Hartwig Jelka, Sotzny Franziska, Bauer Sandra, Heidecke Harald, Riemekasten Gabriela, Dragun Duska, Meisel Christian, Dames Claudia, Grabowski Patricia, Scheibenbogen Carmen
Institute for Medical Immunology, Charité University Medicine Berlin, Berlin, Germany.
CellTrend GmbH, Luckenwalde, Brandenburg, Germany.
Brain Behav Immun Health. 2020 Feb 5;3:100047. doi: 10.1016/j.bbih.2020.100047. eCollection 2020 Mar.
There is emerging evidence of a network of natural autoantibodies against GPCR which is dysregulated in various diseases. β2 adrenergic and M3 and M4 cholinergic receptor (β2 AdR and M3/4 mAChR) antibodies were found to be elevated in a subset of ME/CFS patients.
We comparatively analyzed the effects of polyclonal IgG on β2 AdR signaling and immune cell function . 16 IgG fractions were isolated from serum of 5 ME/CFS patients with elevated (CFS AAB) and 5 with normal levels (CFS AAB) of β2 AdR autoantibodies, and from 6 healthy controls (HC). The effect of each IgG on β-arrestin recruitment and cAMP production in β2 AdR and M3/4R reporter cell lines was studied. Further effect of each IgG on human monocyte cytokine production and on T cell proliferation was analyzed. In addition, studies on cytokine production in β2 AdR wild type and knockout mice splenocytes incubated with IgG fractions were performed.
We found that IgGs from HC could stimulate β-arrestin recruitment and cAMP production in β2 AdR reporter cell lines whereas IgGs from CFS AAB had no effect. The IgG-mediated activation of β2 AdR was confirmed in β2 AdR wt and ko mice. In accordance with previous studies IgG fractions from HC inhibited LPS-induced TNFα and stimulated LPS-induced IL-10 production of monocytes. Further IgG fractions from HC enhanced proliferation of T-cells stimulated with anti-CD3/CD28. IgG fractions from CFS AAB patients had no significant effect on both cytokine production and T cell proliferation, while IgGs from CFS AAB had an intermediate effect. We could also observe that IgG can modulate the signaling of β2 AdR ligands isoprenline and propranolol.
We provide evidence that IgG can activate β2 AdR. The β2 AdR activation by IgG is attenuated in ME/CFS patients. A dysregulation of β2 AdR function could explain many symptoms of ME/CFS.
越来越多的证据表明，存在一个针对GPCR的天然自身抗体网络，该网络在各种疾病中失调。在一部分肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）患者中，发现β2肾上腺素能受体以及M3和M4胆碱能受体（β2 AdR和M3/4 mAChR）抗体水平升高。
我们比较分析了多克隆IgG对β2 AdR信号传导和免疫细胞功能的影响。从5名β2 AdR自身抗体水平升高的ME/CFS患者（CFS AAB）、5名β2 AdR自身抗体水平正常的ME/CFS患者以及6名健康对照者（HC）的血清中分离出16种IgG组分。研究了每种IgG对β2 AdR和M3/4R报告细胞系中β - 抑制蛋白募集和环磷酸腺苷（cAMP）产生的影响。进一步分析了每种IgG对人单核细胞细胞因子产生和T细胞增殖的影响。此外，还进行了用IgG组分孵育β2 AdR野生型和基因敲除小鼠脾细胞后细胞因子产生情况的研究。
我们发现，HC的IgG可刺激β2 AdR报告细胞系中的β - 抑制蛋白募集和cAMP产生，而CFS AAB的IgG则无此作用。在β2 AdR野生型和基因敲除小鼠中证实了IgG介导的β2 AdR激活。与先前的研究一致，HC的IgG组分可抑制脂多糖（LPS）诱导的单核细胞肿瘤坏死因子α（TNFα）产生，并刺激LPS诱导的单核细胞白细胞介素10（IL - 10）产生。此外，HC的IgG组分可增强抗CD3/CD28刺激的T细胞增殖。CFS AAB患者的IgG组分对细胞因子产生和T细胞增殖均无显著影响，而CFS AAB的IgG则有中等程度的影响。我们还观察到，IgG可调节β2 AdR配体异丙肾上腺素和普萘洛尔的信号传导。
我们提供了IgG可激活β2 AdR的证据。在ME/CFS患者中，IgG对β2 AdR的激活作用减弱。β2 AdR功能失调可能解释ME/CFS的许多症状。
