Parkinson’s Disease Also Manifest As Dysregulation of the Immune System Outside the Brain
For decades, Parkinson’s disease (PD) has been considered solely a brain disorder. Today it is well accepted to be a multisystem disease where both central and peripheral nervous systems are affected and where the immune system is also involved. The immune system is a double-edged sword, which protects the host against infections and clearing accumulated unwanted proteins, but if over-activated, the immune system can eventually damage or kill host cells such as neurons in the brain. It is, therefore, crucial to understand the imbalance of the immune system in PD. Only when we understand the imbalance, we can start to correct it to a state of equilibrium with the right amount of protein/alpha-synuclein removal without too much cell death.
In our lab, we not only look at the immune cells in the brain, the microglia cells, but also look at the peripheral immune cells in the blood that eventually can infiltrate the brain. In the blood, we are focusing on the “garbage-clearing” cells called monocytes, equivalent to microglia cells in the brain. In a recent study published in the Journal of Movement Disorders we subjected blood samples from 29 individuals with PD and 20 control individuals to the protein alpha-synuclein. We discovered that the immune cells in the blood from individuals with PD have a significant dysregulation of the cells surface immune molecules CD163 and CD14 and that the PD cells were also less efficient to secrete anti-inflammatory molecules than the cells from control individuals. From these in vitro studies in a petri dish, it also appeared that the blood PD monocytes were exhausted and/or in an activations status different from controls as they produced less soluble CD163 levels. Thus, we found PD-associated changes in blood immune cells supporting the involvement of the immune system outside the brain in PD.
Based on this basic research in the petri dish, we sought to explore the role of CD163 as a biomarker in PD. CD163 is an extremely interesting molecule since it is only found on mononuclear phagocytic “garbage-clearing” cells originating from the blood: monocytes, dendritic cells, and the tissues infiltrating macrophages. CD163 is not expressed on the brain resident immune cells (microglia) nor on neuron or other immune cells such as T and B lymphocytes. Furthermore, CD163 is a scavenger receptor important for clearing big protein complexes such as haptoglobin-hemoglobin. Shedding of this receptor into serum (from blood or peripheral tissue monocytes) or spinal fluid (from meningeal macrophages and brain-infiltrated macrophages) occurs after activation of inflammatory signals, similar to those seen when the pro-inflammatory TNF-alpha is released. Therefore, measurements of CD163 not only specifically tells us about the involvement of mononuclear phagocytes but also about the inflammation status of the person. It is very unique to have a biomarker that is cell type-specific and that has a relevant function. We measured soluble CD163 together with other biomarkers in 108 individuals with PD and 14 controls. In agreement with findings from other diseases with an inflammatory component, such as multiple sclerosis, we found that in PD soluble CD163 is increased in spinal fluid. Interestingly, soluble CD163 was also increased in the serum of females, but not males, with PD, linking this biomarker to the sex-bias of the disease risk and symptomology. Another interesting discovery of this study was that the spinal fluid level of soluble CD163 correlated with the scores of cognitive decline in individuals with PD. Hence, suggesting an involvement of the monocytic immune cells in PD symptoms. These findings are now under revision in the journal of Movement Disorders.
Further studies have to be conducted to understand in which direction the peripheral immune system is dysregulated: too much host damaged by chronic activation or too little protein clearance by exhaustion, or both. Together with clinical collaborators, we are currently analyzing data from our new studies on surface CD163 on blood monocytes from individuals with PD, Rapid eye movement (REM) sleep behavior disorder (RBD), and Multiple System Atrophy (MSA), to investigate how this cell population is modified in these diseases and marked for brain-infiltration. In parallel, our group also uses rodent models to investigate the function of the CD163 receptor in the neurodegenerative process associated with alpha-synuclein. These complementary research lines will help to better understand the cells and relevant receptors involved in the immune changes in PD.
Sara Konstantin Nissen PhD, presented at the poster walk at the 5th World Parkinson Congress in Kyoto, Japan. She is currently a postdoc in the lab of Associate Professor Marina Romero-Ramos, PhD, at the Department of Biomedicine, Aarhus University in Denmark.
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