Voynova Elisaveta, Mahmoud Tamer, Woods Lucas T, Weisman Gary A, Ettinger Rachel, Braley-Mullen Helen
Respiratory, Inflammation and Autoimmunity Group, Medimmune LLC, Gaithersburg, MD 20878.
Department of Biochemistry, Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211.
Immunohorizons. 2018 Jan 1;2(1):54-66. doi: 10.4049/immunohorizons.1700069.
CD40/CD40L interactions play a critical role in immunity and autoimmunity. In this study, we sought to understand the requirement for CD40 signaling in the programmed cell death-1 (PD-1) checkpoint and CD28 costimulatory pathways important for maintenance of peripheral tolerance. Blocking either pathway can result in loss of self-tolerance and development of autoimmunity. We found that primary Sjögren's syndrome (pSS) and autoimmune thyroid diseases (ATDs) that develop spontaneously in CD28-deficient IFN-γ NOD.H-2h4 (CD28) mice required CD40 signaling. Specifically, blockade of CD40L with the anti-CD40L mAb, MR1, inhibited autoantibody production and inflammation in thyroid and salivary gland target tissues. Unexpectedly, however, ATD and pSS in PD-1-deficient IFN-γ NOD.H-2h4 (PD-1) mice developed independently of CD40/CD40L interactions. Treatment with MR1 had no effect and even exacerbated disease development in pSS and ATD, respectively. Most interesting, anti-thyroglobulin and pSS-associated autoantibodies were increased following anti-CD40L treatment, even though MR1 effectively inhibited the spontaneous splenic germinal centers that form in PD-1-deficient mice. Importantly, blockade of the PD-1 pathway by administration of anti-PD-1 mAb in CD28 mice recapitulated the PD-1 phenotype, significantly impacting the ability of MR1 to suppress ATD and pSS in these mice. These results indicate that there can be different pathways and requirements to autoimmune pathogenesis depending on the availability of specific checkpoint and costimulatory receptors, and an intact PD-1 pathway is apparently required for inhibition of autoimmunity by anti-CD40L.
CD40/CD40L相互作用在免疫和自身免疫中起着关键作用。在本研究中，我们试图了解程序性细胞死亡1（PD-1）检查点和CD28共刺激途径中CD40信号传导的需求，这些途径对于维持外周耐受性很重要。阻断任何一条途径都可能导致自身耐受性丧失和自身免疫的发展。我们发现，在CD28缺陷的IFN-γ NOD.H-2h4（CD28）小鼠中自发发生的原发性干燥综合征（pSS）和自身免疫性甲状腺疾病（ATD）需要CD40信号传导。具体而言，用抗CD40L单克隆抗体MR1阻断CD40L可抑制甲状腺和唾液腺靶组织中的自身抗体产生和炎症。然而，出乎意料的是，PD-1缺陷的IFN-γ NOD.H-2h4（PD-1）小鼠中的ATD和pSS独立于CD40/CD40L相互作用而发展。用MR1治疗分别对pSS和ATD没有影响，甚至加剧了疾病发展。最有趣的是，尽管MR1有效地抑制了PD-1缺陷小鼠中形成的自发脾生发中心，但抗CD40L治疗后抗甲状腺球蛋白和pSS相关自身抗体增加。重要的是，在CD28小鼠中给予抗PD-1单克隆抗体阻断PD-1途径重现了PD-1表型，显著影响了MR1抑制这些小鼠中ATD和pSS的能力。这些结果表明，根据特定检查点和共刺激受体的可用性，自身免疫发病机制可能存在不同的途径和需求，并且完整的PD-1途径显然是抗CD40L抑制自身免疫所必需的。
