Activated Immune T-Cells Infiltrate the Brain and Promote Neurodegeneration in Primate Models of Parkinson’s

Activated Immune T-Cells

Activated immune T-cells can infiltrate the brain and promote neurodegeneration in non-human primate models of Parkinson’s during the chronic stages of the disease, a study has found.

Results of the study, “Chronic infiltration of T lymphocytes into the brain in a non-human primate model of Parkinson’s disease,” were published in the journal Neuroscience.

Parkinson’s disease is a neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — together with brain inflammation.

Recent studies have suggested that activated T-cells, which are immune cells that are responsible for destroying other cells or microbes seen as a threat by the immune system, also can play a key role in Parkinson’s neurodegeneration.

Studies in non-human primate models of induced-Parkinson’s have reported the infiltration of these activated T-cells in the brain’s substantia nigra a month after treatment with MPTP during the acute phase of the disease. (MPTP is a neurotoxin that induces brain inflammation and often is used to trigger the onset of Parkinson’s in different animal models.)

“[H]owever, T lymphocyte infiltration into the brain during the chronic phase after MPTP injection in NHP [non-human primate] models remains unclear. We believe that a better understanding of this phenomenon will help identify the neuropathological mechanisms underlying PD [Parkinson’s disease] in humans,” the researchers wrote.

In mice models of the disease, the chemokine RANTES also has been associated with the infiltration of activated T-cells into the brain and with the development of Parkinson’s. (Chemokines are small molecules that mediate and regulate immune and inflammatory responses.)

A team of Korean researchers investigated the mechanisms underlying the infiltration of activated T-cells during the chronic stage of the disease in non-human primate models of induced-Parkinson’s.

In addition to evaluating the infiltration of T-cells in the brain 48 weeks after animals received an injection of MPTP, investigators also assessed changes in the levels of RANTES in the animals’ blood, and assessed microglia activation. (Microglia activation refers to the process by which microglia — nerve cells that support and protect neurons — become overactive, triggering brain inflammation.)

A total of five animals were injected with MPTP and three received a saline injection (controls).

Compared to saline-treated animals, those treated with MPTP showed signs of local chronic infiltration of activated T-cells in different regions of the brain’s striatum — a brain region responsible for controlling body movements — and substantia nigra.

Moreover, in animals treated with MPTP, this was accompanied by the loss of dopaminergic neurons, abnormal microglia morphology, and chronic normalization of the levels of RANTES in the blood 24–48 weeks post-injection, indicative of inflammation.

“This study confirms the involvement of [T-cell] infiltration in MPTP-induced NHP [non-human primates] models of PD. Further, these findings reinforce those of previous studies that identified the mechanisms involved in [T-cell]-induced neurodegeneration,” the researchers wrote.

“The findings of chronic infiltration of T lymphocytes in our NHP model of PD provide novel insights into PD pathogenesis and the development of preventive and therapeutic agents,” they stated.

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IL-17A Accelerates Brain Inflammation and Degeneration in Animal Models of Parkinson’s, Study Finds

Parkinson's and IL-17A

Interleukin-17A (IL-17A) — a molecule that is involved in immune and inflammatory responses — accelerates brain inflammation and degeneration in animal models of Parkinson’s disease, a study has found.

The research, “IL-17A exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of Parkinson’s disease,” was published in Brain, Behavior and Immunity.

Parkinson’s disease is characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — together with brain inflammation caused by the over-activation of microglia, which are cells that support and protect neuronal cells, and are more reactive and proliferative than neurons.

“Our recent results show that Th17 cells contribute to PD [Parkinson’s disease] neuroinflammation and neurodegeneration. In revealing the mechanism by which Th17 cells injure dopaminergic neurons, we found that Th17 cells directly contact and kill neuronal cells by an interaction between two adhesion molecules expressed on membrane of these cells,” the investigators explained.

“Nevertheless, it needs clarification whether IL-17A … can directly damage dopaminergic neurons,” they added.

Of note, Th17 are the subtype of T-cells that produces IL-17 and have been associated with several inflammatory processes; a cytokine is a molecule that mediates and regulates immune and inflammatory responses.

In this study, a group of researchers from Nantong University in China set out to investigate how IL-17A might contribute to the development and progression of Parkinson’s in two different animal models of disease.

To trigger the onset of Parkinson’s, researchers treated mice with MPTP, a neurotoxin that induces brain inflammation, loss of dopaminergic neurons, and motor impairments, as seen in patients with the disease.

In parallel, rats were treated with MPP+, another neurotoxin closely related to MPTP, that also induces the onset of symptoms similar to those experienced by patients with Parkinson’s disease.

Results showed that treatment with both neurotoxins led to a disruption of the blood-brain barrier (BBB, a semipermeable membrane that isolates the brain from the blood that circulates in the body) and to a significant increase in the levels of IL-17A in the substantia nigra of both animal models.

To examine if BBB disruption in response to neurotoxins was sufficient to allow immune cells to enter into the animals’ brains, researchers injected them with T-effector cells that had been activated in a lab dish and measured their level of penetrance into the brain.

Of note, T-effector cells are T-cells that are immediately prepared to fight a pathogen because they have a “memory” of previously encountering it; these cells also include the Th17 subgroup.

Findings revealed that when injected into animals that had been treated with neurotoxins, T-effector cells were able to travel and enter into the animals’ brains. However, when injected into healthy animals that had never been treated with neurotoxins, T-effector cells failed to infiltrate the brain.

In addition, researchers found that when T-effector cells infiltrated the brain, they worsened animals’ symptoms; dopaminergic neurons were destroyed faster, microglia became over-activated faster and motor impairments were more severe.

Conversely, when researchers blocked the activity of IL-17A in rats’ brains (by injecting an anti-IL-17A antibody) they found that all Parkinson-like symptoms the animals experienced were significantly reduced. Likewise, when they performed a similar analysis in mice that had been genetically modified to lack IL-17A, they found that neuron degeneration, microglia activation and motor deficits were decreased greatly.

Additional in vitro experiments revealed that IL-17A had a direct impact on microglia activation, but not on neuron survival. According to the team, IL-17A requires the presence of microglia to accelerate neuronal loss.

Moreover, they discovered this effect was stronger in the presence of tumor necrosis factor alpha (TNF-a), a signaling molecule involved in immune and inflammatory responses, produced and released by activated microglia.

“[These] findings suggest that IL-17A accelerates neurodegeneration in PD [by inducing the] activation [of microglia] and at least partly [by promoting the release of other pro-inflammatory molecules, such as TNF-a],” the researchers wrote.

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Common Anti-inflammatory Medication May Help Prevent Parkinson’s Neurodegeneration, Study Suggests

Cosentyx, neurodegeneration

A type of immune cell called Th17 may be a key a promoter of neurodegeneration in Parkinson’s disease by producing the pro-inflammatory molecule interleukin-17 (IL-17), according to a study.

Researchers also found that the common anti-inflammatory medication Cosentyx (secukinumab), an antibody against IL-17, seems to prevent this mechanism and the death of nerve cells.

The study, “Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson’s Disease,” appeared in the journal Cell Stem Cell.

Responses from the immune system are usually divided into two categories. Innate immune responses are part of the body’s first line of defense and are not specific to a particular pathogen. Adaptive immune responses, however, are specific to certain invaders or molecules, and use a “memory” to boost the response.

Abnormal regulation of T-cells during adaptive immune responses is well-known in chronic inflammatory autoimmune disorders such as multiple sclerosis.

However, unlike the role of inflammation via innate immune cells, the contribution of the adaptive response to neurodegeneration in Parkinson’s — in particular the hallmark loss of dopamine-producing neurons in an area of the brain called substantia nigra — remains largely unexplored.

Studies have shown the presence of specific subsets of T-cells, as well as their activation, in the brains of Parkinson’s patients. Results from animal models also suggested that these cells are important in Parkinson’s, but scientists have been unable to prove that T-cells directly promote neurodegeneration in human neurons.

Aiming to address this question, researchers at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) in Germany collected skin samples from Parkinson’s patients and healthy individuals used as controls, which were used to create midbrain neurons — where the substantia nigra is located.

These cells were then cultured along with T-cells collected from the patients’ blood.

First, the scientists found that amounts of Th17, a type of T-cell implicated in inflammation, in the blood were associated with a greater neuron cell death in culture. This Th17-driven neurodegeneration was not observed in the control group.

The team then found that neuronal death was mediated by elevated amounts of the IL-17 pro-inflammatory protein — which is produced by Th17 cells — and activation of NFkB, a complex of proteins that regulate gene expression and have previously been associated with chronic inflammation and neurodegenerative diseases, among other disorders.

Importantly, blocking IL-17 or its receptor, or adding Cosentyx — an IL-17A antibody approved for the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis — largely prevented neuronal death.

“Overall, our findings indicate a critical role for IL-17-producing T cells in human [Parkinson’s]-associated neuronal cell death,” the researchers wrote.

“Thanks to our investigations, we were able to clearly prove not only that T-cells are involved in causing Parkinson’s disease, but also what role they actually play,” Beate Winner, MD, a stem cell researcher at FAU, said in a press release. “The findings from our study offer a significant basis for new methods of treating Parkinson’s.”

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Source: Parkinson's News Today