Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
Institute for Neuroimmunology and Multiple Sclerosis Research (IMSF), University Medical Center Goettingen, Goettingen, Germany.
Front Immunol. 2023 Apr 5;14:1105432. doi: 10.3389/fimmu.2023.1105432. eCollection 2023.
The intracerebral infection of mice with Theiler's murine encephalomyelitis virus (TMEV) represents a well-established animal model for multiple sclerosis (MS). Because CD28 is the main co-stimulatory molecule for the activation of T cells, we wanted to investigate its impact on the course of the virus infection as well as on a potential development of autoimmunity as seen in susceptible mouse strains for TMEV. In the present study, 5 weeks old mice on a C57BL/6 background with conventional or tamoxifen-induced, conditional CD28-knockout were infected intracerebrally with TMEV-BeAn. In the acute phase at 14 days post TMEV-infection (dpi), both CD28-knockout strains showed virus spread within the central nervous system (CNS) as an uncommon finding in C57BL/6 mice, accompanied by histopathological changes such as reduced microglial activation. In addition, the conditional, tamoxifen-induced CD28-knockout was associated with acute clinical deterioration and weight loss, which limited the observation period for this mouse strain to 14 dpi. In the chronic phase (42 and 147 dpi) of TMEV-infection, surprisingly only 33% of conventional CD28-knockout mice showed chronic TMEV-infection with loss of motor function concomitant with increased spinal cord inflammation, characterized by T- and B cell infiltration, microglial activation and astrogliosis at 33-42 dpi. Therefore, the clinical outcome largely depends on the time point of the CD28-knockout during development of the immune system. Whereas a fatal clinical outcome can already be observed in the early phase during TMEV-infection for conditional, tamoxifen-induced CD28-knockout mice, only one third of conventional CD28-knockout mice develop clinical symptoms later, accompanied by ongoing inflammation and an inability to clear the virus. However, the development of autoimmunity could not be observed in this C57BL/6 TMEV model irrespective of the time point of CD28 deletion.
脑内感染 Theiler's 鼠脑脊髓炎病毒（TMEV）是多发性硬化症（MS）的一种成熟的动物模型。因为 CD28 是 T 细胞激活的主要共刺激分子，我们想研究其对病毒感染过程的影响，以及在 TMEV 易感小鼠品系中观察到的自身免疫的潜在发展。在本研究中，5 周龄的 C57BL/6 背景下的常规或他莫昔芬诱导的条件性 CD28 敲除小鼠经脑内感染 TMEV-BeAn。在 TMEV 感染后 14 天的急性期（dpi），两种 CD28 敲除株都显示病毒在中枢神经系统（CNS）内传播，这在 C57BL/6 小鼠中是一种罕见的发现，伴随着组织病理学变化，如小胶质细胞激活减少。此外，条件性、他莫昔芬诱导的 CD28 敲除与急性临床恶化和体重减轻有关，这限制了该小鼠品系的观察期至 14dpi。在 TMEV 感染的慢性期（42 和 147dpi），令人惊讶的是，只有 33%的常规 CD28 敲除小鼠出现慢性 TMEV 感染，伴随着运动功能丧失，同时脊髓炎症增加，特征为 T 和 B 细胞浸润、小胶质细胞激活和星形胶质细胞增生，发生在 33-42dpi。因此，临床结果在很大程度上取决于免疫系统发育过程中 CD28 敲除的时间点。尽管条件性、他莫昔芬诱导的 CD28 敲除小鼠在 TMEV 感染的早期阶段就已经出现致命的临床结果，但只有三分之一的常规 CD28 敲除小鼠在后期才出现临床症状，同时伴有持续的炎症和清除病毒的能力丧失。然而，在这个 C57BL/6 TMEV 模型中，无论 CD28 缺失的时间点如何，都没有观察到自身免疫的发展。
