Do peripheral protein oligomers in neurodegenerative diseases shape T cell responses beyond the brain?

Abstract

Neurodegenerative diseases place a devastating burden on affected individuals and their families, and new treatments are desperately needed for these common immune‐mediated inflammatory conditions. While large aggregates of abnormal proteins in the brain cause significant damage, it is becoming clear that smaller soluble protein aggregates can also contribute to disease, by both direct and indirect mechanisms. These soluble protein oligomers can be found in patients' serum. Here, we describe recent research that identifies effects of model oligomer molecules on peripheral blood T cells, therefore providing an additional mechanism by which neurodegeneration may be worsened through amplification of peripheral adaptive immune responses.

Modern medicine has changed the course of previously harrowing diseases and saved countless lives. This has resulted in a drastic increase in life expectancy for the populations of many countries over the past 50 years. However, with an ageing population come new challenges – one of the biggest of which in the 21^st century is the burden of neurodegenerative diseases. Parkinson's disease and Alzheimer's disease both belong to the neurodegenerative disease family and are linked by their degenerative nature brought on by neuronal damage and destruction in the central nervous system (CNS). These diseases have been recognized for at least 100 years [1, 2] and affect an estimated 35 million people worldwide [3]. Our understanding of the immunology contributing to them has been limited by the complex nature of the brain and the difficulty studying it [4].

Many neurodegenerative diseases are characterized by the accumulation of deposits of misfolded proteins in the brain, which form large aggregates that disrupt neurons and neuronal networks [5]. Neurodegenerative conditions displaying these large deposits are also commonly associated with characteristic soluble oligomeric proteins, which may also directly mediate pathology [6]. Through multiple mechanisms, including those caused by protein oligomers, the specialized resident immune cells of the CNS become dysregulated. These cells, including microglia and oligodendrocytes, typically act to clear cellular debris and maintain homeostasis. However, in neurodegenerative diseases these cells become chronically activated [7, 8], perpetuating a damaging inflammatory response.

Although the brain is largely separated from the peripheral immune system by the blood–brain barrier, the immune systems of the periphery and the brain are not entirely separate. Peripheral immune dysregulation can therefore contribute to dysregulated immune responses in neurodegenerative diseases. Recent evidence has, for instance, revealed a pathological role for peripheral immune cells in these diseases, as systemic inflammation primes microglia in the brain [9]. Likewise, the soluble protein oligomers derived from the damaged brain have been found in the plasma of people with neurodegenerative diseases. While it is currently unknown how these oligomers may change the peripheral immune system, particularly the adaptive immune response, they are known to drive innate immune responses. They act as damage‐associated molecular patterns and activate inflammatory pathways in responding cells [6]. Given the association of protein oligomers with clinical disease progression, it is important that we understand any effects of protein oligomers on the peripheral immune system, and how these in turn may influence neurodegeneration.

In this issue, we publish new research from Leal‐Lesarte et al [10] in which they aimed to understand how soluble protein oligomers may affect the adaptive arm of the peripheral immune system, and therefore contribute to the dysregulation of the resident immune cells of the CNS in neurodegenerative diseases. To overcome the difficulties of studying human brain material, the team used an established model of disease [6], in which they studied the effects of two well‐characterized protein oligomers with different characteristics, both derived from N‐terminal domain of the HypF protein from E. coli (HypF‐N). These HypF‐N protein oligomers can form two different structures, type A and type B, and have many biological properties in common with the protein oligomers found in neurodegenerative disease.

Leal‐Lesarte et al. aimed to gain a better understanding of how soluble oligomers in the plasma may affect peripheral immune cells in neurodegenerative diseases, focussing on the effects of the oligomers on CD4 T cells from healthy peripheral blood mononuclear cells (PBMCs). The oligomers are not directly toxic. However, when the authors cultured regulatory T cells (Tregs), which usually act to suppress the immune response, with both types of the protein oligomer, they discovered that low doses of both types could expand functional Treg populations. However, only high doses of type A oligomer, but not type B oligomers, drove Treg differentiation, alluding to a potentially greater immunosuppressant capacity from the type A oligomer than type B. Furthermore, the expanded Treg cells from the type A oligomer culture suppressed PBMC proliferation to a greater extent than type B‐treated and untreated Treg cells. The authors then analysed cytokine production from PBMCs cultured with the two oligomers and found that both types induced production of a mix of pro‐ and anti‐inflammatory cytokines, and the type A oligomer induced less pro‐inflammatory cytokine production than type B. Finally, the authors investigated the effect of the oligomers on type 1 helper T (Th1) and Th17 cells, as these are both able to exacerbate inflammation in the CNS. Their experiments revealed that both oligomers induced IFN‐γ⁺ CD4 T cells (Th1) and IL‐17⁺ CD4 T cells (Th17), along with a small population of double‐positive IFN‐γ⁺ IL‐17⁺ CD4 T cells. Thus, these model protein oligomers influence the functions of peripheral CD4 T cells in multiple assays. This raises the possibility that the oligomers generated in the serum of patients with neurodegenerative disease may contribute to pathogenesis by driving peripheral T‐cell responses, exacerbating the damaging inflammatory responses in the brain. The authors argue that the specific T‐cell responses driven by the different types of protein oligomer are characteristic of the different changes seen in Alzheimer's vs. Parkinson's diseases. While this may be true of their model oligomers, it may be difficult to demonstrate with patient‐derived oligomers. The hope is that, in time, understanding the functions of oligomers in serum may be used to develop immune‐based therapies or diagnostic tools to help identify, treat or even prevent these diseases.