B-cells. Furthermore, the high fat diet lowered bone marrow B-cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B-cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA3). DHA, an essential fatty acid with immunomodulatory properties, was tested since its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished antibody titers whereas the Western diet + DHA improved titers. Mechanistically, DHA did not directly target B-cells to elevate antibody levels. Instead, DHA increased the concentration of the downstream specialized pro-resolving lipid mediators (SPMs) 14-HDHA, 17-HDHA, and protectin DX. All three SPMs were found to be effective in elevating murine antibody levels upon influenza infection. Altogether, the results demonstrate that B-cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism.