Parkinson's disease is a common neurodegenerative disease,however,its etiology and pathogenesis are still unclear. PD is considered to be the result of the interaction of multiple factors. In this study, we demonstrated that harmful stimulation induced the individuals with a high tendency of inflammationtoactivate the T cells immune response, increase the stimulating factor, decrease the inhibitory factor, leading to excessive inflammation, spreading to the brain, eventually leading to the damage of neurons. Because the co-inhibitory molecules CTLA-4 and PD-1 on T cells can down-regulate the immune response, weinhibited the expression of CTLA-4 and PD-1, T cells was activated. Although the occurrence of tumor was reduced, the inflammatory response and the degenerative injury of neurons were aggravated in the brain.The results suggested that the body with high inflammatory tendency is at high risk of PD, and the disorder of immune mechanism may be one of the importantfactors of PD.
In this study, under malignant stimulation the incidence of tumor in DBA/1 mice was lower than that in C57BL/6, additionally, the peripheral pro-inflammatory cytokines TNF-α and IL-1β were continuously increased, the anti-inflammatory cytokines IL-10 and IL-4 were decreased, and the degeneration and damage of neurons in the brain was significant.In C57BL/6 mice, TNF-α and IL-1β reached the highest levels at the fourth week after stimulation and then gradually decreased.Weconsidered thatafterfourweeks’ stimulation, theinflammatory responsein wildmicewas initiatedto down-regulated. However, in DBA/1 mice the inflammatory response was gradually increased, suggesting that inflammation in high-inflammation mice was deregulated, eventually leading to apoptosis and damage of dopamine neurons.Clinically, the high levels of IL-1β, TNF-αhavebeenreported in the serum and cerebrospinalfluid of PDpatients.This is consistent with our results,thus it is considered that inflammatory factors may also be involved in the occurrence of central inflammation leading to the damage of dopamine neurons.We considered that the tendency of high inflammation in the body is a double-edged sword, which not only inhibits the tumorigenesis, but also initiates the neuronal damage in the brain.The pathogenesis of PD is closely related to inflammatory response. Combined withthe significantly decreasing of tumor incidence in PD patients, we speculate that the partially cause of PD patients is based on high inflammation tendency in the body, the body was induced to inflammatory response as facing to the various malignant stimulation in environment, however the inflammation is out of control, leading tothe death of dopaminergic neurons in the brain.
In this study, under DEN induction, following with CTLA-4 and PD-1 inhibitors treatment, CD4, CD28 and MHCII in peripheral and intracranial of DBA/1 mice were significantly increased, CTLA-4 and PD1 were significantly decreased, and intracranial pro-inflammatory factors were significantly increased.These results suggested that malignant stimulation could over-activate the T cells in highly inflammatory mice and simultaneously participate in and worsen the intracranial inflammatory response, leading to the occurrence of neurodegenerative injury.T cell activation has always been the research spot of anti-tumor immunity and tumor vaccine research. And T cell activation is also closely related to PD.SaundersEt al. demonstrated that the imbalance between memory T cells and regulatory T cells was closely related to the severity of PD. T cell over-activation is also involved in exacerbating inflammation in the brain.In the studies of PD patient brainand PD animal models, a large number of CD4+ and CD8+ T cells were infiltrated. In addition, various treatment in activating T cell immunity to inhibit tumor growth also cause immune encephalitis, Transverse myelitis. These studies suggesting that the over-activated T cell immune system in peripheral blood can cause inflammation of the central nervous system.Therefore, we considered that highly inflammatory individuals activate T-cell immunity in order to combat malignant stimuli, triggering the strong peripheral inflammation, inhibiting tumor,however, promoting inflammatory response and neurodegeneration in the brain.
In this study, under DEN induction, following with CTLA-4 and PD-1 inhibitor treatment,the tumor incidence rate in DBA/1 mice was decreased, CD28 content in peripheral blood and brain was increased, and the content of CTLA-4 and PD1 was further decreased.The content of pro-inflammatory factors in peripheral blood and brain tissue was also increased, and the content of anti-inflammatory factors was decreased, therefore the damage and apoptosis of dopamine neurons in brain were more significant.It was suggested that the combined application of CTLA-4 and PD-1 inhibitor further promoted T cells activation, aggravated the damage of dopamine neurons, and significantly decreased the incidence of tumor.These results showed that CTLA-4 and PD-1 could regulate the process of T cell activation and resist tumorincidence and aggravate the dopamine neuron injury. The activation of T cells requires dual signals, the first signal comes from the specific binding of MHC-antigen complex of Antigen-presenting cells (APC) withT cell receptor (TCR), and the second signal comes from the binding of co-stimulating molecules (CD28) or co-inhibiting molecules (CTLA-4 and PD-1) on the surface of T cells with the ligands on the APC. CD28, a co-stimulatory molecule on the surface of T cells, can activate T cells and promote inflammation after stimulation.The co-inhibitory molecules CTLA-4 and PD-1 can inhibit the activation of inflammatory T cells. CD28, CTLA-4 and PD-1 can precisely regulate the transition of T cells to pro-inflammatory Th1 oranti-inflammatory Th2, and affecting the activation state of peripheral immunity. The inhibitor of CTLA-4 performed good treatment efficacyin rheumatoid arthritis, Type 1 diabetes,Kidney transplantation immune rejection.On the contrary, co-inhibitory molecules such as CTLA-4 and PD-1 are increasingly expressed in tumors, which inhibit the activation of T cells and weaken the immune surveillanceof tumors, becoming the most important mechanism for tumor-cell escape.This study shows that the combination of CTLA-4 and PD-1 inhibitors can activate T cells in highly inflammation-prone animals and promote excessive inflammation, and increase the transformation of microglia into M1type cells to aggravate the damage of dopamine neurons, promoting the development of PD, however, reducing tumor escape and significantly decreasing the incidence of tumor.
The above results demonstrated that individualswith high inflammatory tendency are the basis for the occurrence of Parkinson's disease. As exposed to harmful stimuli, inflammation is initiated to protect the body from the occurrence of malignant tumors. However, due to their high inflammatory tendency,excessive inflammation is caused and eventually dopamine neurons are injured.The harmful stimulus may be not only confined to DEN, it may also include a variety of microbial infection, chemicals, all kinds of physical and chemical stimulation, etc. These harmful stimuluses induced the excessive inflammation in the individual with high tendency, accumulated gradually in a long period leading to the damage of the central nervous system.This study confirmed that bodywith a high inflammatory tendency are at high risk of excessive inflammatory response to malignant stimulation. In the process, CTLA-4 and PD-1 as important regulatory factors could reduce the inflammatory response.As the block of CTLA-4 and PD-1 together lead to deterioration of inflammation, increasing the damage of neurons in the brain. Although it could curb the occurrence of tumors, increase the risk of nerve degeneration. These finding confirmed thatthe inflammation tendency of genetic background is the pathogenesis of PD risk factors.